Predicting the direction of phenotypic difference.

Predicting phenotypes from genomic data is a key goal in genetics, but for most complex phenotypes, predictions are hampered by incomplete genotype-to-phenotype mapping. Here, we describe a more attainable approach than quantitative predictions, which is aimed at qualitatively predicting phenotypic differences. Despite incomplete genotype-to-phenotype mapping, we show that it is relatively easy to determine which of two individuals has a greater phenotypic value. This question is central in many scenarios, e.g., comparing disease risk between individuals, the yield of crop strains, or the anatomy of extinct vs extant species. To evaluate prediction accuracy, i.e., the probability that the individual with the greater predicted phenotype indeed has a greater phenotypic value, we developed an estimator of the ratio between known and unknown effects on the phenotype. We evaluated prediction accuracy using human data from tens of thousands of individuals from either the same family or the same population, as well as data from different species. We found that, in many cases, even when only a small fraction of the loci affecting a phenotype is known, the individual with the greater phenotypic value can be identified with over 90% accuracy. Our approach also circumvents some of the limitations in transferring genetic association results across populations. Overall, we introduce an approach that enables accurate predictions of key information on phenotypes - the direction of phenotypic difference - and suggest that more phenotypic information can be extracted from genomic data than previously appreciated.

The determinants of proxy treadmilling in evolutionary models of reliable signals.

Identifying the conditions of proxy treadmilling is crucial for determining whether reliable signals can persist over time. I present a framework that maps evolutionary models of reliable signals according to their assumptions regarding the effects of Goodhart's law. This framework can explain the contrasting outcomes of different modelling approaches, and identify in which models proxy treadmilling is expected to occur.

Bedside urine testing for fentanyl in self-reported heroin users in a tertiary Brisbane emergency department.

OBJECTIVE: To determine if patients presenting to our toxicology unit following self-reported heroin use had positive urine immunoassay testing for fentanyl or its analogues. METHODS: Urine samples from consenting patients were tested at the bedside for the presence of opiates or fentanyl and its analogues. RESULTS: Over a 30-month period, 58 patients were recruited. All samples tested positive for opiates, but none tested positive for fentanyl or its analogues. CONCLUSION: In patients presenting to our toxicology unit in Brisbane, we did not find any cases where the urine of patients self-reporting heroin exposure tested positive for fentanyl or its analogues.

DORA: an interactive map for the visualization and analysis of ancient human DNA and associated data.

The ability to sequence ancient genomes has revolutionized the way we study evolutionary history by providing access to the most important aspect of evolution-time. Until recently, studying human demography, ecology, biology, and history using population genomic inference relied on contemporary genomic datasets. Over the past decade, the availability of human ancient DNA (aDNA) has increased rapidly, almost doubling every year, opening the way for spatiotemporal studies of ancient human populations. However, the multidimensionality of aDNA, with genotypes having temporal, spatial and genomic coordinates, and integrating multiple sources of data, poses a challenge for developing meta-analyses pipelines. To address this challenge, we developed a publicly-available interactive tool, DORA, which integrates multiple data types, genomic and non-genomic, in a unified interface. This web-based tool enables browsing sample metadata alongside additional layers of information, such as population structure, climatic data, and unpublished samples. Users can perform analyses on genotypes of these samples, or export sample subsets for external analyses. DORA integrates analyses and visualizations in a single intuitive interface, resolving the technical issues of combining datasets from different sources and formats, and allowing researchers to focus on the scientific questions that can be addressed through analysis of aDNA datasets.

Child sleep problems, maternal sleep and self-efficacy: Sleep's complicated role in maternal depression.

Depression, poor sleep duration and low self-efficacy are common in mothers of children with sleep problems. However, research rarely extends beyond the postpartum period. This study investigated the multifaceted relationship between child sleep and maternal depression in early motherhood. A confidential survey assessed child sleep problems, maternal sleep duration, parental self-efficacy and depressive symptoms in 477 Australian mothers of children aged 3 months to 5 years. We found no relationship between child age and maternal depression, supporting our decision to look beyond postpartum depression. Robust bootstrapped mediation modelling tested the hypothesis that both maternal sleep duration and parental self-efficacy would mediate child sleep problems as predictors of maternal depression. After controlling for child age, results showed a significant parallel mediation effect, demonstrating that maternal sleep duration and parental self-efficacy both mediate the relationship between child sleep problems on maternal depression. While the total effect of child sleep problems on maternal depression was statistically significant, after partialling out the effects of other variables, child sleep problems no longer predicted maternal depression. Akaike information criterion analyses supported the full model, with both mediators explaining meaningful variance in maternal depression. This study expands our knowledge beyond the postpartum period, and divulges the disparate effects of sleep deprivation and parental self-efficacy on the relationship between child sleep and depression in early motherhood. Maternal sleep duration and self-efficacy are modifiable risk factors of maternal depression, indicating possible efficacious treatments. Parental self-efficacy stands out as a direction for clinical practice and further psychobiological study.

Suspected stonefish envenomation in Queensland over eight years: a retrospective series.

INTRODUCTION: Stonefish envenomation results in localized severe pain and swelling and systemic features, including vomiting, arrhythmia, pulmonary oedema, and possibly death. There are limited data regarding the effectiveness of the available antivenom. The aim of this series is to characterize presentations of patients with suspected stonefish envenomation and investigate treatment, including antivenom. METHODS: This is a retrospective observational series of suspected stonefish envenomation as reported to the Queensland Poisons Information Centre or Princess Alexandra Hospital Clinical Toxicology Unit from July 2015 to January 2023. Patients were identified through the databases held by both the Centre and Unit, and data on clinical features and investigations were collected from the patient's electronic medical record. RESULTS: There were 87 suspected stonefish envenomations from July 2015 to January 2023. The median age was 26 (range: 5-69) years, and 69 (79 per cent) patients were male. Pain was reported in 85 (98 per cent) with a median peak pain score of 10 (range 4-12; three rated their pain greater than 10/10). A clear wound was documented in 64 (74 per cent), with local swelling in 63 (72 per cent). A foreign body was retained in eight (9 per cent) presentations. Systemic symptoms were rare, with vomiting in four (5 per cent) and dizziness in two (2 per cent) presentations. There were no instances of hypotension, arrhythmia, or pulmonary oedema. Hot water was administered in 72 (83 per cent) presentations. Oral analgesia was given in 55 (63 per cent). Parenteral analgesia was given in 53 (61 per cent), most commonly opioids. Local anaesthetic block was performed in 19 presentations (22 per cent), with effectiveness documented in 16/19 (84 per cent). Five patients received antivenom for intractable pain, and all received subsequent parenteral analgesia or local anaesthetic block. CONCLUSIONS: Stonefish envenomation is characterized by severe pain. Systemic symptoms were rare and not severe in this series. Local anaesthetic block appeared to be the most effective intervention for severe pain when performed. Antivenom appeared to be ineffective in managing pain.

Rescue by gene swamping as a gene drive deployment strategy.

Gene drives are genetic constructs that can spread deleterious alleles with potential application to population suppression of harmful species. As gene drives can potentially spill over to other populations or species, control measures and fail-safe strategies must be considered. Gene drives can generate a rapid change in the population's genetic composition, leading to substantial demographic decline, processes that are expected to occur at a similar timescale during gene drive spread. We developed a gene drive model that combines evolutionary and demographic dynamics in a two-population setting. The model demonstrates how feedback between these dynamics generates additional outcomes to those generated by the evolutionary dynamics alone. We identify an outcome of particular interest where short-term suppression of the target population is followed by gene swamping and loss of the gene drive. This outcome can prevent spillover and is robust to the evolution of resistance, suggesting it may be suitable as a fail-safe strategy for gene drive deployment.

Incorporating ecology into gene drive modelling.

Gene drive technology, in which fast-spreading engineered drive alleles are introduced into wild populations, represents a promising new tool in the fight against vector-borne diseases, agricultural pests and invasive species. Due to the risks involved, gene drives have so far only been tested in laboratory settings while their population-level behaviour is mainly studied using mathematical and computational models. The spread of a gene drive is a rapid evolutionary process that occurs over timescales similar to many ecological processes. This can potentially generate strong eco-evolutionary feedback that could profoundly affect the dynamics and outcome of a gene drive release. We, therefore, argue for the importance of incorporating ecological features into gene drive models. We describe the key ecological features that could affect gene drive behaviour, such as population structure, life-history, environmental variation and mode of selection. We review previous gene drive modelling efforts and identify areas where further research is needed. As gene drive technology approaches the level of field experimentation, it is crucial to evaluate gene drive dynamics, potential outcomes, and risks realistically by including ecological processes.

Introduction of QScript real-time prescription monitoring system was associated with a fall in pregabalin poisoning presentations to a clinical toxicology unit.

OBJECTIVE: To investigate the impact of QScript implementation on pregabalin-related poisoning presentations to the ED. METHODS: This is a retrospective review of pregabalin-related poisoning presentations to a tertiary Australian ED in the 4 years prior to, and 1 year following the introduction of QScript real-time prescription monitoring system. RESULTS: Pregabalin-related poisoning presentations fell by 28% from an average of 98 presentations annually over the 4 years prior to QScript implementation to 71 in 2022. The severity of poisonings was similar over the periods. CONCLUSIONS: The introduction of QScript was associated with a reduction in pregabalin-related poisoning presentations.

Development and Psychometric Evaluation of the IPV Internalized Stigma Scale.

Self-stigma is the internalization of widespread and negative attitudes around a devalued attribute. Being a victim of intimate partner violence (IPV) is a stigmatized identity, with IPV self-stigma is a potential barrier to help seeking. The lack of an IPV self-stigma scale limits current measurement of this latent trait; this study sought to fill this gap. We developed the IPV Internalized Self-stigma Scale (IPVIS) by revising existing self-stigma and devaluation/discrimination measures and adding new items to fill perceived gaps. Using an online survey, a diverse sample (N = 455, M = 39.51, SD = 12.03) with various relationship types (e.g., heterosexual, same-sex), IPV circumstances (e.g., male or female perpetrators/victims) and different gender and sexual identities was recruited. Participants first completed the item pool (44-items), followed by measures of IPV, anxiety, depression, social health, and self-efficacy with data analyzed using a multi-model approach (e.g., factor analysis, item response theory [IRT]). Factor analyses revealed one dominant factor; IRT analyses further refined the unidimensional item set. The final 11 items had high internal consistency, ω = .90, 95% CI [0.89, 0.91], and were highly informative with moderate to high discrimination levels. The IPVIS demonstrated measurement invariance by demographics, showing no differential item functioning by age groups, sex, residence (urban/suburban/rural), ethnicity (European/Caucasian vs. others), or relationship status (partnered/unpartnered). Initial validity examination revealed significant correlations between the IPVIS and related measures (e.g., depression, anxiety, social health). The IPVIS is suitable for research and has widespread clinical applicability. To the best of our knowledge, the IPVIS is the first scale developed that assesses IPV self-stigma inclusive of a diverse range of clients/participants, relationship types, and IPV circumstances.

Knockout of DDM1 in Physcomitrium patens disrupts DNA methylation with a minute effect on transposon regulation and development.

The Snf2 chromatin remodeler, DECREASE IN DNA METHYLATION 1 (DDM1) facilitates DNA methylation. In flowering plants, DDM1 mediates methylation in heterochromatin, which is targeted primarily by MET1 and CMT methylases and is necessary for silencing transposons and for proper development. DNA methylation mechanisms evolved throughout plant evolution, whereas the role of DDM1 in early terrestrial plants remains elusive. Here, we studied the function of DDM1 in the moss, Physcomitrium (Physcomitrella) patens, which has robust DNA methylation that suppresses transposons and is mediated by a MET1, a CMT, and a DNMT3 methylases. To elucidate the role of DDM1 in P. patens, we have generated a knockout mutant and found DNA methylation to be strongly disrupted at any of its sequence contexts. Symmetric CG and CHG sequences were affected stronger than asymmetric CHH sites. Furthermore, despite their separate targeting mechanisms, CG (MET) and CHG (CMT) methylation were similarly depleted by about 75%. CHH (DNMT3) methylation was overall reduced by about 25%, with an evident hyper-methylation activity within lowly-methylated euchromatic transposon sequences. Despite the strong hypomethylation effect, only a minute number of transposons were transcriptionally activated in Ppddm1. Finally, Ppddm1 was found to develop normally throughout the plant life cycle. These results demonstrate that DNA methylation is strongly dependent on DDM1 in a non-flowering plant; that DDM1 is required for plant-DNMT3 (CHH) methylases, though to a lower extent than for MET1 and CMT enzymes; and that distinct and separate methylation pathways (e.g. MET1-CG and CMT-CHG), can be equally regulated by the chromatin and that DDM1 plays a role in it. Finally, our data suggest that the biological significance of DDM1 in terms of transposon regulation and plant development, is species dependent.

Measuring the suicidal mind: The 'open source' Suicidality Scale, for adolescents and adults.

Clinicians are expected to provide accurate and useful mental health assessments, sometimes in emergency settings. The most urgent challenge may be in calculating suicide risk. Unfortunately, existing instruments often fail to meet requirements. To address this situation, we used a sustainable scale development approach to create a publicly available Suicidality Scale (SS). Following a critical review of current measures, community input, and panel discussions, an international item pool survey included 5,115 English-speaking participants aged 13-82 years. Revisions were tested with two follow-up cross-sectional surveys (Ns = 814 and 626). Pool items and SS versions were critically examined through item response theory, hierarchical cluster, factor and bifactor analyses, resulting in a unidimensional eight-item scale. Psychometric properties were high (loadings > .77; discrimination > 2.2; test-retest r = .87; internal consistency, ω = .96). Invariance checks were satisfied for age, gender, ethnicity, rural/urban residence, first language, self-reported psychiatric diagnosis and suicide attempt history. The SS showed stronger psychometric properties, and significant differences in bivariate associations with depressive symptoms, compared with included suicide measures. The 'open source' Suicidality Scale represents a significant step forward in accurate assessment for people aged 13+, and diverse populations. This study provides an example of sustainable scale development utilizing community input, emphasis on strong psychometric evidence from diverse samples, and a free-to-use license allowing instrument revisions. These methods can be used to develop a wide variety of psychosocial instruments that can benefit clinicians, researchers, and the public.

Overdose and off-label psychotropic prescribing in patients with borderline personality disorder: A retrospective series.

OBJECTIVE: Borderline personality disorder (BPD) is common and poses many clinical challenges. Despite limited evidence of effectiveness, psychotropic medications are often prescribed. We aimed to characterise overdose presentations in patients with BPD. METHOD: This is a retrospective observational series of patients with BPD presenting to a tertiary hospital following an overdose from January 2019 to December 2020. Medical records were reviewed to determine baseline characteristics, overdose details, clinical features, treatment, and disposition. RESULTS: There were 608 presentations in 370 people (76% female), median age 28 years (range 16-75 years). The majority (331[89%]) of patients were prescribed at least one psychotropic medication, with 129 (35%) being prescribed three or more different psychotropic agents. Of the total prescribed psychotropics, 520/1459 (36%) were for off-label indications. The majority of agents (860/1487[58%]) taken in overdose were prescribed. The commonest drug classes taken in overdose were benzodiazepines (241[16%]) and antipsychotics (229[15%]). Severe toxicity occurred in 99 (16%) cases with either coma (GCS<9) or hypotension (systolic BP <90 mmHg). The commonest agent associated with severe toxicity was quetiapine 39/99 (39%). CONCLUSIONS: Psychotropic polypharmacy is common in BPD, often with off-label indications. Prescribed medications are commonly taken in overdose. Quetiapine is over-represented both in off-label prescribing and associated harm.

Case series profile of olanzapine post-injection delirium/sedation syndrome.

Olanzapine pamoate is an intramuscular depot injection for the treatment of schizophrenia. Approximately 1.4% of patients develop a serious adverse event called post-injection delirium/sedation syndrome (PDSS), characterised by drowsiness, anticholinergic and extrapyramidal symptoms. The objective is to investigate olanzapine PDSS presentations including clinical features and treatment approach. This is a retrospective review of olanzapine PDSS patients from three toxicology units and the NSW Poisons Information Centre between 2017 and 2022. Adult patients were included if they had intramuscular olanzapine then developed PDSS criteria. Clinical symptoms, treatment, timing and length of symptoms were extracted into a preformatted Excel database. There were 18 patients included in the series, with a median age of 49 years (interquartile range [IQR]: 38-58) and male predominance (89%). Median onset time post injection was 30 min (IQR: 11-38). PDSS symptoms predominate with drowsiness, confusion and dysarthria. Median length of symptoms was 24 h (IQR: 20-54). Most common treatment included supportive care without any pharmacological intervention (n = 10), benzodiazepine (n = 4) and benztropine (n = 3). In one case, bromocriptine and physostigmine followed by oral rivastigmine were given to manage antidopaminergic and anticholinergic symptoms respectively. This proposed treatment combination could potentially alleviate some of the symptoms but needs further studies to validate the findings. In conclusion, this case series supports the characterisation of PDSS symptomology predominantly being anticholinergic with similar onset (<1 h) and duration (<72 h). Bromocriptine is proposed to manage PDSS if patients develop severe dopamine blockade and physostigmine followed by rivastigmine for anticholinergic delirium.

Ambulance referrals to an Australian Poisons Information Centre: a retrospective series.

INTRODUCTION: For poisoned patients, ambulance services may be the first point of contact for medical attention. With limited training in toxicology, ambulance services are encouraged to contact the Poisons Information Centre (PIC) for advice. This study aims to characterise referrals to a PIC from a state ambulance service with the purpose of improving information delivery and efficient use of these services. METHODS: This was a retrospective observational series of referrals to an Australian state PIC from ambulance staff from 1 January 2020 to 31 December 2020. Referrals were identified through the PIC Pharmhos database where the call originated from either a paramedic or emergency dispatch officer. Call reports were reviewed to extract data on patient demographics, exposure details and advice provided by the PIC. RESULTS: There were 1537 calls regarding 1420 poisoning exposures over the 12-month period, with 117 (7.6%) follow-up calls, representing 4.1% (1537/37835) of total calls to the PIC. Initial calls originated from paramedics in 999/1420 (70.4%) referrals, with dispatch officers referring 421/1420 (29.6%). Paediatric patients aged <15 years were involved in 492/1420 (34.6%) exposures with the commonest age range being 1-4 years. Most referrals involved pharmaceuticals exposures (756/1420 [53.2%]) followed by chemicals (557/1420 [39.2%]) and drugs of abuse (69/1420 [4.9%]). The commonest agents involved were paracetamol followed by quetiapine and sertraline. The PIC advised no treatment following benign exposures in 617/1420 (43.5%) calls, first aid measures in 333/1420 (23.5%) calls, supportive measures in 339/1420 (23.9%) calls and specific treatment in 32/1420 (2.3%) calls. Referral to the hospital was advised in 761/1420 (53.6%) calls, the majority of these were following deliberate self-poisonings (428/1420 [30.1%]). CONCLUSIONS: Ambulance staff commonly contact the PIC following benign exposures where no treatment is required. Ambulance referral to a PIC following suspected poisonings may have a role in preventing unnecessary transfer to hospital in poisoned patients.

Some problems with particularism.

Particularists maintain that conspiracy theories are to be assessed individually, while generalists hold that conspiracy theories may be assessed as a class. This paper seeks to clarify the nature and importance of the debate between particularism and generalism, while offering an argument for a version of generalism. I begin by considering three approaches to the definition of conspiracy theory, and offer reason to prefer an approach that defines conspiracy theories in opposition to the claims of epistemic authorities. I argue that particularists rely on an untenably broad definition of conspiracy theory. Then, I argue that particularism and its counterpart are best understood as constellations of theses, rather than a pair of incompatible theses. While some particularist theses are highly plausible, I argue that one important particularist thesis is false. The argument for this conclusion draws on the history of false conspiracy theories. I then defend this conclusion against a pair of potential objections.

Real Fakes: The Epistemology of Online Misinformation.

Many of our beliefs are acquired online. Online epistemic environments are replete with fake news, fake science, fake photographs and videos, and fake people in the form of trolls and social bots. The purpose of this paper is to investigate the threat that such online fakes pose to the acquisition of knowledge. I argue that fakes can interfere with one or more of the truth, belief, and warrant conditions on knowledge. I devote most of my attention to the effects of online fakes on satisfaction of the warrant condition, as these have received comparatively little attention. I consider three accounts of the conditions under which fakes compromise the warrant condition. I argue for the third of these accounts, according to which the propensity of fakes to exist in an environment threatens warrant acquisition in that environment. Finally, I consider some limitations on the epistemic threat of fakes and suggest some strategies by which this threat can be mitigated.

Acute Opioid Withdrawal Following Intramuscular Administration of Naloxone 1.6 mg: A Prospective Out-Of-Hospital Series.

STUDY OBJECTIVE: Large doses of intramuscular (IM) naloxone are commonly used in out-of-hospital settings to reverse opioid toxicity; however, they are used less commonly in hospitals because of concerns about opioid withdrawal, particularly agitation. We aimed to determine the frequency of severe agitation following a single 1.6 mg IM naloxone dose. METHODS: We undertook a prospective study of adult (>15 years) patients treated by an Australian state ambulance service with 1.6 mg IM administration of naloxone for respiratory depression (respiratory rate <11 breaths/min and/or oxygen saturation <93% in room air) caused by presumed opioid poisoning. The primary outcome was the proportion of presentations with severe agitation (Sedation Assessment Tool score >1) within 1 hour of naloxone administration. Secondary outcomes were the proportion of presentations with acute opioid withdrawal (tachycardia [pulse rate >100 beats/min], hypertension [systolic >140 mm Hg], vomiting, agitation, seizure, myocardial infarction, arrhythmia, or pulmonary edema), and reversal of respiratory depression (respiratory rate >10 breaths/min and saturation >92% or Glasgow Coma Scale score 15). RESULTS: From October 2019 to July 2021, there were 197 presentations in 171 patients, with a median age of 41 years (range, 18 to 80 years); of the total patients, 119 were men (70%). The most common opioids were heroin (131 [66%]), oxycodone (14 [7%]), and morphine (11 [6%]). Severe agitation occurred in 14 (7% [95% confidence interval {CI} 4% to 12%]) presentations. Opioid withdrawal occurred in 76 presentations (39% [95% CI 32% to 46%]), most commonly in the form of tachycardia (18%), mild agitation/anxiety (18%) and hypertension (14%). Three presentations (1.5%) received chemical sedation for severe agitation within 1 hour of naloxone administration. A single 1.6 mg dose of naloxone reversed respiratory depression in 192 (97% [95% CI: 94% to 99%]) presentations. CONCLUSION: Severe agitation was uncommon following the administration of 1.6 mg IM naloxone and rarely required chemical sedation.