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browsing sample metadata alongside additional layers of information, such as population structure, climatic data, and unpublished samples.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.

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.

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.

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.

DNA methylation mutants in Physcomitrella patens elucidate individual roles of CG and non-CG methylation in genome regulation.

Cytosine (DNA) methylation in plants regulates the expression of genes and transposons. While methylation in plant genomes occurs at CG, CHG, and CHH sequence contexts, the comparative roles of the individual methylation contexts remain elusive. Here, we present Physcomitrella patens as the second plant system, besides Arabidopsis thaliana, with viable mutants with an essentially complete loss of methylation in the CG and non-CG contexts. In contrast to A. thaliana, P. patens has more robust CHH methylation, similar CG and CHG methylation levels, and minimal cross-talk between CG and non-CG methylation, making it possible to study context-specific effects independently. Our data found CHH methylation to act in redundancy with symmetric methylation in silencing transposons and to regulate the expression of CG/CHG-depleted transposons. Specific elimination of CG methylation did not dysregulate transposons or genes. In contrast, exclusive removal of non-CG methylation massively up-regulated transposons and genes. In addition, comparing two exclusively but equally CG- or CHG-methylated genomes, we show that CHG methylation acts as a greater transcriptional regulator than CG methylation. These results disentangle the transcriptional roles of CG and non-CG, as well as symmetric and asymmetric methylation in a plant genome, and point to the crucial role of non-CG methylation in genome regulation.

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.

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.

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.

Nonionic Surfactant Properties of Amphiphilic Hyperbranched Polyglycerols.

The surfactant properties of amphiphilic hyperbranched polyglycerols (HPGs) were investigated. The HPGs were prepared by ring-opening multibranching polymerization of glycidol using hydrophobic initiators of varying size and structure. The cloud points for all HPG surfactants were found to be >80 °C in deionized water with >1 wt % NaCl. The HPG surfactants with hydrophilic-lipophilic balance values between 16 and 18 were found to form stable octanol/water (o/w) emulsions within a 24 h period. Several surface properties, including critical micelle concentration (CMC), efficiency of surface tension reduction (pC20), effectiveness of surface tension reduction (γCMC), surface excess concentration at the CMC (Γmax), minimum area/molecule at the interface (Amin), and the CMC/C20 ratio of the HPG surfactants were measured in deionized water at 22.6 °C. In general, increasing HPG size was marked by an increase in minimum surface area per molecule (Amin) at the aqueous liquid/air interface. This increase in size also led to lower CMC and greater pC20 values of HPG surfactants prepared with Tergitol 15-S-7 initiator (HPG 5a-5d), a commercially available ethylene glycol oligomer with a branched hydrophobic tail.

Pregabalin poisoning and rising recreational use: a retrospective observational series.

AIMS: With rising use worldwide, pregabalin is increasingly implicated in poisoning deaths. We aimed to investigate the clinical effects and complications of pregabalin poisoning. METHODS: This is a retrospective review of patients presenting with pregabalin poisoning to two tertiary toxicology units from 1 July 2014 to 30 June 2019. Patients were identified from prospective databases maintained by both units and data were extracted from these in addition to medical records. RESULTS: There were 488 presentations in 413 patients (237 [57%] male) over the five-year period. The median age was 41 years (IQR 31-50 years). Deliberate self-poisonings accounted for 342 (70%) presentations, with 121 (25%) recreational exposures. Recreational exposures increased over the period from 2 (4%) in the first year to 54 (39%) presentations in the final year. The median dose of pregabalin was 1200 mg (IQR 600-3000 mg, range 75-16 800 mg). Co-ingestions occurred in 427 (88%) presentations, with sedating agents being co-ingested in 387 (79%)-most commonly opioids and benzodiazepines in 201 (41%) and 174 (36%) presentations respectively. Coma (GCS < 9) occurred in 89 (18%) cases, with 52 (11%) patients being intubated. Only one (0.2%) of these patients had not co-ingested a sedating agent. Hypotension occurred in 26 (5%) cases, all with co-ingestants. Seizures occurred in 11 (2%) cases, 3/59 (5%) in pregabalin-only overdoses. The median length of stay was 16.5 hours (IQR 10-25 hours). CONCLUSIONS: Pregabalin overdose does not cause severe toxicity, but rather mild sedation and, uncommonly, seizures. Coma is common in the presence of sedating co-ingestants. Recreational use is increasing.

Peripherally Physiological Responses to External Emotions and Their Transitions in Bipolar I Disorder With and Without Hypersexuality.

Hypersexuality is associated with psychiatric disorders such as mania; however, it remains unclear whether bipolar I disorder with (BW) or without (BO) hypersexuality demonstrates different responses to external emotional stimuli and their transitions that were composed of pictures and sounds of same domain. In 21 BW patients, 20 BO patients, and 41 healthy volunteers, we administered polygraph tests (electrocardiogram, electromyogram, electrooculogram, and galvanic skin response) to measure transitions from a primer emotion (i.e., external disgust, erotica, fear, happiness, neutral, and sadness) to a noncongruent emotion (out of the remaining five) and to the primer emotion again (repeat-primer). We also evaluated participants' concurrent states of mania, hypomania, and depression. With neutral as the noncongruent emotion, the heart rate difference in BW was greater than in controls when responses to the primer erotica were subtracted from responses to the repeat-primer erotica, or when to the primer sadness were subtracted from the repeat-primer sadness. The difference of the masseter electromyographic activity in BW was lower than in BO and controls when responses to the noncongruent happiness were subtracted from responses to the repeat-primer neutral, and was lower than in BO when to the noncongruent neutral were subtracted from the repeat-primer erotica. The eyeball movement difference was greater in BW than in BO and controls when responses to the noncongruent sadness were subtracted from responses to the repeat-primer neutral. The heart rate difference when responses to the primer happiness were subtracted from responses to the noncongruent neutral was negatively correlated with mania in BO. BW and BO patients behaved differently to external emotions and their transitions, particularly regarding erotica and sadness, which might characterize unique pathophysiological processes of the two bipolar I disorder subtypes.

Methamphetamine intoxication and acute kidney injury: A prospective observational case series.

AIM: The effects of methamphetamine intoxication on the kidney are not well reported. We aimed to investigate acute kidney injury (AKI) associated with methamphetamine intoxication, in particular its severity, duration and association with rhabdomyolysis. METHODS: This is a prospective observational series of methamphetamine-intoxicated patients presenting to an Emergency Department. Patients self-reporting recent methamphetamine use, with a positive urine drug screen and an elevated creatinine, were eligible for the study. Urinary neutrophil gelatinase-associated lipocalin (NGAL) was measured, and serum creatinine, creatine kinase and cystatin C concentrations were performed on arrival and at several time points until discharge from hospital. Demographic and clinical data were obtained from the medical records. RESULTS: There were 634 presentations with methamphetamine intoxication over a 10-month period, with 73/595(12%) cases having an elevated serum creatinine concentration on arrival. Fifty presentations in 48 patients were included in the study. Most patients (85%) were male with a median age of 32 years. The median serum creatinine concentration on presentation was 125 µmol/L (IQR:113-135 µmol/L) with 45 (90%) presentations meeting diagnostic criteria for AKI. Concurrent rhabdomyolysis occurred in 22 (44%) presentations with a median CK of 2695 U/L (IQR:1598-5060 U/L). Cystatin C was elevated (> 0.98 mg/L) in 18 cases. An elevated NGAL concentration (>150 µg/L) was present in five (10%) cases. No patients required dialysis. The median length of stay was 19 hours (IQR 14-24 hours). CONCLUSION: AKI is common in methamphetamine intoxication. The kidney injury is relatively mild and short-lived, resolving with crystalloid therapy.

Applying the handicap principle to biofilms: condition-dependent signalling in Bacillus subtilis microbial communities.

Bacteria in nature often reside in differentiated communities termed biofilms. These communities, which are composed of a number of functionally-distinct cell types, are an interesting example of division of labour in microbes, and as such have been used as a system to study the evolution of cooperation. The structured population of the biofilm also plays a critical role in the persistence of infections, and biofouling of medical and industrial devices. Biofilm formation involves several stages of differentiation, which are mediated by extracellular factors secreted by cells composing the biofilm. The developmental model of biofilm formation describes this process mechanistically: specific subpopulations of cells synthesize signals within the biofilm, and promote the differentiation of other subpopulations. The handicap principle suggests that signals function because they provide reliable information regarding the state of the signaller; here, we apply the handicap principle to signalling among cells composing Bacillus subtilis biofilms, emphasizing the perspective of secreted factors as sources of information rather than solely as mediators of development. Such information could facilitate competition among phenotypically-similar cells composing the biofilm, affecting local organizational patterns within defined subpopulations.

Phylogeny of the gall midges (Diptera, Cecidomyiidae, Cecidomyiinae): Systematics, evolution of feeding modes and diversification rates.

Gall midges (Cecidomyiidae) constitute one of the largest and most diverse families of Diptera, with close to 6600 described species and thousands of undescribed species worldwide. The family is divided into six subfamilies, the five basal ones comprising only fungivorous taxa, whereas the largest, youngest and most diverse subfamily Cecidomyiinae includes fungivorous as well as herbivorous and predatory species. The currently accepted classification of the Cecidomyiinae is morphology-based, and the few phylogenetic inferences that have previously been suggested for it were based on fragmentary or limited datasets. In a first comprehensive phylogenetic analysis of the Cecidomyiinae we sampled 142 species representing 88 genera of 13 tribes from all feeding guilds and zoogeographic regions in order to test the validity of the systematic division of the subfamily and gain insight into patterns of diversification and the evolution of feeding modes. We used sequences from five mitochondrial and nuclear genes to reconstruct maximum likelihood and Bayesian, time-calibrated phylogenies and conducted ancestral state reconstruction of feeding modes. Our results corroborate to a great extent the morphology-based classification of the Cecidomyiinae, with strong support for all supertribes and tribes, all were apparently established in the Upper Cretaceous concordant with the major radiation of angiosperms. We infer that transitions from fungus-feeding to plant-feeding occurred only once or twice in the evolution of the subfamily and that predation evolved only once, contrary to previous hypotheses. All herbivorous clades in the subfamily are very species rich and have diversified at a significantly greater rate than expected, but we found no support for the assertion that herbivorous clades associated with symbiotic fungi in their galls diversify faster than clades that do not have such associations. Currently available data also do not support the hypothesis that symbiotic clades have broader host ranges than non-symbiotic clades.

Gambling Behaviour, Problem Gambling and Reasons for Gambling Among International Students in Tasmania, Australia.

Individuals who undertake tertiary study outside their home countries ("international students") may be at increased risk of problem gambling behaviour. To inform this issue, we examined gambling behaviour, problem gambling behaviour and reasons for gambling among international students, primarily from Asian countries, attending university in Tasmania, Australia. Online surveys that included established measures of each outcome were completed by these students (n = 382) along with a comparison group of domestic students (n = 1013). While most forms of gambling assessed were less common among international students than among domestic students, rates of problem gambling were higher among international students (2.6%) than among domestic (1.4%) students. Further, whereas rates of problem gambling did not differ by sex among domestic students, problem gambling among international students was confined to males. Hence, rates of problem gambling were markedly elevated in this subgroup (5% of all male international students, 15% of male international students who reported any form of gambling in the past 12 months). International students were more likely than domestic students to report engaging in gambling as a means of regulating their internal states and for a challenge and these and other reasons for gambling were positively correlated with problem gambling behaviour. The findings support the need for population- and campus-based health promotion and early intervention programs targeting international students, male students in particular. Information concerning individuals' reasons for gambling might usefully be included in these programs.

Prediction of Lethality in Suicide Attempts: Gender Matters.

This study explores gender differences in lethality of suicide attempts. Three years of medical records related to suicide attempters (N = 666) were subjected to analysis. Of the sample, 69.2% were female, 30.8% male; 63.8% Chinese, 15.8% Indian, and 15.0 % Malay. Ages ranged from 10 to 85 years old (M = 29.7, SD = 16.1). More males than females made attempts with high perceived lethality (χ2 = 12.10, p < .0001) and high medical lethality (χ2 = 10.59, p < .0001). Available variables were subjected to regression analyses. The regression models predicted more than 60% of high medical lethality suicide attempts and more than 80% of high perceived lethality attempts. Suicide intent and opportunity for rescue were significant predictors for both measures of lethality. Gender differences were examined. Findings were discussed in regard to implications in suicide assessments and interventions.

Dying online: live broadcasts of Chinese emerging adult suicides and crisis response behaviors.

BACKGROUND: Social media and online environments are becoming increasingly popular and integral to modern lives. The online presentation of suicidal behaviors is an example of the importance of communication technologies, and the need for professionals to respond to a changing world. These types of behaviors, however, have rarely been scientifically analyzed. This study aimed to examine the behaviors of both suicide broadcasters and their audience, with attention on prevention/crisis opportunities. METHODS: Multiple case studies were employed to explore live-broadcast suicide by Chinese emerging adults (aged 18-25 years). Six cases were selected (four males, two females; aged 19-24, M = 21.60, SD = 2.25), retrieved from 190 public documents (case range = 5 to 32; M = 11.50, SD = 10.37). A qualitative study based on grounded theory was adopted. Information on case background, stages, participants and their behaviors were collected. RESULTS: (1) Five stages of blogcast suicide incidents were revealed, including: Signaling, Initial reactions, Live blogcast of suicide attempts, Crisis responses, and Final outcomes. (2) Common behavioral trends (e.g., comforting, verbal abuse) were identified from the blogcast participants (e.g., active audience, peers, parents and police). (3) Suicide blogcasters exhibited tendencies to communicated signs of pain and cries for help. CONCLUSIONS: This multi-case study found live presentations of suicidal behaviors offered unique opportunities to respond to suicidal crises, and also to learn more about the relationships between suicidal people and potential help sources. Findings showed many audience members wanted to be helpful but lacked appropriate skills or knowledge. Others engaged in suicide cyberbullying. The social media is an environment in the making. This study revealed that increasing knowledge and skills for crisis response and suicide prevention is needed. Such efforts could lead to empowered netizens and a more hospitable online world.

Evolution of the plankton paleome in the Black Sea from the Deglacial to Anthropocene.

The complex interplay of climate shifts over Eurasia and global sea level changes modulates freshwater and saltwater inputs to the Black Sea. The dynamics of the hydrologic changes from the Late Glacial into the Holocene remain a matter of debate, and information on how these changes affected the ecology of the Black Sea is sparse. Here we used Roche 454 next-generation pyrosequencing of sedimentary 18S rRNA genes to reconstruct the plankton community structure in the Black Sea over the last ca. 11,400 y. We found that 150 of 2,710 species showed a statistically significant response to four environmental stages. Freshwater chlorophytes were the best indicator species for lacustrine conditions (>9.0 ka B.P.), although the copresence of previously unidentified marine taxa indicated that the Black Sea might have been influenced to some extent by the Marmara Sea since at least 9.6 ka calendar (cal) B.P. Dinoflagellates, cercozoa, eustigmatophytes, and haptophytes responded most dramatically to the gradual increase in salinity after the latest marine reconnection and during the warm and moist mid-Holocene climatic optimum. According to paired analysis of deuterium/hydrogen (D/H) isotope ratios in fossil alkenones, salinity increased rapidly with the onset of the dry Subboreal after ~5.2 ka B.P., leading to an increase in marine fungi and the first occurrence of marine copepods. A gradual succession of dinoflagellates, diatoms, and chrysophytes occurred during the refreshening after ~2.5 ka cal B.P. with the onset of the cool and wet Subatlantic climate and recent anthropogenic perturbations.

Is off-label repeat prescription of ketamine as a rapid antidepressant safe? Controversies, ethical concerns, and legal implications.

BACKGROUND: Depressive disorders are a common form of psychiatric illness and cause significant disability. Regulation authorities, the medical profession and the public require high safety standards for antidepressants to protect vulnerable psychiatric patients. Ketamine is a dissociative anaesthetic and a derivative of a hallucinogen (phencyclidine). Its abuse is a major worldwide public health problem. Ketamine is a scheduled drug and its usage is restricted due to its abuse liability. Recent clinical trials have reported that ketamine use led to rapid antidepressant effects in patients suffering from treatment-resistant depression. However, various flaws in study designs, and possible biased reporting of results, may have influenced those findings. Further analyses of ketamine use are needed to ensure patient safety. DISCUSSION: The use of ketamine in research and treatment of depressive disorders is controversial. Recently, mental health professionals raised ethical concerns about an ongoing ketamine trial in the UK. Also, a Canadian agency reviewed the existing evidence and did not recommend prescribing ketamine to treat depressive disorders. Findings obtained from tightly controlled research settings cannot be easily translated to clinical practice as substance abuse is commonly comorbid with depressive disorders. An effective antidepressant should reduce severity of depressive symptoms without liability problems. Although the US FDA has not approved the use of ketamine to treat depressive disorders, some psychiatrists offer off-label repeat prescription of ketamine. Prescribing ketamine for treating depressive disorders requires substantial empirical evidence. Clinicians should also consider research findings on ketamine abuse. Depressive disorders can be chronic conditions and the current evidence does not rule out the risk of substance abuse after repeat prescription of ketamine. Off-label ketamine use in treating depressive disorders may breach ethical and moral standards, especially in countries seriously affected by ketamine abuse. This article presents two real-world clinical vignettes which highlight ethical principles and theories, including autonomy, nonmaleficience, fidelity and consequentialism, as related to off-label ketamine use. CONCLUSION: We urge clinicians to minimise the risk of harming patients by considering the empirical evidence on ketamine properties and attempting all standard antidepressant therapies before considering the off-label use of ketamine.