Ethical considerations for precision psychiatry: A roadmap for research and clinical practice.

Precision psychiatry is an emerging field with transformative opportunities for mental health. However, the use of clinical prediction models carries unprecedented ethical challenges, which must be addressed before accessing the potential benefits of precision psychiatry. This critical review covers multidisciplinary areas, including psychiatry, ethics, statistics and machine-learning, healthcare and academia, as well as input from people with lived experience of mental disorders, their family, and carers. We aimed to identify core ethical considerations for precision psychiatry and mitigate concerns by designing a roadmap for research and clinical practice. We identified priorities: learning from somatic medicine; identifying precision psychiatry use cases; enhancing transparency and generalizability; fostering implementation; promoting mental health literacy; communicating risk estimates; data protection and privacy; and fostering the equitable distribution of mental health care. We hope this blueprint will advance research and practice and enable people with mental health problems to benefit from precision psychiatry.

Timing of primary syphilis treatment and impact on the development of treponemal antibodies: a cross-sectional clinic-based study.

BACKGROUND: Serology is negative in a proportion of primary syphilis cases where Treponema pallidum PCR testing is positive. We aimed to identify discordant, T. pallidum PCR-positive, serology-negative primary syphilis cases and any clinical or laboratory factors associated with failure to subsequently seroconvert. METHODS: Serodiscordant primary syphilis cases that were T. pallidum PCR-positive and serology-negative (including rapid plasma reagin, T. pallidum particle agglutination, T. pallidum enzyme immunoassay or T. pallidum chemiluminescence assay) were identified from the Melbourne Sexual Health Centre electronic records between April 2011 and December 2019. Clinical and laboratory associations were examined. RESULTS: There were 814 primary syphilis cases in the study period and 38 (4.7%) were serodiscordant, 35 in men who have sex with men. Thirty-two had follow-up serology performed a median of 24 days later, of which 16 (50%) seroconverted, mostly (81%) within 6 weeks. Failure to seroconvert was significantly associated with treatment on day 1. Of the 12 cases treated on day 1, 10 (83%) failed to seroconvert compared with 6 of 20 (30%) among those who were treated after day 1. DISCUSSION: Earlier treatment of primary syphilis can prevent the development of serological markers. T. pallidum PCR can identify primary syphilis lesions before the development of serological markers and improve diagnosis of early primary syphilis lesions. Serology alone will miss a proportion of primary syphilis infections and should be repeated if a diagnosis of syphilis is being considered.

Segmental Volume and Circulatory Changes that Occur in Humans and Rhesus Monkeys During 4 Hour, -6 Degree Head Down Tilt.

Nonhuman primates are often used to investigate physiologic processes that occur in man during aerospace/cardiovascular orthostatic research. Few studies have compared nonhuman primates and man under identical test conditions to assess the degree of similarity between the two species. Impedance plethysmography was used to measure calf, thigh, pelvic, thoracic, upper arm, and lower arm volume changes in eight rhesus (Macacca Mulatta) monkeys and twelve human subjects during four hour exposures to -6 degree head down tilt (HDT).

Treponema pallidum detection in lesion and non-lesion sites in men who have sex with men with early syphilis: a prospective, cross-sectional study.

BACKGROUND: Syphilis transmission is increasing, and precisely how Treponema pallidum is transmitted sexually from person to person is unclear. We aimed to determine the frequency of T pallidum shedding from potentially asymptomatic sites and the stage of infection at which shedding is most frequent in men who have sex with men (MSM), who have been disproportionately affected by syphilis. METHODS: We did a prospective, cross-sectional study in MSM recruited from Melbourne Sexual Health Centre (Melbourne, VIC, Australia). Men were eligible if they were aged 18 years or older, reported sex with men during the past 12 months, and had laboratory confirmed primary, secondary, or early latent syphilis, consistent with Australian definitions. Primary and secondary syphilis lesions were swabbed and non-lesion samples were collected via oral rinse, oral cavity swab, anal canal swab, urine, and semen. Samples were tested for T pallidum using PCR assays targeting polA (lesion and non-lesion samples) and 47 kDa (non-lesion samples only) gene targets. The primary outcome was the proportion of men with T pallidum detected from potentially asymptomatic sites-namely, the mouth, anus, urethra, and semen. FINDINGS: Between Nov 30, 2015, and May 23, 2019, 246 MSM were screened for inclusion, of whom 200 had serologically confirmed early syphilis and were included in the study: 54 (27%) of 200 had primary syphilis, 93 (47%) had secondary syphilis, and 53 (27%) had early latent syphilis. T pallidum DNA was detected in 48 (24%; 95% CI 18·3-30·5) of 200 men by oral rinse or oral lesion swab, or both, of whom 24 had no oral lesions. Oral T pallidum detection was most frequent in those with secondary syphilis compared with those at other stages of disease (41 [44%] of 93 vs seven [7%] of 107; p<0·0001), and in men with rapid plasma reagin titres of 1/64 or higher compared with those with lower titres (37 [32%] of 117 vs 11 [13%] of 83; p=0·0026). T pallidum was detected by anal canal swab or anal lesion swab, or both, in 45 (23·0%; 95% CI 17·3-29·5) of 196 men with available samples, of whom ten had no anal lesion. Furthermore, T pallidum was detected in urine samples of 12 (6·1%, 3·2-10·3) of 198 men and in semen samples from six (12·0%, 4·5-24·3) of 50 men who provided samples. Among the 93 men with secondary syphilis, 69 (74%) had T pallidum detected at any site, and 24 (26%) had detection at two or more separate sites. Among the 54 men with primary syphilis, 49 (91%) had T pallidum detected at any site, and 11 (20%) had detection at two or more separate sites. Among the 53 men with early latent syphilis, four (8%) had T pallidum detected at any site and none had T pallidum detected at two or more separate sites. INTERPRETATION: Unrecognised oral and anal shedding of T pallidum occurs in MSM with early syphilis, most frequently in those with secondary syphilis, suggesting secondary syphilis is the most infectious stage and that earlier detection and treatment of syphilis to prevent progression to the secondary stage might improve syphilis control. Future research is needed to ascertain the contribution of shedding of T pallidum from non-lesion sites to transmission of syphilis. FUNDING: Australian National Health and Medical Research Council.

The Role of Digital Technologies in Responding to the Grand Challenges of the Natural Environment: The Windermere Accord.

Digital technology is having a major impact on many areas of society, and there is equal opportunity for impact on science. This is particularly true in the environmental sciences as we seek to understand the complexities of the natural environment under climate change. This perspective presents the outcomes of a summit in this area, a unique cross-disciplinary gathering bringing together environmental scientists, data scientists, computer scientists, social scientists, and representatives of the creative arts. The key output of this workshop is an agreed vision in the form of a framework and associated roadmap, captured in the Windermere Accord. This accord envisions a new kind of environmental science underpinned by unprecedented amounts of data, with technological advances leading to breakthroughs in taming uncertainty and complexity, and also supporting openness, transparency, and reproducibility in science. The perspective also includes a call to build an international community working in this important area.

Segmental Volume Changes that Occur in Nonhuman Primates During Short Term Head Up (HUT) and Head Down (HDT) Tilt.

Nonhuman primates are often used in biomedical research and to investigate physiologic processes that occur in man. Impedance plethysmography was used to measure calf, thigh, pelvic, abdominal, and thoracic volume changes in ten Rhesus and eight squirrel monkeys during five-minute exposures to HUT and HDT at angles of 5, 10, and 20 degrees. Calf, rump and tail measurements were made in three squirrel monkeys at 10 and 20 degrees of HUT and HDT. Fluid volume changes in all segments of the Rhesus monkeys were found to change during HUT an HDT in direct relation to the angle of tilt used. However, the volume changes that occurred in the squirrel monkeys were found to be quite different. Their calf, thigh, and pelvic segments lost volume during both HUT and HDT while their abdominal and thoracic segments responded similarly to those of the Rhesus monkeys. These results and those of the calf/tail measurements of the squirrel monkeys suggest that they may utilize their tails as a compensatory reservoir during postural changes and therefore, may not be an appropriate animal model for man under some orthostatic test conditions.

Why Higher Working Memory Capacity May Help You Learn: Sampling, Search, and Degrees of Approximation.

Algorithms for approximate Bayesian inference, such as those based on sampling (i.e., Monte Carlo methods), provide a natural source of models of how people may deal with uncertainty with limited cognitive resources. Here, we consider the idea that individual differences in working memory capacity (WMC) may be usefully modeled in terms of the number of samples, or "particles," available to perform inference. To test this idea, we focus on two recent experiments that report positive associations between WMC and two distinct aspects of categorization performance: the ability to learn novel categories, and the ability to switch between different categorization strategies ("knowledge restructuring"). In favor of the idea of modeling WMC as a number of particles, we show that a single model can reproduce both experimental results by varying the number of particles-increasing the number of particles leads to both faster category learning and improved strategy-switching. Furthermore, when we fit the model to individual participants, we found a positive association between WMC and best-fit number of particles for strategy switching. However, no association between WMC and best-fit number of particles was found for category learning. These results are discussed in the context of the general challenge of disentangling the contributions of different potential sources of behavioral variability.

Risk of Subsequent HIV Infection Following Sexually Transmissible Infections Among Men Who Have Sex With Men.

BACKGROUND: HIV and bacterial sexually transmissible infection (STI) notifications among men who have sex with men (MSM) have increased in Australia and many other countries. The relationship between HIV infection and other STIs has been demonstrated previously. However, the relationship between the cumulative history of STIs and subsequent HIV infection remains largely unexplored and limits our understanding of the mechanisms underpinning the elevated HIV risk. METHODS: Data from HIV-negative MSM who attended high-HIV caseload primary care clinics in Melbourne, Australia, from 2007 to 2014 with 2 or more HIV and STI tests were included. Controlling for sexual behaviors self-reported at clinic visits, discrete time survival analyses using generalized linear modeling estimated the effect of an STI at the prior test event and the cumulative history of STIs (none, 1, 2, or more [repeated]) on risk of HIV infection. RESULTS: A total of 8941 MSM met the study criteria; 227 (2.5%) were diagnosed with HIV over the follow-up period. Adjusting for sexual behaviors, a cumulative history of repeated rectal gonorrhea infections (adjusted hazard ratio [aHR], 6.27; 95% confidence interval [CI], 2.68-14.50) and a single rectal gonorrhea infection (aHR, 2.09; 95% CI, 1.15-3.79) were associated with increased HIV infection risk. CONCLUSIONS: Repeated and single rectal gonorrhea infections were independently associated with increased HIV infection risk. These findings suggest that MSM with any history of rectal gonorrhea, particularly repeat rectal gonorrhea, represent a group for whom preventive interventions for HIV should be emphasized.

Molecular Basis and Ecological Relevance of Caulobacter Cell Filamentation in Freshwater Habitats.

All living cells are characterized by certain cell shapes and sizes. Many bacteria can change these properties depending on the growth conditions. The underlying mechanisms and the ecological relevance of changing cell shape and size remain unclear in most cases. One bacterium that undergoes extensive shape-shifting in response to changing growth conditions is the freshwater bacterium Caulobacter crescentus When incubated for an extended time in stationary phase, a subpopulation of C. crescentus forms viable filamentous cells with a helical shape. Here, we demonstrated that this stationary-phase-induced filamentation results from downregulation of most critical cell cycle regulators and a consequent block of DNA replication and cell division while cell growth and metabolism continue. Our data indicate that this response is triggered by a combination of three stresses caused by prolonged growth in complex medium, namely, the depletion of phosphate, alkaline pH, and an excess of ammonium. We found that these conditions are experienced in the summer months during algal blooms near the surface in freshwater lakes, a natural habitat of C. crescentus, suggesting that filamentous growth is a common response of C. crescentus to its environment. Finally, we demonstrate that when grown in a biofilm, the filamentous cells can reach beyond the surface of the biofilm and potentially access nutrients or release progeny. Altogether, our work highlights the ability of bacteria to alter their morphology and suggests how this behavior might enable adaptation to changing environments.IMPORTANCE Many bacteria drastically change their cell size and morphology in response to changing environmental conditions. Here, we demonstrate that the freshwater bacterium Caulobacter crescentus and related species transform into filamentous cells in response to conditions that commonly occur in their natural habitat as a result of algal blooms during the warm summer months. These filamentous cells may be better able to scavenge nutrients when they grow in biofilms and to escape from protist predation during planktonic growth. Our findings suggest that seasonal changes and variations in the microbial composition of the natural habitat can have profound impact on the cell biology of individual organisms. Furthermore, our work highlights that bacteria exist in morphological and physiological states in nature that can strongly differ from those commonly studied in the laboratory.

Estimating the syphilis epidemic among gay, bisexual and other men who have sex with men in Australia following changes in HIV care and prevention.

Background Syphilis control remains a challenge in many high-income countries, including Australia, where diagnoses are concentrated among gay, bisexual men and other men who have sex with men (GBM). The aim of this study is to project the syphilis epidemic among GBM under a range of scenarios. METHODS: A dynamic coinfection model of HIV and syphilis transmission among GBM in Victoria, Australia, was parametrised to test data from clinics in Melbourne and syphilis case notifications in Victoria. Projected outcomes were new syphilis infections between 2018 and 2025 under seven testing and behaviour change scenarios. RESULTS: Among HIV-negative GBM, the model estimated that increasing syphilis testing coverage (69% - 75%) and frequency (~8-monthly - 6-monthly) could prevent 5% and 13% of syphilis cases respectively between 2018 and 2025 compared to the status quo. Among HIV-positive GBM, less syphilis testing due to changes in HIV care increased syphilis cases by 29% between 2018 and 2025 compared to the status quo. Under a scenario of 20% HIV pre-exposure prophylaxis (PrEP) coverage among HIV-negative GBM (and associated increased serodiscordant sex, reduced condom use and increased syphilis testing), syphilis cases were estimated to decrease by 6% among HIV-negative GBM and by 3% among HIV-positive GBM compared to the status quo, driven by increased testing among PrEP users. CONCLUSION: The present study findings support syphilis control policies focusing on increased testing among GBM. Current Australian PrEP guidelines of quarterly syphilis testing are likely to negate any increases in syphilis due to risk compensation occurring with PrEP scale-up.

Long-distance stone transport and pigment use in the earliest Middle Stone Age.

Previous research suggests that the complex symbolic, technological, and socioeconomic behaviors that typify Homo sapiens had roots in the middle Pleistocene <200,000 years ago, but data bearing on human behavioral origins are limited. We present a series of excavated Middle Stone Age sites from the Olorgesailie basin, southern Kenya, dating from ≥295,000 to ~320,000 years ago by argon-40/argon-39 and uranium-series methods. Hominins at these sites made prepared cores and points, exploited iron-rich rocks to obtain red pigment, and procured stone tool materials from ≥25- to 50-kilometer distances. Associated fauna suggests a broad resource strategy that included large and small prey. These practices imply notable changes in how individuals and groups related to the landscape and to one another and provide documentation relevant to human social and cognitive evolution.

Time-varying decision boundaries: insights from optimality analysis.

The most widely used account of decision-making proposes that people choose between alternatives by accumulating evidence in favor of each alternative until this evidence reaches a decision boundary. It is frequently assumed that this decision boundary stays constant during a decision, depending on the evidence collected but not on time. Recent experimental and theoretical work has challenged this assumption, showing that constant decision boundaries are, in some circumstances, sub-optimal. We introduce a theoretical model that facilitates identification of the optimal decision boundaries under a wide range of conditions. Time-varying optimal decision boundaries for our model are a result only of uncertainty over the difficulty of each trial and do not require decision deadlines or costs associated with collecting evidence, as assumed by previous authors. Furthermore, the shape of optimal decision boundaries depends on the difficulties of different decisions. When some trials are very difficult, optimal boundaries decrease with time, but for tasks that only include a mixture of easy and medium difficulty trials, the optimal boundaries increase or stay constant. We also show how this simple model can be extended to more complex decision-making tasks such as when people have unequal priors or when they can choose to opt out of decisions. The theoretical model presented here provides an important framework to understand how, why, and whether decision boundaries should change over time in experiments on decision-making.

A tutorial on bridge sampling.

The marginal likelihood plays an important role in many areas of Bayesian statistics such as parameter estimation, model comparison, and model averaging. In most applications, however, the marginal likelihood is not analytically tractable and must be approximated using numerical methods. Here we provide a tutorial on bridge sampling (Bennett, 1976; Meng & Wong, 1996), a reliable and relatively straightforward sampling method that allows researchers to obtain the marginal likelihood for models of varying complexity. First, we introduce bridge sampling and three related sampling methods using the beta-binomial model as a running example. We then apply bridge sampling to estimate the marginal likelihood for the Expectancy Valence (EV) model-a popular model for reinforcement learning. Our results indicate that bridge sampling provides accurate estimates for both a single participant and a hierarchical version of the EV model. We conclude that bridge sampling is an attractive method for mathematical psychologists who typically aim to approximate the marginal likelihood for a limited set of possibly high-dimensional models.

Medication adherence, condom use and sexually transmitted infections in Australian preexposure prophylaxis users.

OBJECTIVE: HIV preexposure prophylaxis (PrEP) decreases risk of HIV acquisition; however, its efficacy is closely dependent on adherence. There is also concern that the preventive effect of PrEP may be offset by risk compensation, notably an increase in condomless anal sex. DESIGN: Multisite, open-label demonstration study that recruited people at current or recent risk of HIV infection in Melbourne, Australia. METHODS: Participants were recruited from three general practice clinics and one sexual health clinic in Melbourne and consented to take daily tenofovir/emtricitabine (TFV/FTC) for 30 months. Sexual practice data, HIV and sexually transmitted infection (STI) test results were collected at baseline and 3-monthly during follow-up. PrEP adherence was evaluated by self-report at clinical visits, online surveys, refill-based assessments and dried blood spot testing. We present a 12-month interim analysis. RESULTS: A total of 114 people were recruited. We observed a significant decline in condom use which occurred concomitantly with a significant increase in STIs over the first 12 months of PrEP. Incidence (per 100 person-years) of any STI was 43.2 and 119.8 at months 0-3 and 3-12, respectively [incidence rate ratio 2.77 (1.52, 5.56)]. Adherence to PrEP medication was high by all measures, including 6 month TFV/FTC levels in dried blood spot. CONCLUSION: We found a significant reduction in condom use and an increase in STIs over the first 12 months of follow-up. High medication adherence rates occurring with a decline in condom use and a rise in STIs, suggest that prevention, early detection and treatment of STIs is a chief research priority in the current era of HIV PrEP.

Drosophila PINK1 and parkin loss-of-function mutants display a range of non-motor Parkinson's disease phenotypes.

Parkinson's disease (PD) is more commonly associated with its motor symptoms and the related degeneration of dopamine (DA) neurons. However, it is becoming increasingly clear that PD patients also display a wide range of non-motor symptoms, including memory deficits and disruptions of their sleep-wake cycles. These have a large impact on their quality of life, and often precede the onset of motor symptoms, but their etiology is poorly understood. The fruit fly Drosophila has already been successfully used to model PD, and has been used extensively to study relevant non-motor behaviours in other contexts, but little attention has yet been paid to modelling non-motor symptoms of PD in this genetically tractable organism. We examined memory performance and circadian rhythms in flies with loss-of-function mutations in two PD genes: PINK1 and parkin. We found learning and memory abnormalities in both mutant genotypes, as well as a weakening of circadian rhythms that is underpinned by electrophysiological changes in clock neurons. Our study paves the way for further work that may help us understand the mechanisms underlying these neglected aspects of PD, thus identifying new targets for treatments to address these non-motor problems specifically and perhaps even to halt disease progression in its prodromal phase.

Overcoming indecision by changing the decision boundary.

The dominant theoretical framework for decision making asserts that people make decisions by integrating noisy evidence to a threshold. It has recently been shown that in many ecologically realistic situations, decreasing the decision boundary maximizes the reward available from decisions. However, empirical support for decreasing boundaries in humans is scant. To investigate this problem, we used an ideal observer model to identify the conditions under which participants should change their decision boundaries with time to maximize reward rate. We conducted 6 expanded-judgment experiments that precisely matched the assumptions of this theoretical model. In this paradigm, participants could sample noisy, binary evidence presented sequentially. Blocks of trials were fixed in duration, and each trial was an independent reward opportunity. Participants therefore had to trade off speed (getting as many rewards as possible) against accuracy (sampling more evidence). Having access to the actual evidence samples experienced by participants enabled us to infer the slope of the decision boundary. We found that participants indeed modulated the slope of the decision boundary in the direction predicted by the ideal observer model, although we also observed systematic deviations from optimality. Participants using suboptimal boundaries do so in a robust manner, so that any error in their boundary setting is relatively inexpensive. The use of a normative model provides insight into what variable(s) human decision makers are trying to optimize. Furthermore, this normative model allowed us to choose diagnostic experiments and in doing so we present clear evidence for time-varying boundaries. (PsycINFO Database Record