Large-scale deep tissue voltage imaging with targeted-illumination confocal microscopy.

Voltage imaging with cellular specificity has been made possible by advances in genetically encoded voltage indicators. However, the kilohertz rates required for voltage imaging lead to weak signals. Moreover, out-of-focus fluorescence and tissue scattering produce background that both undermines the signal-to-noise ratio and induces crosstalk between cells, making reliable in vivo imaging in densely labeled tissue highly challenging. We describe a microscope that combines the distinct advantages of targeted illumination and confocal gating while also maximizing signal detection efficiency. The resulting benefits in signal-to-noise ratio and crosstalk reduction are quantified experimentally and theoretically. Our microscope provides a versatile solution for enabling high-fidelity in vivo voltage imaging at large scales and penetration depths, which we demonstrate across a wide range of imaging conditions and different genetically encoded voltage indicator classes.

Variability in the analysis of a single neuroimaging dataset by many teams.

Data analysis workflows in many scientific domains have become increasingly complex and flexible. Here we assess the effect of this flexibility on the results of functional magnetic resonance imaging by asking 70 independent teams to analyse the same dataset, testing the same 9 ex-ante hypotheses1. The flexibility of analytical approaches is exemplified by the fact that no two teams chose identical workflows to analyse the data. This flexibility resulted in sizeable variation in the results of hypothesis tests, even for teams whose statistical maps were highly correlated at intermediate stages of the analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Notably, a meta-analytical approach that aggregated information across teams yielded a significant consensus in activated regions. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset2-5. Our findings show that analytical flexibility can have substantial effects on scientific conclusions, and identify factors that may be related to variability in the analysis of functional magnetic resonance imaging. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for performing and reporting multiple analyses of the same data. Potential approaches that could be used to mitigate issues related to analytical variability are discussed.

Ascorbic acid export from human donor lenses: Is the lens a source of ascorbic acid in the ocular humors?

In previous work, we have shown that the lens acts a reservoir of the antioxidant glutathione (GSH), capable of exporting this antioxidant into the ocular humors and potentially protecting the tissues of the eye that interface with these humors from oxidative stress. In this study, we have extended this work by examining whether the lens acts as a source of ascorbic acid (AsA) to maintain the high levels of AsA known to be present in the ocular humors either by the direct export of AsA into the humors and/or by functioning as a recycling site for AsA, via the direct uptake of oxidised ascorbate (DHA) from the humors, its regeneration to AsA in the lens and then its subsequent export back into the humors. To test this, human lenses of varying ages were cultured for 1 h under hypoxic conditions and AsA/DHA levels measured in the media and in the lens. Human lenses were also cultured in compartmentalised chambers to determine whether efflux of AsA/DHA occurs at the anterior or posterior surface. Immunohistochemistry was performed on human donor lenses and sections labelled with antibodies against GLUT1, a putative DHA uptake transporter. Vitreous humor was collected from patients undergoing vitrectomy who either had a natural clear lens, an artificial intraocular implant (IOL) or a cataractous lens, and AsA/DHA and GSH and oxidised GSH (GSSG) measured. We found that cultured human donor lenses released both AsA and DHA into the media. Culturing of lenses in a compartmentalised chamber revealed that AsA and DHA efflux occurs at both surfaces, with relatively equal amounts of AsA and DHA released from each surface. The posterior surface of the lens was shown to express the GLUT1 transporter. Analysis of vitreous samples from patients undergoing vitrectomy revealed that vitreous GSH and AsA levels were similar between the natural lens group, IOL and cataractous lens group. Taken together, while human donor lenses were shown to export AsA and DHA into the surrounding media, the amount of AsA and DHA released from donor lenses was low and not sufficient to sustain the high levels of total AsA normally present in the humors. This suggests that although the lens is not the main source for maintaining high levels of AsA in the ocular humors, the lens may help to support local AsA levels close to the lens.

The dimensional structure of the Camouflaging Autistic Traits Questionnaire (CAT-Q) and predictors of camouflaging in a representative general population sample.

OBJECTIVES: Some autistic people "camouflage" their differences by modeling neurotypical behaviors to survive in a neurotypical-dominant social world. It remains elusive whether camouflaging is unique to autism or if it entails similar experiences across human groups as part of ubiquitous impression management (IM). Here we examined camouflaging engagement and theoretical drivers in the general population, drawing on the transactional IM framework and contextualizing findings within both contemporary autism research and the past IM literature. METHODS: A large representative U.S. general population sample (N = 972) completed this survey study. We combined exploratory item factor analysis and graph analysis to triangulate the dimensional structure of the Camouflaging Autistic Traits Questionnaire (CAT-Q) and examined its correspondence with prior autism-enriched psychometric findings. We then employed hierarchical regression and elastic-net regression to identify the predictors of camouflaging, including demographic (e.g., age, gender), neurodivergence (i.e., autistic and ADHD traits), socio-motivational, and cognitive factors. RESULTS: We found a three-factor/dimensional structure of the CAT-Q in the general population, nearly identical to that found in previous autism-enriched samples. Significant socio-motivational predictors of camouflaging included greater social comparison, greater public self-consciousness, greater internalized social stigma, and greater social anxiety. These camouflaging drivers overlap with findings in recent autistic camouflaging studies and prior IM research. CONCLUSIONS: The novel psychometric and socio-motivational evidence demonstrates camouflaging as a shared social coping experience across the general population, including autistic people. This continuity guides a clearer understanding of camouflaging and has key implications for autism scholars, clinicians, and the broader clinical intersecting with social psychology research. Future research areas are mapped to elucidate how camouflaging/IM manifests and functions within person-environment transactions across social-identity and clinical groups.

Not Who You Are, But Who You Are With: Re-examining Women's Less Satisfying Sexual Debuts.

Gender differences in appraisals of first intercourse are among the largest in sexuality research, with women indicating less satisfying "sexual debuts" than men. Dispositional or "actor-level" explanations for this gender gap are pervasive, yet research has largely examined heterosexual debuts in which actor gender and partner gender are confounded. We assessed whether women's less satisfying sexual debuts are better explained by actor gender or partner gender, comparing experiences of women who debuted with men (WDM) with those of men and women who debuted with women (MDW, WDW). Retrospective accounts of sexual debut were collected from 3033 adults. At first intercourse, we found that WDW had equal physical and emotional satisfaction to MDW, and more satisfaction than WDM, suggesting satisfaction gaps owing to partner gender, not actor gender. This pattern did not extend to a comparison event (first masturbation), where WDW and WDM had similar satisfaction, but less satisfaction than MDW, suggesting an actor gender gap. To identify sources of satisfaction gaps, we probed for corresponding differences in the circumstances of sexual debut. Sexual circumstances were more strongly implicated than nonsexual ones, with relative deprivation of glans stimulation explaining relative dissatisfaction at first intercourse, but not first masturbation, and orgasm explaining it at both. Findings challenge the view that the satisfaction gap at first intercourse reflects an inherent difference between genders. Indeed, they demonstrate similarities when partner gender does not differ and suggest strategies for ensuring equal sexual satisfaction-and equal sexual rights realization-at (hetero) sexual debut.

Motivated Categories: Social Structures Shape the Construction of Social Categories Through Attentional Mechanisms.

PUBLIC ABSTRACT: Social categories like race and gender often give rise to stereotypes and prejudice, and a great deal of research has focused on how motivations influence these biased beliefs. Here, we focus on potential biases in how these categories are even formed in the first place, suggesting that motivations can influence the very categories people use to group others. We propose that motivations to share schemas with other people and to gain resources shape people's attention to dimensions like race, gender, and age in different contexts. Specifically, people will pay attention to dimensions to the degree that the conclusions produced from using those dimensions align with their motivations. Overall, we suggest that simply examining the downstream effects of social categorization like stereotyping and prejudice is not enough, and that research should look earlier in the process at how and when we form the categories on which those stereotypes are based.

Deliberative control is more than just reactive: Insights from sequential sampling models.

Activating relevant responses is a key function of automatic processes in De Neys's model; however, what determines the order or magnitude of such activation is ambiguous. Focusing on recently developed sequential sampling models of choice, we argue that proactive control shapes response generation but does not cleanly fit into De Neys's automatic-deliberative distinction, highlighting the need for further model development.

The labelled container: Conceptual development of social group representations.

Pietraszewski contends that group representations that rely on a "containment metaphor" fail to adequately capture phenomena of group dynamics such as shifts in allegiances. We argue, in contrast, that social categories allow for computationally efficient, richly structured, and flexible group representations that explain some of the most intriguing aspects of social group behaviour.

Valence and ownership: object desirability influences self-prioritization.

Research has demonstrated that possession exerts a potent influence on stimulus processing, such that objects are categorized more rapidly when owned-by-self than when they belong to other people. Outstanding theoretical questions remain, however, regarding the extent of this self-prioritization effect. In particular, does ownership enhance the processing of objects regardless of their valence or is self-prioritization restricted to only desirable items? To address this issue, here we explored the speed with which participants categorized objects (i.e., desirable and undesirable posters) that ostensibly belonged to the self and a best friend. In addition, to identify the cognitive processes supporting task performance, data were submitted to a hierarchical drift-diffusion model (HDDM) analysis. The results revealed a self-prioritization effect (i.e., RTself < RTfriend) for desirable posters that was underpinned by differences in the efficiency of stimulus processing. Specifically, decisional evidence was extracted more rapidly from self-owned posters when they were desirable than undesirable, an effect that was reversed for friend-owned posters. These findings advance understanding of when and how valence influences self-prioritization during decisional processing.

Impact of Abstinence and of Reducing Illicit Drug Use Without Abstinence on Human Immunodeficiency Virus Viral Load.

BACKGROUND: Substance use is common among people living with human immunodeficiency virus (PLWH) and a barrier to achieving viral suppression. Among PLWH who report illicit drug use, we evaluated associations between HIV viral load (VL) and reduced use of illicit opioids, methamphetamine/crystal, cocaine/crack, and marijuana, regardless of whether or not abstinence was achieved. METHODS: This was a longitudinal cohort study of PLWH from 7 HIV clinics or 4 clinical studies. We used joint longitudinal and survival models to examine the impact of decreasing drug use and of abstinence for each drug on viral suppression. We repeated analyses using linear mixed models to examine associations between change in frequency of drug use and VL. RESULTS: The number of PLWH who were using each drug at baseline ranged from n = 568 (illicit opioids) to n = 4272 (marijuana). Abstinence was associated with higher odds of viral suppression (odds ratio [OR], 1.4-2.2) and lower relative VL (ranging from 21% to 42% by drug) for all 4 drug categories. Reducing frequency of illicit opioid or methamphetamine/crystal use without abstinence was associated with VL suppression (OR, 2.2, 1.6, respectively). Reducing frequency of illicit opioid or methamphetamine/crystal use without abstinence was associated with lower relative VL (47%, 38%, respectively). CONCLUSIONS: Abstinence was associated with viral suppression. In addition, reducing use of illicit opioids or methamphetamine/crystal, even without abstinence, was also associated with viral suppression. Our findings highlight the impact of reducing substance use, even when abstinence is not achieved, and the potential benefits of medications, behavioral interventions, and harm-reduction interventions.

Decomposing the neural pathways in a simple, value-based choice.

Understanding the neural implementation of value-based choice has been an important focus of neuroscience for several decades. Although a consensus has emerged regarding the brain regions involved, including ventromedial prefrontal cortex (vmPFC), posterior parietal cortex (PPC), and the ventral striatum (vSTR), the multifaceted nature of decision processes is one cause of persistent debate regarding organization of the value-based choice network. In the current study, we isolate neural activity related to valuation and choice selection using a gambling task where expected gains and losses are dissociated from choice outcomes. We apply multilevel mediation analysis to formally test whether brain regions identified as part of the value-based choice network mediate between perceptions of expected value and choice to accept or decline a gamble. Our approach additionally makes predictions regarding interregional relationships to elucidate the chain of processing events within the value-based decision network. Finally, we use dynamic causal modelling (DCM) to compare plausible models of interregional relationships in value-based choice. We observe that activity in vmPFC does not predict take/pass choices, but rather is highly associated with outcome evaluation. By contrast, both PPC and bilateral vSTR (bilaterally) mediate the relationship between expected value and choice. Interregional mediation analyses reveal that vSTR fully mediates between PPC and choice, and this is supported by DCM. Together these results suggest that vSTR, and not vmPFC nor PPC, functions as an important driver of choice.

Adherence to the SEP-1 Sepsis Bundle in Hospital-Onset v. Community-Onset Sepsis: a Multicenter Retrospective Cohort Study.

BACKGROUND: Sepsis is the leading cause of in-hospital death. The SEP-1 sepsis bundle is a protocol for early sepsis care that requires providers to diagnose and treat sepsis quickly. Limited evidence suggests that adherence to the sepsis bundle is lower in cases of hospital-onset sepsis. OBJECTIVE: To compare sepsis bundle adherence in hospital-onset vs. community-onset sepsis. DESIGN: Retrospective cohort study using multivariable analysis of clinical data. PARTICIPANTS: A total of 4658 inpatients age 18 or older were identified by diagnosis codes consistent with sepsis or disseminated infection. SETTING: Four university hospitals in California between 2014 and 2016. MAIN OUTCOMES AND MEASURES: The primary outcome was adherence to key components of the sepsis bundle defined by the Centers for Medicare and Medicaid Services in their core measure, SEP-1. Covariates included clinical characteristics related to the patient, infection, and pathogen. KEY RESULTS: Compared with community-onset, cases of hospital-onset sepsis were less likely to receive SEP-1 adherent care (relative risk 0.33, 95% confidence interval 0.29-0.38, p < 0.001). With the exception of vasopressors (RR 1.11, p = 0.002), each component of SEP-1 evaluated-blood cultures (RR 0.76, p < 0.001), serum lactate (RR 0.51, p < 0001), broad-spectrum antibiotics (RR 0.62, p < 0.001), intravenous fluids (0.47, p < 0.001), and follow-up lactate (RR 0.71, p < 0.001)-was less likely to be performed within the recommended time frame in hospital-onset sepsis. Within the hospital, cases of hospital-onset sepsis arising on the ward were less likely to receive SEP-1-adherent care than were cases arising in the intensive care unit (RR 0.68, p = 0.004). CONCLUSIONS: Inpatients with hospital-onset sepsis receive different management than individuals with community-onset sepsis. It remains to be determined whether system-level factors, provider-level factors, or factors related to measurement explain the observed variation in care or whether variation in care affects outcomes.

Life Chaos is Associated with Reduced HIV Testing, Engagement in Care, and ART Adherence Among Cisgender Men and Transgender Women upon Entry into Jail.

Life chaos, the perceived inability to plan for and anticipate the future, may be a barrier to the HIV care continuum for people living with HIV who experience incarceration. Between December 2012 and June 2015, we interviewed 356 adult cisgender men and transgender women living with HIV in Los Angeles County Jail. We assessed life chaos using the Confusion, Hubbub, and Order Scale (CHAOS) and conducted regression analyses to estimate the association between life chaos and care continuum. Forty-eight percent were diagnosed with HIV while incarcerated, 14% were engaged in care 12 months prior to incarceration, mean antiretroviral adherence was 65%, and 68% were virologically suppressed. Adjusting for sociodemographics, HIV-related stigma, and social support, higher life chaos was associated with greater likelihood of diagnosis while incarcerated, lower likelihood of engagement in care, and lower adherence. There was no statistically significant association between life chaos and virologic suppression. Identifying life chaos in criminal-justice involved populations and intervening on it may improve continuum outcomes.

Parts of me: Identity-relevance moderates self-prioritization.

Recent research has revealed a pervasive bias for self-relevant information during decision-making, a phenomenon termed the self-prioritization effect. Focusing almost exclusively on between-target (e.g., self vs. friend) differences in task performance, however, this work has overlooked the influence stimulus factors potentially exert during decisional processing. Accordingly, based on pertinent social-psychological theorizing (i.e., Identity-Based Motivation Theory), here we explored the possibility that self-prioritization is sensitive to the identity-based relevance of stimuli. The results of three experiments supported this hypothesis. In a perceptual-matching task, stimulus enhancement was greatest when geometric shapes were associated with identity-related information that was important (vs. unimportant) to participants. In addition, hierarchical drift-diffusion modeling revealed this effect was underpinned by differences in the efficiency of visual processing. Specifically, evidence was extracted more rapidly from stimuli paired with consequential compared to inconsequential identity-related components. These findings demonstrate how identity-relevance moderates self-prioritization.

Enhancing Maori and Pasifika graduate interest in ophthalmology surgical training in New Zealand/Aotearoa: Barriers and opportunities.

IMPORTANCE: Improving the representation of indigenous ophthalmologists in New Zealand. BACKGROUND: Maori, indigenous to New Zealand/Aotearoa and Pacific Peoples indigenous to Pacific Island Nations living in New Zealand, experience poorer health outcomes across several ophthalmic conditions. The Royal Australian and New Zealand College of Ophthalmologists have identified indigenous workforce development as a priority. DESIGN: Mixed-methods study, utilizing retrospective analysis of Medical Schools Outcomes Database and Longitudinal Tracking Project responses, and prospective interviews with Maori/Pasifika medical graduates. PARTICIPANTS: This study involved 64 medical graduates from the University of Auckland (UoA) and the University of Otago, and six Maori/Pasifika medical postgraduates in New Zealand. METHODS: Retrospective analysis of medical graduate responses who ranked ophthalmology among their top-three preferred specialties in the Medical Schools Outcomes Database and Longitudinal Tracking Project. Prospective semi-structured interviews with Maori/Pasifika medical postgraduates. MAIN OUTCOME MEASURES: Specialty training influencing factors and prevocational ophthalmology experience. RESULTS: A total of 64 (6.7%) out of 954 medical graduates from the UoA and University of Otago ranked ophthalmology among their top-three preferred training specialties (2012-2017). Of the 64 graduates, six (9.3%) identified as Maori/Pasifika. No significant difference in influencing factors between Maori/Pasifika and non-Maori/Pasifika students was identified. Both groups ranked intellectual content, procedural skills, specialty exposure and mentorship as highly influential. Qualitative interviews with Maori/Pasifika graduates highlighted positive experiences in ophthalmology but limited exposure overall. Negative anecdotes and unclear training pathways discouraged Maori/Pasifika interest in Ophthalmology training. CONCLUSIONS AND RELEVANCE: Maori/Pasifika graduate interest in ophthalmology training was relatively low. Valuable insights include enhancing specialty exposure, mentor development, promoting Maori/Pasifika connections and clarifying training pathways for future graduates.

Belief as a non-epistemic adaptive benefit.

Although rationalization about one's own beliefs and actions can improve an individual's future decisions, beliefs can provide other benefits unrelated to their epistemic truth value, such as group cohesion and identity. A model of resource-rational cognition that accounts for these benefits may explain unexpected and seemingly irrational thought patterns, such as belief polarization.

Photocatalytic α-Tertiary Amine Synthesis via C-H Alkylation of Unmasked Primary Amines.

A practical, catalytic entry to α,α,α-trisubstituted (α-tertiary) primary amines by C-H functionalisation has long been recognised as a critical gap in the synthetic toolbox. We report a simple and scalable solution to this problem that does not require any in situ protection of the amino group and proceeds with 100 % atom-economy. Our strategy, which uses an organic photocatalyst in combination with azide ion as a hydrogen atom transfer (HAT) catalyst, provides a direct synthesis of α-tertiary amines, or their corresponding γ-lactams. We anticipate that this methodology will inspire new retrosynthetic disconnections for substituted amine derivatives in organic synthesis, and particularly for challenging α-tertiary primary amines.

Self-reported antiretroviral therapy adherence and viral load in criminal justice-involved populations.

BACKGROUND: Self-reported antiretroviral therapy (ART) adherence measures that are associated with plasma viral load (VL) are valuable to clinicians and researchers, but are rarely examined among groups vulnerable to dropping out of care. One-seventh of all those living with HIV pass through incarceration annually and criminal-justice (CJ) involved people living with HIV (PLH) are vulnerable to falling out of care. We examined the association of self-reported ART adherence with VL in a criminal-justice sample compared to a routine-care sample. METHODS: Samples: We examined data from a multisite collaboration of studies addressing the continuum of HIV care among CjJ involved persons in the Seek, Test, Treat, and Retain cohort. Data pooled from seven CJ- studies (n = 414) were examined and compared with the routine-care sample from the Centers for AIDS Research Network of Integrated Clinical Systems' seven sites (n = 11,698). MEASURES: In both samples, data on self-reported percent ART doses taken were collected via the visual analogue scale adherence measure. Viral load data were obtained by blood-draw. ANALYSIS: We examined the associations of adherence with VL in both cohorts using mixed effects linear regression of log-VL, and mixed effects logistic regression of binary VL (≥ 200 copies/mL) outcomes. Interactions by CD4 count and self-reported health status were also tested. RESULTS: Among the CJ sample, the coefficient for log-VL was - 0.31 (95% CI = - 0.43, - 0.18; P < 0.01) and that in the routine-care sample was - 0.42 (95% CI = - 0.45, - 0.38; P < 0.01). For the logistic regression of binary detectable VL on 10% increments of adherence we found the coefficient was - 0.26 (95% CI = - 0.37, - 0.14; P < 0.01) and in the routine-care sample it was - 0.38 (95% CI = - 0.41, - 0.35; P < 0.01). There was no significant interaction by CD4 count level in the CJ sample, but there was in the routine-care sample. Conversely, there was a significant interaction by self-reported health status level in the criminal-justice sample, but not in the routine-care sample. CONCLUSIONS: The visual analogue scale is valid and useful to measure ART adherence, supporting treatment for CJ- involved PLH vulnerable to falling out of care. Research should examine adherence and VL in additional populations.

Implicit Cognition and Psychopathology: Looking Back and Looking Forward.

Implicit cognitive processing is theorized to have a central role in many forms of psychopathology. In the current review, we focus on implicit associations, by which we mean evaluative representations in memory that are difficult to control and do not require conscious reflection to influence affect, cognition, or behavior. We consider definitional and measurement challenges before examining recent empirical evidence for these associations in anxiety, obsessive-compulsive, posttraumatic stress, depressive, and alcohol use disorders. This examination is framed by a brief review of the ways that prominent models of psychopathology represent biased implicit processing of disorder-relevant information. We consider to what extent models reflect more traditional automatic/implicit versus strategic/explicit dual-process perspectives or reflect more recent dynamical systems perspectives in which mental representations are iteratively reprocessed, evolving continuously. Finally, we consider the future research needed to better understand the interactive and temporal dynamics of implicit cognition in psychopathology.

Vacuum Selection from Cosmology on Networks of String Geometries.

We introduce network science as a framework for studying the string landscape. Two large networks of string geometries are constructed, where nodes are extra-dimensional six-manifolds and edges represent topological transitions between them. We show that a standard bubble cosmology model on the networks has late-time behavior determined by the largest eigenvector of -(L+D), where L and D are the Laplacian and degree matrices of the networks, which provides a dynamical mechanism for vacuum selection in the string landscape.