Community Support for Harm Reduction and Treatment of Opioid Use Disorder.

As the opioid epidemic continues, availability of evidence-based strategies for harm reduction and treatment in communities is critical to reduce overdose and other consequences of opioid use disorder. Community members' support of harm reduction and treatment services is needed for new programs and to maintain existent programs. This study sought to understand beliefs and attitudes associated with support for three community-based strategies to address opioid misuse and addiction: naloxone, needle exchange, and medication-assisted treatment. We conducted a cross-sectional online survey with 545 adults. Results of the survey showed that participants supported all three strategies, with the strongest support for medication-assisted treatment. Multiple regression showed that stigma and perceived stigma were significant predictors for all three strategies, with inverse relationships. Stigmatizing beliefs predicted less support while perceiving stigma among others was associated with greater support for the strategies. Normative beliefs also significantly predicted support for all three strategies, such that stronger belief that others were supportive of each strategy was associated with greater support for that strategy. Other predictors varied across the three strategies. Support for harm reduction and treatment programs in communities affected by the opioid epidemic may be bolstered by reducing stigma and increasing normative beliefs. Stronger support for medication-assisted treatment may be leveraged and extended to harm reduction strategies. Results of our study contribute insights for bolstering community support for harm reduction and treatment, which is vital for adoption and maintenance of these important programs.

Neuromodulatory influence of norepinephrine during developmental experience-dependent plasticity.

Critical periods represent phases of development during which neuronal circuits and their responses can be readily shaped by stimuli. Experience-dependent plasticity that occurs within these critical periods can be influenced in many ways; however, Shepard et al. (J Neurosci 35: 2432-2437, 2015) recently singled out norepinephrine as an essential driver of this plasticity within the auditory cortex. This work provides novel insight into the mechanisms of critical period plasticity and challenges previous conceptions that a functional redundancy exists between noradrenergic and cholinergic influences on cortical plasticity.

Absence of transient receptor potential vanilloid-1 accelerates stress-induced axonopathy in the optic projection.

How neurons respond to stress in degenerative disease is of fundamental importance for identifying mechanisms of progression and new therapeutic targets. Members of the transient receptor potential (TRP) family of cation-selective ion channels are candidates for mediating stress signals, since different subunits transduce a variety of stimuli relevant in both normal and pathogenic physiology. We addressed this possibility for the TRP vanilloid-1 (TRPV1) subunit by comparing how the optic projection of Trpv1(-/-) mice and age-matched C57 controls responds to stress from elevated ocular pressure, the critical stressor in the most common optic neuropathy, glaucoma. Over a 5 week period of elevated pressure induced by microbead occlusion of ocular fluid, Trpv1(-/-) accelerated both degradation of axonal transport from retinal ganglion cells to the superior colliculus and degeneration of the axons themselves in the optic nerve. Ganglion cell body loss, which is normally later in progression, occurred in nasal sectors of Trpv1(-/-) but not C57 retina. Pharmacological antagonism of TRPV1 in rats similarly accelerated ganglion cell axonopathy. Elevated ocular pressure resulted in differences in spontaneous firing rate and action potential threshold current in Trpv1(-/-) ganglion cells compared with C57. In the absence of elevated pressure, ganglion cells in the two strains had similar firing patterns. Based on these data, we propose that TRPV1 may help neurons respond to disease-relevant stressors by enhancing activity necessary for axonal signaling.

Short-term increases in transient receptor potential vanilloid-1 mediate stress-induced enhancement of neuronal excitation.

Progression of neurodegeneration in disease and injury is influenced by the response of individual neurons to stressful stimuli and whether this response includes mechanisms to counter declining function. Transient receptor potential (TRP) cation channels transduce a variety of disease-relevant stimuli and can mediate diverse stress-dependent changes in physiology, both presynaptic and postsynaptic. Recently, we demonstrated that knock-out or pharmacological inhibition of the TRP vanilloid-1 (TRPV1) capsaicin-sensitive subunit accelerates degeneration of retinal ganglion cell neurons and their axons with elevated ocular pressure, the critical stressor in the most common optic neuropathy, glaucoma. Here we probed the mechanism of the influence of TRPV1 on ganglion cell survival in mouse models of glaucoma. We found that induced elevations of ocular pressure increased TRPV1 in ganglion cells and its colocalization at excitatory synapses to their dendrites, whereas chronic elevation progressively increased ganglion cell Trpv1 mRNA. Enhanced TRPV1 expression in ganglion cells was transient and supported a reversal of the effect of TRPV1 on ganglion cells from hyperpolarizing to depolarizing, which was also transient. Short-term enhancement of TRPV1-mediated activity led to a delayed increase in axonal spontaneous excitation that was absent in ganglion cells from Trpv1(-/-) retina. In isolated ganglion cells, pharmacologically activated TRPV1 mobilized to discrete nodes along ganglion cell dendrites that corresponded to sites of elevated Ca(2+). These results suggest that TRPV1 may promote retinal ganglion cell survival through transient enhancement of local excitation and axonal activity in response to ocular stress.

Rectification of EMG in low force contractions improves detection of motor unit coherence in the beta-frequency band.

Rectification of surface EMG before spectral analysis is a well-established preprocessing method used in the detection of motor unit firing patterns. A number of recent studies have called into question the need for rectification before spectral analysis, pointing out that there is no supporting experimental evidence to justify rectification. We present an analysis of 190 records from 13 subjects consisting of simultaneous recordings of paired single motor units and surface EMG from the extensor digitorum longus muscle during middle finger extension against gravity (unloaded condition) and against gravity plus inertial loading (loaded condition). We directly examine the hypothesis that rectified surface EMG is a better predictor of the frequency components of motor unit synchronization than the unrectified (or raw) EMG in the beta-frequency band (15-32 Hz). We use multivariate analysis and estimate the partial coherence between the paired single units using both rectified and unrectified surface EMG as a predictor. We use a residual partial correlation measure to quantify the difference between raw and rectified EMG as predictor and analyze unloaded and loaded conditions separately. The residual correlation for the unloaded condition is 22% with raw EMG and 3.5% with rectified EMG and for the loaded condition it is 5.2% with raw EMG and 1.4% with rectified EMG. We interpret these results as strong supporting experimental evidence in favor of using the preprocessing step of surface EMG rectification before spectral analysis.

A structural model for binding of the serine-rich repeat adhesin GspB to host carbohydrate receptors.

GspB is a serine-rich repeat (SRR) adhesin of Streptococcus gordonii that mediates binding of this organism to human platelets via its interaction with sialyl-T antigen on the receptor GPIbα. This interaction appears to be a major virulence determinant in the pathogenesis of infective endocarditis. To address the mechanism by which GspB recognizes its carbohydrate ligand, we determined the high-resolution x-ray crystal structure of the GspB binding region (GspB(BR)), both alone and in complex with a disaccharide precursor to sialyl-T antigen. Analysis of the GspB(BR) structure revealed that it is comprised of three independently folded subdomains or modules: 1) an Ig-fold resembling a CnaA domain from prokaryotic pathogens; 2) a second Ig-fold resembling the binding region of mammalian Siglecs; 3) a subdomain of unique fold. The disaccharide was found to bind in a pocket within the Siglec subdomain, but at a site distinct from that observed in mammalian Siglecs. Confirming the biological relevance of this binding pocket, we produced three isogenic variants of S. gordonii, each containing a single point mutation of a residue lining this binding pocket. These variants have reduced binding to carbohydrates of GPIbα. Further examination of purified GspB(BR)-R484E showed reduced binding to sialyl-T antigen while S. gordonii harboring this mutation did not efficiently bind platelets and showed a significant reduction in virulence, as measured by an animal model of endocarditis. Analysis of other SRR proteins revealed that the predicted binding regions of these adhesins also had a modular organization, with those known to bind carbohydrate receptors having modules homologous to the Siglec and Unique subdomains of GspB(BR). This suggests that the binding specificity of the SRR family of adhesins is determined by the type and organization of discrete modules within the binding domains, which may affect the tropism of organisms for different tissues.

From goal to outcome: Analyzing the progression of biomedical sciences PhD careers in a longitudinal study using an expanded taxonomy.

Biomedical sciences PhDs pursue a wide range of careers inside and outside academia. However, there is little data regarding how career interests of PhD students relate to the decision to pursue postdoctoral training or to their eventual career outcomes. Here, we present the career goals and career outcomes of 1452 biomedical sciences PhDs who graduated from Vanderbilt University between 1997 and 2021. We categorized careers using an expanded three-tiered taxonomy and flags that delineate key career milestones. We also analyzed career goal changes between matriculation and doctoral defense, and the reasons why students became more- or less-interested in research-intensive faculty careers. We linked students' career goal at doctoral defense to whether they did a postdoc, the duration of time between doctoral defense and the first non-training position, the career area of the first non-training position, and the career area of the job at 10 years after graduation. Finally, we followed individual careers for 10 years after graduation to characterize movement between different career areas over time. We found that most students changed their career goal during graduate school, declining numbers of alumni pursued postdoctoral training, many alumni entered first non-training positions in a different career area than their goal at doctoral defense, and the career area of the first non-training position was a good indicator of the job that alumni held 10 years after graduation. Our findings emphasize that students need a wide range of career development opportunities and career mentoring during graduate school to prepare them for futures in research and research-related professions.

Role of Trusted Sources and Behavioral Beliefs in Promoting Mitigation Behaviors During the COVID-19 Pandemic: Survey Study.

BACKGROUND: During the ongoing COVID-19 pandemic and in preparation for future public health crises, it is important to understand the relationship between individuals' health beliefs, including their trust in various sources of health information, and their engagement in mitigation behaviors. OBJECTIVE: We sought to identify relationships between trust in various sources of health information and the behavioral beliefs related to vaccination and mask wearing as well as to understand how behavioral beliefs related to vaccination differ by willingness to be vaccinated. METHODS: We conducted an online survey of 1034 adults in the United States and assessed their trust in federal, local, and media sources of health information; their beliefs about vaccination; and their masking intention and vaccination willingness. RESULTS: Using regression, masking intention was predicted by trust in the World Health Organization (P<.05) and participants' state public health offices (P<.05), while vaccine willingness was predicted by trust in participants' own health care providers (P<.05) and pharmaceutical companies (P<.001). Compared to individuals with low willingness to be vaccinated, individuals with high willingness indicated greater endorsement of beliefs that vaccines would support a return to normalcy, are safe, and are a social responsibility (P<.001 for all). CONCLUSIONS: Results can be used to inform ongoing public health messaging campaigns to manage the COVID-19 pandemic and increase readiness for the next pandemic. Additionally, results support the need to bolster the public's trust in health care agencies as well as to enhance trust and respect in health care providers to increase people's adoption of mitigation behaviors.

Analysis of post-operative changes in serum protein expression profiles from colorectal cancer patients by MALDI-TOF mass spectrometry: a pilot methodological study.

BACKGROUND: Mass spectrometry-based protein expression profiling of blood sera can be used to discriminate colorectal cancer (CRC) patients from unaffected individuals. In a pilot methodological study, we have evaluated the changes in protein expression profiles of sera from CRC patients that occur following surgery to establish the potential of this approach for monitoring post-surgical response and possible early prediction of disease recurrence. METHODS: In this initial pilot study, serum specimens from 11 cancer patients taken immediately prior to surgery and at approximately 6 weeks following surgery were analysed alongside 10 normal control sera by matrix-assisted laser desorption ionisation time of-flight-mass spectrometry (MALDI-TOF MS). Using a two-sided t-test the top 20 ranked protein peaks that discriminate normal from pre-operative sera were identified. These were used to classify post-operative sera by hierarchical clustering analysis (Spearman's Rank correlation) and, as an independent 'test' dataset, by k-nearest neighbour and weighted voting supervised learning algorithms. RESULTS: Hierarchical cluster analysis classified post-operative sera from all six early Dukes' stage (A and B) patients as normal. The remaining five post-operative sera from more advanced Dukes' stages (C1 and C2) were classified as cancer. Analysis by supervised learning algorithms similarly grouped all advanced Dukes' stages as cancer, with four of the six post-operative sera from early Dukes' stages being classified as normal (P = 0.045; Fisher's exact test). CONCLUSIONS: The results of this pilot methodological study illustrate the proof-of-concept of using protein expression profiling of post-surgical blood sera from individual patients to monitor disease course. Further validation on a larger patient cohort and using an independent post-operative sera dataset would be required to evaluate the potential clinical relevance of this approach. Prospective data, including follow-up on patient survival, could in the future, then be evaluated to inform decisions on individualised treatment modalities.

Traffic safety culture and prosocial driver behavior for safer vehicle-bicyclist interactions.

INTRODUCTION: Bicyclist safety is a growing concern as more adults use this form of transportation for recreation, exercise, and mobility. Most bicyclist fatalities result from a crash with a vehicle. Often, the behaviors of the driver are responsible for the crash. METHOD: This survey study of Montana and North Dakota residents (n = 938) examined the influence of traffic safety culture on driver behaviors that affect safe interactions with bicyclists. RESULTS: Prosocial driver behavior was most common and appeared to be intentional. Intention was increased by positive attitudes, normative perceptions, and perceived control. However, normative perceptions appear to offer the most opportunity for change. Practical Application: Strategies that increase perceptions that prosocial driver behavior is normal may increase prosocial intentions, thereby increasing bicyclist safety.

Preparation of many-body states for quantum simulation.

While quantum computers are capable of simulating many quantum systems efficiently, the simulation algorithms must begin with the preparation of an appropriate initial state. We present a method for generating physically relevant quantum states on a lattice in real space. In particular, the present algorithm is able to prepare general pure and mixed many-particle states of any number of particles. It relies on a procedure for converting from a second-quantized state to its first-quantized counterpart. The algorithm is efficient in that it operates in time that is polynomial in all the essential descriptors of the system, the number of particles, the resolution of the lattice, and the inverse of the maximum final error. This scaling holds under the assumption that the wave function to be prepared is bounded or its indefinite integral is known and that the Fock operator of the system is efficiently simulatable.

Developing a theoretical foundation to change road user behavior and improve traffic safety: Driving under the influence of cannabis (DUIC).

OBJECTIVES: This study explored a theoretical model to assess the influence of culture on willingness and intention to drive under the influence of cannabis (DUIC). This model is expected to guide the design of strategies to change future DUIC behavior in road users. METHODS: This study used a survey methodology to obtain a nationally representative sample (n = 941) from the AmeriSpeak Panel. Survey items were designed to measure aspects of a proposed definition of traffic safety culture and a predictive model of its relationship to DUIC. RESULTS: Although the percentage of reported past DUIC behaviors was relatively low (8.5%), this behavior is still a significant public health issue-especially for younger drivers (18-29 years), who reported more DUIC than expected. Findings suggest that specific cultural components (attitudes, norms) reliably predict past DUIC behavior, general DUIC willingness, and future DUIC intention. Most DUIC behavior appears to be deliberate, related significantly to willingness and intention. Intention and willingness both appear to fully moderate the relationship between traffic safety culture and DUIC behavior. CONCLUSIONS: This study explored a theoretical model to understand road user behavior involving drug (cannabis)-impaired driving as a significant risk factor for traffic safety. By understanding the cultural factors that increase DUIC behavior, we can create strategies to transform this culture and sustain safer road user behavior.

Seatbelt use among military personnel during operational deployment.

OBJECTIVE: This study analyzed the wearing of seatbelts among British Forces personnel in Iraq and explored the various factors that prevented their use. METHODS: Questionnaires were administered to 237 British Forces personnel in southern Iraq from December 2003 to January 2004. Data analysis was by percentages. RESULTS: A total of 78% of respondents knew the seatbelt regulations (i.e., to wear seatbelts always). Respondents perceived the biggest threats to driving to be bad roads, speeding, security dangers, and Iraqi drivers. Seatbelt usage by drivers was 52% always, 25% sometimes, and 22% never. This was similar to usage by front seat passengers (52%, 27%, and 21%, respectively). The main reasons for not wearing seatbelts for drivers and front seat passengers were inhibition of exit and weapons. A total of 66% of back seat passengers in Land Rovers never wore seatbelts. CONCLUSIONS: The wearing of seatbelts is mandatory. The Ministry of Defence seatbelt policy is clear and is understood by most service personnel. However, this study shows a disparity between awareness regarding the mandatory use of seatbelts and actual use. Soldiers perceive the use of seatbelts as restrictive in a hostile environment. More effective education is needed and should emphasize the importance of seatbelt usage even in hostile areas such as Iraq.

Modulatory compartments in cortex and local regulation of cholinergic tone.

Neuromodulatory signaling is generally considered broad in its impact across cortex. However, variations in the characteristics of cortical circuits may introduce regionally-specific responses to diffuse modulatory signals. Features such as patterns of axonal innervation, tissue tortuosity and molecular diffusion, effectiveness of degradation pathways, subcellular receptor localization, and patterns of receptor expression can lead to local modification of modulatory inputs. We propose that modulatory compartments exist in cortex and can be defined by variation in structural features of local circuits. Further, we argue that these compartments are responsible for local regulation of neuromodulatory tone. For the cholinergic system, these modulatory compartments are regions of cortical tissue within which signaling conditions for acetylcholine are relatively uniform, but between which signaling can vary profoundly. In the visual system, evidence for the existence of compartments indicates that cholinergic modulation likely differs across the visual pathway. We argue that the existence of these compartments calls for thinking about cholinergic modulation in terms of finer-grained control of local cortical circuits than is implied by the traditional view of this system as a diffuse modulator. Further, an understanding of modulatory compartments provides an opportunity to better understand and perhaps correct signal modifications that lead to pathological states.

Air-water CO2 outgassing in the Lower Lakes (Alexandrina and Albert, Australia) following a millennium drought.

Lakes are an important source and sink of atmospheric CO2, and thus are a vital component of the global carbon cycle. However, with scarce data on potentially important subtropical and tropical areas for whole continents such as Australia, the magnitude of large-scale lake CO2 emissions is unclear. This study presents spatiotemporal changes of dissolved inorganic carbon and water - to - air interface CO2 flux in the two of Australia's largest connected, yet geomorphically different freshwater lakes (Lake Alexandrina and Lake Albert, South Australia), during drought (2007 to September-2010) and post-drought (October 2010 to 2013). Lake levels in the extreme drought were on average approximately 1m lower than long-term average (0.71 m AHD). Drought was associated with an increase in the concentrations of dissolved inorganic species, organic carbon, nitrogen, Chl-a and major ions, as well as water acidification as a consequence of acid sulfate soil (ASS) exposure, and hence, had profound effects on lake pCO2 concentrations. Lakes Alexandrina and Albert were a source of CO2 to the atmosphere during the drought period, with efflux ranging from 0.3 to 7.0 mmol/m(2)/d. The lake air-water CO2 flux was negative in the post-drought, ranging between -16.4 and 0.9 mmol/m(2)/d. The average annual CO2 emission was estimated at 615.5×10(6) mol CO2/y during the drought period. These calculated emission rates are in the lower range for lakes, despite the potential for drought conditions that shift the lakes from sink to net source for atmospheric CO2. These observations have significant implications in the context of predicted increasing frequency and intensity of drought as a result of climate change. Further information on the spatial and temporal variability in CO2 flux from Australian lakes is urgently warranted to revise the global carbon budget for lakes.

Systems analysis of stress and positive perceptions in mothers and fathers of pre-school children with autism.

Systemic analyses of psychological functioning in families of children with autism have typically shown that parents report different experiences (e.g., stress) and that siblings may also be affected. The purpose of the present research was more explicitly to address relationships between child, partner, and parent variables. Parents of 48 children with autism (41 mother-father pairs) reported on child characteristics, and their own stress and mental health. Mothers were found to report both more depression and more positive perceptions than fathers. Regression analyses revealed that paternal stress and positive perceptions were predicted by maternal depression; maternal stress was predicted by their children's behavior problems (not adaptive behavior or autism symptoms) and by their partner's depression. The future testing of the mechanisms underlying these results is discussed. In addition, the need is emphasized for more systemic analyses to understand the psychological functioning of children with autism and their siblings and parents.

A systems analysis of the Ladbroke Grove rail crash.

On 5 October 1999, near London Paddington Station, two trains collided on a main line near Ladbroke Grove. The immediate "human error" that preceded this crash was a Signal Passed At Danger (SPAD). Thirty-one people lost their lives and many more were injured. The crash prompted an extensive multi-disciplinary investigation and hearing to identify the factors that contributed to the Signal Passed At Danger event. This included the involvement of psychologists to consider the human factors "responsible" for the crash and the broader system context, including the operational and organizational environment that may have contributed. This paper summarizes the key factors identified in relation to this crash within a system analysis framework. This framework considers multiple sources of influence upon the driver in relation to the committed Signal Passed At Danger. These influences include direct factors attributable to the driver and the immediate circumstances of the event, as well as indirect, or latent, factors within the operational procedures and the management of the organization. This systemic combination of factors, not an isolated case of human error, conspired to propagate the events that resulted in the Signal Passed At Danger event and subsequent crash. This particular case demonstrates that train crashes cannot be distilled to a single causal factor. Rather, such crashes result from a system failure in which unpredicted interactions between direct and indirect influences coincide at an inopportune instant.

Coping strategies in mothers and fathers of preschool and school-age children with autism.

Despite the theoretical and demonstrated empirical significance of parental coping strategies for the wellbeing of families of children with disabilities, relatively little research has focused explicitly on coping in mothers and fathers of children with autism. In the present study, 89 parents of preschool children and 46 parents of school-age children completed a measure of the strategies they used to cope with the stresses of raising their child with autism. Factor analysis revealed four reliable coping dimensions: active avoidance coping, problem-focused coping, positive coping, and religious/denial coping. Further data analysis suggested gender differences on the first two of these dimensions but no reliable evidence that parental coping varied with the age of the child with autism. Associations were also found between coping strategies and parental stress and mental health. Practical implications are considered including reducing reliance on avoidance coping and increasing the use of positive coping strategies.

Activation of transient receptor potential vanilloid-1 (TRPV1) influences how retinal ganglion cell neurons respond to pressure-related stress.

Our recent studies implicate the transient receptor potential vanilloid-1 (TRPV1) channel as a mediator of retinal ganglion cell (RGC) function and survival. With elevated pressure in the eye, TRPV1 increases in RGCs, supporting enhanced excitability, while Trpv1 -/- accelerates RGC degeneration in mice. Here we find TRPV1 localized in monkey and human RGCs, similar to rodents. Expression increases in RGCs exposed to acute changes in pressure. In retinal explants, contrary to our animal studies, both Trpv1 -/- and pharmacological antagonism of the channel prevented pressure-induced RGC apoptosis, as did chelation of extracellular Ca(2+). Finally, while TRPV1 and TRPV4 co-localize in some RGC bodies and form a protein complex in the retina, expression of their mRNA is inversely related with increasing ocular pressure. We propose that TRPV1 activation by pressure-related insult in the eye initiates changes in expression that contribute to a Ca(2+)-dependent adaptive response to maintain excitatory signaling in RGCs.