Cell-type-specific origins of locomotor rhythmicity at different speeds in larval zebrafish.

Different speeds of locomotion require heterogeneous spinal populations, but a common mode of rhythm generation is presumed to exist. Here, we explore the cellular versus synaptic origins of spinal rhythmicity at different speeds by performing electrophysiological recordings from premotor excitatory interneurons in larval zebrafish. Chx10-labeled V2a neurons are divided into at least two morphological subtypes proposed to play distinct roles in timing and intensity control. Consistent with distinct rhythm generating and output patterning functions within the spinal V2a population, we find that descending subtypes are recruited exclusively at slow or fast speeds and exhibit intrinsic cellular properties suitable for rhythmogenesis at those speeds, while bifurcating subtypes are recruited more reliably at all speeds and lack appropriate rhythmogenic cellular properties. Unexpectedly, however, phasic firing patterns during locomotion in rhythmogenic and non-rhythmogenic V2a neurons alike are best explained by distinct modes of synaptic inhibition linked to cell type and speed. At fast speeds reciprocal inhibition in descending V2a neurons supports phasic firing, while recurrent inhibition in bifurcating V2a neurons helps pattern motor output. In contrast, at slow speeds recurrent inhibition in descending V2a neurons supports phasic firing, while bifurcating V2a neurons rely on reciprocal inhibition alone to pattern output. Our findings suggest cell-type-specific, not common, modes of rhythmogenesis generate and coordinate different speeds of locomotion.

The Tumour Immune Microenvironment Drives Survival Outcomes and Therapeutic Response in an Integrated Molecular Analysis of Gastric Adenocarcinoma.

PURPOSE: We performed an integrated analysis of molecular classification systems proposed by The Cancer Genome Atlas (TCGA), the Asian Cancer Research Group (ACRG) and the Tumour Microenvironment Score (TME) to identify which classification scheme(s) are most promising to pursue in subsequent translational investigations. EXPERIMENTAL DESIGN: Supervised machine learning classifiers were created using 10-fold nested cross-validation for TCGA, ACRG and TME subtypes and applied to 2,202 gastric cancer patients from 11 separate publicly available datasets. Overall survival was assessed with a multivariable Cox proportional hazards model. A propensity score matched analysis was performed to evaluate the subgroup effect of adjuvant chemotherapy on molecular subtypes. A public external cohort comprised of metastatic gastric cancer treated with immunotherapy was used to externally validate the molecular subtypes. RESULTS: Classification models for TCGA, ACRG and TME achieved an accuracy ± standard deviation of 89.5% ± 0.04, 84.7% ± 0.04 and 89.3% ± 0.02, respectively. We identified the TME score as the only significantly prognostic classification system (HR 0.54 [95% CI 0.39, 0.74], global Wald test p<0.001). In our subgroup analysis, patients who received adjuvant chemotherapy achieved greater survival with increasing TME score (HR 0.47 [95% CI 0.29, 0.74], interaction p<0.05). The combination of TME High and microsatellite instability (MSI) scores significantly outperformed MSI as a univariable predictor of immunotherapy response. CONCLUSIONS: We conclude that the Tumour Microenvironment Score is a predominate driver of prognosis as well as chemotherapy and immunotherapy-related outcomes in gastric cancer. This paper provides a foundation for additional analyses and translational work.

Post-polypectomy surveillance: follow-up recommendations from the Alberta Colorectal Cancer Screening Program.

In 2013, the Alberta Colorectal Cancer Screening Program (ACRCSP) initially published recommendations for post-colonoscopy follow-up and polypectomy. Over time, emerging evidence and evolving surveillance guidelines from various expert groups necessitated a comprehensive review to align with the healthcare landscape in Alberta. To accomplish this, an expert panel was convened. Using the Agree II tool, we identified high-quality Clinical Practice Guidelines that were relevant to the Alberta medical context. Recommendations from these guidelines were adapted to fit the specific needs of Alberta. Recognizing inconsistencies and gaps within the existing guidelines, we conducted targeted literature reviews to ensure a comprehensive and evidence-based approach to our recommendations. Our revised recommendations build upon the assumption that a high-quality index colonoscopy has been performed at baseline. They are intended to enhance the quality of care and reduce unnecessary procedures. As well, they align with the growing consensus in the scientific literature that individuals with low-risk tubular adenomas may not require aggressive colonoscopy surveillance. The updated Alberta recommendations aim to provide clear recommendations for practicing endoscopists, referring physicians, and their patients. They address crucial questions such as determining which patients should commence surveillance via colonoscopy and which individuals should return to average-risk screening using the fecal immunochemical test (FIT). Additionally, our recommendations outline the appropriate surveillance intervals for those requiring continued monitoring.

Release from response interference in color-word contingency learning.

In identifying the print colors of words when some combinations of color and word occur more frequently than others, people quickly show evidence of learning these associations. This contingency learning effect is evident in faster and more accurate responses to high-contingency combinations than to low-contingency combinations. Across four experiments, we systematically varied the number of response-irrelevant word stimuli connected to response-relevant colors. In each experiment, one group experienced the typical contingency learning paradigm with three colors linked to three words; other groups saw more words (six or twelve) linked to the same three colors. All four experiments disconfirmed a central prediction derived from the Parallel Episodic Processing (PEP 2.0) model (Schmidt et al., 2016)-that the magnitude of the contingency learning effect should remain stable as more words are added to the response-irrelevant dimension, as long as the color-word contingency ratios are maintained. Responses to high-contingency items did slow down numerically as the number of words increased between groups, consistent with the prediction from PEP 2.0, but these changes were unreliable. Inconsistent with PEP 2.0, however, overall response time did not slow down and responses to low-contingency items actually sped up as the number of words increased across groups. These findings suggest that the PEP 2.0 model should be modified to incorporate response interference caused by high-probability associations when responding to low-probability combinations.

Cell-type-specific origins of locomotor rhythmicity at different speeds in larval zebrafish.

Different speeds of locomotion require heterogeneous spinal populations, but a common mode of rhythm generation is presumed to exist. Here, we explore the cellular versus synaptic origins of spinal rhythmicity at different speeds by performing electrophysiological recordings from premotor excitatory interneurons in larval zebrafish. Chx10-labeled V2a neurons are divided into at least two morphological subtypes proposed to play distinct roles in timing and intensity control. Consistent with distinct rhythm generating and output patterning functions within the spinal V2a population, we find that descending subtypes are recruited exclusively at slow or fast speeds and exhibit intrinsic cellular properties suitable for rhythmogenesis at those speeds, while bifurcating subtypes are recruited more reliably at all speeds and lack appropriate rhythmogenic cellular properties. Unexpectedly, however, phasic firing patterns during locomotion in rhythmogenic and non-rhythmogenic V2a neurons alike are best explained by distinct modes of synaptic inhibition linked to cell-type and speed. At fast speeds reciprocal inhibition in descending V2a neurons supports phasic firing, while recurrent inhibition in bifurcating V2a neurons helps pattern motor output. In contrast, at slow speeds recurrent inhibition in descending V2a neurons supports phasic firing, while bifurcating V2a neurons rely on reciprocal inhibition alone to pattern output. Our findings suggest cell-type-specific, not common, modes of rhythmogenesis generate and coordinate different speeds of locomotion.

Developing a text-message library for tobacco prevention among adolescents: A qualitative study.

INTRODUCTION: Communicating the risks associated with nicotine and tobacco use to adolescents can be challenging, especially with the current tobacco market's attempt to capture the attention of youths. Text message interventions have emerged to address the need to improve tobacco risk communication. This article informs the design of a message library for tobacco risk communication that is based on the transtheoretical model and addresses the risk of multiple tobacco products. METHODS: We draw findings from this study from two phases. Phase 1 involved six remote focus group discussions (n = 25) and an in-depth interview, and Phase 2 involved online ideation sessions (n = 11) that led to the current version of the messages. We conducted the study within a larger project for the design and testing of a tobacco prevention program. With thematic analysis and the affinity mapping technique, two research team members identified repeated topics and relevant quotes to organize them into themes and subthemes. RESULTS: In Phase 1, thematic analysis revealed four major themes: 1) Adolescents' gap in tobacco knowledge, 2) Social influence and popularity, 3) Attitude toward marketing, and 4) Text message framing preferences. During Phase 2, participants generated 1-to-7 iterations of the original messages. Votings and discussions resulted in a library of 306 messages under 7 sections, categorized based on the processes of change from the transtheoretical model. CONCLUSION: The current study presents key insights crucial for developing and evaluating a library of tobacco prevention text messages that is scientifically valid and successfully resonates with today's adolescents. Our future plan is to go beyond this initial message development and vet the message library by adolescents and expert reviewers in tobacco risk communication. Future research may consider developing messages that are tailored based on gender, ethnicity, and other factors that are predictive of tobacco use.

Reading text aloud benefits memory but not comprehension.

The production effect-that reading aloud leads to better memory than does reading silently-has been defined narrowly with reference to memory; it has been explored largely using word lists as the material to be read and remembered. But might the benefit of production extend beyond memory and beyond individual words? In a series of four experiments, passages from reading comprehension tests served as the study material. Participants read some passages aloud and others silently. After each passage, they completed multiple-choice questions about that passage. Separating the multiple-choice questions into memory-focused versus comprehension-focused questions, we observed a consistent production benefit only for the memory-focused questions. Production clearly improves memory for text, not just for individual words, and also extends to multiple-choice testing. The overall pattern of findings fits with the distinctiveness account of production-that information read aloud stands out at study and at test from information read silently. Only when the tested information is a very close match to the studied information, as is the case for memory questions but not for comprehension questions, does production improve accuracy.

Identifying adolescents' gaming preferences for a tobacco prevention social game: A qualitative study.

INTRODUCTION: Considering the dangers of adolescent tobacco use, the successful design of behavioral programs is crucial for tobacco prevention. According to preliminary research, social game interventions can improve adolescent tobacco outcomes. The current qualitative study aims to (1) uncover the gaming elements that adolescents deem important for a positive learning experience, and (2) confirm these gaming elements with adolescents who are presented with a tobacco prevention game concept that applies these elements. METHODS: Findings from this study are drawn from two phases. Phase 1 involved in-person focus group discussions (n = 15) and Phase 2 included three online focus groups and a paired interview with another set of adolescents (n = 15). The study was conducted under a project that aimed to design and test a social game-based tobacco prevention program for adolescents (Storm-Heroes). With open coding and thematic analysis, two research team members identified repeated topics and relevant quotes to organize them into themes. The themes evolved as new content was identified during the process. This process was repeated until thematic saturation was reached. RESULTS: Thematic analysis across Phase 1 and Phase 2 revealed four major themes: 1) Balance during gaming challenges, 2) Healthy social interaction, 3) Performance and creative freedom, and 4) Fictional world and game mechanics for tobacco prevention. CONCLUSION: This study identified specific intervention features that best fit the needs of adolescents in the context of a social game for tobacco prevention. For future research, we will use a participatory approach to allow adolescents to take part in the design process, improve Storm-Heroes, and develop health promotional messages that can be incorporated into the program. Ultimately, a board game for tobacco prevention is expected to bring adolescents together to create lasting memories that nudge them away from tobacco use and the harm it can cause.

Synaptic variance and action potential firing of cerebellar output neurons during motor learning in larval zebrafish.

The cerebellum regulates both reflexive and acquired movements. Here, by recording voltage-clamped synaptic currents and spiking in cerebellar output (eurydendroid) neurons in immobilized larval zebrafish, we investigated synaptic integration during reflexive movements and throughout associative motor learning. Spiking coincides with the onset of reflexive fictive swimming but precedes learned swimming, suggesting that eurydendroid signals may facilitate the initiation of acquired movements. Although firing rates increase during swimming, mean synaptic inhibition greatly exceeds mean excitation, indicating that learned responses cannot result solely from changes in synaptic weight or upstream excitability that favor excitation. Estimates of spike threshold crossings based on measurements of intrinsic properties and the time course of synaptic currents demonstrate that noisy excitation can transiently outweigh noisy inhibition enough to increase firing rates at swimming onset. Thus, the millisecond-scale variance of synaptic currents can regulate cerebellar output, and the emergence of learned cerebellar behaviors may involve a time-based code.

Spinal Basis of Direction Control during Locomotion in Larval Zebrafish.

Navigation requires steering and propulsion, but how spinal circuits contribute to direction control during ongoing locomotion is not well understood. Here, we use drifting vertical gratings to evoke directed "fictive" swimming in intact but immobilized larval zebrafish while performing electrophysiological recordings from spinal neurons. We find that directed swimming involves unilateral changes in the duration of motor output and increased recruitment of motor neurons, without impacting the timing of spiking across or along the body. Voltage-clamp recordings from motor neurons reveal increases in phasic excitation and inhibition on the side of the turn. Current-clamp recordings from premotor interneurons that provide phasic excitation or inhibition reveal two types of recruitment patterns. A direction-agnostic pattern with balanced recruitment on the turning and nonturning sides is primarily observed in excitatory V2a neurons with ipsilateral descending axons, while a direction-sensitive pattern with preferential recruitment on the turning side is dominated by V2a neurons with ipsilateral bifurcating axons. Inhibitory V1 neurons are also divided into direction-sensitive and direction-agnostic subsets, although there is no detectable morphologic distinction. Our findings support the modular control of steering and propulsion by spinal premotor circuits, where recruitment of distinct subsets of excitatory and inhibitory interneurons provide adjustments in direction while on the move.SIGNIFICANCE STATEMENT Spinal circuits play an essential role in coordinating movements during locomotion. However, it is unclear how they participate in adjustments in direction that do not interfere with coordination. Here we have developed a system using larval zebrafish that allows us to directly record electrical signals from spinal neurons during "fictive" swimming guided by visual cues. We find there are subsets of spinal interneurons for coordination and others that drive unilateral asymmetries in motor neuron recruitment for direction control. Our findings suggest a modular organization of spinal premotor circuits that enables uninterrupted adjustments in direction during ongoing locomotion.

Chemoselective Oxidation of Alcohols in the Presence of Amines Using an Oxoammonium Salt.

The oxidation of alcohols in the presence of reactive amines employing the commercially available oxoammonium cation, "Bobbitt's salt" is described. The oxidation is accomplished under acidic conditions and subsequent treatment with a suitable base affords a convenient one-pot method to access imines in good to excellent isolated yields (74-99%).

Mixed synapses reconcile violations of the size principle in zebrafish spinal cord.

Mixed electrical-chemical synapses potentially complicate electrophysiological interpretations of neuronal excitability and connectivity. Here, we disentangle the impact of mixed synapses within the spinal locomotor circuitry of larval zebrafish. We demonstrate that soma size is not linked to input resistance for interneurons, contrary to the biophysical predictions of the 'size principle' for motor neurons. Next, we show that time constants are faster, excitatory currents stronger, and mixed potentials larger in lower resistance neurons, linking mixed synapse density to resting excitability. Using a computational model, we verify the impact of weighted electrical synapses on membrane properties, synaptic integration and the low-pass filtering and distribution of coupling potentials. We conclude differences in mixed synapse density can contribute to excitability underestimations and connectivity overestimations. The contribution of mixed synaptic inputs to resting excitability helps explain 'violations' of the size principle, where neuron size, resistance and recruitment order are unrelated.

In-verse reflection: structured creative writing exercises to promote reflective learning in medical students.

Medical educators recognize the value of reflection for medical students and the role creative writing can play in fostering this. However, direct creative writing tasks can be challenging for many students, particularly those with limited experience in the arts and humanities. An alternative strategy is to utilize an indirect approach, engaging students with structured tasks that obliquely encourage reflection. This paper reports one such approach. We refer to this approach as in-verse reflection, playing on both the structure of the writing and its novel approach to reflection. Students were invited to write, in verse-like structures, about their personal and clinical experiences as medical students. Thematic analysis of their creative outputs and reactions identified four principal themes: the challenges of life as a medical student, the emotional demands of the medical course, a sense of connectedness and solidarity with fellow students, and a sense of marginality within the hospital system. Students generally found the tasks highly engaging and conducive to reflection, producing texts representing significant insights into their experiences as medical students. The reported method offers a relatively simple, structured, and guided approach to reflective writing, adding to the repertoire of methods available to educators in the medical humanities.

Voltage imaging and spinal circuits get along swimmingly.

Voltage imaging promises to unite optical and electrical approaches to accelerate circuit discovery. In this issue of Neuron, Böhm et al. (2022) use voltage imaging to explore the structure and functional dynamics of spinal excitatory interneurons in larval zebrafish and reveal the role of V3 neurons in adaptive locomotor control.

Occupational exposures to pesticides and other chemicals: a New Zealand motor neuron disease case-control study.

OBJECTIVES: To assess associations between occupational exposures to pesticides and other chemicals and motor neuron disease (MND). METHODS: A population-based case-control study that included 319 MND cases (64% male/36% female) recruited through the New Zealand MND Association complemented with hospital discharge data, and 604 controls identified from the Electoral Roll. For each job held, a questionnaire collected information on 11 exposure categories (dust, fibres, tobacco smoke, fumes, gas, fumigants, oils/solvents, acids/alkalis, pesticides, other chemicals and animals/animal products). ORs were estimated using logistic regression adjusting for age, sex, ethnicity, socioeconomic status, education, smoking, alcohol consumption, physical activities, head/spine injury and other occupational exposures. RESULTS: Two exposure categories were associated with increased MND risks: pesticides (OR 1.70, 95% CI 1.17 to 2.48) and fumigants (OR 3.98, 95% CI 1.81 to 8.76), with risks increasing with longer exposure duration (p<0.01). Associations were also observed for: methyl bromide (OR 5.28, 95% CI 1.63 to 17.15), organochlorine insecticides (OR 3.28, 95% CI 1.18 to 9.07), organophosphate insecticides (OR 3.11, 95% CI 1.40 to 6.94), pyrethroid insecticides (OR 6.38, 95% CI 1.13 to 35.96), inorganic (copper) fungicides (OR 4.66, 95% CI 1.53 to 14.19), petrol/diesel fuel (OR 2.24, 95% CI 1.27 to 3.93) and unspecified solvents (OR 1.91, 95% CI 1.22 to 2.99). In women, exposure to textile fibres (OR 2.49, 95% CI 1.13 to 5.50), disinfectants (OR 9.66, 95% CI 1.29 to 72.44) and cleaning products (OR 3.53, 95% CI 1.64 to 7.59) were also associated with MND; this was not observed in men (OR 0.80, 95% CI 0.44 to 1.48; OR 0.72, 95% CI 0.29 to 1.84; OR 0.57, 95% CI 0.21 to 1.56, respectively). CONCLUSIONS: This study adds to the evidence that pesticides, especially insecticides, fungicides, and fumigants, are risk factors for MND.

Sports and trauma as risk factors for Motor Neurone Disease: New Zealand case-control study.

OBJECTIVES: To assess whether sports, physical trauma and emotional trauma are associated with motor neurone disease (MND) in a New Zealand case-control study (2013-2016). METHODS: In total, 321 MND cases and 605 population controls were interviewed collecting information on lifetime histories of playing sports, physical trauma (head injury with concussion, spine injury) and emotional trauma (14 categories). ORs were estimated using logistic regression adjusting for age, sex, ethnicity, socioeconomic status, education, smoking status, alcohol consumption and mutually adjusting for all other exposures. RESULTS: Head injury with concussion ≥3 years before diagnosis was associated with MND (OR 1.51, 95% CI: 1.09-2.09), with strongest associations for two (OR 4.01, 95% CI: 1.82-8.86), and three or more (OR 2.34, 95% CI: 1.00-5.45) head injuries. Spine injury was not associated with MND (OR 0.81, 95% CI: 0.48-1.36). Compared to never playing sports, engaging in sports throughout childhood and adulthood increased MND risk (OR 1.81, 95% CI: 1.01-3.25), as was more than 12 years playing football/soccer (OR 2.35, 95% CI: 1.19-4.65). Reporting emotionally traumatic events in more than three categories was associated with MND (OR 1.88, 95% CI: 1.17-3.03), with physical childhood abuse the only specific emotional trauma associated with MND (OR 1.82, 95% CI: 1.14-2.90), particularly for those reporting longer abuse duration (OR(5-8 years) 2.26, 95% CI: 1.14-4.49; OR(>8 years) 3.01, 95% CI: 1.18-7.70). For females, having witnessed another person being killed, seriously injured or assaulted also increased MND risk (OR 2.68, 95% CI: 1.06-6.76). CONCLUSIONS: This study adds to the evidence that repeated head injury with concussion, playing sports in general, and playing football (soccer) in particular, are associated with an increased risk of MND. Emotional trauma, that is physical abuse in childhood, may also play a role.

Intention and performance when reading aloud: Context is everything.

A widely held account asserts that single words are automatically identified in the absence of an intent to process them in the form of identifying a task set, and implementing it. We provide novel evidence that there is no fixed relation between intention and visual word identification. Subjects were randomly cued on a trial-by-trial basis as to whether to read aloud a single target word (Go) or not (No-go). When the Go-No Go probability was 50% (Experiment 1) the effect of stimulus quality (bright vs. dim targets) was the same size as in a separate block of 100% Go trials. In Experiment 2, where the Go-No Go probability was 80% in the cued condition, the stimulus quality effect was smaller than in the block of all Go trials. These results can be understood in terms of Go trial probability moderating whether subjects (i) hold off beginning to process the target until an intention in the form of a Task Set has been implemented, or (ii) begin to identify the target during the time taken to implement a Task Set. The additivity of stimulus quality and cueing conditions in Experiment 1 support the view that target processing only begins when a Task Set is in place, whereas the under-additivity of stimulus quality and cueing condition in Experiment 2 supports the interpretation that target identification can start during the time that a Task Set is being implemented. Taken together with other results, we conclude that there is no fixed relation between an intention and word identification; context is everything.

Locomotor control: Inhibiting actions locally and senses globally.

Locomotion requires the segmental coordination of activity along the body. A new study in zebrafish reveals that spinal inhibitory interneurons are wired to execute different functions depending on whether their targets are nearby or further away.

On the determination of eye gaze and arrow direction: Automaticity reconsidered.

It is a widely held view that the determination of eye gaze direction is "automatic" in various senses (e.g., innate; informationally encapsulated; triggered without intent). The determination of arrow direction is also held to be automatic (following a certain amount of learning) despite not being innate. The present experiments evaluate the automaticity assumption of both eyes and arrows in terms of an interference criterion. The results of 10 experiments support the inference that explicit judgements of eye gaze direction, when participants respond with a lateralized key press, are (a) neither automatic in the strong sense (they are interfered with by an uninformative, incongruent arrow in the display) and (b) nor are they are automatic in a weaker sense (uninformative, incongruent arrows interfere more strongly with the determination of eye gaze direction than uninformative, incongruent eyes interfere with the arrow direction task). However, the determination of arrow direction is also not strongly automatic, given that it is interfered with by irrelevant eyes. At least with respect to an interference criterion, the determination of eye gaze direction appears less prepotent than the determination of arrow direction, which itself is only weakly automatic. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Attention spreads between students in a learning environment.

We propose a novel phenomenon, attention contagion, defined as the spread of attentive (or inattentive) states among members of a group. We examined attention contagion in a learning environment in which pairs of undergraduate students watched a lecture video. Each pair consisted of a participant and a confederate trained to exhibit attentive behaviors (e.g., leaning forward) or inattentive behaviors (e.g., slouching). In Experiment 1, confederates sat in front of participants and could be seen. Relative to participants who watched the lecture with an inattentive confederate, participants with an attentive confederate: (a) self-reported higher levels of attentiveness, (b) behaved more attentively (e.g., took more notes), and (c) had better memory for lecture content. In Experiment 2, confederates sat behind participants. Despite confederates not being visible, participants were still aware of whether confederates were acting attentively or inattentively, and participants were still susceptible to attention contagion. Our findings suggest that distraction is one factor that contributes to the spread of inattentiveness (Experiment 1), but this phenomenon apparently can still occur in the absence of distraction (Experiment 2). We propose an account of how (in)attentiveness spreads across students and discuss practical implications regarding how learning is affected in the classroom. (PsycInfo Database Record (c) 2021 APA, all rights reserved).