Comparing the Pathology, Clinical, and Demographic Characteristics of Younger and Older-Onset Multiple Sclerosis.

OBJECTIVE: Older people with multiple sclerosis (MS) have a less active radiological and clinical presentation, but many still attain significant levels of disability; but what drives worsening disability in this group? METHODS: We used data from the UK MS Register to characterize demographics and clinical features of late-onset multiple sclerosis (LOMS; symptom onset at ≥50 years), compared with adult-onset MS (AOMS; onset 18-49 years). We performed a pathology study of a separate MS cohort with a later onset (n = 18, mean age of onset 54 years) versus AOMS (n = 23, mean age of onset 29 years). RESULTS: In the Register cohort, there were 1,608 (9.4%) with LOMS. When compared with AOMS, there was a lower proportion of women, a higher proportion of primary progressive MS, a higher level of disability at diagnosis (median MS impact scale 36.7 vs. 28.3, p < 0.001), and a higher proportion of gait-related initial symptoms. People with LOMS were less likely to receive a high efficacy disease-modifying treatment and attained substantial disability sooner. Controlling for age of death and sex, neuron density in the thalamus and pons decreased with onset-age, whereas actively demyelinating lesions and compartmentalized inflammation was greatest in AOMS. Only neuron density, and not demyelination or the extent of compartmentalized inflammation, correlated with disability outcomes in older-onset MS patients. INTERPRETATION: The more progressive nature of older-onset MS is associated with significant neurodegeneration, but infrequent inflammatory demyelination. These findings have implications for the assessment and treatment of MS in older people. ANN NEUROL 2024;95:471-486.

Rapid trial-and-error learning with simulation supports flexible tool use and physical reasoning.

Many animals, and an increasing number of artificial agents, display sophisticated capabilities to perceive and manipulate objects. But human beings remain distinctive in their capacity for flexible, creative tool use-using objects in new ways to act on the world, achieve a goal, or solve a problem. To study this type of general physical problem solving, we introduce the Virtual Tools game. In this game, people solve a large range of challenging physical puzzles in just a handful of attempts. We propose that the flexibility of human physical problem solving rests on an ability to imagine the effects of hypothesized actions, while the efficiency of human search arises from rich action priors which are updated via observations of the world. We instantiate these components in the "sample, simulate, update" (SSUP) model and show that it captures human performance across 30 levels of the Virtual Tools game. More broadly, this model provides a mechanism for explaining how people condense general physical knowledge into actionable, task-specific plans to achieve flexible and efficient physical problem solving.

Ultrasound-Guided Paravenous Saphenous Nerve Block for Lower Extremity Abscess Incision and Drainage in a Male Adolescent.

ABSTRACT: The use of ultrasound-guided regional anesthesia is growing as a modality for analgesia provision within the pediatric emergency department. We present a case in which a paravenous saphenous nerve block was used for anesthesia during incision and drainage of a lower extremity abscess. We further review the technique and literature concerning this straightforward and effective procedure.

The Modification of Offspring Stress-Related Behavior and the Expression of Drd1, Drd2, and Nr3c1 by a Western-Pattern Diet in Mus Musculus.

The impact of early developmental experience on neurobiological pathways that may contribute to the association between diet and behavior have not yet been elucidated. The focus of the current study was to determine whether the impact of prenatal stress (PS) could be mitigated by a diet that stimulates the same neuroendocrine systems influenced by early stress, using a mouse model. Behavioral and genetic approaches were used to assess how a Western-pattern diet (WPD) interacts with PS and sex to impact the expression of anxiety-like behavior in an open-field arena, as well as the expression of the glucocorticoid receptor in the hippocampus, D1 dopamine receptors in the nucleus accumbens, and D2 dopamine receptors in the ventral tegmental area. Overall, the results demonstrated that a prenatal WPD mitigates the effects of maternal stress in dams and offspring. These results help to elucidate the relationship between pre- and post-natal nutrition, gene expression, and behaviors that lead to long-term health effects.

Context-dependent modulation of natural approach behaviour in mice.

Specific features of visual objects innately draw approach responses in animals, and provide natural signals of potential reward. However, visual sampling behaviours and the detection of salient, rewarding stimuli are context and behavioural state-dependent and it remains unclear how visual perception and orienting responses change with specific expectations. To start to address this question, we employed a virtual stimulus orienting paradigm based on prey capture to quantify the conditional expression of visual stimulus-evoked innate approaches in freely moving mice. We found that specific combinations of stimulus features selectively evoked innate approach or freezing responses when stimuli were unexpected. We discovered that prey capture experience, and therefore the expectation of prey in the environment, selectively modified approach frequency, as well as altered those visual features that evoked approach. Thus, we found that mice exhibit robust and selective orienting responses to parameterized visual stimuli that can be robustly and specifically modified via natural experience. This work provides critical insight into how natural appetitive behaviours are driven by both specific features of visual motion and internal states that alter stimulus salience.

Using games to understand the mind.

Board, card or video games have been played by virtually every individual in the world. Games are popular because they are intuitive and fun. These distinctive qualities of games also make them ideal for studying the mind. By being intuitive, games provide a unique vantage point for understanding the inductive biases that support behaviour in more complex, ecological settings than traditional laboratory experiments. By being fun, games allow researchers to study new questions in cognition such as the meaning of 'play' and intrinsic motivation, while also supporting more extensive and diverse data collection by attracting many more participants. We describe the advantages and drawbacks of using games relative to standard laboratory-based experiments and lay out a set of recommendations on how to gain the most from using games to study cognition. We hope this Perspective will lead to a wider use of games as experimental paradigms, elevating the ecological validity, scale and robustness of research on the mind.

Access to Firearms: Initiation of Firearm Screening Among Psychiatric Patients in a Pediatric Emergency Department.

OBJECTIVE: Increase provider screening rates for firearm access among patients presenting to the pediatric emergency department (PED) for a psychiatric chief complaint. METHODS: In this resident-driven quality improvement project, a retrospective chart review examined firearm access screening rates among patients presenting to the PED with the chief complaint of "psychiatric evaluation." After establishing our baseline screening rate, the first phase of our plan, do, study, act (PDSA) cycle included implementing Be SMART education for pediatric residents. We made Be SMART handouts available in the PED, created electronic medical record (EMR) templates to facilitate documentation, and emailed routine reminders to residents during their PED block. In the second PDSA cycle, the pediatric emergency medicine (PEM) fellows expanded our efforts to increase project awareness from a supervisory role. RESULTS: The baseline screening rate was 14.7% (50 of 340). After PDSA 1, a center line shift occurred, and screening rates increased to 34.3% (297 of 867). After PDSA 2, screening rates increased to 35.7% (226 of 632). In the intervention phase, providers who received training screened 39.5% (238 of 603) of encounters versus providers who did not receive training screened 30.8% (276 of 896) of encounters. Of all encounters screened, 39.2% (205 of 523) screened positive for in-home firearms. CONCLUSIONS: We improved firearm access screening rates in the PED using provider education, EMR prompts, and PEM fellow participation. Opportunities remain to promote firearm access screening and secure storage counseling in the PED.

Lifelong learning of cognitive styles for physical problem-solving: The effect of embodied experience.

'Embodied cognition' suggests that our bodily experiences broadly shape our cognitive capabilities. We study how embodied experience affects the abstract physical problem-solving styles people use in a virtual task where embodiment does not affect action capabilities. We compare how groups with different embodied experience - 25 children and 35 adults with congenital limb differences versus 45 children and 40 adults born with two hands - perform this task, and find that while there is no difference in overall competence, the groups use different cognitive styles to find solutions. People born with limb differences think more before acting but take fewer attempts to reach solutions. Conversely, development affects the particular actions children use, as well as their persistence with their current strategy. Our findings suggest that while development alters action choices and persistence, differences in embodied experience drive changes in the acquisition of cognitive styles for balancing acting with thinking.

Elucidating regulatory processes of intense physical activity by multi-omics analysis.

BACKGROUND: Physiological and biochemical processes across tissues of the body are regulated in response to the high demands of intense physical activity in several occupations, such as firefighting, law enforcement, military, and sports. A better understanding of such processes can ultimately help improve human performance and prevent illnesses in the work environment. METHODS: To study regulatory processes in intense physical activity simulating real-life conditions, we performed a multi-omics analysis of three biofluids (blood plasma, urine, and saliva) collected from 11 wildland firefighters before and after a 45 min, intense exercise regimen. Omics profiles post- versus pre-exercise were compared by Student's t-test followed by pathway analysis and comparison between the different omics modalities. RESULTS: Our multi-omics analysis identified and quantified 3835 proteins, 730 lipids and 182 metabolites combining the 3 different types of samples. The blood plasma analysis revealed signatures of tissue damage and acute repair response accompanied by enhanced carbon metabolism to meet energy demands. The urine analysis showed a strong, concomitant regulation of 6 out of 8 identified proteins from the renin-angiotensin system supporting increased excretion of catabolites, reabsorption of nutrients and maintenance of fluid balance. In saliva, we observed a decrease in 3 pro-inflammatory cytokines and an increase in 8 antimicrobial peptides. A systematic literature review identified 6 papers that support an altered susceptibility to respiratory infection. CONCLUSION: This study shows simultaneous regulatory signatures in biofluids indicative of homeostatic maintenance during intense physical activity with possible effects on increased infection susceptibility, suggesting that caution against respiratory diseases could benefit workers on highly physical demanding jobs.

Telephone versus In-Person Pharmacist-Led Medication Reviews in Home Dialysis Patients: Evaluating Quality of Care and Patient Satisfaction.

The COVID-19 pandemic required pharmacists in a provincial Home Dialysis Clinic to adapt from in-person to telephone-based medication reviews. Studies have shown that in-person pharmacist interventions in patients with chronic kidney disease (CKD) lead to a reduction of drug therapy problems (DTPs), however, it's unknown if telephone interventions provide similar outcomes. The purpose of this study was to evaluate whether differences in quality of care exist between in-person vs. telephone medication reviews in home dialysis patients and to evaluate patient satisfaction with telephone medication reviews. Data from the two most recent in-person medication reviews was compared with the two most recent telephone medication reviews for each patient (n = 46). There were no statistically significant differences in DTPs identified between in-person and telephone medication reviews (p = 0.431). Physician acceptance of pharmacist recommendations was higher for in-person medication reviews (p = 0.009). Patients were satisfied with the care they received with pharmacist-led telephone medication reviews, however, 29% (n = 7) would prefer an in-person medication review once per year with telephone medication reviews the rest of the time. Overall, patients were satisfied with the care they received from telephone medication reviews.

EGD for Refractory Toxidromes: Is It Time to Add to the Algorithm?

Toxic ingestions are an increasing concern among pediatric patients in the United States. Less common, but troubling, are those patients with persistent toxicity symptoms despite stabilization, resuscitative, and decontamination efforts. We report a case of refractory serotonin toxicity in an adolescent for whom endoscopic removal of medication remnants led to the resolution of his clinical course. A 14-year-old male patient with anxiety and depression, treated with escitalopram and clonidine, presented to an outside hospital (OSH) emergency department (ED) with tonic-clonic seizure activity and altered mental status. Non-contrast head computed tomography (CT), complete blood count, and basic metabolic panel were unrevealing. Repeated seizure activity that occurred in the OSH ED prompted transfer to a tertiary pediatric care facility for ongoing management. Based on the constellation of symptoms (tachycardia, muscle rigidity, and lower extremity clonus) and his medication history, there was concern for serotonin toxicity. His clinical course worsened, despite treatment with midazolam and cyproheptadine, requiring intubation for respiratory failure. Because of his refractory symptoms and concern for ongoing medication side effects, on hospital day 4, he underwent an esophagogastroduodenoscopy (EGD), which revealed 20 partially digested pills firmly adhered to the gastric mucosa. The pill fragments were removed and whole bowel irrigation was started, and the patient improved rapidly, allowing for extubation within 24 hours. An EGD is not routinely used for the management of toxic ingestions. In addition to this case, evidence from prior case reports supports the judicious use of EGD as a diagnostic and therapeutic decontamination modality for severe toxicities.

A binocular perception deficit characterizes prey pursuit in developing mice.

Integration of binocular information at the cellular level has long been studied in the mouse model to uncover the fundamental developmental mechanisms underlying mammalian vision. However, we lack an understanding of the corresponding ontogeny of visual behavior in mice that relies on binocular integration. To address this major outstanding question, we quantified the natural visually guided behavior of postnatal day 21 (P21) and adult mice using a live prey capture assay and a computerized-spontaneous perception of objects task (C-SPOT). We found a robust and specific binocular visual field processing deficit in P21 mice as compared to adults that corresponded to a selective increase in c-Fos expression in the anterior superior colliculus (SC) of the juveniles after C-SPOT. These data link a specific binocular perception deficit in developing mice to activity changes in the SC.

Foundations of intuitive power analyses in children and adults.

Decades of research indicate that some of the epistemic practices that support scientific enquiry emerge as part of intuitive reasoning in early childhood. Here, we ask whether adults and young children can use intuitive statistical reasoning and metacognitive strategies to estimate how much information they might need to solve different discrimination problems, suggesting that they have some of the foundations for 'intuitive power analyses'. Across five experiments, both adults (N = 290) and children (N = 48, 6-8 years) were able to precisely represent the relative difficulty of discriminating populations and recognized that larger samples were required for populations with greater overlap. Participants were sensitive to the cost of sampling, as well as the perceptual nature of the stimuli. These findings indicate that both young children and adults metacognitively represent their own ability to make discriminations even in the absence of data, and can use this to guide efficient and effective exploration.

Interactions Increase Forager Availability and Activity in Harvester Ants.

Social insect colonies use interactions among workers to regulate collective behavior. Harvester ant foragers interact in a chamber just inside the nest entrance, here called the 'entrance chamber'. Previous studies of the activation of foragers in red harvester ants show that an outgoing forager inside the nest experiences an increase in brief antennal contacts before it leaves the nest to forage. Here we compare the interaction rate experienced by foragers that left the nest and ants that did not. We found that ants in the entrance chamber that leave the nest to forage experienced more interactions than ants that descend to the deeper nest without foraging. Additionally, we found that the availability of foragers in the entrance chamber is associated with the rate of forager return. An increase in the rate of forager return leads to an increase in the rate at which ants descend to the deeper nest, which then stimulates more ants to ascend into the entrance chamber. Thus a higher rate of forager return leads to more available foragers in the entrance chamber. The highest density of interactions occurs near the nest entrance and the entrances of the tunnels from the entrance chamber to the deeper nest. Local interactions with returning foragers regulate both the activation of waiting foragers and the number of foragers available to be activated.

Successful vaccination of immune suppressed recipients using Listeria vector HIV-1 vaccines in helminth infected mice.

Vaccines for HIV, malaria and TB remain high priorities, especially for sub-Saharan populations. The question is: will vaccines currently in development for these diseases function in populations that have a high prevalence of helminth infection? Infection with helminth parasites causes immune suppression and a CD4+ Th2 skewing of the immune system, thereby impairing Th1-type vaccine efficacy. In this study, we conduct HIV vaccine trials in mice with and without chronic helminth infection to mimic the human vaccine recipient populations in Sub-Saharan Africa and other helminth parasite endemic regions of the world, as there is large overlap in global prevalence for HIV and helminth infection. Here, we demonstrate that Listeria monocytogenes functions as a vaccine vector to drive robust and functional HIV-specific cellular immune responses, irrespective of chronic helminth infection. This observation represents a significant advance in the field of vaccine research and underscores the concept that vaccines in the developmental pipeline should be effective in the target populations.

A national survey of hemochromatosis patients.

BACKGROUND: Hereditary hemochromatosis (HH) is a common genetic disease in the United States, but little is known about the diagnosis from the patient's perspective. The purpose of this study was to characterize the circumstances surrounding the diagnosis of HH and assess treatments and health information needs. METHODS: We surveyed US adults aged 18 years and older who were diagnosed with HH after 1996. Response rate was 46%, with a total sample size of 979. Respondents were asked about the use of genetic and clinical markers in their diagnosis, current treatments, and health information needs. RESULTS: Results were stratified by age, education, and income status. Total of 90.0% of women and 75.5% of men were genetically tested for HH (P < .01). Approximately half (52.5%) were diagnosed by a gastroenterologist, hematologist, or other specialty physician and half were diagnosed by a primary care provider. Most of the respondents thought their HH had improved with the initial treatment and most patients were still receiving treatment for HH. Patient interest in learning more about specific hemochromatosis topics was generally high. CONCLUSIONS: Since the introduction of genetic identification of HH, these tests have been used in the diagnosis of the majority of patients. Primary care physicians may need to be more aware HH and strategies for diagnosis.