Targeted therapy improves cellular dysfunction, ataxia, and seizure susceptibility in a model of a progressive myoclonus epilepsy.

The recurrent variant KCNC1-p.Arg320His causes progressive myoclonus epilepsy (EPM) type 7, defined by progressive myoclonus, epilepsy, and ataxia, and is without effective treatment. KCNC1 encodes the voltage-gated potassium channel subunit Kv3.1, specifically expressed in high-frequency-firing neurons. Variant subunits act via loss of function; hence, EPM7 pathogenesis may involve impaired excitability of Kv3.1-expressing neurons, while enhancing Kv3 activity could represent a viable therapeutic strategy. We generate a mouse model, Kcnc1-p.Arg320His/+, which recapitulates the core features of EPM7, including progressive ataxia and seizure susceptibility. Kv3.1-expressing cerebellar granule cells and neocortical parvalbumin-positive GABAergic interneurons exhibit abnormalities consistent with Kv3 channel dysfunction. A Kv3-specific positive modulator (AUT00206) selectively enhances the firing frequency of Kv3.1-expressing neurons and improves motor function and seizure susceptibility in Kcnc1-Arg320His/+ mice. This work identifies a cellular and circuit basis of dysfunction in EPM7 and demonstrates that Kv3 positive modulators such as AUT00206 have therapeutic potential for the treatment of EPM7.

Inactivation of face-selective neurons alters eye movements when free viewing faces.

During free viewing, faces attract gaze and induce specific fixation patterns corresponding to the facial features. This suggests that neurons encoding the facial features are in the causal chain that steers the eyes. However, there is no physiological evidence to support a mechanistic link between face-encoding neurons in high-level visual areas and the oculomotor system. In this study, we targeted the middle face patches of the inferior temporal (IT) cortex in two macaque monkeys using an functional magnetic resonance imaging (fMRI) localizer. We then utilized muscimol microinjection to unilaterally suppress IT neural activity inside and outside the face patches and recorded eye movements while the animals free viewing natural scenes. Inactivation of the face-selective neurons altered the pattern of eye movements on faces: The monkeys found faces in the scene but neglected the eye contralateral to the inactivation hemisphere. These findings reveal the causal contribution of the high-level visual cortex in eye movements.

Inactivation of face selective neurons alters eye movements when free viewing faces.

During free viewing, faces attract gaze and induce specific fixation patterns corresponding to the facial features. This suggests that neurons encoding the facial features are in the causal chain that steers the eyes. However, there is no physiological evidence to support a mechanistic link between face encoding neurons in high-level visual areas and the oculomotor system. In this study, we targeted the middle face patches of inferior temporal (IT) cortex in two macaque monkeys using an fMRI localizer. We then utilized muscimol microinjection to unilaterally suppress IT neural activity inside and outside the face patches and recorded eye movements while the animals free viewing natural scenes. Inactivation of the face selective neurons altered the pattern of eye movements on faces: the monkeys found faces in the scene but neglected the eye contralateral to the inactivation hemisphere. These findings reveal the causal contribution of the high-level visual cortex in eye movements. Significance: It has been shown, for more than half a century, that eye movements follow distinctive patterns when free viewing faces. This suggests causal involvement of the face-encoding visual neurons in the eye movements. However, the literature is scant of evidence for this possibility and has focused mostly on the link between low-level image saliency and eye movements. Here, for the first time, we bring causal evidence showing how face-selective neurons in inferior temporal cortex inform and steer eye movements when free viewing faces.

Image-dependence of the detectability of optogenetic stimulation in macaque inferotemporal cortex.

Artificial activation of neurons in early visual areas induces perception of simple visual flashes.1,2 Accordingly, stimulation in high-level visual cortices is expected to induce perception of complex features.3,4 However, results from studies in human patients challenge this expectation. Stimulation rarely induces any detectable visual event, and never a complex one, in human subjects with closed eyes.2 Stimulation of the face-selective cortex in a human patient led to remarkable hallucinations only while the subject was looking at faces.5 In contrast, stimulations of color- and face-selective sites evoke notable hallucinations independent of the object being viewed.6 These anecdotal observations suggest that stimulation of high-level visual cortex can evoke perception of complex visual features, but these effects depend on the availability and content of visual input. In this study, we introduce a novel psychophysical task to systematically investigate characteristics of the perceptual events evoked by optogenetic stimulation of macaque inferior temporal (IT) cortex. We trained macaque monkeys to detect and report optogenetic impulses delivered to their IT cortices7,8,9 while holding fixation on object images. In a series of experiments, we show that detection of cortical stimulation is highly dependent on the choice of images presented to the eyes and it is most difficult when fixating on a blank screen. These findings suggest that optogenetic stimulation of high-level visual cortex results in easily detectable distortions of the concurrent contents of vision.

Barriers to COVID-19 vaccine acceptance to improve messages for vaccine uptake in indigenous populations in the central highlands of Guatemala: a participatory qualitative study.

INTRODUCTION: As of July 2022, a little over one-third of Guatemalans were fully vaccinated. While COVID-19 vaccination rates are not officially reported nationally by racial/ethnic groups, non-governmental organisations and reporters have observed that COVID-19 vaccination rates are especially low among high-risk Indigenous populations. We conducted one of the first studies on COVID-19 vaccine acceptance in Indigenous populations in the Central Highlands of Guatemala, which aimed to better understand the barriers to COVID-19 vaccine uptake and how to improve vaccine promotional campaigns. METHODS: In November 2021, we conducted eight focus group discussions (FGDs) with 42 Indigenous men and women and 16 in-depth interviews (IDIs) with community health workers, nurses and physicians in Chimaltenango and Sololá. Using a participatory design approach, our qualitative analysis used constant comparative methods to understand the inductive and deductive themes from the FGD and IDI transcripts. RESULTS: We found three major overarching barriers to vaccination within the sampled population: (1) a lack of available easily understandable, linguistically appropriate and culturally sensitive COVID-19 vaccine information; (2) vaccine access and supply issues that prevented people from being vaccinated efficiently and quickly; and (3) widespread misinformation and disinformation that prey on people's fears of the unknown and mistrust of the medical establishment and government. CONCLUSION: When developing COVID-19 vaccine messages, content should be culturally relevant, appropriate for low-literacy populations and in the languages that people prefer to speak. Promotional materials should be in multiple modalities (print, radio and social media) and also have specific Maya cultural references (dress, food and concepts of disease) to ensure messaging connects with intended targets. This study supports the need for more robust research into best practices for communicating about COVID-19 vaccines to marginalised communities globally and suggests that policy makers should invest in targeted local solutions to increase vaccine uptake.

Behavioral detectability of optogenetic stimulation of inferior temporal cortex varies with the size of concurrently viewed objects.

We have previously demonstrated that macaque monkeys can behaviorally detect a subtle optogenetic impulse delivered to their inferior temporal (IT) cortex. We have also shown that the ability to detect the cortical stimulation impulse varies depending on some characteristics of the visual images viewed at the time of brain stimulation, revealing the visual nature of the perceptual events induced by stimulation of the IT cortex. Here we systematically studied the effect of the size of viewed objects on behavioral detectability of optogenetic stimulation of the central IT cortex. Surprisingly, we found that behavioral detection of the same optogenetic impulse highly varies with the size of the viewed object images. Reduction of the object size in four steps from 8 to 1 degree of visual angle significantly decreased detection performance. These results show that identical stimulation impulses delivered to the same neural population induce variable perceptual events depending on the mere size of the objects viewed at the time of brain stimulation.

Evaluating the impact of a linguistically and culturally tailored social media ad campaign on COVID-19 vaccine uptake among indigenous populations in Guatemala: a pre/post design intervention study.

OBJECTIVES: To evaluate the impact of culturally and linguistically tailored informational videos delivered via social media campaigns on COVID-19 vaccine uptake in Indigenous Maya communities in Guatemala. METHODS: Our team designed a series of videos utilising community input and evaluated the impact using a pre-post intervention design. In-person preintervention surveys were collected from a sample of respondents in four rural municipalities in Guatemala in March 2022. Facebook, Instagram and browser ads were flooded with COVID-19 vaccine informational videos in Spanish, Kaqchikel and Kiche for 3 weeks. Postintervention surveys were conducted by telephone among the same participants in April 2022. Logistic regression models were used to estimate the OR of COVID-19 vaccine uptake following exposure to the intervention videos. RESULTS: Preintervention and postintervention surveys were collected from 1572 participants. The median age was 28 years; 63% (N=998) identified as women, and 36% spoke an Indigenous Mayan language. Twenty-one per cent of participants (N=327) reported watching the intervention content on social media. At baseline, 89% (N=1402) of participants reported having at least one COVID-19 vaccine, compared with 97% (N=1507) in the follow-up. Those who reported watching the videos had 1.78 times the odds (95% CI 1.14 to 2.77) of getting vaccinated after watching the videos compared with those who did not see the videos when adjusted by age, community, sex and language. CONCLUSION: Our findings suggest that culturally and linguistically tailored videos addressing COVID-19 vaccine misinformation deployed over social media can increase vaccinations in a rural, indigenous population in Guatemala, implying that social media content can influence vaccination uptake. Providing accurate, culturally sensitive information in local languages from trusted sources may help increase vaccine uptake in historically marginalised populations.

A longitudinal case series of IM ketamine for patients with severe and enduring eating disorders and comorbid treatment-resistant depression.

Severe and enduring eating disorders (EDs) have the highest mortality rate of all psychiatric illnesses (Arch Gen Psychiatry, 2011, 68, 724), especially when comorbid with treatment-resistant depression (TRD) (Psychiatr Res, 2016, 244, 45). We report on four patients with enduring EDs and TRD treated with repeat ketamine over 12 + months, showing improvement in depression with only modest changes in ED symptoms.

Morbidity and Mortality after Bariatric Surgery in Adolescents Versus Adults.

BACKGROUND: Despite the increasing prevalence and severity of childhood obesity, the national utilization of adolescent bariatric surgery has plateaued. Concern about the perioperative safety of adolescent bariatric surgery has limited referrals and insurance coverage. The purpose of this study was to compare the 30-d complication rate of minimally invasive bariatric surgery in adolescents and adults. MATERIALS AND METHODS: The Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program 2015 data set was queried for primary minimally invasive bariatric procedures in adolescents and adults. Adolescents were defined as age 19 y or younger. Univariate analyses were performed to determine if there was an increased incidence of the adolescent 30-d complication rate as compared with adults. RESULTS: Of the cases who met inclusion criteria, 1076 (0.8%) were adolescents and 142,704 (99.2%) were adults. Laparoscopic sleeve gastrectomy was the most commonly performed procedure for both patient populations, although at a higher rate in adolescents (73.9% versus 68.8% in adults, P = 0 < 0.0001). The overall 30-d complication rate was comparable in adolescents and adults (6.3% versus 7.3%; P = 0.21) with similar rates of intervention, reoperation, readmission, and mortality. There was no significant difference in any specific perioperative complication class reported between adolescents and adults, except wound disruption (0.2% versus 0.0%, P < 0.0001) and postlaparoscopic sleeve gastrectomy coma >24 h (0.1% versus 0.0%, P < 0.0001). CONCLUSIONS: Bariatric surgery in adolescents shares a similar perioperative safety profile as found in adults. This data support the utilization and extension of adult criteria for bariatric surgery to adolescents with morbid obesity.

Effects of Long-Term Meditation Practices on Sensorimotor Rhythm-Based Brain-Computer Interface Learning.

Sensorimotor rhythm (SMR)-based brain-computer interfaces (BCIs) provide an alternative pathway for users to perform motor control using motor imagery. Despite the non-invasiveness, ease of use, and low cost, this kind of BCI has limitations due to long training times and BCI inefficiency-that is, the SMR BCI control paradigm may not work well on a subpopulation of users. Meditation is a mental training method to improve mindfulness and awareness and is reported to have positive effects on one's mental state. Here, we investigated the behavioral and electrophysiological differences between experienced meditators and meditation naïve subjects in one-dimensional (1D) and two-dimensional (2D) cursor control tasks. We found numerical evidence that meditators outperformed control subjects in both tasks (1D and 2D), and there were fewer BCI inefficient subjects in the meditator group. Finally, we also explored the neurophysiological difference between the two groups and showed that the meditators had a higher resting SMR predictor, more stable resting mu rhythm, and a larger control signal contrast than controls during the task.

Primary care providers' attitudes and knowledge of bariatric surgery.

BACKGROUND: Despite the increasing obesity prevalence among American adults, relatively few qualified patients proceed to bariatric surgery. Suggested explanations include referral barriers for weight loss management at primary care provider (PCP) visits. This study aims to assess the referral and practice patterns of PCPs treating patients with obesity. Our goal is to understand treatment barriers in order to implement targeted interventions that enhance quality of care. METHODS: A 39-question electronic survey was emailed to PCPs at a single academic institution with community physicians. Questions explored providers' demographics, referral patterns, and knowledge of pathophysiologic obesity mechanisms and bariatric surgery qualifications. Frequency and univariate analyses were performed and compared providers' demographics, positions, and BMIs between referring providers and non-referring providers. RESULTS: Of 121 surveys distributed, we achieved a 33.9% response rate (n = 41). 78.0% stated that > 15% of their patients in the preceding year were classified as obese. PCPs indicated initiating weight loss management conversations < 50% of the time with 48.8% of patients. Provider-identified barriers to discussing weight loss surgery included being unsure if patient's insurance would cover the procedure or if patients would qualify (24.4% vs. 19.5%). In addition, 43.9% of providers felt that the risks of bariatric surgery outweigh the benefits. CONCLUSION: Despite a large percentage of patients cared for by PCPs being classified as obese, few providers initiate discussions on weight loss options with potentially eligible surgical candidates. The barriers identified indicate an opportunity for improved education on patient qualifications, strategies for streamlining conversations and referrals, and reinforcement of the safety of surgical weight loss. Providers' desire for this education demonstrates an opportunity to work toward minimizing the referral gap by increasing patient conversations about these topics.

A process approach to verbal memory assessment: Exploratory evidence of inefficient learning in women remitted from anorexia nervosa.

Introduction: Anorexia nervosa (AN) is associated with deficits in set-shifting and cognitive flexibility, yet less is known about the persistence of these deficits after recovery and how they might contribute to reported difficulties organizing and learning new information. To address this question, the current study applied a process-focused approach, that accounts for errors and strategies by which a score is achieved, to investigate the relationship between verbal memory and executive function in women remitted from AN. Method: Twenty-six women remitted from anorexia nervosa (RAN) and 25 control women (CW) aged 19-45 completed the California Verbal Learning Test, Second edition (CVLT-II) and the Wisconsin Card Sorting Test (WCST). Groups were compared on overall achievement scores, and on repetition, intrusion, and perseverative errors on both tests. Associations between learning and memory performance and WCST errors were also examined. Results: RAN and CW groups did not differ on overall CVLT-II learning and memory performance or errors on the WCST, though the RAN group trended towards greater WCST non-perseverative and total errors. On the CVLT-II, the RAN group made significantly more repetition errors than CW (p = 0.010), and within-trial perseveration (WTP) errors (p = 0.044). For the CW group, CVLT-II learning and memory performance were negatively associated with errors on the WCST, whereas among RAN, primarily delayed memory was negatively correlated with WCST errors. Notably, for RAN, greater WCST perseverative responses were correlated with greater CVLT-II repetition and WTP errors, showing the convergence of perseverative responding across tasks. Conclusions: Despite similar overall learning and memory performance, difficulties with executive control seem to persist even after symptom remission in patients with AN. Results indicate an inefficient learning process in the cognitive phenotype of AN and support the use of process approaches to refine neuropsychological assessment of AN by accounting for strategy use.

Neuroendocrinology of reward in anorexia nervosa and bulimia nervosa: Beyond leptin and ghrelin.

The pathophysiology of anorexia nervosa (AN) and bulimia nervosa (BN) are still poorly understood, but psychobiological models have proposed a key role for disturbances in the neuroendocrines that signal hunger and satiety and maintain energy homeostasis. Mounting evidence suggests that many neuroendocrines involved in the regulation of homeostasis and body weight also play integral roles in food reward valuation and learning via their interactions with the mesolimbic dopamine system. Neuroimaging data have associated altered brain reward responses in this system with the dietary restriction and binge eating and purging characteristic of AN and BN. Thus, neuroendocrine dysfunction may contribute to or perpetuate eating disorder symptoms via effects on reward circuitry. This narrative review focuses on reward-related neuroendocrines that are altered in eating disorder populations, including peptide YY, insulin, stress and gonadal hormones, and orexins. We provide an overview of the animal and human literature implicating these neuroendocrines in dopaminergic reward processes and discuss their potential relevance to eating disorder symptomatology and treatment.

A Transient Developmental Window of Fast-Spiking Interneuron Dysfunction in a Mouse Model of Dravet Syndrome.

Dravet syndrome is a severe, childhood-onset epilepsy largely due to heterozygous loss-of-function mutation of the gene SCN1A, which encodes the type 1 neuronal voltage-gated sodium (Na+) channel α subunit Nav1.1. Prior studies in mouse models of Dravet syndrome (Scn1a+/- mice) indicate that, in cerebral cortex, Nav1.1 is predominantly expressed in GABAergic interneurons, in particular in parvalbumin-positive fast-spiking basket cell interneurons (PVINs). This has led to a model of Dravet syndrome pathogenesis in which Nav1.1 mutation leads to preferential dysfunction of interneurons, decreased synaptic inhibition, hyperexcitability, and epilepsy. However, such studies have been implemented at early developmental time points. Here, we performed electrophysiological recordings in acute brain slices prepared from male and female Scn1a+/- mice as well as age-matched wild-type littermate controls and found that, later in development, the excitability of PVINs had normalized. Analysis of action potential waveforms indirectly suggests a reorganization of axonal Na+ channels in PVINs from Scn1a+/- mice, a finding supported by immunohistochemical data showing elongation of the axon initial segment. Our results imply that transient impairment of action potential generation by PVINs may contribute to the initial appearance of epilepsy, but is not the mechanism of ongoing, chronic epilepsy in Dravet syndrome.SIGNIFICANCE STATEMENT Dravet syndrome is characterized by normal early development, temperature-sensitive seizures in infancy, progression to treatment-resistant epilepsy, developmental delay, autism, and sudden unexplained death due to mutation in SCN1A encoding the Na+ channel subunit Nav1.1. Prior work has revealed a preferential impact of Nav1.1 loss on the function of GABAergic inhibitory interneurons. However, such data derive exclusively from recordings of neurons in young Scn1a+/- mice. Here, we show that impaired action potential generation observed in parvalbumin-positive fast-spiking interneurons (PVINs) in Scn1a+/- mice during early development has normalized by postnatal day 35. This work suggests that a transient impairment of PVINs contributes to epilepsy onset, but is not the mechanism of ongoing, chronic epilepsy in Dravet syndrome.

What roles do middle managers play in implementation of innovative practices?

BACKGROUND: Middle managers play key roles in hospitals as the bridge between senior leaders and frontline staff. Yet relatively little research has focused on their role in implementing new practices. PURPOSE: The aim of this study was to expand the understanding of middle managers' influence in organizations by looking at their activities through the lens of two complementary conceptual frameworks. METHODOLOGY/APPROACH: We analyzed qualitative data from 17 Veterans Affairs Medical Centers with high and low potential to change organizational practices. We analyzed 98 interviews with staff ranging from senior leaders to frontline staff to identify themes within an a priori framework reflecting middle manager activities. FINDINGS: Analyses yielded 14 emergent themes that allowed us to classify specific expressions of middle manager commitment to implementation of innovative practices (e.g., facilitate improvement innovation, garner staff buy-in). In comparing middle manager behaviors in high and low change potential sites, we found that most emergent themes were present in both groups. However, the activities and interactions described differed between the groups. PRACTICE IMPLICATIONS: Middle managers can use the promising strategies identified by our analyses to guide and improve their effectiveness in implementing new practices. These strategies can also inform senior leaders striving to guide middle managers in those efforts.

Thrombin generation and international normalized ratio in inherited thrombophilia patients receiving thromboprophylactic therapy.

BACKGROUND: Thrombin generation assay (TGA) is useful as a global functional test for assessing bleeding or thrombotic risk and its modification with therapy. We investigated TGA to assess anticoagulation status compared with the international normalized ratio (INR) system in patients with primary thrombophilia receiving and not undergoing thromboprophylaxis. MATERIALS AND METHODS: We studied 50 patients with at least one thrombotic event and a confirmed diagnosis of inherited thrombophilia. Thrombin generation was measured in platelet-poor plasma by calibrated automated thrombography (CAT). RESULTS: Patients in optimal anticoagulation (INR: 2.0-3.0) showed an endogenous thrombin potential (ETP) of 14-56% of normal and a peak of 18-55% of normal. A significant inverse relationship between INR and thrombin generation parameters (ETP, peak and velocity index) and a linear correlation for lag time was found in patients treated with vitamin-K antagonists (VKA). Receiver-operating characteristics (ROC) analysis showed that the optimal cutoff for ETP was 1600.2 nM · min (111.6% of normal, with a sensitivity of 96.6% and a specificity of 92.9%) and for the peak was 298.3 nM (112.1% of normal, with a sensitivity of 96.4% and a specificity of 100%). According to this analysis, ETP was able to identify patients with increased thrombotic and hemorrhagic risk, correlating with severe clinical complications. CONCLUSION: TGA showed excellent sensitivity and specificity for assessing anticoagulation status in patients with primary thrombophilia receiving VKA, with significant advantages with regard to INR. Clinical data strongly support ETP as a valuable indicator of thrombotic or hemorrhagic risk in patients receiving or not receiving thromboprophylaxis.

Choosing the right physician practices.

A process for evaluating physician practices by their strategic alignment with a health system's mission separates the practices into four categories: "Must-have"--Strategically and financially beneficial. "Cash is king"--Financially beneficial but not a strategic priority. "Dream big"--strategically important but currently not financially beneficial. "Avoid acquiring"--neither strategically nor financially beneficial.