The autism spectrum disorder risk gene NEXMIF over-synchronizes hippocampal CA1 network and alters neuronal coding.

Mutations in autism spectrum disorder (ASD) risk genes disrupt neural network dynamics that ultimately lead to abnormal behavior. To understand how ASD-risk genes influence neural circuit computation during behavior, we analyzed the hippocampal network by performing large-scale cellular calcium imaging from hundreds of individual CA1 neurons simultaneously in transgenic mice with total knockout of the X-linked ASD-risk gene NEXMIF (neurite extension and migration factor). As NEXMIF knockout in mice led to profound learning and memory deficits, we examined the CA1 network during voluntary locomotion, a fundamental component of spatial memory. We found that NEXMIF knockout does not alter the overall excitability of individual neurons but exaggerates movement-related neuronal responses. To quantify network functional connectivity changes, we applied closeness centrality analysis from graph theory to our large-scale calcium imaging datasets, in addition to using the conventional pairwise correlation analysis. Closeness centrality analysis considers both the number of connections and the connection strength between neurons within a network. We found that in wild-type mice the CA1 network desynchronizes during locomotion, consistent with increased network information coding during active behavior. Upon NEXMIF knockout, CA1 network is over-synchronized regardless of behavioral state and fails to desynchronize during locomotion, highlighting how perturbations in ASD-implicated genes create abnormal network synchronization that could contribute to ASD-related behaviors.

Theta and gamma rhythmic coding through two spike output modes in the hippocampus during spatial navigation.

Hippocampal CA1 neurons generate single spikes and stereotyped bursts of spikes. However, it is unclear how individual neurons dynamically switch between these output modes and whether these two spiking outputs relay distinct information. We performed extracellular recordings in spatially navigating rats and cellular voltage imaging and optogenetics in awake mice. We found that spike bursts are preferentially linked to cellular and network theta rhythms (3-12 Hz) and encode an animal's position via theta phase precession, particularly as animals are entering a place field. In contrast, single spikes exhibit additional coupling to gamma rhythms (30-100 Hz), particularly as animals leave a place field. Biophysical modeling suggests that intracellular properties alone are sufficient to explain the observed input frequency-dependent spike coding. Thus, hippocampal neurons regulate the generation of bursts and single spikes according to frequency-specific network and intracellular dynamics, suggesting that these spiking modes perform distinct computations to support spatial behavior.

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

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

Parvalbumin neurons enhance temporal coding and reduce cortical noise in complex auditory scenes.

Cortical representations supporting many cognitive abilities emerge from underlying circuits comprised of several different cell types. However, cell type-specific contributions to rate and timing-based cortical coding are not well-understood. Here, we investigated the role of parvalbumin neurons in cortical complex scene analysis. Many complex scenes contain sensory stimuli which are highly dynamic in time and compete with stimuli at other spatial locations. Parvalbumin neurons play a fundamental role in balancing excitation and inhibition in cortex and sculpting cortical temporal dynamics; yet their specific role in encoding complex scenes via timing-based coding, and the robustness of temporal representations to spatial competition, has not been investigated. Here, we address these questions in auditory cortex of mice using a cocktail party-like paradigm, integrating electrophysiology, optogenetic manipulations, and a family of spike-distance metrics, to dissect parvalbumin neurons' contributions towards rate and timing-based coding. We find that suppressing parvalbumin neurons degrades cortical discrimination of dynamic sounds in a cocktail party-like setting via changes in rapid temporal modulations in rate and spike timing, and over a wide range of time-scales. Our findings suggest that parvalbumin neurons play a critical role in enhancing cortical temporal coding and reducing cortical noise, thereby improving representations of dynamic stimuli in complex scenes.

Developing a Healthy Lifestyle Program for Recent Kidney Transplant Recipients.

INTRODUCTION: Many kidney transplant recipients experience weight gain in the first year after transplantation. RESEARCH QUESTION: The objective of this research study was to assess the desires of recent kidney transplant patients about the design features of a healthy lifestyle program to counter unnecessary weight gain. DESIGN: In this descriptive study, recent recipients at 2 transplant centers were invited to participate in an online survey. Survey items included sociodemographic information, current medications, health conditions, weight change posttransplant, diet behaviors, physical activity participation, and desired features of a lifestyle program. RESULTS: Fifty-three participants, mean age 60.5 (11.2) years, primarily males, completed surveys. Forty percent gained weight posttransplantation with many indicating struggling with their diet. Physical activity levels stayed the same (17%) or decreased (40%) posttransplantation. Eighty-seven percent of participants indicated they would participate in an online lifestyle program and 76% wanted online physical activity and nutrition sessions to meet at least once weekly. Suggestions about the type of information and activities, included eating strategies (eg, how to eat healthfully at restaurants, grocery shopping tips, and recipes), resources for at-home physical activities, access to cooking classes, and apps to track both activity and food intake. CONCLUSION: Recent kidney transplant recipients would benefit from and desired to join a lifestyle program featuring tailored nutrition education and physical activity coaching. Gathered information will be used to inform and tailor a lifestyle program. Identifying features for the prevention of unnecessary weight gain with patients' input is essential for promoting and sustaining healthy behaviors.

A retrospective study of the range of cutaneous clinical and histological features of erythema multiforme in five ferrets (Mustela putorius furo).

BACKGROUND: Erythema multiforme (EM) is an uncommon cutaneous reaction pattern characterised by panepidermal keratinocyte apoptosis with lymphocytic satellitosis, and is reported in domestic animal species, livestock and rarely ferrets. HYPOTHESIS/OBJECTIVES: The aim of this study was to analyse the spectrum of cutaneous clinical and histological features in ferrets with EM and to evaluate history and treatment outcomes. ANIMALS: Five client-owned ferrets with biopsy-confirmed EM. MATERIALS AND METHODS: Retrospective review of electronic medical records and histopathological reports from 2002 to 2021. Tissue blocks, haematoxylin and eosin re-cuts, and unstained slides were collected to review EM lesions and evaluate for infectious agents with special stains. Immunohistochemical staining was performed to assess cases for viral pathogens. RESULTS: Panepidermal cytotoxic dermatitis consistent with EM was identified in all cases and involved haired skin in four of five and mucous membranes in one of five ferrets. Skin lesions included variably pruritic alopecia, erythema, scaling, crusts and erosions/ulcerations. Histological features included primarily parakeratotic hyperkeratosis, panepidermal keratinocyte apoptosis, lymphocytic satellitosis and interface dermatitis. Superficial colonisation by bacteria, yeasts or by both was a common finding. Four of five ferrets had concurrent adrenal disease, one of which had resolution of skin lesions with deslorelin acetate treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Awareness of the distinct clinical and histological features is key to the diagnosis of EM in ferrets. Clinical resolution was observed with gonadotropin-releasing hormone agonists in two cases, suggesting that adrenal disease should be ruled out as a potential trigger of EM in ferrets.

Deep brain stimulation creates informational lesion through membrane depolarization in mouse hippocampus.

Deep brain stimulation (DBS) is a promising neuromodulation therapy, but the neurophysiological mechanisms of DBS remain unclear. In awake mice, we performed high-speed membrane voltage fluorescence imaging of individual hippocampal CA1 neurons during DBS delivered at 40 Hz or 140 Hz, free of electrical interference. DBS powerfully depolarized somatic membrane potentials without suppressing spike rate, especially at 140 Hz. Further, DBS paced membrane voltage and spike timing at the stimulation frequency and reduced timed spiking output in response to hippocampal network theta-rhythmic (3-12 Hz) activity patterns. To determine whether DBS directly impacts cellular processing of inputs, we optogenetically evoked theta-rhythmic membrane depolarization at the soma. We found that DBS-evoked membrane depolarization was correlated with DBS-mediated suppression of neuronal responses to optogenetic inputs. These results demonstrate that DBS produces powerful membrane depolarization that interferes with the ability of individual neurons to respond to inputs, creating an informational lesion.

Rifampicin treatment of canine multidrug-resistant meticillin-resistant staphylococcal pyoderma: A retrospective study of 51 cases.

BACKGROUND: Rifampicin (RFP) is a potential treatment for canine multidrug-resistant (MDR) meticillin-resistant staphylococci (MRS), yet the use of lower doses based on recent MIC data has not been evaluated in vivo. HYPOTHESIS/OBJECTIVES: To provide information on the efficacy and safety of low-dose range RFP (≤6 mg/kg/day) for the treatment of canine MDR MRS pyoderma. ANIMALS: Fifty-one client-owned dogs. MATERIALS AND METHODS: Retrospective review of dogs medical records. Dogs were from 11 US dermatology referral practices and had oral RFP at ≤6 mg/kg/day. Data evaluated included response to treatment, adverse events, and serum changes in alanine aminotransferase (ALT) and alkaline phosphatase (ALP). RESULTS: Complete resolution of pyoderma occurred in 39 of 51 dogs (76.5%). Topical antimicrobials were used concurrently in most cases (47 of 51; 92.2%). ALP elevation >1.5-fold of baseline or the high end of the reference range occurred in nine of 37 (24.3%) dogs, while ALT elevation above baseline and the high end of the reference range occurred in two of 36 (5.6%). Only six of 51 (11.8%) had clinical adverse events during treatment; five of six (83.3%) were mild reactions consisting of lethargy and gastrointestinal signs, while one dog had a possible cutaneous adverse drug reaction. Of those that experienced clinical adverse events, four of six (66.7%) did not have concurrent increased liver enzyme activity, while two of six (33.3%) had elevations in ALP alone. CONCLUSIONS AND CLINICAL RELEVANCE: Low-dose RFP (≤6 mg/kg/day) appears to be a relatively safe and effective single-agent systemic antibiotic in combination with topical antimicrobials for canine MDR MRS pyoderma.

CONTEXTE: La rifampicine (RFP) est un traitement potentiel des staphylocoques canins multirésistants (MDR) résistants à la méticilline (MRS), mais l'utilisation de doses plus faibles sur la base de données récentes sur la CMI n'a pas été évaluée in vivo. Hypothèse/Objectifs : Fournir des informations sur l'efficacité et l'innocuité des RFP à faible dose (≤ 6 mg/kg/jour) pour le traitement de la pyodermite MDR-MR canine. Animaux : Cinquante et un chiens de propriétaires. Matériels et méthodes : Revue rétrospective de chiens ayant reçu RFP par voie orale à des doses ≤ 6 mg/kg/jour provenant des dossiers médicaux de 11 centres de référés en dermatologie aux États-Unis. Les données évaluées comprenaient la réponse au traitement, les événements indésirables et les modifications sériques de l'alanine aminotransférase (ALT) et de la phosphatase alcaline (ALP). Résultats : Une résolution complète de la pyodermite s'est produite chez 39 des 51 chiens (76,5 %). Des antimicrobiens topiques ont été utilisés simultanément dans la plupart des cas (47 sur 51 ; 92,2 %). Une élévation de l'ALP> 1,5 fois la ligne de base ou l'extrémité supérieure de la plage de référence s'est produite chez neuf des 37 (24,3%) chiens, tandis qu'une élévation de l'ALT au-dessus de la ligne de base et de l'extrémité supérieure de la plage de référence s'est produite chez deux des 36 (5,6%). Seuls six sur 51 (11,8 %) ont eu des événements indésirables cliniques pendant le traitement ; cinq des six (83,3 %) étaient des réactions bénignes consistant en une léthargie et des signes gastro-intestinaux, tandis qu'un chien a eu un possible effet indésirable cutané au médicament. Parmi ceux qui ont subi des événements indésirables cliniques, quatre sur six (66,7 %) n'ont pas eu d'augmentation simultanée de l'activité des enzymes hépatiques, tandis que deux sur six (33,3 %) ont présenté des élévations de l'ALP seule. Conclusions et pertinence clinique : La RFP à faible dose (≤ 6 mg/kg/jour) semble être un antibiotique systémique à agent unique relativement sûr et efficace en association avec des antimicrobiens topiques pour la pyodermite MDR MRS canine.

Introducción- la rifampicina (RFP) es un tratamiento potencial para los estafilococos resistentes a múltiples fármacos (MDR) y meticilina (MRS), sin embargo, el uso de dosis más bajas basado en datos recientes de MIC no se ha evaluado in vivo. Hipótesis/Objetivos- Proporcionar información sobre la eficacia y seguridad de RFP en el rango de dosis bajas (≤6 mg/kg/día) para el tratamiento de la pioderma canina MDR MRS. Animales- Cincuenta y un perros propietarios particulares. Materiales y métodos- revisión retrospectiva de perros que recibieron RFP oral a dosis ≤6 mg/kg/día obtenida de historiales clínicos de 11 prácticas de referencia de dermatología de los Estados Unidos. Los datos evaluados incluyeron la respuesta al tratamiento, los eventos adversos y los cambios séricos en la alanina aminotransferasa (ALT) y la fosfatasa alcalina (ALP). Resultados- una resolución completa de la pioderma ocurrió en 39 de 51 perros (76,5 %). Antimicrobianos tópicos se usaron al mismo tiempo en la mayoría de los casos (47 de 51; 92,2%). En nueve de 37 (24,3 %) perros se produjo una elevación de ALP >1,5 veces respecto al valor inicial o el extremo superior del rango de referencia, mientras que en dos de 36 (5,6 %) se produjo una elevación de ALT por encima del valor inicial y en el límite superior del rango de referencia. Solo seis de 51 (11,8%) tuvieron eventos adversos clínicos durante el tratamiento; cinco de seis (83,3 %) fueron reacciones leves que consistieron en letargo y signos gastrointestinales, mientras que un perro tuvo una posible reacción cutánea adversa al medicamento. De los que experimentaron eventos adversos clínicos, cuatro de seis (66,7 %) no tuvieron un aumento simultáneo de la actividad de las enzimas hepáticas, mientras que dos de seis (33,3 %) tuvieron elevaciones en la ALP por sí sola. Conclusiones y relevancia clínica- la dosis baja de RFP (≤6 mg/kg/día) parece ser un antibiótico sistémico de uso único relativamente seguro y efectivo en combinación con antimicrobianos tópicos para la pioderma canina MDR MRS.

Contexto - A rifampicina (RFP) é um tratamento potencial para estafilococos resistentes à meticilina (MRS) multirresistentes (MDR) e a utilização de doses mais baixas baseado em dados recentes de MIC não foi avaliada in vivo. Hipótese/Objetivos: Fornecer informações sobre a eficácia e segurança de RFP em menor dosagem (≤6 mg/kg/dia) para o tratamento de piodermite canina por MRS MDR. Animais: Cinquenta e um cães de clientes. Materiais e métodos: Uma revisão retrospectiva dos prontuários de cães que receberam RFP oral na dose de ≤6 mg/kg/dia em 11 clínicas dermatológicas nos Estados Unidos. Os dados avaliados incluíram resposta ao tratamento, eventos adversos, alterações séricas de alanina aminotransferase (ALT) e fosfatase alcalina (FA). Resultados: Resolução completa da piodermite ocorreu em 39 de 51 dos cães (76,5%). Antimicrobianos tópicos foram utilizados concomitantemente na maioria dos casos (47 de 51; 92,2%). Elevação de mais de 1,5 vezes na FA ou para o limite superior do intervalo de referência ocorreu em nove de 37 cães (24,3%), enquanto a elevação de ALT acima do valor inicial e o limite superior do valor de referência ocorreu em dois de 36 (5,6%). Apenas cinco de 51 (11,8%) apresentaram efeitos adversos durante o tratamento; cinco de seis (83,3%) tiveram reações leves caracterizadas por letargia e sinais gastrointestinais, enquanto um cão apresentou uma possível farmacodermia. Dos que apresentaram eventos adversos, quatro de seis (66,7%) não apresentaram aumento concomitante de enzimas hepáticas, enquanto dois de seis (33,3%) tiveram aumento de FA isoladamente. Conclusões e relevância clínica - RFP em baixa dosagem (≤6 mg/kg/dia) aparenta ser relativamente segura e eficaz em monoterapia no tratamento da piodermite canina por MRS MDR por via sistêmica, associada a antimicrobianos tópicos.

Identifying patient perceptions and attitudes regarding statin-associated diabetes mellitus: a mixed-methods study.

Aim: The aims of this study were to explore factors that influence initiation and continuation of statin therapy. Patients & methods: Mixed-method design employed with 73 patients completing surveys and 14 patients participating in semi-structured interviews. Results: When lower total cholesterol is achieved, patients' views are favorable while views of statin therapy diminish among those with higher total cholesterol values. All patients are concerned with adverse events including the potential for developing diabetes. However, overall patients believe the benefits of statins outweigh the risk of diabetes. Conclusion: Barriers remain that prevent patients from achieving cholesterol goals and maintaining or initiating statin therapy. Effective strategies to provide accurate information about the risks and benefits of statin therapy, and implementation of shared decision-making to improve medication adherence and persistence are needed.

The statin medications are commonly prescribed agents used to lower cholesterol and prevent cardiovascular events, such as heart attacks. Although these medications are prescribed often, researchers and clinicians have limited understanding regarding the influences involving patients' decision to start or stop a statin. This study was conducted to gain insight on patients' beliefs and attitudes involving statin therapy. We observed that when patients' had lower cholesterol values, favorable views of statins were more common, while views became less favorable when cholesterol levels were higher. All patients were concerned about statin-associated side effects; but overall believed that the benefits of statins outweighed the risks. It is essential that patients' are provided accurate information from their healthcare team regarding the advantages and disadvantages of statin therapy. Such discussions may allow patients to make more informed decisions and help with continuing a statin long term.

A retrospective analysis of the concordance of in-house fungal culture and a commercial quantitative PCR from 16 dermatology referral practices across the USA (2018-2019).

BACKGROUND: Commercial quantitative (q)PCR and fungal culture can be used concurrently or individually to test for dermatophytosis with a reported high sensitivity and specificity. HYPOTHESIS/OBJECTIVES: The aims of this retrospective study were: (i) to evaluate the concordance of a commercial qPCR with in-house fungal culture for the initial diagnosis of dermatophytosis and for monitoring for mycological cure during treatment in dermatology private practice; and (ii) determine the sensitivity and specificity of qPCR overall, (iii) for initial diagnosis and (iv) for treatment monitoring in dogs and cats. ANIMALS: Four-hundred and twenty-seven client-owned dogs and 188 client-owned cats. MATERIALS AND METHODS: Retrospective evaluation of electronic medical records from 615 client-owned dogs and cats presented to 16 dermatology referral practices across the USA from 2018 to 2019. Concordance of qPCR with in-house fungal culture and sensitivity and specificity were determined from 667 paired samples. RESULTS: qPCR agreed with in-house fungal culture in 63 of 85 positive tests and 571 of 582 negative tests, with an overall sensitivity and specificity of 74.1% [95% confidence interval (CI) 63.5-83.0] and 98.1% (95%CI 96.6-99.0), respectively. qPCR sensitivity and specificity for the initial diagnosis of dermatophytosis and for treatment monitoring were 72.4% (95%CI 59.1-83.3) and 98.7% (95%CI 97.3-99.5), and 77.8% (95%CI 57.7-91.4) and 92.0% (95%CI 80.1-97.8), respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Compared to in-house fungal culture, qPCR was less sensitive and more specific than reported previously. These findings suggest that a diagnosis of dermatophytosis and determining mycological cure should continue to be based on a combination of complementary diagnostic tests.

CONTEXTE: La PCRq quantitative commerciale et la culture fongique peuvent être utilisées simultanément ou individuellement pour le diagnostic de dermatophytose avec une sensibilité et une spécificité élevées. Hypothèses/Objectifs: Les objectifs de cette étude rétrospective étaient : (i) d'évaluer la concordance d'une PCRq commerciale avec culture fongique interne pour le diagnostic initial de dermatophytose et pour le suivi de la guérison mycologique lors d'un traitement en cabinet libéral de dermatologie ; et (ii) déterminer la sensibilité et la spécificité de la PCRq dans son ensemble, (iii) pour le diagnostic initial et (iv) pour le suivi du traitement chez les chiens et les chats. Animaux: Quatre cent vingt-sept chiens de clients et 188 chats de clients. Matériels et méthodes: Évaluation rétrospective des dossiers médicaux électroniques de 615 chiens et chats appartenant à des clients présentés à 16 consultations de référence en dermatologie aux États-Unis de 2018 à 2019. La concordance de Qpcr avec la culture fongique interne et la sensibilité et la spécificité ont été déterminées à partir de 667 paires d'échantillons. Résultats: La PCRq concordait avec la culture fongique interne dans 63 des 85 tests positifs et 571 des 582 tests négatifs, avec une sensibilité et une spécificité globales de 74,1 % [intervalle de confiance (IC) à 95 % 63,5-83,0] et 98,1 % (95 % IC 96,6-99,0), respectivement. La sensibilité et spécificité de la qPCR pour le diagnostic initial de dermatophytose et pour le suivi du traitement étaient de 72,4 % (IC à 95 % 59,1-83,3) et 98,7 % (IC à 95 % 97,3-99,5), et 77,8 % (IC à 95 % 57,7-91,4) et 92,0 % (IC à 95 % 80,1-97,8), respectivement. Conclusions et pertinence clinique : Par rapport à la culture fongique interne, la PCRq était moins sensible et plus spécifique que celle rapportée précédemment. Ces résultats suggèrent que le diagnostic de dermatophytose et la détermination de la guérison mycologique doivent continuer à reposer sur une combinaison de tests diagnostiques complémentaires.

Introducción- la (q)PCR cuantitativa comercial y el cultivo de hongos se pueden usar de forma simultánea o individual para detectar dermatofitosis con una alta sensibilidad y especificidad reportadas. Hipótesis/Objetivos- Los objetivos de este estudio retrospectivo fueron: (i) evaluar la concordancia de una qPCR comercial con cultivo fúngico interno para el diagnóstico inicial de dermatofitosis y para el seguimiento de la curación micológica durante el tratamiento en la práctica privada de dermatología; y (ii) determinar la sensibilidad y especificidad de la qPCR en general, (iii) para el diagnóstico inicial y (iv) para el seguimiento del tratamiento en perros y gatos. Animales- 427 perros y 188 gatos de propietarios particulares. Materiales y métodos: evaluación retrospectiva de historiales clínicos electrónicos de 615 perros y gatos de propietarios particulares presentados en 16 prácticas de referencia de dermatología en los EE.UU. de 2018 a 2019. La concordancia de qPCR con el cultivo y la sensibilidad y especificidad de cada uno se determinó en 667 muestras pareadas. Resultados: qPCR presentó concordancia con el cultivo fúngico interno en 63 de 85 pruebas positivas y 571 de 582 pruebas negativas, con una sensibilidad y especificidad generales del 74,1 % [95 % intervalo de confianza (IC) 63,5-83,0] y 98,1 % (IC 95 % 96,6-99,0), respectivamente. La sensibilidad y especificidad de qPCR para el diagnóstico inicial de dermatofitosis y para el seguimiento del tratamiento fueron 72,4% (IC 95% 59,1-83,3) y 98,7% (IC 95% 97,3-99,5), y 77,8% (IC 95% 57,7-91,4) y 92,0% (IC 95% 80,1-97,8 ), respectivamente. Conclusiones y relevancia clínica- en comparación con el cultivo de hongos interno, la qPCR fue menos sensible y más específica que lo informado anteriormente. Estos hallazgos sugieren que el diagnóstico de dermatofitosis y la determinación de la curación micológica debe seguir basándose en una combinación de pruebas diagnósticas complementarias.

Spike ripples in striatum correlate with seizure risk in two mouse models.

Epilepsy biomarkers from electroencephalogram recordings are routinely used to assess seizure risk and localization. Two widely adopted biomarkers include: (i) interictal spikes, and (ii) high frequency ripple oscillations. The combination of these two biomarkers, ripples co-occurring with spikes (spike ripples), has been proposed as an improved biomarker for the epileptogenic zone and epileptogenicity in humans and rodent models. Whether spike ripples translate to predict seizure risk in rodent seizure models is unknown. Further, recent evidence suggests ictal networks can include deep gray nuclei in humans. Whether pathologic spike ripples and seizures are also observed in the basal ganglia in rodent models has not been explored. We addressed these questions using local field potential recordings from mice with and without striatal seizures after carbachol or 6-hydroxydopamine infusions into the striatum. We found increased spike ripples in the interictal and ictal periods in mice with seizures compared to pre-infusion and post-infusion seizure-free recordings. These data provide evidence of electrographic seizures involving the striatum in mice and support the candidacy of spike ripples as a translational biomarker for seizure risk in mouse models.

Improving appropriate imaging for non-specific low back pain.

Non-specific low back pain (LBP) is a common condition in the USA, with approximately 80% of adults who will have LBP at some point during their life and roughly 30% of the adult population suffering from LBP at any given time. Although LBP is the most common cause of disability in the USA, it often has no identifiable anatomic or physiologic cause. Many patients seeking care for non-specific LBP receive X-rays and other imaging studies. However, for most acute LBP patients, symptoms resolve within 4 weeks and the use of routine imaging may result in unnecessary radiation exposure and add unnecessary costs and wasted time for patients without contributing to patient outcomes. The specific aim of the quality improvement (QI) project was to determine the effect of a multicomponent intervention to enhance the appropriate imaging utilisation for acute LBP to ≥90%. During the first 6 months of the QI project, 191 patients with LBP were seen. Of those patients, 156 (81.7%) received appropriate imaging over the 6-month intervention period, missing our targeted goal. Furthermore, this rate declined to baseline values after termination of the intervention, suggesting the need for additional prompts to sustain the initial intervention effect. Following a health system-wide deployment of practice-based alerts and quality score cards, the appropriate utilisation rate increased again and quickly to the target rate of 90%. To reduce variability in our clinical practice and to sustain an appropriate utilisation rate will require continued work. Health systems must find efficient methods to reduce LBP imaging and increase appropriate management of non-specific LBP in primary care. Increasing concordance with imaging guidelines can lessen harm associated with unnecessary radiation exposure and result in significant cost savings.

Large-scale voltage imaging in behaving mice using targeted illumination.

Recent improvements in genetically encoded voltage indicators enabled optical imaging of action potentials and subthreshold transmembrane voltage in vivo. To perform high-speed voltage imaging of many neurons simultaneously over a large anatomical area, widefield microscopy remains an essential tool. However, the lack of optical sectioning makes widefield microscopy prone to background cross-contamination. We implemented a digital-micromirror-device-based targeted illumination strategy to restrict illumination to the cells of interest and quantified the resulting improvement both theoretically and experimentally with SomArchon expressing neurons. We found that targeted illumination increased SomArchon signal contrast, decreased photobleaching, and reduced background cross-contamination. With the use of a high-speed, large-area sCMOS camera, we routinely imaged tens of spiking neurons simultaneously over minutes in behaving mice. Thus, the targeted illumination strategy described here offers a simple solution for widefield voltage imaging of many neurons over a large field of view in behaving animals.

Distinct neuronal populations contribute to trace conditioning and extinction learning in the hippocampal CA1.

Trace conditioning and extinction learning depend on the hippocampus, but it remains unclear how neural activity in the hippocampus is modulated during these two different behavioral processes. To explore this question, we performed calcium imaging from a large number of individual CA1 neurons during both trace eye-blink conditioning and subsequent extinction learning in mice. Our findings reveal that distinct populations of CA1 cells contribute to trace conditioned learning versus extinction learning, as learning emerges. Furthermore, we examined network connectivity by calculating co-activity between CA1 neuron pairs and found that CA1 network connectivity patterns also differ between conditioning and extinction, even though the overall connectivity density remains constant. Together, our results demonstrate that distinct populations of hippocampal CA1 neurons, forming different sub-networks with unique connectivity patterns, encode different aspects of learning.

Blood Pressure Changes While Hiking at Moderate Altitudes: A Prospective Cohort Study.

Recreational hiking in the mountains is a common activity, whether for a single day or for several days in a row. We sought to measure blood pressure (BP) response during a 10-day trek at moderate-altitude elevation (6500-13,000 feet) and observe for uncontrolled hypertension and/or adverse cardiovascular outcomes. A total of 1279 adult participants completed an observational study of resting BP during a 10-day trek in the Sangre de Cristo mountains. Following initial recruitment, participants were issued a trail data card to record BP measurements at day 0 (basecamp), day 3, day 6 and day 9. BP was measured using a sphygmomanometer and auscultation. Demographic data, height, weight, home altitude, daily water and sports drink intake, existence of pre-arrival hypertension and BP medication class were also recorded. We observed a rise in mean blood pressure for the cohort during all exposures to moderate altitudes. The increases were greatest for individuals with pre-existing hypertension and/or obesity. There were no observed life-threatening cardiovascular events for participants. We conclude that for individuals with a modestly controlled blood pressure of 160/95 mmHg, hiking at a moderate altitude is a safe activity.

CaMKIIα-Positive Interneurons Identified via a microRNA-Based Viral Gene Targeting Strategy.

Single-cell analysis is revealing increasing diversity in gene expression profiles among brain cells. Traditional promotor-based viral gene expression techniques, however, cannot capture the growing variety among single cells. We demonstrate a novel viral gene expression strategy to target cells with specific miRNA expression using miRNA-guided neuron tags (mAGNET). We designed mAGNET viral vectors containing a CaMKIIα promoter and microRNA-128 (miR-128) binding sites, and labeled CaMKIIα+ cells with naturally low expression of miR-128 (Lm128C cells) in male and female mice. Although CaMKIIα has traditionally been considered as an excitatory neuron marker, our single-cell sequencing results reveal that Lm128C cells are CaMKIIα+ inhibitory neurons of parvalbumin or somatostatin subtypes. Further evaluation of the physiological properties of Lm128C cell in brain slices showed that Lm128C cells exhibit elevated membrane excitability, with biophysical properties closely resembling those of fast-spiking interneurons, consistent with previous transcriptomic findings of miR-128 in regulating gene networks that govern membrane excitability. To further demonstrate the utility of this new viral expression strategy, we expressed GCaMP6f in Lm128C cells in the superficial layers of the motor cortex and performed in vivo calcium imaging in mice during locomotion. We found that Lm128C cells exhibit elevated calcium event rates and greater intrapopulation correlation than the overall CaMKIIα+ cells during movement. In summary, the miRNA-based viral gene targeting strategy described here allows us to label a sparse population of CaMKIIα+ interneurons for functional studies, providing new capabilities to investigate the relationship between gene expression and physiological properties in the brain.SIGNIFICANCE STATEMENT We report the discovery of a class of CaMKIIα+ cortical interneurons, labeled via a novel miRNA-based viral gene targeting strategy, combinatorial to traditional promoter-based strategies. The fact that we found a small, yet distinct, population of cortical inhibitory neurons that express CaMKIIα demonstrates that CaMKIIα is not as specific for excitatory neurons as commonly believed. As single-cell sequencing tools are providing increasing insights into the gene expression diversity of neurons, including miRNA profile data, we expect that the miRNA-based gene targeting strategy presented here can help delineate many neuron populations whose physiological properties can be readily related to the miRNA gene regulatory networks.

Feasibility and acceptability of a televideo physical activity and nutrition program for recent kidney transplant recipients.

BACKGROUND: Post-transplant weight gain affects 50-90% of kidney transplant recipients adversely affecting survival, quality of life, and risk for diabetes and cardiovascular disease. Diet modification and physical activity may help prevent post-transplant weight gain. Methods for effective implementation of these lifestyle modifications are needed. The objective of this study is to assess the feasibility and acceptability of a remotely delivered nutrition and physical activity intervention among kidney transplant recipients. Secondary aims were to estimate the effectiveness of the intervention in producing changes in physical activity, qualify of life, fruit and vegetable intake, and consumption of whole grains and water from baseline to 6 months. METHODS: A randomized controlled study for stable kidney transplant recipients between 6 and 12 months post-transplantation was conducted. Participants were randomly assigned 1:1 to a technology-based, lifestyle modification program (intervention) or to enhanced usual care (control). RESULTS: The first 10 kidney transplant recipients screened were eligible and randomized into the intervention and control groups with no significant between-group differences at baseline. Health coaching attendance (78%) and adherence to reporting healthy behaviors (86%) were high. All participants returned for final assessments. The weight in controls remained stable, while the intervention arm showed weight gain at 3 and 6 months. Improvements were found for physical activity, quality of life, and fruit and vegetable intake in both groups. All participants would recommend the program to other transplant recipients. CONCLUSIONS: Our data suggest that a remotely delivered televideo nutrition and physical activity intervention is feasible and valued by patients. These findings will aid in the development of a larger, more prescriptive, randomized trial to address weight gain prevention. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT03697317. Retrospectively registered on October 5, 2018.

A Viral Toolbox of Genetically Encoded Fluorescent Synaptic Tags.

Fibronectin intrabodies generated with mRNA display (FingRs) are a recently developed tool for labeling excitatory or inhibitory synapses, with the benefit of not altering endogenous synaptic protein expression levels or synaptic transmission. Here, we generated a viral vector FingR toolbox that allows for multi-color, neuron-type-specific labeling of excitatory or inhibitory synapses in multiple brain regions. We screened various fluorophores, FingR fusion configurations, and transcriptional control regulations in adeno-associated virus (AAV) and retrovirus vector designs. We report the development of a red FingR variant and demonstrated dual labeling of excitatory and inhibitory synapses in the same cells. Furthermore, we developed cre-inducible FingR AAV variants and demonstrated their utility, finding that the density of inhibitory synapses in aspiny striatal cholinergic interneurons remained unchanged in response to dopamine depletion. Finally, we generated FingR retroviral vectors, which enabled us to track the development of excitatory and inhibitory synapses in hippocampal adult-born granule cells.

Appropriate utilisation of cardiac telemetry monitoring: a quality improvement project.

For hospitals located in the United States, appropriate use of cardiac telemetry monitoring can be achieved resulting in cost savings to healthcare systems. Our institution has a limited number of telemetry beds, increasing the need for appropriate use of telemetry monitoring to minimise delays in patient care, reduce alarm fatigue, and decrease interruptions in patient care. This quality improvement project was conducted in a single academic medical centre in Kansas City, Kansas. The aim of the project was to reduce inappropriate cardiac telemetry monitoring on intermediate care units. Using the 2004 American Heart Association guidelines to guide appropriate telemetry utilisation, this project team sought to investigate the effects of two distinct interventions to reduce inappropriate telemetry monitoring, huddle intervention and mandatory order entry. Telemetry utilisation was followed prospectively for 2 years. During our initial intervention, we achieved a sharp decline in the number of patients on telemetry monitoring. However, over time the efficacy of the huddle intervention subsided, resulting in a need for a more sustained approach. By requiring physicians to input indication for telemetry monitoring, the second intervention increased adherence to practice guidelines and sustained reductions in inappropriate telemetry use.