Allelic strengths of encephalopathy-associated UBA5 variants correlate between in vivo and in vitro assays.

Protein UFMylation downstream of the E1 enzyme UBA5 plays essential roles in development and endoplasmic reticulum stress. Variants in the UBA5 gene are associated with developmental and epileptic encephalopathy 44 (DEE44), an autosomal recessive disorder characterized by early-onset encephalopathy, movement abnormalities, global developmental delay, intellectual disability, and seizures. DEE44 is caused by at least 12 different missense variants described as loss of function (LoF), but the relationships between genotypes and molecular or clinical phenotypes remain to be established. We developed a humanized UBA5 fly model and biochemical activity assays in order to describe in vivo and in vitro genotype-phenotype relationships across the UBA5 allelic series. In vivo, we observed a broad spectrum of phenotypes in viability, developmental timing, lifespan, locomotor activity, and bang sensitivity. A range of functional effects was also observed in vitro across comprehensive biochemical assays for protein stability, ATP binding, UFM1 activation, and UFM1 transthiolation. Importantly, there is a strong correlation between in vivo and in vitro phenotypes, establishing a classification of LoF variants into mild, intermediate, and severe allelic strengths. By systemically evaluating UBA5 variants across in vivo and in vitro platforms, this study provides a foundation for more basic and translational UBA5 research, as well as a basis for evaluating current and future individuals afflicted with this rare disease.

Although rare diseases only impact a small fraction of the population, they still affect hundreds of millions of people around the world. Many of these conditions are caused by variations in inherited genetic material, which nowadays can be readily detected using advanced sequencing technologies. However, establishing a connection between these genetic changes and the disease they cause often requires further in-depth study. One such rare inherited disorder is developmental and epileptic encephalopathy type 44 (DEE44), which is caused by genetic variations within the gene for UBA5 (short for ubiquitin-like modifier activating enzyme 5). For DEE44 to occur, both copies of the gene for UBA5, known as alleles, must contain one or more detrimental variation. Although all these variations prevent UBA5 from working correctly, the level of disruption they cause, known as allelic strength, varies between them. However, it remained unclear whether the severity of the DEE44 disease directly corresponds with the allelic strength of these variants. To answer this question, Pan et al. tested how different genetic variants found in patients with DEE44 affected the behavior and health of fruit flies. These results were then compared against in vitro biochemical assays testing how alleles containing these variants impacted the function of UBA5. When the fly gene for the enzyme was replaced with the human gene containing variations associated with DEE44, flies exhibited changes in their survival rates, developmental progress, lifespan, and neurological well-being. However, not all of the variants caused ill effects. Using this information, the patient variants were classified into three categories based on the severity of their effect: mild, intermediate, and severe. Biochemical assays supported this classification and revealed that the variants that caused more severe symptoms tended to inhibit the activity of UBA5 more significantly. Pan et al. further analyzed the nature of the variants in the patients and showed that most patients typically carried one mild and one strong variant, although some individuals did have two intermediate variants. Notably, no patients carried two severe variants. This indicates that DEE44 is the result of UBA5 only partially losing its ability to work correctly. The study by Pan et al. provides a framework for assessing the impact of genetic variants associated with DEE44, aiding the diagnosis and treatment of the disorder. However, further research involving more patients, more detailed clinical data, and testing other newly identified DEE44-causing variants is needed to solidify the correlation between allelic strength and disease severity.

Allelic strengths of encephalopathy-associated UBA5 variants correlate between in vivo and in vitro assays.

Protein UFMylation downstream of the E1 enzyme UBA5 plays essential roles in development and ER stress. Variants in the UBA5 gene are associated with developmental and epileptic encephalopathy 44 (DEE44), an autosomal recessive disorder characterized by early-onset encephalopathy, movement abnormalities, global developmental delay, intellectual disability, and seizures. DEE44 is caused by at least twelve different missense variants described as loss of function (LoF), but the relationships between genotypes and molecular or clinical phenotypes remains to be established. We developed a humanized UBA5 fly model and biochemical activity assays in order to describe in vivo and in vitro genotype-phenotype relationships across the UBA5 allelic series. In vivo, we observed a broad spectrum of phenotypes in viability, developmental timing, lifespan, locomotor activity, and bang sensitivity. A range of functional effects was also observed in vitro across comprehensive biochemical assays for protein stability, ATP binding, UFM1 activation, and UFM1 transthiolation. Importantly, there is a strong correlation between in vivo and in vitro phenotypes, establishing a classification of LoF variants into mild, intermediate, and severe allelic strengths. By systemically evaluating UBA5 variants across in vivo and in vitro platforms, this study provides a foundation for more basic and translational UBA5 research, as well as a basis for evaluating current and future individuals afflicted with this rare disease.

A Beta Version of an Application Based on Computer Vision for the Assessment of Knee Valgus Angle: A Validity and Reliability Study.

BACKGROUND: In handball, the kinematics of the frontal plane seem to be one of the most important factors for the development of lower limb injuries. The knee valgus angle is a fundamental axis for injury prevention and is usually measured with 2D systems such as Kinovea software (Version 0.9.4.). Technological advances such as computer vision have the potential to revolutionize sports medicine. However, the validity and reliability of computer vision must be evaluated before using it in clinical practice. The aim of this study was to analyze the test-retest and inter-rater reliability and the concurrent validity of a beta version app based on computer vision for the measurement of knee valgus angle in elite handball athletes. METHODS: The knee valgus angle of 42 elite handball athletes was measured. A frontal photo during a single-leg squat was taken, and two examiners measured the angle by the beta application based on computer vision at baseline and at one-week follow-up to calculate the test-retest and inter-rater reliability. A third examiner assessed the knee valgus angle using 2D Kinovea software to calculate the concurrent validity. RESULTS: The knee valgus angle in the elite handball athletes was 158.54 ± 5.22°. The test-retest reliability for both examiners was excellent, showing an Intraclass Correlation Coefficient (ICC) of 0.859-0.933. The inter-rater reliability showed a moderate ICC: 0.658 (0.354-0.819). The standard error of the measurement with the app was stated between 1.69° and 3.50°, and the minimum detectable change was stated between 4.68° and 9.70°. The concurrent validity was strong r = 0.931; p < 0.001. CONCLUSIONS: The computer-based smartphone app showed an excellent test-retest and inter-rater reliability and a strong concurrent validity compared to Kinovea software for the measurement of the knee valgus angle.

Assessing Values and Preferences Toward SARS-CoV-2 Self-testing Among the General Population and Their Representatives, Health Care Personnel, and Decision-Makers: Protocol for a Multicountry Mixed Methods Study.

BACKGROUND: Accessible, safe, and client-centered SARS-CoV-2 testing services are an effective way to halt its transmission. Testing enables infected individuals to isolate or quarantine to prevent further transmission. In countries with limited health systems and laboratory capacity, it can be challenging to provide accessible and safe screening for COVID-19. Self-testing provides a convenient, private, and safe testing option; however, it also raises important concerns about lack of counseling and ensuring timely reporting of self-test results to national surveillance systems. Investigating community members' views and perceptions regarding SARS-CoV-2 self-testing is crucial to inform the most effective and safe strategies for implementing said testing. OBJECTIVE: We aimed to determine whether SARS-CoV-2 self-testing was useful to diagnose and prevent the spread of SARS-CoV-2 for populations in low-resource settings and under which circumstances it would be acceptable. METHODS: This multisite, mixed methods, observational study will be conducted in 9 countries-Brazil, India, Indonesia, Kenya, Malawi, Nigeria, Peru, the Philippines, and South Africa-and will consists of 2 components: cross-sectional surveys and interviews (semistructured and group) among 4 respondent groupings: the general population, general population representatives, health care workers, and decision-makers. General population and health care worker survey responses will be analyzed separately from each other, using bivariate and multivariate inferential analysis and descriptive statistics. Semistructured interviews and group interviews will be audiorecorded, transcribed, and coded for thematic comparative analysis. RESULTS: As of November 19, 2021, participant enrollment is ongoing; 4364 participants have been enrolled in the general population survey, and 2233 participants have been enrolled in the health care workers survey. In the qualitative inquiry, 298 participants have been enrolled. We plan to complete data collection by December 31, 2021 and publish results in 2022 via publications, presentations at conferences, and dissemination events specifically targeted at local decision-makers, civil society, and patient groups. CONCLUSIONS: The views and perceptions of local populations are crucial in the discussion of the safest strategies for implementing SARS-CoV-2 self-testing. We intend to identify sociocultural specificities that may hinder or accelerate the widespread utilization of SARS-CoV-2 self-testing. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/33088.

The positive carbon stocks-biodiversity relationship in forests: co-occurrence and drivers across five subclimates.

Carbon storage in forests and its ability to offset global greenhouse gas emissions, as well as biodiversity and its capacity to support ecosystem functions and services, are often considered separately in landscape planning. However, the potential synergies between them are currently poorly understood. Identifying the spatial patterns and factors driving their co-occurrence across different climatic zones is critical to more effectively conserve forest ecosystems at the regional level. Here, we integrated information of National Forest Inventories and Breeding Bird Atlases across Europe and North America (Spain and Quebec, respectively), covering five subclimates (steppe, dry Mediterranean, humid Mediterranean, boreal, and temperate). In particular, this study aimed to (1) determine the spatial patterns of both forest carbon stocks and biodiversity (bird richness, tree richness, and overall biodiversity) and the factors that influence them; (2) establish the relationships between forest carbon stocks and biodiversity; and (3) define and characterize the areas of high (hotspots) and low (coldspots) values of carbon and biodiversity, and ultimately quantify their spatial overlap. Our results show that the factors affecting carbon and biodiversity vary between regions and subclimates. The highest values of carbon and biodiversity were found in northern Spain (humid Mediterranean subclimate) and southern Quebec (temperate subclimate) where there was more carbon as climate conditions were less limiting. High density and structural diversity simultaneously favored carbon stocks, tree, and overall biodiversity, especially in isolated and mountainous areas, often associated with steeper slopes and low accessibility. In addition, the relationship between carbon stocks and biodiversity was positive in both regions and all subclimates, being stronger where climate is a limiting factor for forest growth. The spatial overlap between hotspots of carbon and biodiversity provides an excellent opportunity for landscape planning to maintain carbon stocks and conserve biodiversity. The variables positively affecting carbon and biodiversity were also driving the hotspots of both carbon and biodiversity, emphasizing the viability of "win-win" solutions. Our results highlight the need to jointly determine the spatial patterns of ecosystem services and biodiversity for an effective and sustainable planning of forest landscapes that simultaneously support conservation and mitigate climate change.

Extreme fire severity patterns in topographic, convective and wind-driven historical wildfires of Mediterranean pine forests.

Crown fires associated with extreme fire severity are extremely difficult to control. We have assessed fire severity using differenced Normalized Burn Ratio (dNBR) from Landsat imagery in 15 historical wildfires of Pinus halepensis Mill. We have considered a wide range of innovative topographic, fuel and fire behavior variables with the purposes of (1) determining the variables that influence fire severity patterns among fires (considering the 15 wildfires together) and (2) ascertaining whether different variables affect extreme fire severity within the three fire types (topographic, convective and wind-driven fires). The among-fires analysis showed that fires in less arid climates and with steeper slopes had more extreme severity. In less arid conditions there was more crown fuel accumulation and closer forest structures, promoting high vertical and horizontal fuel continuity and extreme fire severity. The analyses carried out for each fire separately (within fires) showed more extreme fire severity in areas in northern aspects, with steeper slopes, with high crown biomass and in climates with more water availability. In northern aspects solar radiation was lower and fuels had less water limitation to growth which, combined with steeper slopes, produced more extreme severity. In topographic fires there was more extreme severity in northern aspects with steeper slopes and in areas with more water availability and high crown biomass; in convection-dominated fires there was also more extreme fire severity in northern aspects with high biomass; while in wind-driven fires there was only a slight interaction between biomass and water availability. This latter pattern could be related to the fact that wind-driven fires spread with high wind speed, which could have minimized the effect of other variables. In the future, and as a consequence of climate change, new zones with high crown biomass accumulated in non-common drought areas will be available to burn as extreme severity wildfires.

Gastric Perforation and Phlegmon Formation by Foreign BodyIngestion.

This is a case report of foreign body ingestion in a suicide attempt resulting in gastric perforation and phlegmon formation during a subsequent 6 month period that eventually required surgical intervention. The patient had a prolonged course because she did not report a history of foreign body ingestion and the initial evaluating physicians had no suspicion about possible foreign body ingestion and may have missed important findings on physical examination. Gastric perforation by a foreign object may have a slow course rather than presenting acute abdomen. The realization of a proper physical examination in the emergency department is key to an accurate diagnosis.

Encefalitis rábica humana secundaria a mordedura por gato infectado por un virus rábico de origen silvestre / Encephalitis Due to Rabies Secondary to the Bite of a Cat Infected With a Rabies Virus of Silvester Origen

La rabia es una enfermedad viral zoonótica, producida por un virus del genero Lyssavirus de la Familia Rhabdoviridae, cuya principal fuente de transmisión es la mordedura de animales a humanos. Es una enfermedad fatal y se han descrito casos por ciclos urbanos y rurales. El caso que reportamos es el de una joven de 22 años, quien ingresa por un cuadro de dolor de características neuropáticas en el miembro superior derecho, con antecedente de mordedura por un gato de varios meses atrás, hospitalizada por el servicio de Neurología por sospecha de lesión de plejo braquial, con resonancia de columna cervical y líquido cefalorraquídeo (LCR) normales, quien posteriormente presenta deterioro clínico tórpido a un proceso encefalopático que en pocos días la llevó a la muerte. Se confirmó que la paciente presentó una encefalitis por un virus de rabia. Expondremos cómo fue el manejo de la paciente y todos los nexos epidemiológicos.

Rabies is a zoonotic viral disease, caused by a virus of the genus Lyssavirus of the Rhabdoviridae family. Its main source is transmission from animals to humans bite. The disease is fatal and has been reported to occur in rural and urban cycles. This reported case is a 22-year old, who was admitted with symptoms of neuropathic pain in the right arm, with a history of being bitten by a cat a few months earlier. The patient was hospitalized in the Neurology Department for suspected brachial plexopathy, and normal spinal MRI and cerebrospinal fluid (CSF) were found. The patient subsequently presented encephalopathic decline that resulted in death within a few days. It was confirmed that the patient had encephalitis due to the rabies virus. We present the management of the patient and all epidemiological links.

Medidas generales en el servicio de urgencias para el paciente pediátrico intoxicado / General Measures in the Emergency Department for Pediatric Patients Poisoned

Introducción: La exposición a sustancias tóxicas es frecuente en pediatría. En Colombia, entre 2006 y 2008 se presentaron 40061 casos de intoxicaciones, de las cuales 19 723 correspondieron a menores de 14 años de edad. En 2009 se presentaron187 muertes, lo que corresponde a una tasa de mortalidad de 0,6 casos por cada 100 000 habitantes y una tasa de letalidad de 9,48 por cada 100 000 casos de pacientes intoxicados.Objetivo: Evaluar en la literatura el papel de las medidas generales como tratamiento en el paciente pediátrico intoxicado y determinar cuáles han demostrado ser seguras y eficaces.Método: Selección de artículos (búsqueda en inglés y español en Medline, PubMed, Academic Search Complete, Science Direct y SciELO) y extracción de datos, según la aplicación de las medidas generales en el manejo de los pacientes intoxicados en el servicio de urgencias.Conclusiones: Es importante conocer el mecanismo de acción de las técnicaspara disminuir la absorción o aumentar la eliminación de sustancias tóxicas y las indicaciones y contraindicaciones para su aplicación, y brindar un adecuado y efectivo tratamiento en los servicios de urgencias...

Introduction: Exposure to toxic substances is common in pediatrics. In Colombia in between the 2006 and 2008 there were 40 061 cases ofpoisoning, of which 19 723 were in younger than 14 years old. In 2009 there were a total of 187 deaths which corresponds to a mortality rate of0.6 cases per 100000 inhabitants, and a fatality rate of 9.48 per 100 000 cases of poisoned patients. Objective: Evaluate in the literature the role ofgeneral measures for treatment in pediatric patients intoxicated and determine which are the measures that have proven safe and effective. Method: Selection articles (in English and Spanish, from Medline, PubMed, Academic Search Complete, Science Direct, and SciELO) and data extraction (focused on the implementation of general measures in the management of poisoned patients in the emergency department). Conclusions: Knowledge of the mechanism of action of different techniques to decrease absorptionor enhance elimination of toxic substances, the indications and contraindications for use are important to provide adequate and effectivetreatment in the emergency department...