Tacrolimus as a Promising Drug for Epistaxis and Gastrointestinal Bleeding in HHT.

BACKGROUND: Hereditary Hemorrhagic Telangiectasia (HHT) is a vascular autosomically inherited rare disease. Epistaxis (nose bleeds) is the most common symptom in HHT, leading to anemia and affecting the patient's quality of life. In addition to epistaxis, gastrointestinal bleeding (GI), more often at older ages, may lead to severe anemia and the need for blood transfusions. Thus, finding drugs to control both types of bleeding is a primary necessity in HHT. METHODS: A cross-sectional observational study was conducted in a series of 11 HHT patients treated with low tacrolimus doses (0.5-2 mg/day) on an off-label prescription basis. Patients showed refractory bleeding to previous treatments. The epistaxis severity score (ESS) and hemoglobin levels were the parameters used to evaluate the impact of tacrolimus. The occurrence of side effects was also recorded. RESULTS: Tacrolimus was well tolerated in all of the patients except 2 (who stopped the treatment). The remaining patients tolerated the treatment, with a general improvement in their health condition. Epistaxis was significantly reduced when comparing the ESS before and after the treatment. Hemoglobin levels significantly increased, overcoming the anemia, during the course of the treatment. CONCLUSION: Tacrolimus at low doses should be considered as a promising treatment for epistaxis and gastrointestinal bleeding in HHT.

All-cause mortality attributable to sitting time and physical inactivity in chilean adults.

BACKGROUND: Evidence on all-cause mortality attributable to joint sitting time and physical inactivity is lacking. In this study, we estimated the proportion and number of deaths attributable to sitting time and physical inactivity in Chilean adults. METHODS: A sample of 5834 adults aged 20-96 years from a 2016-2017 Chilean National Health Survey was included to describe the prevalence of 16 joint categories of sitting time and physical activity. Relative risks for the joint association of sitting time and physical inactivity were obtained from a meta-analysis of individual participant data. We retrieved the number of deaths in adults ≥ 20 years in 2019 from the Chilean Ministry of Health. RESULTS: Participants with high sitting time (> 8 h/day) and low physical activity (< 2.5 MET-hour/week) were more likely to be women, 20-64 years, non-indigenous ethnicity, lived in the urban areas, had middle education level and monthly household income, and had public health insurance. Reducing sitting time and increasing physical activity to a theoretical minimum risk exposure level could prevent up to 11,470 deaths or 10.4% of all deaths. Increasing physical activity to >35.5 MET-hour/week and maintaining sitting time could prevent approximately 10,477 deaths or 9.5% of all deaths. Reducing sitting time to < 4 h/day and maintaining physical activity would not reduce the number of deaths (-3.4% or 38 deaths). CONCLUSION: Reducing sitting time may be ancillary for preventing mortality. Therefore, increasing physical activity should be the primary focus of interventions and policies in Chile.

Future burden of non-communicable diseases attributable to overweight in Chile: a multistate life table modeling study.

BACKGROUND: Previous studies have quantified the current burden of diseases attributable to overweight in Chile. However, no study has estimated the attributable burden of overweight in the future. Herein, we estimated the potential impact of different trajectories in the prevalence of overweight on the incidence and mortality from non-communicable diseases (NCDs) in Chilean adults from 2019 to 2030. METHODS: A multistate life table modelling was used to estimate the business-as-usual (BAU: if the current rate of increase in BMI persist through the next 11 years; i.e., 0.4% per year from 2003 to 2017) and three counterfactual scenarios (1: the increase rate of overweight is reduced by half; 2: maintanance of the current prevalence of overweight; 3: the prevalence of overweight is reduced by 6.7%) over a 11-year simulation period for burden of NCDs attributable to overweight in Chilean adults aged 20 to 80 years. The model inputs included nationally representative data of body mass index, national official demographic records, NCDs from the Global Burden of Disease study in 2019, and relative risks from a published meta-analysis. RESULTS: If the current trends of increase in overweight are maintained in Chile, approximately, 669 thousand cases and 117 thousand deaths from NCDs will occur from 2020 to 2030. In case the increase rate of overweight is reduced by half during this period, around 7 thousand cases and 1.4 thousand deaths from NCDs would be prevented, while achieving no increase in the prevalence of overweight would avert 10 thousand cases and 2 thousand deaths. In the optimistic scenario of reducing the prevalence of overweight by 6.7% until 2030, approximately 25 thousand cases and 5 thousand deaths from NCDs would be prevented. CONCLUSION: We estimated that the number of NCDs cases and deaths that could be avoided by decreasing the prevalence of overweight in Chilean adults. Preventive programs aimed to reduce overweight may have a high impact on the future burden of NCDs in Chile.

Characteristics of RCTs focusing on health promotion in community samples: a scoping review protocol based on the d-CoSPICO framework.

INTRODUCTION: Developing the capabilities of individuals, groups and communities to enhance their health has received a great deal of attention in the literature. One essential source of results is evidence-based intervention programmes, which often involve a number of different variables. This paper describes a methodology for carrying out a scoping review that maps available evidence on randomised controlled trials focusing on health promotion intervention programmes. METHODS AND ANALYSIS: The scoping review protocol follows the general Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Joanna Briggs Institute guidelines. It also incorporates some modifications to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Review flowchart and complements its methodological framework. This new format, called documents, Concept, Studies, Participants, Interventions, Comparator, and Outcomes (d-CoSPICO), guides the review sequence, which is represented in a flowchart. The search will focus on different sources of information using formal (searches in thematic -PubPsych, ERIC, MedLine, PsychINFO- and multidisciplinary databases -Academic Search Ultimate, Core Collection Web of Science, Scopus and ProQuest-, repositories and other websites), informal (contact with researchers), and retrospective (previous reviews on this topic) strategies to identify relevant publications until 2021, including grey literature. Coding, identification, selection, and data extraction will be carried out following the generation of a database in which each retrieved record's content (abstract and/or full text) can be analysed. The review is expected to be completed in 2023. ETHICS AND DISSEMINATION: Ethical approval is not required for this review. The d-CoSPICO framework and the results will be disseminated through (a) peer-reviewed publications; (b) presentations at scientific dissemination events and (c) training activities for applying this protocol.

Combined association of physical activity and sitting time with cardiometabolic risk factors in Chilean adults.

In this study we examined the combined association of physical activity and sitting time with cardiometabolic risk factors in adults in Chile. This is a cross-sectional study based on 3201 adults aged from 18 to 98 years from the Chilean National Health Survey (2016-2017) who responded to the GPAQ questionnaire. Participants were considered inactive if spent < 600 METs-min/wk-1 in physical activity. High sitting time was defined as ≥ 8 h/day. We classified participants into the following 4 groups: active and low sitting time; active and high sitting time; inactive and low sitting time; inactive and high sitting time. The cardiometabolic risk factors considered were metabolic syndrome, body mass index, waist circumference, total cholesterol, and triglycerides. Multivariable logistic regression models were performed. Overall, 16.1% were classified as inactive and high sitting time. Compared to active participants with low sitting time, both inactive participants with low (OR: 1.51; 95% CI 1.10, 1.92) and high sitting time (1.66; 1.10, 2.22) had higher body mass index. Similar results were found for high waist circumference: inactive participants with low (1.57; 1.14, 2.00) and high sitting time (1.84; 1.25, 2.43). We found no combined association of physical activity and sitting time with metabolic syndrome, total cholesterol, and triglycerides. These findings may be useful to inform programs focused on obesity prevention in Chile.

Primary Validation of the Submandibular Skinfold as an Anthropometric Measurement of Cardiometabolic Risk in People with Intellectual Disabilities.

The accumulation of body fat is an important cardiometabolic risk factor; however, there is no consensus about which measure is more reliable for the assessment of cardiometabolic risk in people with intellectual disabilities. The aim of the present study was to primarily validate the submandibular skinfold as an anthropometric measurement of cardiometabolic risk in children, adolescents, and adults with intellectual disabilities, using a cross-sectional study made up of 131 people (67.2% men) with mild and moderate intellectual disability. The cardiometabolic risk indicators used were: body mass index (kg/m2), neck circumference (cm), waist circumference (cm), calf circumference (cm) and waist-to-height ratio. Moderate correlations were demonstrated between the submandibular skinfold measure and the anthropometric measurements analyzed in the three age categories, showing the highest correlation (r = 0.70) between the submandibular skinfold and BMI in the adolescent group and waist-to-height ratio in adults. The implementation of the submandibular skinfold measurement is suggested as an easy, fast, and minimally invasive anthropometric measurement as part of the physical and nutritional evaluation for the assessment of cardiometabolic risk in people with intellectual disabilities.

Reference Values of Absolute and Relative Handgrip Strength in Chilean Schoolchildren with Intellectual Disabilities.

Handgrip strength is a simple measure of general muscle strength and is related to functionality in people with intellectual disabilities. The objective of this research was to describe the normative values of absolute and relative handgrip strength in children, adolescents and adults according to sex. The sample was made up of 264 schoolchildren (n = 168 men) belonging to five special education schools in Santiago of Chile. The results show higher levels of absolute handgrip strength in males compared to females. The maximum peak of the absolute manual handgrip is reached in females in adolescence with a decrease in adulthood. Relative handgrip strength levels are similar in boys and girls. In females, the relative handgrip strength is similar in childhood and adolescence. Relative handgrip strength declines in both sexes from adolescence to adulthood. The reference values of this study can be used by professionals in the areas of health and education as a guide for interpretation, monitoring and follow-up of Chilean schooled people with intellectual disabilities.

Physical activity and daily steps cut offs points for overweight/obesity prevention among eight Latin American countries.

This study aims to establish cut-off points for the number of minutes of physical activity intensity and the number of daily steps that identify overweight/obesity in adolescents, adults, and older adults. This study examined data from 2737 participants. Physical activity intensity and the number of daily steps were assessed using GT3X+ ActiGraph model accelerometers. Body mass index, waist-to-height ratio, and waist-to-hip ratio were used as indicators of overweight/obesity. The cut-off points for moderate-to-vigorous physical activity for the prevention of overweight/obesity according to body mass index in women ranged from 15.1 to 30.2 min/day; in men, the values were from 15.4 to 33.8 min/day. The lowest cut-off point for daily steps was established in the adolescent group for women and men (7304 and 5162). The highest value in women was 11,412 (51-65 years) and 13,234 in men (18-30 years). Results from measurements different from BMI, show average cut-off points for moderate-to-vigorous physical activity and daily steps of 29.1/8348 and 43.5/10,456 according to waist-to-height ratio; and results of 29.3/11,900 and 44.3/11,056 according to the waist-to-hip ratio; in women and men respectively. A more specific recommendation of physical activity and daily steps adjusted by sex and age range is suggested to prevent overweight/obesity.

Perceived Neighborhood Safety and Active Transportation in Adults from Eight Latin American Countries.

Neighborhood built environment is associated with domain-specific physical activity. However, few studies with representative samples have examined the association between perceived neighborhood safety indicators and domain-specific active transportation in Latin America. This study aimed to examine the associations of perceived neighborhood safety with domain-specific active transportation in adults from eight Latin American countries. Data were obtained from the Latin American Study of Nutrition and Health (n = 8547, aged 18-65). Active transportation (walking and cycling) was assessed using the long form of the International Physical Activity Questionnaire. Specifically, traffic density and speed as well as street lightening, visibility of residents regarding pedestrians and bicyclists, traffic lights and crosswalks, safety of public spaces during the day and at night, crime rate during the day and at night were used to evaluate perceived neighborhood safety. Slow traffic speeds, unsafe public spaces during the day, and crime during the day were associated with ≥10 min/week vs. <10 min/week of walking. Furthermore, drivers exceeding the speed limit and crime rate during the day were associated with reporting ≥10 min/week vs. <10 min/week of cycling. These results indicate a stronger association of the perceived neighborhood safety with walking compared to cycling.

Effectiveness of Teaching Mini Handball through Non-Linear Pedagogy in Different Socioeconomic Contexts: A Pilot Study.

Mini handball is among the sports included as part of school physical education in Chile to improve children's motor skills and to motivate their adherence to a healthy and active lifestyle in response to concerns about this country's high level of childhood obesity. To this end, non-linear pedagogy (NLP) has been used to develop motor skills through mini handball in the school context. However, socioeconomic differences that influence the development of children's motor skills have not been considered to determine whether the methodology applies to everyone. The aim of the present observational study is to describe and compare the effectiveness of the previously applied NLP methodology in two contrasting socioeconomic contexts to determine whether it helps to develop motor skills through mini handball in both school contexts. The Levine test was used to determine the homogeneity of the variances (p < 0.05), as the distribution of the data was not normal. The Kruskal-Wallis H statistical test was used to analyse within-group data. Additionally, the Mann-Whitney U test was applied for comparisons between groups. The results show significant improvements in the acquisition of the expected motor skills specific to mini handball. Additionally, a shortening of the gap was evidenced between the groups during the training process, with no significant differences at the end of the progression. Therefore, the investigated NLP is equally as effective for schoolchildren in two opposite socioeconomic contexts.

A Meta-analytic Study on Executive Function Performancein Children/Adolescents with OCD / Un Estudio Meta-analítico sobre el Rendimiento en Funciones Ejecutivas en Niños/Adolescentes con TOC

Introducción: El objetivo general de este estudio fue llevar a cabo un estudio meta-analítico con el fin de examinar el rendimiento de las funciones ejecutivas en niños/adolescentes con trastorno obsesivo-compulsivo (TOC). Método: Se llevó a cabo una búsqueda exhaustiva de la literatura desde 1984 hasta septiembre de 2021, seleccionando un total de 20 estudios publicados que comparaban los resultados en funciones ejecutivas entre un grupo de niños y/o adolescentes con TOC y un grupo de control sano. Resultados: Los resultados mostraron que la puntuación total en la escala de calidad de los estudios osciló entre los 3 y los 8.5 puntos (en una escala de 0 a 9), con una media de 6.6. Los tamaños del efecto en las distintas funciones ejecutivas fueron: Inhibición (d+= -0.221), Flexibilidad cognitiva (d+= -0.418), toma de decisiones (d+= -0.169) y planificación (d+= -0.319), indicando un menor rendimiento en los grupos con TOC frente a los grupos de control sano. Los resultados fueron clínicamente significativos en todos los dominios excepto en Toma de decisiones. El sesgo de publicación sólo se pudo llevar a cabo en flexibilidad e inhibición de respuesta. Conclusiones: Los pacientes con TOC presentaron peor rendimiento ejecutivo que los controles sanos en todas las funciones ejecutivas, destacando flexibilidad cognitiva y planificación. No obstante, los resultados deben interpretarse con cautela debido al pequeño tamaño muestral.(AU)

Background:The main objective of this work was to carry out a meta-analytical study to examine performance in executive functions in children/adolescents with obsessive-compulsive disorder (OCD). Method:A comprehensive literature search from 1984 to September 2021 was conducted, selecting a total of 20 published studies comparing executive function outcomes among a group of children and/or adolescents with OCD and a healthy control group. Results:Results showed that the total score on the quality scale of studies ranged between 3 and 8.5 points (on a scale of 0 to 9), with a mean of 6.6. The effect sizes in the different executive functions were as follows: Inhibition (d+= -0.221), Cognitive flexibility (d+= -0.418), Decision making (d+= -0.169) and Planning (d+=-0.319), indicating a lower performance in the OCD groups compared to the healthy control groups. Results were clinically significant in all domains except decision making. Publication bias could only be carried out in flexibility and response inhibition.Conclusions: OCD patients presented worse executive performance than healthy controls in all functions, highlighting cognitive flexibility and planning. However, results should be interpreted with caution due to the small sample size.(AU)

Anthropometric Indicators of the Cardiometabolic Risk, Muscle Strength, and Functional Capacity of Schoolchildren with Intellectual Disabilities during Lockdown in Chile.

Lockdown due to the COVID-19 pandemic has negatively impacted the social, psychological, and physical well-being of the world population. In the case of people with intellectual disabilities, the impact of lockdown on their physical condition and functionality is not completely clear. This study aimed to determine the effects of COVID-19 lockdown on the anthropometric indicators of cardiometabolic risk, muscle strength, and functionality on schoolchildren with intellectual disabilities. The sample was composed of 132 students of both sexes (n = 74 pre-lockdown; n = 58 lockdown) belonging to two special education centers from the Metropolitan Region of Santiago, Chile. Our results showed significant reductions (p ≤ 0.05) in absolute and relative handgrip strength, as well as in functionality, when comparing pre-lockdown and lockdown measurements, with a greater loss in girls than boys. The design and implementation of physical exercise programs centered on strength training are necessary for the physical and functional reconditioning of this population. These programs need to be implemented in special education centers considering the general well-being, quality of life and work needs of people with intellectual disabilities.

Meeting 24-h movement guidelines and markers of adiposity in adults from eight Latin America countries: the ELANS study.

This study aimed to compare compliance with 24-h movement guidelines across countries and examine the associations with markers of adiposity in adults from eight Latin American countries. The sample consisted of 2338 adults aged 18-65 years. Moderate-to-vigorous physical activity (MVPA) and sedentary behavior (SB) data were objectively measured using accelerometers. Sleep duration was self-reported using a daily log. Body mass index and waist circumference were assessed as markers of adiposity. Meeting the 24-h movement guidelines was defined as ≥ 150 min/week of MVPA; ≤ 8 h/day of SB; and between 7 and 9 h/day of sleep. The number of guidelines being met was 0.90 (95% CI 0.86, 0.93) with higher value in men than women. We found differences between countries. Meeting two and three movement guidelines was associated with overweight/obesity (OR: 0.75, 95% CI 0.58, 0.97 and OR: 0.69, 95% CI 0.51, 0.85, respectively) and high waist circumference (OR: 0.74, 95% CI 0.56, 0.97 and OR: 0.77, 95% CI 0.62, 0.96). Meeting MVPA and SB recommendations were related to reduced adiposity markers but only in men. Future research is needed to gain insights into the directionality of the associations between 24-h movement guidelines compliance and markers of adiposity but also the mechanisms underlying explaining differences between men and women.

Ex vivo effect of JAK inhibition on JAK-STAT1 pathway hyperactivation in patients with dominant-negative STAT3 mutations.

PURPOSE: STAT1 gain-of-function (GOF) and dominant-negative (DN) STAT3 syndromes share clinical manifestations including infectious and inflammatory manifestations. Targeted treatment with Janus-kinase (JAK) inhibitors shows promising results in treating STAT1 GOF-associated symptoms while management of DN STAT3 patients has been largely supportive. We here assessed the impact of ruxolitinib on the JAK-STAT1/3 pathway in DN STAT3 patients' cells. METHODS: Using flow cytometry, immunoblot, qPCR, and ELISA techniques, we examined the levels of basal STAT1 and phosphorylated STAT1 (pSTAT1) of cells obtained from DN STAT3, STAT1 GOF patients, and healthy donors following stimulation with type I/II interferons (IFNs) or interleukin (IL)-6. We also describe the impact of ruxolitinib on cytokine-induced STAT1 signaling in these patients. RESULTS: DN STAT3 and STAT1 GOF resulted in a similar phenotype characterized by increased STAT1 and pSTAT1 levels in response to IFNα (CD3+ cells) and IFNγ (CD14+ monocytes). STAT1-downstream gene expression and C-X-C motif chemokine 10 secretion were higher in most DN STAT3 patients upon stimulation compared to healthy controls. Ex vivo treatment with the JAK1/2-inhibitor ruxolitinib reduced cytokine responsiveness and normalized STAT1 phosphorylation in DN STAT3 and STAT1 GOF patient' cells. In addition, ex vivo treatment was effective in modulating STAT1 downstream signaling in DN STAT3 patients. CONCLUSION: In the absence of effective targeted treatment options for AD-HIES at present, modulation of the JAK/STAT1 pathway with JAK inhibitors may be further explored particularly in those AD-HIES patients with autoimmune and/or autoinflammatory manifestations.

Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain of Function (GOF) Mutations-10 Children and Review of the Literature.

INTRODUCTION: Since the first description of gain of function (GOF) mutations in signal transducer and activator of transcription (STAT) 1, more than 300 patients have been described with a broad clinical phenotype including infections and severe immune dysregulation. Whilst Jak inhibitors (JAKinibs) have demonstrated benefits in several reported cases, their indications, dosing, and monitoring remain to be established. METHODS: A retrospective, multicenter study recruiting pediatric patients with STAT1 GOF under JAKinib treatment was performed and, when applicable, compared with the available reports from the literature. RESULTS: Ten children (median age 8.5 years (3-18), receiving JAKinibs (ruxolitinib (n = 9) and baricitinib (n = 1)) with a median follow-up of 18 months (2-42) from 6 inborn errors of immunity (IEI) reference centers were included. Clinical profile and JAKinib indications in our series were similar to the previously published 14 pediatric patients. 9/10 (our cohort) and 14/14 patients (previous reports) showed partial or complete responses. The median immune deficiency and dysregulation activity scores were 15.99 (5.2-40) pre and 7.55 (3-14.1) under therapy (p = 0.0078). Infection, considered a likely adverse event of JAKinib therapy, was observed in 1/10 patients; JAKinibs were stopped in 3/10 children, due to hepatotoxicity, pre-HSCT, and absence of response. CONCLUSIONS: Our study supports the potentially beneficial use of JAKinibs in patients with STAT1 GOF, in line with previously published data. However, consensus regarding their indications and timing, dosing, treatment duration, and monitoring, as well as defining biomarkers to monitor clinical and immunological responses, remains to be determined, in form of international prospective multicenter studies using established IEI registries.

Expanded Mesenchymal Stromal Cells in knee osteoarthritis: A systematic literature review.

OBJECTIVE: To analyse the efficacy and safety of intra-articular injection of expanded Mesenchymal Stromal Cells (MSCs) in knee osteoarthritis. METHODS: Systematic Literature Review. A pre-defined search strategy was run in Medline, Embase and Cochrane Library until February 2018. INCLUSION CRITERIA: knee osteoarthritis (grades II-IV Kellgren-Lawrence); intra-articular injection of MSCs (without surgical co-treatments); Randomized Controlled Trials (RCTs) or Quasi-experimental Clinical Trials (QCTs) N ≥ 10 and ≥6 months of follow-up were included. Evidence was assigned according to the Scottish Intercollegiate Guidelines Network (SIGN). RESULTS: The search identified 252 articles. Nine proof-of-concept trials (3 RCTs, 6 QCTs) were included (N = 169). Evidence showed clinical improvement in 60% of patients. Structural benefit was reported in half of patients. Clinical benefit was observed from the 3rd month and structural improvement from the 6th. All studies reported maximum clinical and structural benefit a year following the implant. This benefit was sustained for up to 24 months. Studies with doses ≥40 × 106 showed more consistent clinical and structural benefits than those with lower doses. No systemic adverse reactions were reported. The most common adverse effect was pain and/or inflammation in the puncture area (13-53%). The use of donor cells was as safe as autologous implants. CONCLUSIONS: Intra-articular implants of MSCs seem to be safe with no serious adverse effects. Low-quality evidence precludes conclusions regarding efficacy in this review. However, the clinical and structural benefits observed provide a rationale for using expanded MSCs implants in osteoarthritis patients. High-quality evidence trials are needed to further determine best protocols to maximize clinical and structural improvement.

Tratamiento de la artrosis de rodilla con células mesenquimales estromales expandidas: revisión sistemática de la literatura / Expanded Mesenchymal Stromal Cells in Knee Osteoarthritis: A Systematic Literature Review

Objetivo: Analizar la eficacia y la seguridad de los implantes de células mesenquimales estromales expandidas (MSCs, por sus siglas en inglés) en la artrosis de rodilla. Métodos: Revisión sistemática de la literatura. Estrategia de búsqueda en Medline, Embase y Cochrane Library hasta febrero del 2018. Inclusión: artrosis de rodilla (II-IV Kellgren); inyección intra-articular de MSCs; ensayos controlados aleatorizados (ECA) y ensayos clínicos cuasi-experimentales (ECC)≥6 meses y N≥10. Resultados: De 252 artículos identificados, se incluyeron 3 ECA y 6 ECC (N=169). El 60% de los pacientes mejoraron clínicamente y el 50% estructuralmente hasta 2 años después del implante. El beneficio máximo se alcanzó al año con dosis ≥40×106 MSCs. La intervención fue bien tolerada, igualmente segura en implantes alogénicos y autólogos. Conclusiones: Las MSCs intra-articulares son seguras. La baja calidad de la evidencia analizada no admite conclusiones sobre la eficacia, pero prueba un fundamento para su uso en la artrosis como modificador de síntoma y de estructura que debe ser constatado en ensayos de alta calidad.(AU)

Objective: To analyse the efficacy and safety of intra-articular injection of expanded Mesenchymal Stromal Cells (MSCs) in knee osteoarthritis. Methods: Systematic Literature Review. A pre-defined search strategy was run in Medline, Embase and Cochrane Library until February 2018. Inclusion criteria: knee osteoarthritis (grades II-IV Kellgren-Lawrence); intra-articular injection of MSCs (without surgical co-treatments); Randomized Controlled Trials (RCTs) or Quasi-experimental Clinical Trials (QCTs) N≥10 and ≥6 months of follow-up were included. Evidence was assigned according to the Scottish Intercollegiate Guidelines Network (SIGN). Results: The search identified 252 articles. Nine proof-of-concept trials (3 RCTs, 6 QCTs) were included (N=169). Evidence showed clinical improvement in 60% of patients. Structural benefit was reported in half of patients. Clinical benefit was observed from the 3rd month and structural improvement from the 6th. All studies reported maximum clinical and structural benefit a year following the implant. This benefit was sustained for up to 24 months. Studies with doses ≥40×106 showed more consistent clinical and structural benefits than those with lower doses. No systemic adverse reactions were reported. The most common adverse effect was pain and/or inflammation in the puncture area (13-53%). The use of donor cells was as safe as autologous implants. Conclusions: Intra-articular implants of MSCs seem to be safe with no serious adverse effects. Low-quality evidence precludes conclusions regarding efficacy in this review. However, the clinical and structural benefits observed provide a rationale for using expanded MSCs implants in osteoarthritis patients. High-quality evidence trials are needed to further determine best protocols to maximize clinical and structural improvement.(AU)

Effects of a Self-Regulated Training Program on the Repeated Power in Female College Handball Players: An Intervention Study.

Several resistance training programs using conventional methodologies have been implemented with the purpose of improving the ability to perform power actions in handball, especially during the competitive season. In contrast, methodologies based on a contemporary perspective, which considers the human being as a self-regulating biological entity, and designed specifically for female college players, are scarce. The aim of this research was to investigate the effects of an eight-week resistance training program, in which the athletes were able to control the loads according to their self-perceived effort and rest on their repeated shuttle sprint and jump ability. The sample was composed of 16 female players of a handball team from the faculty of physics and mathematics sciences of a Chilean university. The RSSJA test was used to evaluate players' conditions pre- and post-training program, and the self-perceived effort scale called OMNI-RES was used for the prediction and control of loads. Results indicated that, after the application of an eight-week resistance training program, significant improvements p ≤ 0.05 on the jump height (pre: 1836.4 W; average post: 2088.9 W) and running speed (average pre: 3.2 m/s; average post: 4.0 m/s) were obtained, as well as a significant reduction in the loss of power and speed between each set of the applied test.

Biallelic TRAF3IP2 variants causing chronic mucocutaneous candidiasis in a child harboring a STAT1 variant.

BACKGROUND: Inherited chronic mucocutaneous candidiasis (CMC) is often caused by inborn errors of immunity, impairing the response to, or the production of IL-17A and IL-17F. About half of the cases carry STAT1 gain-of-function (GOF) mutations. Only few patients have been reported with mutations of TRAF3IP2, a gene encoding the adaptor ACT1 essential for IL-17 receptor(R) signaling. We investigated a 10-year-old girl with CMC, carrying a heterozygous variant of STAT1 and compound heterozygous variants of TRAF3IP2. METHODS: By flow cytometry, STAT1 levels and phosphorylation (CD14+) as well as IL-17A, IL-22, IFN-γ, and IL-4 production (memory CD4+ T cells) were determined. ACT1 expression and binding to IL-17RA were assessed by Western blot and co-immunoprecipitation in HEK-293T cells transfected with plasmids encoding wild-type or mutant HA-tagged ACT1 and Flag-IL-17RA. We evaluated IL-17A responses by measuring luciferase induction under a NF-κB-driven reporter system in HEK-293T cells and Gro-α secretion in fibroblasts. RESULTS: A STAT1 variant (c.1363G>A/p.V455I) was identified by next-generation sequencing and classified as likely non-pathogenic as functional testing revealed normal STAT1 expression and phosphorylation upon IFN-γ. We also found compound heterozygous variants (c.1325A>G/p.D451G and c.1335delA/p.K454fs11*) of TRAF3IP2. By overexpression, despite normal protein expression, and impaired (K454fs11*) or normal (D451G) interaction with IL-17RA, both mutant alleles resulted in impaired NF-κB activation. Patient's fibroblasts displayed abolished GRO-α secretion upon IL-17A stimulation. Finally, ex vivo CD4+ T cells showed increased IL-17A, IL-22, and IL-4 and normal low IFN-γ expression upon stimulation. CONCLUSION: We identify novel compound heterozygous variants of TRAFP3IP2 causing autosomal recessive ACT1 deficiency in a child with CMC and provide a review of the current literature.