Trajectories of positive attributes from childhood to young adulthood and its associations with threat and deprivation.

OBJECTIVE: The aims of this study are to investigate the trajectory of positive attributes from childhood to early adulthood and to explore how those trajectories can be modified by two domains of childhood adversity - threat and deprivation. METHODS: A large prospective school-based community cohort of youths (n=2,511, 6-14 years of age, 45% female) was assessed and followed up for 3 years (80% retention) and 6 years (71% retention). Positive attributes were assessed by the Youth Strength Inventory (YSI). Childhood exposure to threat and deprivation were assessed by a composite measure using multiple indicators. RESULTS: Trajectories of YSI scores were non-linear and distinct for boys and girls. While boys presented a more stable trajectory; girls showed higher levels of positive attributes early in life that decrease over time around adolescence. Both exposure to threat and deprivation presented negative linear association with YSI over time. Furthermore, we found interactions between developmental stage and both adversity domains meaning that the effects of exposure to adversity were stronger at earlier developmental stages and almost non-significant closer to early adulthood. CONCLUSION: Our findings provide new evidence on trajectories of positive attributes in youth and reveal and how experiences of adversity in early life impact not only mental disorder but also positive aspects of mental health.

Understanding priorities and needs for child and adolescent mental health in Greece from multiple informants: an open resource dataset.

The Child and Adolescent Mental Health Initiative (CAMHI) aims to enhance mental health care capacity for children and adolescents across Greece. Considering the need for evidence-based policy, the program developed an open-resource dataset for researching the field within the country. A comprehensive, mixed-method, community-based research was conducted in 2022/2023 assessing the current state, needs, barriers, and opportunities according to multiple viewpoints. We surveyed geographically distributed samples of 1,756 caregivers, 1,201 children/adolescents, 404 schoolteachers, and 475 health professionals using validated instruments to assess mental health symptoms, mental health needs, literacy and stigma, service use and access, professional practices, training background, and training needs and preferences. Fourteen focus groups were conducted with informants from diverse populations (including underrepresented minorities) to reach an in-depth understanding of those topics. A dataset with quantitative and qualitative findings is now available for researchers, policymakers, and society [ https://osf.io/crz6h/ and https://rpubs.com/camhi/sdashboard ]. This resource offers valuable data for assessing the needs and priorities for child and adolescent mental health care in Greece. It is now freely available to consult, and is expected to inform upcoming research and evidence-based professional training. This initiative may inspire similar ones in other countries, informing methodological strategies for researching mental health needs.

Translation and cross-cultural adaptation of seventeen widely-used assessment instruments for child and adolescent mental health in Greece.

BACKGROUND: In the context of Greece, many instruments measuring constructs pertinent to child and adolescent mental health lacked a locally-validated, freely-available version. As part of a nationwide survey, we translated and cross-culturally adapted a collection of seventeen brief, largely-employed assessment tools that can be used at scale. METHODS: This study is part of the Child and Adolescent Mental Health Initiative in Greece (CAMHI), a capacity-building program focusing on enhancing mental health care for children and adolescents living in Greece. We conducted a nationwide survey assessing mental health symptoms, parenting practices, service availability and quality, mental health literacy and stigma, and professional practices within the country. As part of this process, we selected outcomes and instruments after consulting the International Consortium for Health Outcomes Measurement (ICHOM) and the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). From our selection, we identified 17 instruments that did not have a Greek-validated version available for use. These instruments were translated and cross-culturally adapted following a structured procedure, including independent back-and-forth translations, synthesis of versions, expert revision, and pilot testing. Some instruments were slightly modified to meet CAMHI survey purposes. RESULTS: A cross-culturally adapted version in Greek was made available for the following instruments: Pediatric Symptoms Checklist (PSC); Deliberate Self Harm Inventory (DSH) (modified); Child and Adolescent Trauma Screen-2 (CATS-2); ABCD Screen Use (modified); Swanson, Nolan, and Pelham-IV (SNAP-IV); Parent Behavior Inventory (PBI); Mental Health Literacy Scale (MHLS)-(modified); Australian Mental Health Vignettes; Reported and Intended Behavior Scale (RIBS); Barriers to Access to Care (BACE) (modified); Experience of Service Questionnaire (ESQ) (modified); and Multitheoretical List of Therapeutic Interventions (MULTI-30) (modified). CONCLUSION: A collection of these widely-used assessment tools is now adapted for the local context and freely accessible at [ https://osf.io/crz6h/ ]. Researchers and health professionals in Greece can utilize this resource to screen, evaluate, and monitor various constructs related to mental health in accordance with the most effective practices.

Safety and Tolerability of SGLT2 Inhibitors in Cardiac Amyloidosis-A Clinical Feasibility Study.

Sodium-glucose transport protein 2 inhibitors (SGLT2i) slow the progression of renal dysfunction and improve the prognosis of patients with heart failure. Amyloidosis constitutes an important subgroup for which evidence is lacking. Amyloidotic fibrils originating from misfolded transthyretin and light chains are the causal agents in ATTR and AL amyloidosis. In these most frequent subtypes, cardiac involvement is the most common organ manifestation. Because cardiac and renal function frequently deteriorate over time, even under best available treatment, SGLT2i emerge as a promising treatment option due to their reno- and cardioprotective properties. We retrospectively analyzed patients with cardiac amyloidosis, who received either dapagliflozin or empagliflozin. Out of 79 patients, 5.1% had urinary tract infections; 2 stopped SGLT2i therapy; and 2.5% died unrelated to the intake of SGLT2i. No genital mycotic infections were observed. As expected, a slight drop in the glomerular filtration rate was noted, while the NYHA functional status, cardiac and hepatic function, as well as the 6 min walk distance remained stable over time. These data provide a rationale for the use of SGLT2i in patients with amyloidosis and concomitant cardiac or renal dysfunction. Prospective randomized data are desired to confirm safety and to prove efficacy in this increasingly important group of patients.

Contribution of cosmetic ingredients and skin care textures to emotions.

OBJECTIVE: Emotions play an important role in consumers' perception of a sensory experience. The objective of this work was to investigate the ability of basic skin care formulas (i.e. without interference of odour, colour and packaging) and pillar ingredients (i.e. emollients and rheology modifiers) to elicit emotions. Another objective was to track, as claimed by neurocosmetics, the possible effect of formulas to trigger emotions from their direct biochemical effects on the skin. METHODS: Standard methodologies were mobilized, combining subjective and behavioural parameters (i.e. verbatim, prosody and gesture). Sense and Story methodology based on a collection of metaphoric verbatim was conducted after an induction phase. In addition, an experimental electrophysiological real-time visualization method was tried as a first experience in cosmetics. Finally, the ability of formulations with emotional benefits to modulate the release of neuropeptides by sensory neurons was evaluated on a 3D human model (epidermis co-cultured with sensory neurons). RESULTS: Skin care formulas were shown to play a role in emotional potential and the types of emotion generated, while changing one ingredient mostly acted on the intensity of the emotions. Verbatim provided contrasted answers depending on the protocol, highlighting the interest of non-verbal approaches to detect subtle effects. The in vitro model substantiated physiological effects of skin care formulas with emotional potential on human skin sensory neuron activity. CONCLUSION: Emotions were impacted by the change in ingredients and were better captured through non-verbal methods.

OBJECTIF: Les émotions jouent un rôle important dans la perception qu'ont les consommateurs d'une expérience sensorielle. L'objectif de ce travail était d'étudier la capacité de formules de soins pour la peau de base (c'est­à­dire sans interférence d'odeur, de couleur, d'emballage) et d' ingrédients essentiels (c'est­à­dire les émollients et les modificateurs de rhéologie) à susciter des émotions. Un autre objectif était de suivre, comme le prétendent les neurocosmétiques, l'effet possible des formules à déclencher des émotions à partir de leurs effets biochimiques directs sur la peau. MÉTHODES: Des méthodologies standards ont été mises en œuvre, combinant des paramètres subjectifs et comportementaux (c'est­à­dire verbatim, prosodie et gestuelle). La méthodologie Sense & Story basée sur un ensemble de verbatim métaphoriques a été mise en œuvre après une phase d'induction. En outre, une méthode expérimentale de visualisation électrophysiologique en temps réel a été testée comme première expérience dans le domaine des cosmétiques. Enfin, la capacité des formulations présentant des bénéfices émotionnels à moduler la libération de neuropeptides par les neurones sensoriels a été évaluée sur un modèle humain 3D (épiderme co­cultivé avec des neurones sensoriels). RÉSULTATS: Il a été démontré que les formules de soins pour la peau jouent un rôle dans le potentiel émotionnel et les types d'émotions générées, tandis que le changement d'un ingrédient agit principalement sur l'intensité des émotions. Le verbatim a fourni des réponses contrastées selon le protocole, soulignant l'intérêt des approches non verbales pour détecter les effets subtils. Le modèle in vitro a confirmé les effets physiologiques des formules de soins pour la peau ayant un potentiel émotionnel sur l'activité des neurones sensoriels de la peau humaine. CONCLUSION: Les émotions ont été affectées par le changement d'ingrédients et ont été mieux saisies par des méthodes non verbales.

In Silico and In Vitro Identification of P-Glycoprotein Inhibitors from a Library of 375 Phytochemicals.

Cancer therapy with clinically established anticancer drugs is frequently hampered by the development of drug resistance of tumors and severe side effects in normal organs and tissues. The demand for powerful, but less toxic, drugs is high. Phytochemicals represent an important reservoir for drug development and frequently exert less toxicity than synthetic drugs. Bioinformatics can accelerate and simplify the highly complex, time-consuming, and expensive drug development process. Here, we analyzed 375 phytochemicals using virtual screenings, molecular docking, and in silico toxicity predictions. Based on these in silico studies, six candidate compounds were further investigated in vitro. Resazurin assays were performed to determine the growth-inhibitory effects towards wild-type CCRF-CEM leukemia cells and their multidrug-resistant, P-glycoprotein (P-gp)-overexpressing subline, CEM/ADR5000. Flow cytometry was used to measure the potential to measure P-gp-mediated doxorubicin transport. Bidwillon A, neobavaisoflavone, coptisine, and z-guggulsterone all showed growth-inhibitory effects and moderate P-gp inhibition, whereas miltirone and chamazulene strongly inhibited tumor cell growth and strongly increased intracellular doxorubicin uptake. Bidwillon A and miltirone were selected for molecular docking to wildtype and mutated P-gp forms in closed and open conformations. The P-gp homology models harbored clinically relevant mutations, i.e., six single missense mutations (F336Y, A718C, Q725A, F728A, M949C, Y953C), three double mutations (Y310A-F728A; F343C-V982C; Y953A-F978A), or one quadruple mutation (Y307C-F728A-Y953A-F978A). The mutants did not show major differences in binding energies compared to wildtypes. Closed P-gp forms generally showed higher binding affinities than open ones. Closed conformations might stabilize the binding, thereby leading to higher binding affinities, while open conformations may favor the release of compounds into the extracellular space. In conclusion, this study described the capability of selected phytochemicals to overcome multidrug resistance.

The science of child and adolescent mental health in Greece: a nationwide systematic review.

Evidence-based information is essential for effective mental health care, yet the extent and accessibility of the scientific literature are critical barriers for professionals and policymakers. To map the necessities and make validated resources accessible, we undertook a systematic review of scientific evidence on child and adolescent mental health in Greece encompassing three research topics: prevalence estimates, assessment instruments, and interventions. We searched Pubmed, Web of Science, PsycINFO, Google Scholar, and IATPOTEK from inception to December 16th, 2021. We included studies assessing the prevalence of conditions, reporting data on assessment tools, and experimental interventions. For each area, manuals informed data extraction and the methodological quality were ascertained using validated tools. This review was registered in protocols.io [68583]. We included 104 studies reporting 533 prevalence estimates, 223 studies informing data on 261 assessment instruments, and 34 intervention studies. We report the prevalence of conditions according to regions within the country. A repository of locally validated instruments and their psychometrics was compiled. An overview of interventions provided data on their effectiveness. The outcomes are made available in an interactive resource online [ https://rpubs.com/camhi/sysrev_table ]. Scientific evidence on child and adolescent mental health in Greece has now been cataloged and appraised. This timely and accessible compendium of up-to-date evidence offers valuable resources for clinical practice and policymaking in Greece and may encourage similar assessments in other countries.

Characterization of three new SERPINA1 variants PiQ0Heidelberg II, PiQ0Heidelberg III and PiQ0Heidelberg IV in patients with severe alpha-1 antitrypsin deficiency.

Background: The clinical and molecular characteristics of three patients with previously unreported SERPINA1 mutations associated with severe alpha-1 antitrypsin deficiency (AATD) are described. The pathophysiology of the chronic obstructive pulmonary disease (COPD) present in these patients was characterized through clinical, biochemical, and genetic examinations. Case presentations: Case 1: A 73-year-old male with bilateral centri-to panlobular emphysema and multiple increasing ventrobasal bullae and incomplete fissures, COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade III B), progressive dyspnea on exertion (DOE), AAT level of 0.1-0.2 g/L. Genetic testing revealed a unique SERPINA1 mutation: Pi*Z/c.1072C > T. This allele was designated PiQ0Heidelberg II. Case 2: A 47-year-old male with severely heterogenous centri-to panlobular emphysema concentrated in the lower lobes, COPD GOLD IV D with progressive DOE, AAT <0.1 g/L. He also had a unique Pi*Z/c.10del mutation in SERPINA1. This allele was named PiQ0Heidelberg III. Case 3: A 58-year-old female with basally accentuated panlobular emphysema, GOLD II B COPD, progressive DOE. AAT 0.1 g/L. Genetic analysis revealed Pi*Z/c.-5+1G > A and c.-472G > A mutations in SERPINA1. This variant allele was named PiQ0Heidelberg IV. Conclusions: Each of these patients had a unique and previously unreported SERPINA1 mutation. In two cases, AATD and a history of smoking led to severe lung disease. In the third case, timely diagnosis, and institution of AAT replacement stabilized lung function. Wider screening of COPD patients for AATD could lead to faster diagnosis and earlier treatment of AATD patients with AATD which could slow or prevent progression of their disease.

Childhood poverty and mental health disorders in early adulthood: evidence from a Brazilian cohort study.

BACKGROUND: We examined the association between childhood poverty and mental health disorders (MHD) in childhood and early adulthood. We also investigated whether the association between poverty in childhood and MHD is mediated by exposure to stressful life events (SLE). METHODS: We used data from a prospective community cohort of young people assessed at baseline (M = 9.7 years, SD = 1.9), first (M = 13.5 years, SD = 1.9), and second (M = 18.2 years, SD = 2.0) follow-ups (N = 1,590) in Brazil. Poverty was assessed using a standardized classification. Exposure to 20 different SLE was measured using the Life History instrument. Psychiatric diagnoses were evaluated using the Development and Well-Being Assessment. Latent growth models investigated the association between poverty at baseline and the growth of any MHD, externalizing, and internalizing disorders. Mediation models evaluated whether the association between childhood poverty and MHD in early adulthood was mediated by exposure to SLE. RESULTS: Poverty affected 11.4% of the sample at baseline and was associated with an increased propensity for presenting externalizing disorders in adolescence or early adulthood (standardized estimate = 0.27, p = 0.016). This association was not significant for any disorder or internalizing disorders. Childhood poverty increased the likelihood of externalizing disorders in early adulthood through higher exposure to SLE (OR = 1.07, 95 CI% 1.01-1.14). Results were only replicated among females in stratified analyses. CONCLUSIONS: Childhood poverty had detrimental consequences on externalizing MHD in adolescence, especially among females. Poverty and SLE are preventable risk factors that need to be tackled to reduce the burden of externalizing disorders in young people.

Validation of the Brazilian Portuguese version of the Quick Inventory of Depressive Symptomatology and Self-Report (QIDS-SR16) for the Brazilian population.

OBJECTIVES: To evaluate the psychometric properties of the Quick Inventory of Depressive Symptomatology (QID-SR16), a self-report instrument based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria that assesses the severity of depression symptoms, in the Brazilian population. METHODS: Participants were 4,400 Brazilians over the age of 15 years recruited for an online survey assessing depressive symptoms during the early phase of the coronavirus disease 2019 (COVID-19) pandemic in Brazil. The internal consistency, construct validity, and convergent and discriminant validity of the QIDS-SR16 were evaluated. RESULTS: The model tested was considered an adequate fit to the data (comparative fit index [CFI] = 0.947, Tucker-Lewis index [TLI] = 0.927, and root-mean-square error of approximation [RMSEA] = 0.051) and its internal consistency was good, with a Cronbach's alpha of 0.71 and an average item correlation of 0.23. The correlations between the total QIDS-SR16 score and the total scores of the Patient Health Questionnaire (PHQ-9) instruments (r = 0.67, p < 0.001), the Posttraumatic Symptoms Checklist (PCL-5) (r = 0.61, p < 0.001), and the Patient-Reported Outcomes Measurement Information System (PROMIS) (r = 0.60, p < 0.001) indicate good concurrent and convergent validity. CONCLUSION: The QIDS-SR16 has robust psychometric properties in terms of its internal consistency, construct validity, and convergent and discriminant validity. The Portuguese version of the QIDS-SR16 is an adequate instrument for assessment of depressive symptoms in the context of an online survey.

Threat and deprivation are associated with distinct aspects of cognition, emotional processing, and psychopathology in children and adolescents.

Exposure to childhood adversity has been consistently associated with poor developmental outcomes, but it is unclear whether these associations vary across different forms of adversity. We examined cross-sectional and longitudinal associations between threat and deprivation with cognition, emotional processing, and psychopathology in a middle-income country. The sample consisted of 2511 children and adolescents (6-17 years old) from the Brazilian High-Risk Cohort for Mental Conditions. Parent reports on childhood adversity were used to construct adversity latent constructs. Psychopathology was measured by the Child Behavior Checklist (CBCL) to generate a measure of general psychopathology (the "p" factor). Executive function (EF) and attention orienting toward angry faces were assessed using cognitive tasks. All measures were acquired at two time-points 3 years apart and associations were tested using general linear models. Higher levels of psychopathology were predicted by higher levels of threat cross-sectionally and longitudinally, and by deprivation longitudinally. For EF, worse performance was associated only with deprivation at baseline and follow-up. Finally, threat was associated with attention orienting towards angry faces cross-sectionally, but neither form of adversity was associated with changes over time in attention bias. Our results suggest that threat and deprivation have differential associations with cognitive development and psychopathology. Exposure to adversity during childhood is a complex phenomenon with meaningful influences on child development. Because adversity can take many forms, dimensional models might help to disentangle the specific developmental correlates of different types of early experience. A video abstract of this article can be viewed at https://www.youtube.com/watch?v=uEU0L8exyTM.

Validation of the Brazilian Portuguese version of the Quick Inventory of Depressive Symptomatology and Self-Report (QIDS-SR16) for the Brazilian population

Abstract Objectives To evaluate the psychometric properties of the Quick Inventory of Depressive Symptomatology (QID-SR16), a self-report instrument based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria that assesses the severity of depression symptoms, in the Brazilian population. Methods Participants were 4,400 Brazilians over the age of 15 years recruited for an online survey assessing depressive symptoms during the early phase of the coronavirus disease 2019 (COVID-19) pandemic in Brazil. The internal consistency, construct validity, and convergent and discriminant validity of the QIDS-SR16 were evaluated. Results The model tested was considered an adequate fit to the data (comparative fit index [CFI] = 0.947, Tucker-Lewis index [TLI] = 0.927, and root-mean-square error of approximation [RMSEA] = 0.051) and its internal consistency was good, with a Cronbach's alpha of 0.71 and an average item correlation of 0.23. The correlations between the total QIDS-SR16 score and the total scores of the Patient Health Questionnaire (PHQ-9) instruments (r = 0.67, p < 0.001), the Posttraumatic Symptoms Checklist (PCL-5) (r = 0.61, p < 0.001), and the Patient-Reported Outcomes Measurement Information System (PROMIS) (r = 0.60, p < 0.001) indicate good concurrent and convergent validity. Conclusion The QIDS-SR16 has robust psychometric properties in terms of its internal consistency, construct validity, and convergent and discriminant validity. The Portuguese version of the QIDS-SR16 is an adequate instrument for assessment of depressive symptoms in the context of an online survey.

ADHD in childhood predicts BMI and body composition measurements over time in a population-based birth cohort.

BACKGROUND/OBJECTIVES: Obesity has been reported as an attention-deficit hyperactivity disorder (ADHD) comorbidity. So far, few studies have aimed to explore the potential causal relationship between ADHD and obesity, as well as used other measures of body composition like fat-free mass (FFM) and fat mass (FM) as measures of obesity. This study aimed to test the association between ADHD and body composition (body mass index [BMI] and others) and to evaluate the potential causal relationship with obesity. SUBJECTS/METHODS: Data from the 1993 Pelotas (Brazil) birth cohort at age 11-, 15-, 18-, and 22-year follow-up was used. We performed a cross-lagged panel model (CLPM) analysis between ADHD symptoms and BMI to explore the causal relationship between both traits. Finally, we tested whether ADHD, inattention, and hyperactivity symptom scales were associated with BMI, FM, and FFM at 22 years. RESULTS: In the CLPM, higher ADHD scores at age 11 predicted higher BMI at age 15 (ß = 0.055, 95% CI [0.037; 0.073]). ADHD symptoms at age 11 was also associated with a decrease in the FFM (ß = -0.16, 95% CI [-0.28; -0.05]), and an increase in the BMI (ß = 0.17, 95% CI [0.10; 0.23]) and FM (ß = 0.17, 95% CI [0.06; 0.29]) at 22 years. At 22 years of age, ADHD was associated with FFM and FM. Moreover, an increase in BMI was observed with an increase in several symptoms of ADHD in general (ß = 0.06, 95% CI [0.004; 0.12]), and hyperactivity symptoms (ß = 0.15, 95% CI [0.05; 0.25]). CONCLUSION: ADHD at 11 years predicted a higher BMI at 15 years, and body fat composition in adulthood, suggesting higher scores on ADHD symptoms in early life may be a critical point for body composition in early adulthood. The hyperactivity symptoms may play an important role in the BMI increase.

Mental health conditions in Lesbian, Gay, Bisexual, Transgender, Queer and Asexual youth in Brazil: A call for action.

BACKGROUND: Lesbian, Gay, Bisexual, Transgender, Queer, and Asexual (LGBTQA+) youth have a greater chance of experiencing stressful life events when compared to cisgender heterosexual peers, which can lead to mental health problems. We aimed to estimate the prevalence of mental disorders among LGBTQA+ youths from two large cities in Brazil. METHODS: Participants were 13-22 years old youths from the 3rd wave of the Brazilian High-Risk Cohort for Psychiatric Disorders (n = 1475). Mental disorders were assessed using the Development and Well-Being Behavior Assessment. Sexual orientation and gender identity were assessed using a self-report confidential questionnaire. Data were analyzed through logistic regressions (adjusting for sociodemographic) using sampling weights to account for attrition and our oversampling high-risk design. RESULTS: 15.18% of the sample described themselves as LGBTQA+. The LGBTQA+ group presented higher rates of anxiety disorders (30.14% vs. 13.37%; OR = 3.37; 95%CI:2.51-4.50), depressive disorders (27.75% vs. 15.34%; OR = 2.17; 95%CI:1.60-2.93) and post-traumatic stress disorder (4.98% vs. 2.25%; OR = 4.20; 95%CI:2.24-7.82), if compared with the cisgender heterosexual group. No difference was found for conduct disorders (2.97% vs. 5.21%; OR = 0.82; 95%CI:0.35-1.65) or attention deficit hyperactivity disorder (5.92% vs. 3.28%; OR = 1.56; 95%CI:0.83-2.79). LIMITATIONS: Although recruitment was performed at 57 schools in the two cities, sampling was non-probabilistic and included only urban areas, which might bias prevalence estimates and group comparisons. CONCLUSIONS: Our results elucidate the mental health disparities between LGBTQA+ people and cisgender heterosexuals in Brazil. It highlights the need to promote the inclusion of this population in policy formulation and support actions to mitigate the suffering related to sexual orientation and gender identity.

Macrophage-activating lipoprotein (MALP)-2 impairs the healing of partial tendon injuries in mice.

Tendon injuries are accounted for up to 50% of musculoskeletal injuries and often result in poor outcomes. Inflammation is a major hallmark of tendon regeneration. Therefore, we analyzed in this study whether the topical application of the pro-inflammatory mediator macrophage-activating lipoprotein (MALP)-2 improves the healing of partial tendon injuries. C57BL/6 mice underwent a partial tenotomy of the flexor digitorum longus tendon of the left hind limb, which was treated with a solution containing either 0.5 µg MALP-2 or vehicle (control). Repetitive gait analyses were performed prior to the surgical intervention as well as postoperatively on days 1, 3, 7, 14 and 36. The structural stability of the tendons was biomechanically tested on day 7 and 36. In addition, Western blot analyses were performed on isolated tendons that were treated in vitro with MALP-2 or vehicle. In both groups, partial tenotomy resulted in a pathological gait pattern during the initial postoperative phase. On day 7, the gait pattern normalized in vehicle-treated animals, but not in MALP-2-treated mice. Moreover, the tendons of MALP-2-treated mice exhibited a significantly reduced biomechanical stiffness after 7 and 36 days when compared to controls. Western blot analyses revealed a significantly higher expression of heme oxygenase (HO)-1 and lower expression of cyclin D in MALP-2-treated tendons. These findings indicate that MALP-2 delays the healing of injured tendons most likely due to increased intracellular stress and suppressed cell proliferation in this naturally bradytrophic tissue. Hence, the application of MALP-2 cannot be recommended for the treatment of tendon injuries.

Multiple breath washout (MBW) testing using sulfur hexafluoride: reference values and influence of anthropometric parameters.

BACKGROUND: Multiple breath washout (MBW) using sulfur hexafluoride (SF6) has the potential to reveal ventilation heterogeneity which is frequent in patients with obstructive lung disease and associated small airway dysfunction. However, reference data are scarce for this technique and mostly restricted to younger cohorts. We therefore set out to evaluate the influence of anthropometric parameters on SF6-MBW reference values in pulmonary healthy adults. METHODS: We evaluated cross-sectional data from 100 pulmonary healthy never-smokers and smokers (mean 51 (SD 20), range 20-88 years). Lung clearance index (LCI), acinar (Sacin) and conductive (Scond) ventilation heterogeneity were derived from triplicate SF6-MBW measurements. Global ventilation heterogeneity was calculated for the 2.5% (LCI2.5) and 5% (LCI5) stopping points. Upper limit of normal (ULN) was defined as the 95th percentile. RESULTS: Age was the only meaningful parameter influencing SF6-MBW parameters, explaining 47% (CI 33% to 59%) of the variance in LCI, 32% (CI 18% to 47%) in Sacin and 10% (CI 2% to 22%) in Scond. Mean LCI increases from 6.3 (ULN 7.4) to 8.8 (ULN 9.9) in subjects between 20 and 90 years. Smoking accounted for 2% (CI 0% to 8%) of the variability in LCI, 4% (CI 0% to 13%) in Sacin and 3% (CI 0% to 13%) in Scond. CONCLUSION: SF6-MBW outcome parameters showed an age-dependent increase from early adulthood to old age. The effect was most pronounced for global and acinar ventilation heterogeneity and smaller for conductive ventilation heterogeneity. No influence of height, weight and sex was seen. Reference values can now be provided for all important SF6-MBW outcome parameters over the whole age range. TRIAL REGISTRATION NUMBER: NCT04099225.

Testing the Stability and Validity of an Executive Dysfunction Classification Using Task-Based Assessment in Children and Adolescents.

OBJECTIVE: It is unclear if pediatric executive dysfunction assessed only with cognitive tasks predicts clinically relevant outcomes independently of psychiatric diagnoses. This study tested the stability and validity of a task-based classification of executive function. METHOD: A total of 2,207 individuals (6-17 years old) from the Brazilian High-Risk Cohort Study participated in this study (1,930 at baseline, 1,532 at follow-up). Executive function was measured using tests of working memory and inhibitory control. Dichotomized age- and sex-standardized performances were used as input in latent class analysis and receiver operating curves to create an executive dysfunction classification (EDC). The study tested EDC's stability over time, association with symptoms, functional impairment, a polymorphism in the CADM2 gene, polygenic risk scores (PRS), and brain structure. Analyses covaried for age, sex, social class, IQ, and psychiatric diagnoses. RESULTS: EDC at baseline predicted itself at follow-up (odds ratio [OR] = 5.11; 95% CI 3.41-7.64). Participants in the EDC reported symptoms spanning several domains of psychopathology and exhibited impairment in multiple settings, including more adverse school events (OR = 2.530; 95% CI 1.838-3.483). Children in the EDC presented higher attention-deficit/hyperactivity disorder and lower educational attainment PRS at baseline; higher schizophrenia PRS at follow-up; and lower chances of presenting a polymorphism in a gene previously linked to high performance in executive function (CADM2 gene). They also exhibited smaller intracranial volumes and smaller bilateral cortical surface areas in several brain regions. CONCLUSION: Task-based executive dysfunction is associated with several validators, independently of psychiatric diagnoses and intelligence. Further refinement of task-based assessments might generate clinically useful tools.

Gene expression changes associated with trajectories of psychopathology in a longitudinal cohort of children and adolescents.

We aimed to identify blood gene expression patterns associated to psychopathological trajectories retrieved from a large community, focusing on the emergence and remission of general psychiatric symptoms. Hundred and three individuals from the Brazilian High-Risk Cohort Study (BHRCS) for mental disorders were classified in four groups according to Child Behavior Checklist (CBCL) total score at the baseline (w0) and after 3 years (w1): low-high (L-H) (N = 27), high-low (H-L) (N = 12), high-high (H-H) (N = 34) and low-low (L-L) groups (N = 30). Blood gene expression profile was measured using Illumina HT-12 Beadchips, and paired analyses comparing w0 and w1 were performed for each group. Results: 98 transcripts were differentially expressed comparing w0 and w1 in the L-H, 33 in the H-L, 177 in the H-H and 273 in the L-L. Of these, 66 transcripts were differentially expressed exclusively in the L-H; and 6 only in the H-L. Cross-Lagged Panel Models analyses revealed that RPRD2 gene expression at w1 might be influenced by the CBCL score at w0. Moreover, COX5B, SEC62, and NDUFA2 were validated with another technique and were also differentially regulated in postmortem brain of subjects with mental disorders, indicating that they might be important not only to specific disorders, but also to general psychopathology and symptoms trajectories. Whereas genes related to metabolic pathways seem to be associated with the emergence of psychiatric symptoms, mitochondrial inner membrane genes might be important over the course of normal development. These results suggest that changes in gene expression can be detected in blood in different psychopathological trajectories.

Feasibility and clinical applications of multiple breath wash-out (MBW) testing using sulphur hexafluoride in adults with bronchial asthma.

Ventilation heterogeneity is frequent in bronchial asthma and can be assessed using multiple breath wash-out testing (MBW). Most data is available in paediatric patients and using nitrogen as a tracer gas. We aimed to evaluate sulphur hexafluoride (SF6) MBW in adult asthmatics. Spirometry, whole-body plethysmography, impulse oscillometry and SF6-MBW were prospectively performed. MBW parameters reflecting global (lung clearance index, LCI), acinar (Sacin) and conductive (Scond) ventilation heterogeneity were derived from three consecutive wash-outs. LCI was calculated for the traditional 2.5% and an earlier 5% stopping point that has the potential to reduce wash-out times. 91 asthmatics (66%) and 47 non-asthmatic controls (34%) were included in final analysis. LCI2.5 and LCI5 were higher in asthmatics (p < 0.001). Likewise, Sacin and Scond were elevated (p < 0.001 and p < 0.01). Coefficient of variation was 3.4% for LCI2.5 and 3.5% for LCI5 in asthmatics. Forty-one asthmatic patients had normal spirometry. ROC analysis revealed an AUC of 0.906 for the differentiation from non-asthmatic controls exceeding diagnostic performance of individual and conventional parameters (AUC = 0.819, p < 0.05). SF6-MBW is feasible and reproducible in adult asthmatics. Ventilation heterogeneity is increased as compared to non-asthmatic controls persisting in asthmatic patients with normal spirometry. Diagnostic performance is not affected using an earlier LCI stopping point while reducing wash-out duration considerably.