ReMindCare, an app for daily clinical practice in patients with first episode psychosis: A pragmatic real-world study protocol

[EN] Aim Despite the potential benefits of e-health interventions for patients with psychosis, the integration of these applications into the clinical workflow and analysis of their long-term effects still face significant challenges. To address these issues, we developed the ReMindCare app. This app aims to improve the treatment quality for patients with psychosis. We chose to study the app in real world and pragmatic manner to ensure results will be generalizable. Methods This is a naturalistic empirical study of patients in a first episode of psychosis programme. The app was purpose-designed based on two previous studies, and it offers the following assessments: (a) three daily questions regarding anxiety, sadness and irritability; and (b) 18 weekly questions about medication adherence, medication side effects, medication attitudes and prodromal symptoms. The app offers preset alerts, reminders and the ability for patients to reach out to their clinicians. Data captured by the app are linked to the electronic medical record of the patient. Patients will use the app as part of their ongoing care for a maximum period of 5 years, and assessments will occur at baseline and at the end of the first, second and fifth years of app use. Results Recruitment started in October 2018 and is still ongoing. Conclusions The ReMindCare app represents early real-world use of digital mental health tools that offer direct integration into clinical care. High retention and compliance rates are expected, and this will in turn lead to improved quality of assessments and communication between patients and clinicians.Centro de Investigacion Biomedica en Red de Salud Mental; European Social Fund, Grant/Award Number: 2017/9830; Generalitat Valenciana, Grant/Award Number: PROMETEO/2016/082; Instituto de Salud Carlos III, Grant/Award Numbers: PI01399, PI13/00447, PI17/00402Bonet, L.; Torous, J.; Arce Grilo, AD.; Blanquer Espert, I.; Sanjuán, J. (2021). 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ReMindCare App for Early Psychosis: Pragmatic Real World Intervention and Usability Study

[EN] Background: eHealth interventions are widely used in clinical trials and increasingly in care settings as well; however, their efficacy in real-world contexts remains unknown. ReMindCare is a smartphone app that has been systematically implemented in a first episode of psychosis program (FEPP) for patients with early psychosis since 2018. Objective: The objective of this study was to assess the efficacy of ReMindCare after 19 months of use in the clinic and varying use by individual patients. Methods: The integration of the ReMindCare app into the FEPP started in October 2018. Patients with early psychosis self-selected to the app (ReMindCare group) or treatment as usual (TAU group). The outcome variables considered were adherence to the intervention and number of relapses, hospital admissions, and visits to urgent care units. Data from 90 patients with early psychosis were analyzed: 59 in the ReMindCare group and 31 in the TAU group. The mean age of the sample was 32.8 (SD 9.4) years, 73% (66/90) were males, 91% (83/90) were White, and 81% (74/90) were single. Results: Significant differences between the ReMindCare and TAU groups were found in the number of relapses, hospitalizations, and visits to urgent care units, with each showing benefits for the app. Only 20% (12/59) of patients from the ReMindCare group had a relapse, while 58% (18/31) of the TAU patients had one or more relapses (chi(2) =13.7, P=.001). Moreover, ReMindCare patients had fewer visits to urgent care units (chi(2) =7.4, P=.006) and fewer hospitalizations than TAU patients (chi(2) =4.6, P=.03). The mean of days using the app was 352.2 (SD 191.2; min/max: 18-594), and the mean of engagement was 84.5 (SD 16.04). Conclusions: To our knowledge, this is the first eHealth intervention that has preliminarily proven its benefits in the real-world treatment of patients with early psychosis.This study was supported by the Sanitary Research Institute of the University Clinic Hospital and the Mental Health Networking Biomedical Centre. It was also supported by the Generalitat Valenciana and the Program for Scientific Research, Technological Development, and Innovation in the Generalitat Valenciana of the European Union (2017/9830). It was also supported by grants from the Generalitat Valenciana (PROMETEO/2016/082, PROMETEO/2020/024), Carlos III Health Institute (PI13/00447; PI17/00402), and European Union through the European Regional Development Fund.Bonet, L.; Torous, J.; Arce Grilo, AD.; Blanquer Espert, I.; Sanjuan, J. (2020). ReMindCare App for Early Psychosis: Pragmatic Real World Intervention and Usability Study. 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JMIR Mental Health, 5(3), e51. doi:10.2196/mental.9950Hau, Y. S., Kim, J. K., Hur, J., & Chang, M. C. (2020). How about actively using telemedicine during the COVID-19 pandemic? Journal of Medical Systems, 44(6). doi:10.1007/s10916-020-01580-zBucci, S., Berry, N., Morris, R., Berry, K., Haddock, G., Lewis, S., & Edge, D. (2019). «They Are Not Hard-to-Reach Clients. We Have Just Got Hard-to-Reach Services.» Staff Views of Digital Health Tools in Specialist Mental Health Services. Frontiers in Psychiatry, 10. doi:10.3389/fpsyt.2019.00344Arango, C., Bernardo, M., Bonet, P., Cabrera, A., Crespo-Facorro, B., Cuesta, M. J., … Melau, M. (2017). Cuando la asistencia no sigue a la evidencia: el caso de la falta de programas de intervención temprana en psicosis en España. Revista de Psiquiatría y Salud Mental, 10(2), 78-86. doi:10.1016/j.rpsm.2017.01.001Camacho, E., Levin, L., & Torous, J. (2019). 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Journal of Medical Internet Research, 21(1), e11696. doi:10.2196/11696Rus-Calafell, M., & Schneider, S. (2020). Are we there yet?!—a literature review of recent digital technology advances for the treatment of early psychosis. mHealth, 6, 3-3. doi:10.21037/mhealth.2019.09.14Choi, K. R., Heilemann, M. V., Fauer, A., & Mead, M. (2020). A Second Pandemic: Mental Health Spillover From the Novel Coronavirus (COVID-19). Journal of the American Psychiatric Nurses Association, 26(4), 340-343. doi:10.1177/107839032091980

Utilización de tecnologías móviles en pacientes con psicosis: una revisión sistemática.

[EN] There is a growing interest in mobile Health interventions (m-Health) in patients with psychosis. The aim of this study is to conduct a systematic review in order to analysethe current state of research in this area. The search of articles was carried out following the PRISMA criteria, focusing on those studies that used mobile technologies in patients with psychosis during the period from 1990 to 2016. A total of 20 articles were selected from the 431 studies found. Three types of studies are distinguished: 1) Analysis of quality and usability, 2) Improving treatment adherence and reducing hospital admissions, and 3) Analysisof patient symptoms. CONCLUSIONS: m-Health interventions are feasible, and are easy to use for patients with psychosis. They evaluate the evolution of psychotic symptoms more efficiently, and improve adherence to treatment, as well as symptoms and hospital admissions. However, a particular strategy does not stand out over the rest, because differences in methodology make them difficult to compare.[ES] Introducción: Hay un creciente interés en las intervenciones mobile Health (m-Health) en pacientes con psicosis. El objetivo de este estudio es realizar una revisión sistemática para analizar el estado actual de la investigación en este ámbito. Metodología: Búsqueda en las bases de datos PsycINFO, PubMED, SCOPUS, Medline, ISI Web of Knowledge e IME del CSIC. Intervenciones con tecnologías móviles en pacientes con psicosis. Resultados: De un total de 431 artículos se seleccionaron 20. Se diferencian tres tipos de intervenciones: (1) Análisis de calidad y usabilidad, (2) Mejora de la adherencia, síntomas y reducción de hospitalizaciones, (3) Análisis de la sintomatología del paciente. Conclusiones: Las intervenciones m-Health son viables y resultan fáciles de utilizar para los pacientes con psicosis. Evalúan de forma más eficiente la evolución de los síntomas psicóticos y mejoran la adherencia al tratamiento, síntomas y hospitalizaciones. No se puede destacar una estrategia sobre las demás debido a que las diferencias en la metodología las hace difícilmente comparables.A ‘‘Prometeo’’ support grant from the Conselleria de Sanidad de la Comunidad Valenciana.Bonet, L.; Izquierdo, C.; Escartí, MJ.; Sancho, JV.; Arce Grilo, AD.; Blanquer Espert, I.; Sanjuan Arias, J. (2017). Use of mobile technologies in patients with psychosis: A systematic review. Revista de Psiquiatría y Salud Mental. 10(3):168-178. doi:10.1016/j.rpsm.2017.01.003S16817810

Comparison of two-drug combinations, amikacin/tigecycline/imipenem and amikacin/tigecycline/clarithromycin against Mycobacteroides abscessus subsp. abscessus using the in vitro time-kill assay

Nontuberculous mycobacteria include 198 mycobacterial species. Among these, Mycobacteroides abscessus is a rapidly growing mycobacteria that causes lung and skin infections. M. abscessus lung infections are difficult to treat due to the high levels of resistance to several classes of antibiotics. The current treatment is based on combining at least two or three antibiotics. However, treatment outcomes remain very poor. The objective was to compare the in vitro activity of amikacin, tigecycline, imipenem, and clarithromycin, alone and in two different three-drug combinations (amikacin/tigecycline/imipenem and amikacin/tigecycline/clarithromycin) against seven M. abscessus subsp. abscessus clinical isolates using the time-kill assay. The two combinations showed greater activity than the antibiotics tested individually. Even though both combinations showed similar activity as well as no antagonistic activity, the combination including imipenem could not be an alternative treatment against M. abscessus subsp. abscessus lung infections caused by clarithromycin susceptible isolates. However, this combination could be considered against clarithromycin resistant isolates. Future studies are necessary to confirm this hypothesis

Differences in the Use and Opinions About New eHealth Technologies Among Patients With Psychosis: Structured Questionnaire

[EN] Background: Despite a growing interest in the use of technology in order to support the treatment of psychotic disorders, limited knowledge exists about the viability and acceptability of these eHealth interventions in relation to the clinical characteristics of patients. Objective: The objective of this study was to assess the access and use of, as well as experiences and interest in, new technologies using a survey of patients diagnosed with early psychosis compared with a survey of patients diagnosed with chronic psychotic disorders. Methods: We designed a structured questionnaire. This questionnaire was divided into five parts: (1) clinical and demographic information, (2) access and use of the internet, (3) use of the internet in relation to mental health, (4) experiences with technology, and (5) patients¿ interest in eHealth services. In total, 105 patients were recruited from early psychosis units (n=65) and recovery units (n=40). Results: In this study, 84.8% (89/105) of the patients had access to the internet and 88.6% (93/105) owned an electronic internet device. In total, 71.3% (57/80) of patients who owned a mobile phone were interested in eHealth systems and 38.2% (37/97) reported negative experiences related to the internet usage. We observed differences between the groups in terms of device ownership (P=.02), the frequency of internet access (P<.001), the use of social media (P=.01), and seeking health information (P=.04); the differences were found to be higher in the early psychosis group. No differences were found between the groups in terms of the use of internet in relation to mental health, experiences and opinions about the internet, or interest in eHealth interventions (P=.43). Conclusions: The availability and use of technology for the participants in our survey were equivalent to those for the general population. The differences found between the groups in relation to the access or use of technology seemed to due to age-related factors. The use of technology involving mental health and the interest in eHealth interventions were mainly positive and equivalent between the groups. Accordingly, this group of patients is a potential target for the emerging eHealth interventions, regardless of their clinical status. However, 28.7% (23/80) of the studied patients rejected the use of internet interventions and 38.2% (37/97) had unpleasant experiences related to its usage; thus, more in-depth studies are needed to better define the profile of patients with psychosis who may benefit from eHealth treatments.This study was supported by Generalitat Valenciana (PROMETEO/2016/082 grant) and CIBERSAM and Fondo de Investigacion Sanitaria (PI01399, PI13/00447; PI17/00402, Cofunded FEDER).Bonet, L.; Llácer, B.; Hernandez-Viadel, M.; Arce Grilo, AD.; Blanquer Espert, I.; Cañete, C.; Escartí, MJ.... (2018). Differences in the Use and Opinions About New eHealth Technologies Among Patients With Psychosis: Structured Questionnaire. JMIR Mental Health. 5(3):1-12. https://doi.org/10.2196/mental.9950S11253Perkins, D. O., Gu, H., Boteva, K., & Lieberman, J. A. (2005). Relationship Between Duration of Untreated Psychosis and Outcome in First-Episode Schizophrenia: A Critical Review and Meta-Analysis. American Journal of Psychiatry, 162(10), 1785-1804. doi:10.1176/appi.ajp.162.10.1785Marshall, M., & Rathbone, J. (2011). Early intervention for psychosis. Cochrane Database of Systematic Reviews. doi:10.1002/14651858.cd004718.pub3Amos, A. (2012). Assessing the cost of early intervention in psychosis: A systematic review. Australian & New Zealand Journal of Psychiatry, 46(8), 719-734. doi:10.1177/0004867412450470Bonet, L., Izquierdo, C., Escartí, M. J., Sancho, J. V., Arce, D., Blanquer, I., & Sanjuan, J. (2017). Utilización de tecnologías móviles en pacientes con psicosis: una revisión sistemática. Revista de Psiquiatría y Salud Mental, 10(3), 168-178. doi:10.1016/j.rpsm.2017.01.003World Health Organization2007Global Observatory for eHealth http://www.who.int/goe/en/Bucci, S., Barrowclough, C., Ainsworth, J., Morris, R., Berry, K., Machin, M., … Haddock, G. (2015). Using mobile technology to deliver a cognitive behaviour therapy-informed intervention in early psychosis (Actissist): study protocol for a randomised controlled trial. Trials, 16(1). doi:10.1186/s13063-015-0943-3Schlosser, D., Campellone, T., Kim, D., Truong, B., Vergani, S., Ward, C., & Vinogradov, S. (2016). Feasibility of PRIME: A Cognitive Neuroscience-Informed Mobile App Intervention to Enhance Motivated Behavior and Improve Quality of Life in Recent Onset Schizophrenia. JMIR Research Protocols, 5(2), e77. doi:10.2196/resprot.5450Garety, P. A., Ward, T., Freeman, D., Fowler, D., Emsley, R., Dunn, G., … Hardy, A. (2017). SlowMo, a digital therapy targeting reasoning in paranoia, versus treatment as usual in the treatment of people who fear harm from others: study protocol for a randomised controlled trial. Trials, 18(1). doi:10.1186/s13063-017-2242-7Depp, C. A., Harmell, A. L., Vahia, I. V., & Mausbach, B. T. (2015). Neurocognitive and functional correlates of mobile phone use in middle-aged and older patients with schizophrenia. Aging & Mental Health, 20(1), 29-35. doi:10.1080/13607863.2015.1008987National Alliance on Mental Illness (NAMI)2017-10-10Health and Technology Study 2014https://www.nami.org/About-NAMI/Publications-Reports/Survey-Reports/Health-and-Technology-Study-(2014)SmithAThe Smartphone difference: U.S. Smartphone Use in2015Washington, DCPew Research Centrehttp://www.pewinternet.org/2015/04/01/us-smartphone-use-in-2015Tobitt, S., & Percival, R. (2017). Switched on or switched off? A survey of mobile, computer and Internet use in a community mental health rehabilitation sample. Journal of Mental Health, 28(1), 4-10. doi:10.1080/09638237.2017.1340623Firth, J., Cotter, J., Torous, J., Bucci, S., Firth, J. A., & Yung, A. R. (2015). Mobile Phone Ownership and Endorsement of «mHealth» Among People With Psychosis: A Meta-analysis of Cross-sectional Studies. Schizophrenia Bulletin, 42(2), 448-455. doi:10.1093/schbul/sbv132Thomas, N., Foley, F., Lindblom, K., & Lee, S. (2017). Are people with severe mental illness ready for online interventions? Access and use of the Internet in Australian mental health service users. Australasian Psychiatry, 25(3), 257-261. doi:10.1177/1039856217689913Gitlow, L., Abdelaal, F., Etienne, A., Hensley, J., Krukowski, E., & Toner, M. (2017). Exploring the Current Usage and Preferences for Everyday Technology among People with Serious Mental Illnesses. Occupational Therapy in Mental Health, 33(1), 1-14. doi:10.1080/0164212x.2016.1211061Trefflich, F., Kalckreuth, S., Mergl, R., & Rummel-Kluge, C. (2015). Psychiatric patients׳ internet use corresponds to the internet use of the general public. Psychiatry Research, 226(1), 136-141. doi:10.1016/j.psychres.2014.12.037Gay, K., Torous, J., Joseph, A., Pandya, A., & Duckworth, K. (2016). Digital Technology Use Among Individuals with Schizophrenia: Results of an Online Survey. JMIR Mental Health, 3(2), e15. doi:10.2196/mental.5379Berry, N., Lobban, F., Emsley, R., & Bucci, S. (2016). Acceptability of Interventions Delivered Online and Through Mobile Phones for People Who Experience Severe Mental Health Problems: A Systematic Review. Journal of Medical Internet Research, 18(5), e121. doi:10.2196/jmir.5250Birnbaum, M. L., Rizvi, A. F., Correll, C. U., Kane, J. M., & Confino, J. (2015). Role of social media and the Internet in pathways to care for adolescents and young adults with psychotic disorders and non-psychotic mood disorders. Early Intervention in Psychiatry, 11(4), 290-295. doi:10.1111/eip.12237Ben-Zeev, D., Scherer, E. A., Gottlieb, J. D., Rotondi, A. J., Brunette, M. F., Achtyes, E. D., … Kane, J. M. (2016). mHealth for Schizophrenia: Patient Engagement With a Mobile Phone Intervention Following Hospital Discharge. JMIR Mental Health, 3(3), e34. doi:10.2196/mental.6348Kannisto, K. A., Adams, C. E., Koivunen, M., Katajisto, J., & Va lima ki, M. (2015). Feedback on SMS reminders to encourage adherence among patients taking antipsychotic medication: a cross-sectional survey nested within a randomised trial. BMJ Open, 5(11), e008574-e008574. doi:10.1136/bmjopen-2015-008574Instituto Nacional de EstadísticaEncuesta sobre equipamiento y uso de tecnologías de información y comunicación en los hogares2016 http://www.ine.es/dyngs/INEbase/es/operacion.htm?c=Estadistica_C&cid=1254736176741&menu=ultiDatos&idp=1254735976608Robotham, D., Satkunanathan, S., Doughty, L., & Wykes, T. (2016). Do We Still Have a Digital Divide in Mental Health? A Five-Year Survey Follow-up. Journal of Medical Internet Research, 18(11), e309. doi:10.2196/jmir.6511Miller, B. J., Stewart, A., Schrimsher, J., Peeples, D., & Buckley, P. F. (2015). How connected are people with schizophrenia? Cell phone, computer, email, and social media use. Psychiatry Research, 225(3), 458-463. doi:10.1016/j.psychres.2014.11.067Borzekowski, D. L. G., Leith, J., Medoff, D. R., Potts, W., Dixon, L. B., Balis, T., … Himelhoch, S. (2009). Use of the Internet and Other Media for Health Information Among Clinic Outpatients With Serious Mental Illness. Psychiatric Services, 60(9), 1265-1268. doi:10.1176/ps.2009.60.9.1265Aref-Adib, G., O’Hanlon, P., Fullarton, K., Morant, N., Sommerlad, A., Johnson, S., & Osborn, D. (2016). A qualitative study of online mental health information seeking behaviour by those with psychosis. BMC Psychiatry, 16(1). doi:10.1186/s12888-016-0952-0Baup, H., & Verdoux, H. (2017). 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Null cyp1b1 Activity in Zebrafish Leads to Variable Craniofacial Defects Associated with Altered Expression of Extracellular Matrix and Lipid Metabolism Genes

CYP1B1 loss of function (LoF) is the main known genetic alteration present in recessive primary congenital glaucoma (PCG), an infrequent disease characterized by delayed embryonic development of the ocular iridocorneal angle; however, the underlying molecular mechanisms are poorly understood. To model CYP1B1 LoF underlying PCG, we developed a cyp1b1 knockout (KO) zebrafish line using CRISPR/Cas9 genome editing. This line carries the c.535_667del frameshift mutation that results in the 72% mRNA reduction with the residual mRNA predicted to produce an inactive truncated protein (p.(His179Glyfs*6)). Microphthalmia and jaw maldevelopment were observed in 23% of F0 somatic mosaic mutant larvae (144 hpf). These early phenotypes were not detected in cyp1b1-KO F3 larvae (144 hpf), but 27% of adult (four months) zebrafish exhibited unior bilateral craniofacial alterations, indicating the existence of incomplete penetrance and variable expressivity. These phenotypes increased to 86% in the adult offspring of inbred progenitors with craniofacial defects. No glaucoma-related phenotypes were observed in cyp1b1 mutants. Transcriptomic analyses of the offspring (seven dpf) of cyp1b1-KO progenitors with adult-onset craniofacial defects revealed functionally enriched differentially expressed genes related to extracellular matrix and cell adhesion, cell growth and proliferation, lipid metabolism (retinoids, steroids and fatty acids and oxidation–reduction processes that include several cytochrome P450 genes) and inflammation. In summary, this study shows the complexity of the phenotypes and molecular pathways associated with cyp1b1 LoF, with species dependency, and provides evidence for the dysregulation of extracellular matrix gene expression as one of the mechanisms underlying the pathogenicity associated with cyp1b1 disruption

Synthesis and biological evaluation of benzochromenopyrimidinones as cholinesterase inhibitors and potent antioxidant, non-hepatotoxic agents for Alzheimer’s disease

We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 μM), good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line.JMC thanks Government of Spain for support (SAF2016-65586-R), JJ and OS thank MH CZ- DRO (UHHK 00179906).We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI)

Role of GUCA1C in Primary Congenital Glaucoma and in the Retina: Functional Evaluation in Zebrafish

Primary congenital glaucoma (PCG) is a heterogeneous, inherited, and severe optical neuropathy caused by apoptotic degeneration of the retinal ganglion cell layer. Whole-exome sequencing analysis of one PCG family identified two affected siblings who carried a low-frequency homozygous nonsense GUCA1C variant (c.52G > T/p.Glu18Ter/rs143174402). This gene encodes GCAP3, a member of the guanylate cyclase activating protein family, involved in phototransduction and with a potential role in intraocular pressure regulation. Segregation analysis supported the notion that the variant was coinherited with the disease in an autosomal recessive fashion. GCAP3 was detected immunohistochemically in the adult human ocular ciliary epithelium and retina. To evaluate the ocular effect of GUCA1C loss-of-function, a guca1c knockout zebrafish line was generated by CRISPR/Cas9 genome editing. Immunohistochemistry demonstrated the presence of GCAP3 in the non-pigmented ciliary epithelium and retina of adult wild-type fishes. Knockout animals presented up-regulation of the glial fibrillary acidic protein in Müller cells and evidence of retinal ganglion cell apoptosis, indicating the existence of gliosis and glaucoma-like retinal damage. In summary, our data provide evidence for the role of GUCA1C as a candidate gene in PCG and offer new insights into the function of this gene in the ocular anterior segment and the retina.This research was funded by research grants from the “Instituto de Salud Carlos III/European Regional Development Fund (ERDF)” (PI15/01193, PI19/00208 and RD16/0008/0019, OFTARED), the Regional Ministry of Science and Technology of the Board of the Communities of “Castilla-La Mancha” (SBPLY/17/180501/000404; http://www.educa.jccm.es/idiuniv/es). SA-M was sponsored by the Regional Ministry of Science and Technology of the Board of the Communities of “Castilla-La Mancha” (PREJCCM2016/28)

How Did the COVID-19 Lockdown Affect Children and Adolescent's Well-Being: Spanish Parents, Children, and Adolescents Respond.

Background: During the COVID-19 pandemic, lockdown strategies have been widely used to contain SARS-CoV-2 virus spread. Children and adolescents are especially vulnerable to suffering psychological effects as result of such measures. In Spain, children were enforced to a strict home lockdown for 42 days during the first wave. Here, we studied the effects of lockdown in children and adolescents through an online questionnaire. Methods: A cross-sectional study was conducted in Spain using an open online survey from July (after the lockdown resulting from the first pandemic wave) to November 2020 (second wave). We included families with children under 16 years-old living in Spain. Parents answered a survey regarding the lockdown effects on their children and were instructed to invite their children from 7 to 16 years-old (mandatory scholar age in Spain) to respond a specific set of questions. Answers were collected through an application programming interface system, and data analysis was performed using R. Results: We included 1,957 families who completed the questionnaires, covering a total of 3,347 children. The specific children's questionnaire was completed by 167 kids (7-11 years-old), and 100 adolescents (12-16 years-old). Children, in general, showed high resilience and capability to adapt to new situations. Sleeping problems were reported in more than half of the children (54%) and adolescents (59%), and these were strongly associated with less time doing sports and spending more than 5 h per day using electronic devices. Parents perceived their children to gain weight (41%), be more irritable and anxious (63%) and sadder (46%). Parents and children differed significantly when evaluating children's sleeping disturbances. Conclusions: Enforced lockdown measures and isolation can have a negative impact on children and adolescent's mental health and well-being. In future waves of the current pandemic, or in the light of potential epidemics of new emerging infections, lockdown measures targeting children, and adolescents should be reconsidered taking into account their infectiousness potential and their age-specific needs, especially to facilitate physical activity and to limit time spent on electronic devices. Keywords: COVID-19; adolescent; children; lockdown; mental health; well-being

Knockout of myoc Provides Evidence for the Role of Myocilin in Zebrafish Sex Determination Associated with Wnt Signalling Downregulation

Myocilin is a secreted glycoprotein with a poorly understood biological function and it is mainly known as the first glaucoma gene. To explore the normal role of this protein in vivo we developed a myoc knockout (KO) zebrafish line using CRISPR/Cas9 genome editing. This line carries a homozygous variant (c.236_239delinsAAAGGGGAAGGGGA) that is predicted to result in a loss-of-function of the protein because of a premature termination codon p.(V75EfsX60) that resulted in a significant reduction of myoc mRNA levels. Immunohistochemistry showed the presence of myocilin in wild-type embryonic (96 h post-fertilization) anterior segment eye structures and caudal muscles. The protein was also detected in different adult ocular and non-ocular tissues. No gross macroscopic or microscopic alterations were identified in the KO zebrafish, but, remarkably, we observed absence of females among the adult KO animals and apoptosis in the immature juvenile gonad (28 dpf) of these animals, which is characteristic of male development. Transcriptomic analysis showed that adult KO males overexpressed key genes involved in male sex determination and presented differentially expressed Wnt signalling genes. These results show that myocilin is required for ovary differentiation in zebrafish and provides in vivo support for the role of myocilin as a Wnt signalling pathway modulator. In summary, this myoc KO zebrafish line can be useful to investigate the elusive function of this protein, and it provides evidence for the unexpected function of myocilin as a key factor in zebrafish sex determination