The comorbidity between attention-deficit/hyperactivity disorder and other neurodevelopmental disorders : aetiology, treatment and outcomes

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder (ND) defined by the presence of impairing levels of inattentiveness, hyperactivity, and impulsivity. These symptoms are often accompanied by impairment in several functional domains, and by the presence of symptoms or diagnoses of other disorders, especially other NDs, including Autism Spectrum Disorder (ASD). In addition, risky behaviours and health issues are more common among individuals with ADHD, as compared to their peers who do not display ADHD symptoms. The overall aim of this thesis is to investigate the comorbidity between ADHD, ASD and other NDs, in order to clarify shared aetiology, treatment effectiveness and adverse health outcomes. Study 1 examined the association between clinically diagnosed ASD and ADHD across different types of relatives and explored potential differences between low- and highfunctioning ASD (that is, with or without intellectual disability) in the link with ADHD. Data for the study came from a linkage of national Swedish registers in order to identify different types of relatives, from twins to cousins, and clinical diagnoses of ASD and ADHD. Logistic regression was used to estimate the association between ASD and ADHD within the same person (within-individual association) and within relative pairs (within-family association). Results demonstrated that individuals diagnosed with ASD and their relatives had an increased risk of ADHD. The association in twins and siblings was higher than the association in cousins. The magnitude of the association was larger in high-functioning ASD. Study 2 focused on the phenotypic and aetiological overlap between traits related to ADHD and ASD in young adult twins from the general population. Data for the study came from a web-based survey within the Swedish Twin Registry. Four different trait dimensions were considered: inattention (IA), hyperactivity/impulsivity (HI), repetitive and restricted behaviours (RRB), social interaction and communication difficulties (SIC). Structural equation modelling was used to decompose the covariance across these trait dimensions into genetic and non-genetic influences. Results showed that at the phenotypic level, the correlation between IA and RRB was similar to the one between IA and SIC, while the correlation between HI and RRB was stronger than the one between HI and SIC. Genetic and non-genetic contributions accounted for a similar amount of the covariation across all trait dimensions under study. The largest genetic correlation between traits related to ADHD and traits related to ASD was between HI and RRB. Taken together, results from Study 1 and 2 suggest that comorbidity between ADHD and ASD may reflect shared aetiological factors, which are in part of genetic origin and which may be specific to certain symptom domains. Study 3 tested the association between use of ADHD medication and risk of unintentional injuries in children and adolescents with ADHD, including those with co-occurring NDs. Data for the study came from a linkage of national Swedish registers. All residents in Sweden with at least one diagnosis of ADHD and one diagnosis of unintentional injury were included and followed during the study period. Follow-up time was divided into consecutive periods, which may be on-treatment or off-treatment, and the rate of injuries during periods on-treatment was compared to the rate of injuries during periods off-treatment within the same individual, using stratified Cox regression. Results indicated that ADHD medication use was associated with a lower rate of all unintentional injuries, among children and adolescents, among males and females, and among individuals with NDs, as well as among the subgroup with ASD. Study 4 investigated the association between different NDs and the risk of violent victimization in adolescents and young adults, considering the role of familial and mediating factors. Similarly to Study 1 and 3, a linkage of national Swedish registers was used to identify diagnoses of different NDs and inpatient or outpatient visits or deaths due to assault in the study population. The association between the NDs and violent victimization was explored using Cox regression. Results revealed that being diagnosed with any ND was associated with an increased risk of later violent victimization in males and females. After adjustment for familial factors and mediators, all the associations were attenuated and only ADHD was associated with an increased risk of violent victimization among males and females. Taken together, results from Study 3 and 4 suggest that comorbidity between ADHD and other NDs does not seem to affect treatment effectiveness with regard to ADHD medication and injuries. On the other hand, risk of violent victimization, which seemed to be related to NDs as a group, may be specifically linked to ADHD. In conclusion, the work presented in this thesis supports the notion that NDs are a group of disorders characterised by both general and specific aspects in terms of aetiology, treatment effectiveness and negative outcomes

Long-term follow-up of recovered MPN patients with COVID-19

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Neoplàsies mieloproliferatives cròniquesCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Neoplasias mieloproliferativas crónicasCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Chronic myeloproliferative neoplasmsDuring the first wave of SARS-CoV-2 infection a European observational study was launched under the auspices of the European Leukemia Net (ELN), aiming at gathering information about the clinical epidemiology of COVID-19 in patients with chronic myeloproliferative neoplasms (MPN-COVID study).The study was supported by a research grant by the COVID “3×1 project”, BREMBO S.p.A., Bergamo, Italy (TB) and by AIRC 5×1000 call “Metastatic disease: the key unmet need in oncology” to MYNERVA project, #21267 (MYeloid NEoplasms Research Venture AIRC). A detailed description of the MYNERVA project is available at https://progettomynerva.it (AMV, PG). The study was also supported by HARMONY PLUS, which is funded through the Innovative Medicines Initiative (IMI), Europe’s largest public-private initiative aiming to speed up the development of better and safer medicines for patients. The HARMONY Alliance has received funding from IMI 2 Joint Undertaking and is listed under grant agreement No. 945406. This Joint Undertaking receives support from the European Union’s Horizon 2020 Research and Innovation Programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA). IMI supports collaborative research projects and builds networks of industrial and academic experts in order to boost pharmaceutical innovation in Europe

Breakthrough infections in MPN-COVID vaccinated patients

Myeloproliferative diseaseEnfermedad mieloproliferativaMalaltia mieloproliferativaThe study was supported by a research grant by the COVID “3 × 1 project”, BREMBO S.p.A., Bergamo, Italy (T.B.) and by AIRC 5 × 1000 call “Metastatic disease: the key unmet need in oncology” to MYNERVA project, #21267 (MYeloid NEoplasms Research Venture AIRC). A detailed description of the MYNERVA project is available at https://progettomynerva.it (A.M.V., P.G.). The study was also supported by HARMONY PLUS, which is funded through the Innovative Medicines Initiative (IMI), Europe’s largest public–private initiative aiming to speed up the development of better and safer medicines for patients. The HARMONY Alliance has received funding from IMI 2 Joint Undertaking and is listed under grant agreement No. 945406. This Joint Undertaking receives support from the European Union’s Horizon 2020 Research and Innovation Programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA). IMI supports collaborative research projects and builds networks of industrial and academic experts in order to boost pharmaceutical innovation in Europe

Enantio- and Diastereoconvergent Cyclocondensation Reactions: Synthesis of Enantiopure cis-Decahydroquinolines.

Up to four stereocenters with a well-defined configuration are generated in a single synthetic step by the cyclocondensation of (R)-phenylglycinol or (1S,2R)-1-amino-2-indanol with stereoisomeric mixtures (racemates, meso forms, diastereoisomers) of cyclohexanone-based δ-keto-acid and δ-keto-diacid derivatives in enantio- and diastereoconvergent processes that involve dynamic kinetic resolution and/or desymmetrization of enantiotopic groups. A detailed analysis of the stereochemical outcome of this process is presented. This method provides easy access to enantiopure 8- and 6,8-substituted cis-decahydroquinolines, including alkaloids of the myrioxazine family

Risk of Psychosis Among Individuals Who Have Presented to Hospital With Self-harm:A Prospective Nationwide Register Study in Sweden

BACKGROUND AND HYPOTHESIS: Recent research showed that young people who presented to hospital with self-harm in Finland had a significantly elevated risk of later psychosis. We investigated the prospective relationship between hospital presentation for self-harm and risk of psychosis in an unprecedentedly large national Swedish cohort.STUDY DESIGN: We used inpatient and outpatient healthcare registers to identify all individuals born between 1981 and 1993 who were alive and living in Sweden on their 12th birthday and who presented to hospital one or more times with self-harm. We compared them with a matched cohort, followed up for up to 20 years, and compared the cumulative incidence of psychotic disorders. Furthermore, we examined whether the strength of the relationship between hospital presentation for self-harm and later psychosis changed over time by examining for cohort effects.STUDY RESULTS: In total, 28 908 (2.0%) individuals presented to hospital with self-harm without prior psychosis diagnosis during the follow-up. For individuals who presented to hospital with self-harm, the cumulative incidence of diagnosed psychosis was 20.7% at 20 years follow-up (hazard radio = 13.9, 95% CI 13.3-14.6, P-value &lt;5 × 10-308). There was no evidence of a dilution of the effect over time: while the incidence of hospital self-harm presentation increased, this did not result in an attenuation over time of the strength of the relationship between hospital self-harm presentation and subsequent psychosis.CONCLUSIONS: Individuals who present to hospital with self-harm in their teens and 20s represent an important risk group for psychosis prediction and prevention.</p

Familial and genetic associations between autism spectrum disorder and other neurodevelopmental and psychiatric disorders

Background Familial and genetic associations between autism spectrum disorder (ASD) and other neurodevelopmental and psychiatric disorders have been reported, sometimes with conflicting results. We estimated familial and genetic associations between ASD and nine disorder groups, and explored differences in these associations for ASD in the context of intellectual disability, epilepsy, chromosomal abnormalities, and congenital malformations. Methods Individuals born between 1985 and 2009 living in Sweden on their seventh birthday were linked to their biological parents in order to identify different types of relatives. We retrieved information on all the disorders considered from the National Patient Register. Logistic regression was used to estimate the familial association between ASD and other neurodevelopmental and psychiatric disorders in the different groups of relatives. Structural equation modeling was used to estimate phenotypic (rp) and genetic associations (rg), as well as the contribution of genetic influences to rp. Results The study included 2,398,608 individuals. Among relatives of individuals diagnosed with ASD, there was an increased risk of the disorders considered, compared to relatives of individuals who were not diagnosed with ASD. Stronger associations were detected for ASD without any additional diagnosis of intellectual disability, epilepsy, chromosomal abnormalities, and congenital malformations. The strongest genetic correlation was estimated between ASD and other neurodevelopmental disorders (rg = 0.73; 95% CI = 0.66–0.79). Moderate genetic correlations were estimated for anxiety disorders (rg = 0.47; 95% CI = 0.33–0.61), depression (rg = 0.52; 95% CI = 0.37–0.66), and intentional self-harm (rg = 0.54; 95% CI = 0.36–0.71). Conclusions ASD shows familial and genetic association not only with other neurodevelopmental disorders, but also with other psychiatric disorders, such as anxiety, depression, and intentional self-harm. Family history of ASD comorbid with intellectual disability, epilepsy, congenital malformations, or chromosomal abnormalities is less related to other psychiatric disorders, potentially suggesting a different etiology for this subgroup of patients

Investigating sex-specific effects of familial risk for ADHD and other neurodevelopmental disorders in the Swedish population

Background: Many psychiatric disorders show sex differences in prevalence. Recent studies suggest that females diagnosed with anxiety and depression carry more genetic risks related to attention deficit hyperactivity disorder (ADHD), compared to affected males. Aims: In this register-based study, we aimed to test whether females who received clinical diagnoses of anxiety, depressive, bipolar, and eating disorders are at higher familial risk for ADHD and other neurodevelopmental disorders (NDs), compared to diagnosed males. Method: We analysed data from a record-linkage of several Swedish national registers, including 151,025 sibling pairs from 103,941 unique index individuals diagnosed with anxiety, depressive, bipolar, or eating disorders, as well as data from 646,948 cousin pairs. We compared the likelihood of having a relative diagnosed with ADHD/NDs in index males and females. Results: Females with anxiety disorders were more likely than affected males to have a brother with ADHD [OR(CIs)=1.13(1.05-1.22)]. Results for broader NDs were similar and were driven by ADHD diagnoses. Follow-up analyses revealed similar point estimates for several categories of anxiety disorders, with the strongest effect observed for agoraphobia [OR(CIs)=1.64(1.12-2.39)]. No significant associations were found in individuals with depressive, bipolar, or eating disorders, or in cousins. Conclusions: These results provide modest support for the possibility that familial/genetic risks for ADHD may show sex-specific phenotypic expression. Alternatively, there could be sex-specific biases in diagnoses of anxiety and ADHD. These factors could play a small role in the observed sex differences in prevalence of ADHD and anxiety

Precedentes Romanos acerca de la protección al más débil

La protección de la parte más débil en toda relación jurídica, fuere de índole contractual o no, debe ser objetivo prioritario del Derecho. Ahora bien, éste se plasma en normas que son las que rigen la vida social, las cuales muchas veces no contemplan estas prioridades. Lo que crea la paradoja de que existan normas legales, pero no legítimas. El desarrollo social hace que esas leyes queden retrasadas, lo que las hace devenir inútiles para los fines que se tuvieron en vista al crearlas. Partiendo de aquí es importante recurrir al Derecho Romano. Quien piense a éste como una colección de reglas añejas y obsoletas, se equivoca. Quien lo considere arqueología jurídica, también se equivoca. Y yerra igualmente el que limita (y degrada) su importancia reduciéndolo a un mero antecedente de los códigos actuales. Es la equivocación de los dogmáticos, pero una visión humanista razona diferente. El Derecho Romano es la ratio scripta, el Derecho Natural en acto, y como tal conserva su vigencia. El extremo y salvaje liberalismo olvidó y desnaturalizó muchos de sus principios, cuya actualidad deseamos rescatar: El respeto a la ancianidad, regímenes tuitivos, como el amparo del pródigo, la defensa del más débil en un contrato. El trabajo y el trabajador, el asesoramiento gratuito. Los ejemplos resultan numerosísimos. Sobre este tema pretendemos investigar, presentando soluciones romanas a problemas actuales, y demostrando así que un marco normativo superador del que actualmente tenemos es posible.Fil: Ghirardi, Juan Carlos. Universidad Católica de Córdoba. Facultad de Derecho y Ciencias Sociales; ArgentinaFil: Filippi, María Cristina. Universidad Católica de Córdoba. Facultad de Derecho y Ciencias Sociales; Argentin

Régimen jurídico de los sepulcros. Una proyección desde el Derecho Romano hasta la Legislación Argentina actual

El tema del sepulcro es algo que preocupa al hombre desde el inicio mismo de la Historia, no en vano dos de las siete maravillas del mundo antiguo son sepulturas, las pirámides y la tumba de Mausolo. Es algo sobre cuyo régimen no se ha escrito demasiado, quizás porque resulta incómodo; el hombre se encuentra enfrentado a su propia finitud, lo que a veces perturba. Sin embargo, es riquísimo como veta de investigación. Conocer acerca del régimen de los sepulcros nos enseña mucho, no solamente acerca de la formativa al respecto, sino también sobre las costumbres sociales. El culto privado (los dioses manes, o sean los antepasados), el régimen de las cosas (por definición fuera del patrimonio, también del comercio), las costumbres acerca de la manera en que se disponía de los restos fúnebres (enterramiento o incineración), nos pueden decir mucho acerca de un pueblo. Para estudiar la cuestión (que abordaremos partiendo del Derecho romano, y desechando, no por falta de valor, el precedente anterior) es, entonces, necesario abordarla desde un buen número de vertientes diferentes. En primer lugar, el culto privado y las creencias religiosas (curiosamente, si se las analiza a fondo, hallaremos que la religión cristiana y lo que ella enseña no es original, sino un desarrollo natural del pensamiento romano). Para continuar, debemos ir a la vertiente social, los usos y costumbres vigentes en Roma, la contraposición entre “enterradores” e “incineradotes”, que entran en un conflicto recién zanjado por Justiniano cuando dispone que “enterrar es más piadoso”. No olvidemos la vinculación con los derechos reales, los sepulcros son res “extra patrimonium”, y también fuera del comercio (aunque esta clasificación no se haya explicitado jamás en Derecho Romano). Sin embargo, y aunque no se pueda hablar de “dominium” en relación a los mismos, hay sí un derecho específico, el “ius sepulcrum”, que confiere implícitamente una servidumbre, el “iter ad sepulcrum”. La violación de sepulturas era cuestión que daba acción para perseguir al violador, la que correspondía al sepulcro violado, el hecho de ser violador de sepulturas, conforme la regulación justinianea constituía causal de divorcio. En fin, el tema es materia de regulación por parte del derecho público, dado que el enterramiento dentro de los límites del “poemerium” estaba prohibido. ¿Ecología incipiente, como han dicho algunos? ¿Superstición? Recordemos que no era siquiera lícito pronunciar la palabra “muerte”. Cicerón, cuando refiere al pueblo que los cómplices de Catilina fueron ejecutados, se cuida mucho de emplear ese vocablo, simplemente se limita a proclamar “ya han vivido”. ¿O quizás un motivo meramente económico, que buscaba evitar que los fundos urbanos saliesen del comercio? Luego debemos por fuerza analizar las Leyes de Partidas, para ver cómo se transfunde esto en el derecho español, base del nuestro. Para culminar con la legislación argentina actual. Los cementerios, ¿son públicos o privados? Hoy no hay duda, existen de ambas naturalezas pero, entonces, ¿cuál es el régimen jurídico? ¿Están dentro del patrimonio? ¿Son un activo más, apto para figurar en un balance? ¿No lo son? Existe un régimen especial para los cementerios privados. Más aún, ¿debería haberlo? En su caso, ¿cuál? ¿De qué interés jurídicamente protegido estaríamos hablando? ¿De propiedad privada, de creencias religiosas, y la forma de resguardarlas? En definitiva, ¿qué es un cadáver, jurídicamente hablando? ¿A quién pertenece? Al hombre que fuera en vida, indudablemente no. ¿A sus sucesores? En su caso, ¿porqué? Tal el tema a investigar.Fil: Ghirardi, Juan Carlos. Universidad Católica de Córdoba. Facultad de Derecho y Ciencias Sociales; ArgentinaFil: Filippi, María Cristina. Universidad Católica de Córdoba. Facultad de Derecho y Ciencias Sociales; ArgentinaFil: Alba Crespo, Juan José. Universidad Católica de Córdoba. Facultad de Derecho y Ciencias Sociales; Argentin