Abstract: The amygdala is a key hub for the acquisition, storage and extinction of fear memories, which are important in adaptive behaviors. The intercalated cell clusters (ITCs) are groups of inhibitory cells within the amygdaloid complex that have been recently shown to play an important role in fear-related states, especially in the context of fear extinction. Apart from the canonical view that points ITCs as feedforward and feedback inhibitors between the input and output stations towards motor centers, it has been starting to suggest that they could have diverse outputs to different regions beyond the amygdaloid complex. Although some preliminary studies have given some indications of this potential new role of the ITCs, indicating an increase in the complexity of their function in fear behavior and emotional processing, very little is still known. In this thesis, two ITC clusters –lateral and dorsomedial– are the object of the study and two main questions are addressed: (1) Do lateral and dorsomedial ITCs (latITCs and dmITCs) extend long-range projections towards the non-lemniscal (NL) thalamus and the dopaminergic (DA) midbrain? If yes, are their innervation patterns different from each other across these structures? I evaluated the outward latITCs and dmITCs projections to the NL-thalamic and DA-midbrain subnuclei, using anterograde tracing upon Cre-dependent expression of ChR2-EYFP in FoxP2-Cre transgenic mice and less extensively, using retrograde tracing to confirm the results from the anterograde tracing. With these methodological approaches I showed that latITCs and dmITCs do send long-range projections in a differential fashion towards the distinct examined subnuclei. I also showed that these projections are inhibitory (most likely GABAergic) and also, that to assess the innervation pattern, it is necessary to make either automated counting of the fibers, or measure the general innervation in terms of at least two variables–area coverage and fibers’ density– that indirectly provide a more comprehensive innervation index. Resumen: La amígdala es un centro fundamental en la adquisición, almacenamiento y extinción de memorias de miedo, que son importantes para los comportamientos adaptativos. Los grupos de células intercaladas (ITCs) se localizan del complejo de la amígdala, y la regulación inhibitoria sobre ésta, ha demostrado demostrado tener un papel importante en los estados relacionados con el miedo, especialmente en el contexto de la extinción. Aparte de la visión canónica que señala a las ITCs como inhibidores retroalimentadores y proalimentadores entre las estaciones de input y output hacia los centros motores, se ha empezado a sugerir que podrían tener diversas salidas hacia diferentes regiones más allá del complejo de la amígdala. A pesar de que algunos estudios preliminares han dado algunos indicios que soportan este nuevo rol de las ITCs, indicando un aumento de la complejidad de su función en el comportamiento del miedo y el procesamiento emocional, actualmente se conoce muy poco sobre este rol extendido. En esta tesis, dos grupos de células intercaladas diferentes -lateral y dorsomedial- son objeto de estudio y se abordan dos cuestiones principales (1) ¿Los ITCs laterales y dorsomediales (latITCs y dmITCs) extienden proyecciones extendidas hacia núcleos no lemniscales del tálamo (NL) y el cerebro medio dopaminérgico (DA)? En caso de hacerlo, ¿se presenta un patrón inervación diferencial hacia estas estructuras? Para responder esto, he evaluado las proyecciones de los grupos latITCs y dmITCs hacia múltiples subnúcleos del tálamo no lemniscal y del mesencéfalo dopaminérgico, utilizando el trazado viral anterógrado tras la expresión de ChR2-EYFP, que es dependiente del sistema Cre, en ratones transgénicos FoxP2-Cre y, de forma menos extensa, utilizando el trazado retrógrado para confirmar los resultados del trazado anterógrado. Con estos enfoques metodológicos me fue posible demostrar que los grupos de latITCs y dmITCs envían proyecciones extendidas hacia los distintos subnúcleos examinados, de forma diferencial. También demostré que estas proyecciones son inhibitorias (muy probablemente GABAérgicas) y también, que para evaluar el patrón de inervación, es necesario hacer un recuento automatizado de las fibras (por medio de un algoritmo), o medir la inervación general en términos de al menos dos variables -cobertura de área y densidad de fibras- que de forma indirecta, proporcionan un índice de inervación más completo.

Abstract: Latin American countries are experiencing a significant increase in the reports of mistreatment that women experience while using the maternity healthcare services, a phenomenon acknowledged as “Obstetric Violence” (OV). The Latin American region is crucial for the recognition of OV, not only because the term OV was originated there, but also because of its particular response to the matter. The present Scoping Review aimed to identify and review the available evidence about the response of Latin American countries to OV. As a result, it was found, firstly, that the emergence of the concept of OV in Latin America demonstrated to be a transformative tool useful to raise awareness about the mistreatment women face when giving birth. This OV concept also positions this problematic as subset of gendered violence and as a type of structural violence, through which the need to address it systemically is highlighted. Secondly, the used categorization of OV appears to be the broadest and more inclusive typology, emphasizing that OV might stem from both intentional and unintentional actions of healthcare professionals, as well as from conditions within healthcare organizations. Moreover, the identified variables that influence the response to OV in Latin America were synthetized into a theoretical framework, which offers insight into how the problem has been addressed until now and subsequently, provides useful lessons for other countries seeking approaches to combat mistreatment of women during childbirth. Lastly, it was determined that, in order to address OV and allow the progression of public policies to become regionally available, a broadened view encompassing a human rights-based approach is necessary. This research allowed to conclude that OV is a multi-faceted and complex phenomenon whose solution requires a multidimensional and multidisciplinary approach. Furthermore, OV should be understood as more than a simple act of mistreatment, but rather be viewed as a set of socially constructed symbolic, and violent, meanings allowing different stakeholders to reframe the abuse and violence that women undergoing childbirth experience as natural, expected, and accepted, reinforcing specific gender dynamics not merely in maternity care but in society overall. Finally, the framework to tackle OV within the human rights approach developed by the author is expected to be advantageous for the development of further research, programs, and policies to prevent OV in Latin America and beyond.

Background: Post-stroke fatigue (PSF) is one of the most challenging clinical consequences to manage after stroke as no effective treatment has been developed. However, the mechanisms of PSF remain unclear. Aims: This study aimed to replicate Vecchio et al (2017) using resting-state EEG in stroke patients suffering from varying degrees of fatigue to describe the functional organisation within sensory and motor networks. Methods: Resting-state eyes-open EEG was recorded in 22 strokesurvivors. Upper limb functional tests (grip strength, Nine Hole Peg Test), symbol digit modalities test (SDTM), anxiety and depression scale (HADS), Fatigue Severity Scale (FSS-7), state fatigue, and Neurological Fatigue Index (NFI-stroke) were measured. Graph theory was used to calculate the small-world (SW) index. SW was calculated in four separate networks, motor and sensory within the left and right hemispheres. Exact low-resolution brain electromagnetic tomography (eLORETA) was applied using seven frequency bands (delta, theta, alpha1, alpha2, beta1, beta2, and gamma). Results: Correlation analysis demonstrated a positive association between SW in the right motor network in beta2 band and higher FSS-7 score and a negative correlation between SW in the left sensory network in alpha1 and higher state fatigue. Conclusion: Beta oscillations have been associated with top-down processes which are crucial for perceptual inference and alpha oscillations are involved in sensorimotor information processing. The interaction between the top-down and bottom-up processes, and perceived error explains the sensory attenuation model of fatigue. Our results were consistent this model of fatigue as stroke survivors had difficulty in attenuating the sensory input leading to higher perceived effort.

Abstract: SEPSIS-3 IN PREGNANT WOMEN IN LABOUR Abstract Introduction: Maternal sepsis represents 10.7% of maternal deaths worldwide, ranking as the third cause of mortality after haemorrhage and hypertensive disorders. Despite its high incidence, it still lacks a gold standard diagnosis. The latest update that proposed new sepsis criteria and scores, Sepsis-3, did not mention pregnancy as part of the study population. This study aims to evaluate the inclusion or exclusion of Sepsis- 3 pregnancy. Methods: This is a literature review of the Sepsis-3 database looking for the inclusion or exclusion of pregnancy from the latest update in sepsis and the basis of current definitions and guidelines. In addition, I reported the retrospective measurement of qSOFA and SOFA scores in 100 pregnant patients in labour from the EPIFEVER-2 cohort at the Royal London Hospital compared to their infection status. Results: Sepsis-3 investigators evaluated the predictive validity of the SOFA and qSOFA score for mortality in sepsis among nearly 1 million patients, however, pregnant women were not included. The SOFA and qSOFA score overlap with the normal physiological changes of pregnancy and labour, in the EPIFEVER-2 cohort 16% of uninfected pregnant patients during labour scored 1 point on qSOFA and 17% 1 point on SOFA score. The highest SOFA score of 3 points was obtained in a patient with bleeding rather than infection. Conclusion: Pregnant patients were not included in the Sepsis-3 databases. Therefore, qSOFA and SOFA score have not been validated for use in this population. Furthermore, as they are not modified for the normal physiological changes of pregnancy, detection of patients without infection has been reported. Further validation of qSOFA or modified SOFA scores as sepsis-specific maternal warning scores is expected in future research.

Abstract: Background: Deep brain stimulation (DBS) surgery is a treatment in the advanced stage of Parkinson's disease (PD). Despite close follow-up, multiple evaluations, and several months of timeconsuming programming sessions, the clinical response may not be optimal in some cases. Imageguided programming (I-GP) could help optimize programming sessions with better clinical outcomes. Objective: To evaluate clinical and quality of life (QoL) outcomes with I-GP in PD patients with DBS of the subthalamic nucleus (STN) and suboptimal clinical improvement and refractory symptoms to conventional clinical programming. Methods: A prospective study in 16 patients with a diagnosis of PD with STN-DBS and remaining adverse effects or symptoms despite a clinical programming adjustment. We simulate potentially effective stimulation based on volume tissue activated (VTA) using commercially available software tools. Clinical outcomes were assessed with motor and quality of life scales. Results: The most frequent suboptimal symptom was gait disorder 33.3% (n=9), residual motor symptoms 25.9%(n=7), and speech 25.9%(n=7). Statistically significant results (p=0.001) were found after I-GP with change in the global Deep Brain Stimulation – Impairment score (41%), The 8- item version of the Parkinson's Disease Questionnaire (47%), EuroQol visual analogue scale (62%), and motor scale (24%). Conclusions: In suboptimal cases of patients with PD and STN-DBS, especially with ongoing and residual motor symptoms, I-GP could be useful to optimize the programming of DBS and improve patients' QoL.

Abstract: Sexual reproduction depends on the transmission of exactly one copy of each chromosome by the maternal and paternal gametes. This is accomplished during meiosis when diploid progenitors undergo two consecutive rounds of chromosome segregation following a single round of DNA replication. In most organisms, this relies on the establishment of bivalent chromosomes consisting of replicated parental homologues physically linked at sites of meiotic recombination. In female mammals, bivalents are formed during fetal development when the lifetime stock of primordial-stage oocytes is established. However, they are not resolved until shortly before ovulation. Extending this period beyond ~35 years results in a dramatic increase in embryo aneuploidy. Depletion of the lifetime stock of oocytes during ageing culminates in menopause. Our previous studies indicate that Rec8-containing cohesin complexes also become depleted from oocyte chromosomes during female ageing. Consistent with cohesin’s role in maintaining chromosome structure, depletion of Rec8 is associated with destabilisation of bivalents chromosomes. Nevertheless, the mechanisms and timing of cohesin depletion remain unknown. Here, I investigated the possibility that age-related cohesion depletion is a consequence of leaky inhibition of the protease separase, which cleaves Rec8 during anaphase. I found that oocyte-specific deletion of separase did not prevent depletion of oocyte cohesin during female ageing. I, therefore, conclude that age-related depletion occurs by a separaseindependent mechanism. I next investigated the timing, during oogenesis, at which cohesin loss occurs. I found that cohesin is predominantly lost at the primordial stage before oocytes are recruited for growth. In addition, using an oocyte-specific deletion of Pten, I determined that this occurs independently of the decline in the ovarian stock of primordial-stage oocytes. Together, these results indicate that age-related cohesin depletion occurs at the primordial stage by a separase-independent mechanism. Other possible of mechanisms of cohesin depletion include protein damage and/or agerelated deterioration of chromatin structure. From a clinical perspective, my work suggests that “rejuvenation’ of fertility by activating the residual pool of primordial oocytes is unlikely to be successful in older women.

Abstract: Background: Although Latin American migrants (LAMs) are one of the fastest-growing migrant populations in England, they still face health barriers that make them unaware of their HIV status, leading to late HIV diagnosis, AIDS, and even death. Thus, this study aims to assess the differences in HIV outcomes among newly HIV-diagnosed LAMs compared to other England populations. Methods: Data on new HIV/AIDS diagnoses in the UK during the 2011-2020 period were obtained from the HIV and AIDS New Diagnoses and Deaths Database (HANDD) and the HIV and AIDS Reporting System (HARS). Potential associations between the region of birth and late HIV diagnosis, AIDS at HIV diagnosis, and mortality were analysed by logistic regression. Furthermore, a comparison between LAMs and the main populations living in the UK was examined. Lastly, a descriptive trend analysis was made. Results: From 2011 to 2020, 47,828 new HIV diagnoses were reported in the UK, with almost a third (29.2%) being late diagnoses. Over half of new diagnoses (52%) were made in migrants, LAMs representing 9.3% of those diagnoses. In general, newly diagnosed HIV LAMs are not more likely to be diagnosed late than UK residents (aRRR: 1.02; 95%CI: 0.90–1.15). However, some subgroups are more likely to be diagnosed late than their UK counterparts (e.g., 15-24 years old). Regarding AIDS and mortality, LAMs are less likely to be diagnosed with AIDS (aOR: 0.50; 95%CI: 0.35–0.71) or die by any cause (aOR: 0.29; 95%CI: 0.16–0.52) than UK residents. Finally, the number of new HIV diagnoses among LAMs increased in those ten years, but the number of late diagnoses remained nearly constant. Conclusions: Although the current HIV epidemiological situation of LAMs living in the UK is not troublesome, the expansion of the LAM population and their increasing number of new HIV diagnoses could become a public health challenge in the coming years. Therefore, to accomplish the 2030 zero HIV transmission goal, it is necessary to integrate the migrant community into future public policies and categorise them as the ‘sixth’ HIV key population in the UK.

Abstract: The evolution of multidrug resistance in Klebsiella species in response to selective pressure and the extent to which this may be reversible is not fully understood. The spread of carbapenemresistant Enterobacteriaceae (CRE) is considered a public health threat by the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC). As such, more studies are needed to understand the evolution of antibiotic resistance mechanisms to determine if it is possible to reverse this trend. Highlighted In this study, a comprehensive characterisation of a clinical Klebsiella quasipneumoniae isolate called FK688 is performed. The FK688 strain is resistant to multiple antibiotics, including third-generation cephalosporins and carbapenems and caused a bloodstream infection in a hospitalised patient. A combinational approach of genomic, enzymatic, and machine learning analyses did not uncover any carbapenemase-encoding genes in FK688. Rather, this research showed that epistatic changes are necessary for FK688 to acquire a CRE phenotype. Evolution experiments demonstrated the fitness burden associated with antimicrobial resistance determinants and the reversion to a carbapenem-susceptible phenotype in an antibiotic-free environment. Fitness assays showed that a low concentration of ceftazidime selects for a ?- lactamase gene and can potentiate evolution to carbapenem resistance by a single-step mutation in the porin OmpK36. This study demonstrated the importance of epistatic events and how variation in drug exposure can shape the evolutionary pathway to antibiotic resistance in bacteria.

Background and aim: Mental health services in Colombia have had a complex history shaped by 50 of years armed conflict, disproportionate clinical approach and social factors such as stigma. Nevertheless, recent global tendencies and interventions have suggested basing mental health services on communities and the recovery approach and considering the social determinants of mental health during planning. Colombia has involved these approaches in its legal and practical framework in recent years, but multiple internal and external factors have retarded an accurate implementation. This systematic review aims to contribute to mental health services understanding in Colombia, offering an implementation research approach. Methods: A comprehensive strategy search was developed to include peer-reviewed studies where mental health services were mentioned or described. The review was conducted in five databases (Medline (OVID), PubMed, Scopus, Scielo and BVS), three languages (English, Spanish & Portuguese) and was limited to the last ten years. Moreover, it followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and used the Consolidated Framework for Implementation Research (CFIR) to identify barriers and facilitators during the implementation of mental health services. Results: Twelve articles were selected. The principal reported barriers were lack of coordination, workloads, and funding. Implementation differences between public and private settings were significant and repeatedly reported. On the other hand, good planning strategies and the involvement of communities, stakeholders, users, and external champions facilitated implementation. Remarkable efforts to adopt community-based mental health services were described as well. Conclusions: Overall, this review offers significant insight into current mental health services, their implementation status, and principal barriers to effective implementation. It is suggested to continue applying community and recovery approaches in mental health services, but also to improve coordination between all actors (e.g., public and private organisations, non-governmental organisations (NGOs), and users and their families).

Abstract: Objective: To describe the prevalence pattern of anemia among Indigenous children in Latin America. Methods: PRISMA guidelines were followed. Records were identified from the databases PubMed, Google Scholar, and Lilacs by two independent researchers between May and June 2021. Studies were included if the following criteria were met: a) studied Indigenous people b) was about children (from 0 to 12 years old); c) reported a prevalence estimate of anemia; d) had been conducted in any of the countries of Latin America; e) was published either in English, Portuguese, or Spanish; f) is a peer-reviewed article; and g) was published at any date. Results: Out of 2,401 unique records retrieved, 42 articles met the inclusion criteria. A total of 39 different Indigenous communities were analyzed in the articles, and in 21 of them (54.0%) child anemia was a severe public health problem (prevalence ? 40%). Those communities were the Aymara (Bolivia); Aruak, Guaraní, Kamaiurá, Karapotó, Karibe, Kaxinanuá, Ma-cro-Jê, Suruí, Terena, Xavante (Brazil); Cabécar (Costa Rica), Achuar, Aguaruna, Awajún, Urarina, Yomybato (Peru); Piaroa and Yucpa (Venezuela); and Quechua (Peru and Bolivia). Children below two years had the highest prevalence of anemia (between 16.2% and 86.1%). Among Indigenous people, risk factors for anemia include nutrition, poor living conditions, access to health services, racism, and discrimination. Bolivia and Guatemala are scarcely studied, despite having the highest proportion of Indigenous communities in Latin America. Conclusions: Anemia constitutes a poorly documented public health problem among Indigenous children in 21 Indigenous communities in Bolivia, Brazil, Colombia, Costa Rica, Ecuador, Guatemala, Mexico, and Peru. In all Indigenous communities included in this study child anemia was an issue, especially in younger children. Resumen: Objetivo: Describir el patrón de prevalencia de anemia en niños indígenas de América Latina. Métodos: Se siguieron las directrices PRISMA. Los registros fueron identificados en las bases de datos PubMed, Google Scholar y Lilacs por dos investigadores independientes entre mayo y junio de 2021. Los estudios se incluyeron si cumplían los siguientes criterios: a) estudiaban a indígenas; b) eran sobre niños (de 0 a 12 años); c) reportaban una estimación de prevalencia de anemia; d) se habían realizado en cualquiera de los países de América Latina; e) se publicaron en inglés, portugués o español; f) eran artículos revisados por pares; y g) se publicaron en cualquier fecha. Resultados: De los 2.401 registros únicos recuperados, 42 artículos cumplían los criterios de inclusión. Un total de 39 comunidades indígenas diferentes fueron analizadas en los artículos, y en 21 de ellas (54,0%) la anemia infantil era un problema grave de salud pública (prevalencia ? 40%). Esas comunidades eran aymara (Bolivia); aruak, guaraní, kamaiurá, karapotó, karibe, kaxinanuá, macro- jê, suruí, terena, xavante (Brasil); cabécar (Costa Rica), achuar, aguaruna, awajún, urarina, yomybato (Perú); piaroa y yucpa (Venezuela); y quechua (Perú y Bolivia). Los niños menores de dos años presentaban la mayor prevalencia de anemia (entre el 16,2% y el 86,1%). Entre los indígenas, los factores de riesgo de la anemia son la nutrición, las malas condiciones de vida, el acceso a los servicios sanitarios, el racismo y la discriminación. Bolivia y Guatemala están escasamente estudiados, a pesar de tener la mayor proporción de comunidades indígenas de América Latina. Conclusiones: La anemia constituye un problema de salud pública poco documentado entre los niños indígenas de 21 comunidades indígenas de Bolivia, Brasil, Colombia, Costa Rica, Ecuador, Guatemala, México y Perú. En todas las comunidades indígenas incluidas en este estudio, la anemia infantil era un problema, especialmente en los niños más pequeños.