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The study aimed to analyze the microbiological characteristics of water from artisanal wells in the municipality of Guajará in Amazonas, verifying the presence of Escherichia coli and total coliforms. The collections were carried out in residences in the center of the city in 10 points. COLItest Kits were used, which have substances, nutrients and MUG in their formulation that, properly balanced, inhibit the growth of Gram-positive bacteria, favoring the growth of bacteria from the coliform group and facilitating the identification of E. coli through fluorescence after incubation at 37 °C in 48 hours. In the qualitative analysis of the water, it was observed the presence of total coliforms in 80% of them and in 20% they presented absence of microorganisms. The samples that showed total coliforms, it was possible to observe that in 75% there was contamination by E. coli, representing a great risk to the health of those who consume water from these points without adequate treatment. However, measures for the preservation of water sources, the treatment of water for human consumption and the practice of using chlorine or boiling the water in the places where they were collected are necessary actions to reduce the occurrence of total coliforms and Escherichia coli.

ZusammenfassungSchwangerschaft und Geburt eines Kindes stellen eine prägende Erfahrung mit Auswirkungen auf das Körpergefühl und die Sexualität einer Mutter dar. Dabei wird in der Literatur bereits ein Einfluss des Geburtsmodus auf die postpartale Sexualität diskutiert. Ziel dieser Studie ist es nun, die Wiederaufnahme von vaginalem Geschlechtsverkehr (vag. GV.) und das Auftreten einer Dyspareunie in Abhängigkeit von primärer vs. sekundärer Sectio zu untersuchen. Ebenso werden ein möglicher Einfluss des Stillens, der (Still-)Amenorrhoe und hormoneller Kontrazeptiva auf die Wiederaufnahme des vag. GV näher evaluiert. Methodik Von Oktober 2019 bis Juni 2020 wurden 525 Frauen nach erfolgter Sectio für eine prospektive, multizentrische Studie zur Erhebung von Häufigkeit und assoziierten Beschwerden bei einer Isthmozele drei (3 M. pp.) und sechs Monate postpartal (6 M. pp.) rekrutiert. Im Rahmen dieser Studie wurden die Studienteilnehmerinnen zudem mittels Fragebögen zur Wiederaufnahme des vag. GV, zum Stillen und zu potentieller Symptome wie „Dyspareunie“ und „Unterbauchschmerzen“ befragt. Eingeschlossen wurden Frauen im Alter zwischen 18 und 40 Jahren, mit Einlings- oder Geminigravidität, ohne Plazentationsstörung. Ergebnisse 66,4% der befragten Frauen gaben 3 M. pp. an wieder vag. GV aufgenommen zu haben, zu 6 M. pp. 79,7% (p Schlussfolgerungen Auch wenn sekundären Sectiones oftmals verzögerte Geburtsphasen vorangehen und der Eingriff unter erschwerten Bedingungen durchgeführt werden muss, zeigt sich in dieser Studie kein Einfluss auf die postpartale Sexualität. Eine (Still-)Amenorrhö wurde hingegen als Faktor identifiziert, der vermehrt zu einer Dyspareunie führen kann.

RESUMO: O objetivo deste artigo é apresentar como tem sido organizado e realizado o trabalho do Grupo de Trabalho e Estudos em Educação Inclusiva - GTEEI da Associação dos Municípios do Oeste do Paraná - AMOP na última década, com vistas a relatar e discutir sobre esse processo de formação de professores, no sentido de sua contribuição, tanto para a inclusão escolar, como para a continuidade dos estudos de alunos com deficiência/NEE, os quais, por estarem sendo atendidos de modo orientado desde a tenra infância, têm tido a oportunidade de uma mediação qualificada e, consequentemente, muitos deles, provavelmente, têm podido dar seguimento a seus estudos, de forma a ter acesso ao Ensino Superior. O estudo – sob a forma de relato de experiência, com caráter qualitativo - foi organizado por meio de uma apresentação dos projetos e avaliações arquivadas ao longo dos anos de 2012 a 2022 com relação a: objetivos, justificativas, metodologias e alguns resultados dos cursos, uma vez que eles vêm apresentando - no nível da educação básica e no Atendimento Educacional Especializado – AEE - regularidade e consistência teórico-metodológica que podem apontar para indicadores de qualidade que permitam a esses alunos com deficiência/NEE os fundamentos e as bases para a superação das dificuldades impostas pela deficiência/NEE. Os resultados vêm demonstrar a permanência e persistência do grupo de professores ao longo dos anos, o aprofundamento dos estudos e a elaboração de materiais a partir dos fundamentos da Teoria Histórico-Cultural - THC e da Pedagogia Histórico-Crítica - PHC. Tem havido, ainda, um aumento crescente de professores inscritos, o que possibilita a ampliação de oportunidades de qualificação pessoal e profissional desses professores, de forma a que seus alunos com deficiência/NEE possam receber uma educação de qualidade com vistas a galgarem os mais altos níveis de ensino, inclusive o acesso ao ensino superior.

Purpose The purpose of this study was to determine the frequency of detection of isthmoceles by ultrasound 6 months after caesarean section (CS) and which symptoms associated with isthmocele formation occur after CS. Subsequently, it was determined how often the ultrasound finding “isthmocele” coincided with the presence of complaints. Methods A prospective multicentre cohort study was conducted with 546 patients from four obstetric centres in Berlin, who gave birth by primary or secondary CS from October 2019 to June 2020. 461 participants were questioned on symptoms 3 months after CS; 329 participants were included in the final follow-up 6 months after CS. The presence of isthmoceles was determined by transvaginal sonography (TVS) 6 months after CS, while symptoms were identified by questionnaire. Results Of the 329 women, 146 (44.4%) displayed an isthmocele in the TVS. There was no statistically significant difference in the manifestation of symptoms between the two groups of women with and without isthmocele; however, when expressed on a scale from 1 to 10 the intensity of both scar pain and lower abdominal pain was significantly higher in the set of women that had shown to have developed an isthmocele (p = 0.014 and p = 0.031, respectively). Conclusion The prevalence of isthmoceles 6 months after CS was 44.4%. Additionally, scar pain and lower abdominal pain were more pronounced when an isthmocele was also observed in the TVS. Trial registration Trial registration number DRKS00024977. Date of registration 17.06.2021, retrospectively registered.

Purpose Hyponatremia occurs in about 30% of patients with pneumonia, including those with SARS-CoV-2 (COVID-19) infection. Hyponatremia predicts a worse outcome in several pathologic conditions and in COVID-19 has been associated with a higher risk of non-invasive ventilation, ICU transfer and death. The main objective of this study was to determine whether early hyponatremia is also a predictor of long-term sequelae at follow-up. Methods In this observational study, we collected 6-month follow-up data from 189 laboratory-confirmed COVID-19 patients previously admitted to a University Hospital. About 25% of the patients (n = 47) had hyponatremia at the time of hospital admission. Results Serum [Na+] was significantly increased in the whole group of 189 patients at 6 months, compared to the value at hospital admission (141.4 ± 2.2 vs 137 ± 3.5 mEq/L, p 2/FiO2 increased. Accordingly, pulmonary involvement, evaluated at the chest X-ray by the RALE score, decreased. However, in patients with hyponatremia at hospital admission, higher levels of LDH, fibrinogen, troponin T and NT-ProBNP were detected at follow-up, compared to patients with normonatremia at admission. In addition, hyponatremia at admission was associated with worse echocardiography parameters related to right ventricular function, together with a higher RALE score. Conclusion These results suggest that early hyponatremia in COVID-19 patients is associated with the presence of laboratory and imaging parameters indicating a greater pulmonary and right-sided heart involvement at follow-up.

COVID-19 has several mechanisms that can lead to lymphocyte depletion/exhaustion. The checkpoint inhibitor molecule programmed death protein 1 (PD-1) and its programmed death-ligand 1 (PDL-1) play an important role in inhibiting cellular activity as well as the depletion of these cells. In this study, we evaluated PD-1 expression in TCD4+, TCD8+, and CD19+ lymphocytes from SARS-CoV-2-infected patients. A decreased frequency of total lymphocytes and an increased PD-1 expression in TCD4+ and CD19+ lymphocytes were verified in severe/critical COVID-19 patients. In addition, we found a decreased frequency of total monocytes with an increased PD-1 expression on CD14+ monocytes in severe/critical patients in association with the time of infection. Moreover, we observed an increase in sPD-L1 circulant levels associated with the severity of the disease. Overall, these data indicate an important role of the PD-1/PDL-1 axis in COVID-19 and may provide a severity-associated biomarker and therapeutic target during SARS-CoV-2 infection.

Fewer than 10% of emergency medical system (EMS) calls concern children and adolescents younger than 18 years. Studies have shown that the preclinical care of children differs from that of adults regarding assessment, interventions, and monitoring. The aims of this study were to describe the preclinical care and emergency transport of pediatric patients in Vorarlberg, Austria and to compare trauma and nontrauma cases.This is a population-based study, analyzing medical records of EMS calls to children and adolescents. We received all patient records of EMS calls to children and adolescents younger than 18 years (n = 4390 in total) from the 2 local EMS providers, the Red Cross Vorarlberg and the Austrian Mountain Rescue Service (Christophorus 8 and Gallus 1) covering a study period of 7 years, from 2013 to 2019. The record data were extracted by automation with an in-house program and subsequently anonymized. Statistical analyses were performed with SPSS Statistics.During the study period, 7.9% of all EMS calls concerned children and adolescents younger than 18 years. For our study, 3761 records were analyzed and 1270 trauma cases (33.8%) were identified. The most common injuries were injuries of the extremities and traumatic brain injury. The frequency of National Advisory Committee of Aeronautics Scores of 4 or higher was 17.7%, similar for all age groups and for trauma as well as nontrauma patients. Mean Glasgow Coma Scale scores were higher in the trauma group than in the nontrauma group (14.2 vs 11.2). In 62.9% of all patients, 1 or more vital parameters were documented. A majority of these values was in the pathologic range for the respective age group. The rate of pulsoxymetry monitoring during transport was low (42.1% in trauma and 30.3% in nontrauma patients) and decreased significantly with patient age. Moreover, while the placing of intravenous lines and monitoring during transport were significantly more frequent in trauma patients, the administration of medication or oxygen was significantly more frequent in nontrauma patients.The pediatric population lacks assessments and monitoring in preclinical care, especially the youngest children and nontrauma patients, although emergency severity scores are similar.

We study the Bellman equation in the Wasserstein space arising in the study of mean field control problems, namely stochastic optimal control problems for McKean-Vlasov diffusion processes.Using the standard notion of viscosity solution \`a la Crandall-Lions extended to our Wasserstein setting,we prove a comparison result under general conditions on the drift and reward coefficients, whichcoupled with the dynamic programming principle, implies that the value function is the unique viscosity solution of the Master Bellman equation.This is the first uniqueness result in such a second-order context. The classical arguments used in the standard cases of equations in finite-dimensional spaces or in infinite-dimensional separable Hilbert spaces do not extend to the present framework, due to the awkward nature of the underlying Wasserstein space. The adopted strategy is based on finite-dimensional approximations of the value function obtained in terms of the related cooperative $n$-player game, and on the construction of a smooth gauge-type function, built starting from a regularization of a sharp estimate of the Wasserstein metric; such a gauge-type function is used to generate maxima/minima through a suitable extension of the Borwein-Preiss generalization of Ekeland's variational principle on the Wasserstein space.

The global pandemic of COVID-19 has underlined the need for more coordinated responses to emergent pathogens. These responses need to balance epidemic control in ways that concomitantly minimize hospitalizations and economic damages. We develop a hybrid economic-epidemiological modeling framework that allows us to examine the interaction between economic and health impacts over the first period of pathogen emergence when lockdown, testing, and isolation are the only means of containing the epidemic. This operational mathematical setting allows us to determine the optimal policy interventions under a variety of scenarios that might prevail in the first period of a large-scale epidemic outbreak. Combining testing with isolation emerges as a more effective policy than lockdowns, substantially reducing deaths and the number of infected hosts, at lower economic cost. If a lockdown is put in place early in the course of the epidemic, it always dominates the “laissez-faire” policy of doing nothing.

Funding Acknowledgements Type of funding sources: None. Background The COVID-19 pandemic has highlighted the role of telemedicine in reducing face-to-face visits. Telemedicine requires either the use of digital support methods and a minimum technological knowledge of the patients. Digital health literacy, defined as the use of digital literacy skills to find and use health information and services, may influence the use of telemedicine in most patients, particularly in specific groups such as those with frailty. Aim To explore the association between frailty status, patients' use of digital tools and digital health literacy to determine whether it would be possible to implement control visits in patients followed in a cardiac arrhythmias outpatient clinic. Methods We prospectively enrolled consecutive patients referring to arrhythmias outpatient clinics of our department from March to September 2022. Patients were divided according to frailty status as defined by the Edmonton Frail Scale (EFS) into three subgroups: robust, pre-frail, and frail. The degree of health digital literacy was assessed through the Digital Health Literacy Instrument (DHLI) Scale. The DHLI explores 7 digital skill categories measured by 21 self-report questions. The self-report questions require participants to rate on a 4-point scale how difficult different tasks are and how frequently they encounter certain difficulties on the Internet. The total DHLI and each skill category score were calculated by summing the received scores in every single domain (3 questions per each skill category) and reported as mean and median. A multivariable logistic regression analysis was also use to evaluate the association between the non-use of the Internet and frailty status. Results A total of 300 patients were enrolled (36.3% females, median age 75 [66-84]) and stratified according to frailty status as: (i) Robust (EFS ≤ 5; n = 212, 70.7%), (ii) Pre-Frail (EFS 6-7; n = 47, 15.7%), and (iii) Frail (EFS ≥ 8; n = 41, 13.7%). Frail patients used less frequently smartphones, PC and emails and had less availability of Wi-Fi at home compared to robust patients (Table 1). At the multivariable logistic regression analysis, frailty was significantly associated with the non-use of the Internet (adjusted odds ratio, 2.58 95% confidence interval 1.92-5.61). Digital health literacy score decreased as the level of frailty increased in all the domains explored (operational skills, navigation skills, information searching, evaluating the reliability of the information, determining the relevance of online information, adding self-generated content and protecting privacy while using the internet, all p Conclusions Frail patients are characterized by a lower use of digital tools and access to the Internet even though these patients would benefit the most from telemedicine. Digital skills are strongly influenced by frail status highlighting the need to implement digital health literacy with specific interventions in this population.

Previous studies have adopted an edge-centric framework to study fine-scale dynamics in human fMRI. To date, however, no studies have applied this same framework to data collected from model organisms. Here, we analyze structural and functional imaging data from lightly anesthetized mice through an edge-centric lens. We find evidence of “bursty” dynamics and events – brief periods of high-amplitude network connectivity. Further, we show that on a per-frame basis events best explain static FC and can be divided into a series of hierarchically-related clusters. The co-fluctuation patterns associated with each centroid link distinct anatomical areas and largely adhere to the boundaries of algorithmically detected functional brain systems. We then investigate the anatomical connectivity undergirding high-amplitude co-fluctuation patterns. We find that events induce modular bipartitions of the anatomical network of inter-areal axonal projections. Finally, we replicate these same findings in a human imaging dataset. In summary, this report recapitulates in a model organism many of the same phenomena observed in previously edge-centric analyses of human imaging data. However, unlike human subjects, the murine nervous system is amenable to invasive experimental perturbations. Thus, this study sets the stage for future investigation into the causal origins of fine-scale brain dynamics and high-amplitude co-fluctuations. Moreover, the cross-species consistency of the reported findings enhances the likelihood of future translation.

Determining the background values of chemical components in environmental matrices is a difficult task. This is particularly true in regions where the human impact due to industrial, mining, agricultural and urban activities coexists with a geological (geogenic) anomaly, which influences the concentration of certain elements in soils, waters and air. In these cases, the term geochemical baseline (GB) is preferable, since it considers the actual content of that element in the superficial environment at a given point in time, including both geogenic and anthropogenic contribution. In this study, a total of 102 top- and sub-soil (collected at 10-50 cm and 50-154 cm depth, respectively) samples and seven rocks, onto which the soils developed, were collected for the determination of GBs for selected chalcophile (As, Cu, Hg and Sb) and siderophile (Co, Cr, Ni, and V) elements in 25.6 km2 around the former mining area of Abbadia San Salvatore (Mt. Amiata, Southern Tuscany, Italy). For about one century, cinnabar (HgS) ore deposits have been exploited to produce liquid mercury from the Mt. Amiata volcanic system and its surroundings, which represents a world-class mercury district. The < 2 mm (as required by the national regulamentation) fraction of the samples was pulverized and analysed by ICP-MS (As, Hg and Sb) and ICP-AES (Co, Cr, Ni, and V) after aqua regia digestion. The compositional data analysis of multivariate compositional vectors, based on the log-ratio approach was used to assess the nature of the geochemical . According to our findings, the centred log-ratio (clr) opposed to that of raw/log transformation, enhances the spatial mapping. This also allowed to obtain better-separated variables in the robust Principal Component Analysis (rPCA). Log-ratio geographical maps evidenced that the underlying bedrock geology (parent lithologies), rather than anthropogenic causes, controls the distribution of the great majority of the elements in the top- and sub-soils. The resulting clr-PCA approach, associated with the geological features, indicates that the geochemical pattern of Hg-As is to be related to the volcanic rocks and ore-deposits, although an anthropogenic influence due to the past mining activity in the topsoils cannot be ruled out. Sb, Co, Cr, Ni, and V distribution patterns are in most cases attributed to calcareous and clay lithologies. The anomalous content of Sb found within the volcanic rocks was likely due to the presence of previously undetected old mining dump. The two data populations (volcanic and calcareus-clay lithologis) were separated into two different databases and the outliers were removed when necessary. By processing the two datasets, the US-EPA’s ProUCL software was used for calculating the GBs for the selected suite of elements. The obtained values are paramount for establishing specific guidelines and quality standards in environmental legislation and policy-making to be applied by the Municipality of Abbadia San Salvatore

O ingresso na universidade, ainda que traga sentimentos positivos relacionados ao alcance de uma meta programada, por vezes pode se tornar um período crítico, de maior vulnerabilidade para o início e a manutenção do uso de drogas psicotrópicas. A prevalência do uso de drogas na população universitária, demonstraram que o consumo dessas é maior nesse grupo quando comparado aos estudantes do ensino médio e ao restante da população em geral. Trata-se de um estudo de revisão bibliográfica, de caráter descritivoe de abordagem qualitativa, com objetivo de identificar, na literatura, os riscos e malefícios do uso de drogas licitas e ilícitas por graduandos do curso de medicina. A partir dessa leitura preliminar, foram selecionados 19 artigos que mantinham coerências com os descritores acima apresentados e com os objetivos do estudo. Posterior à leitura reflexiva emergiram duas categorias: Impactos do curso de graduação de medicina na saúde do graduando; Riscos e malefícios do uso de drogas licitas e ilícitas por graduandos do curso de medicina; possíveis estratégias preventivas frente ao uso de drogas no curso de medicina. Portanto, os estudos apontam relevante prevalência de uso de drogas licitas e ilícitas entre os universitários da área da saúde no Brasil, estando ligado aos altos níveis de estresse e desenvolvimento de sintomas depressivos que são provocados pela carga horária exaustiva, fragilidade na rede de apoio familiar e social, redução dos momentos de lazer e frequente vivência de momentos de morte e sofrimento.

Weitere Nicht-UDE Autoren sind nicht mit aufgeführt. in press

Background Although patients with AE-ILD and UIP pattern may experience severe acute respiratory failure requiring invasive MV, physiological data on lung mechanics during these events are lacking. We aimed to describe the physiological effect of lung protective ventilation in patients with AE-ILD-UIP and to compare it with primary ARDS.Methods Partitioned lung and chest wall mechanics were compared between patients AE-ILD-UIP and 1:1 matched primary ARDS (based on BMI and PaO2/FiO2 ratio) within a PEEP trial performed within 24 h from intubation and comprising three levels of PEEP [(ZEEP), 4–8 cmH2O (PEEPLOW) and PEEP titrated to achieve positive end-expiratory transpulmonary pressure (PL,EE) (PEEPTITRATED)]Results Ten patients with AE-ILD-UIP and 10 matched with primary ARDS were included. In AE-ILD-UIP median PL,EE at ZEEP was − 4.3 [-7.6 – -2.3] cmH2O and lung elastance (EL) 44 [40–51] cmH2O/L. At PEEPLOW, PL,EE remained negative and EL did not change (p = 0.995) versus ZEEP. At PEEPTITRATED, PL,EE increased to 0.8 [0.3–1.5] cmH2O and EL to 49 [59–43] (p = 0.004 and p LOW, respectively). ΔPL decreased at PEEPLOW (p = 0.018) and increased at PEEPTITRATED (p = 0.003). Differently than AE-ILD-UIP, in ARDS matched controls PEEP titration to obtain a positive PL,EE did not result in changes in EL and ΔPL.Conclusions In mechanically ventilated AE-ILD-UIP, lower PEEP levels did not impact on EL and ΔPL whereas, differently than in patients with primary ARDS, PEEP titrated to obtain a positive PL,EE worsened EL and ΔPL.

A large number of recent studies consider a compartmental SIR model to study optimal control policies aimed at containing the diffusion of COVID-19 while minimizing the economic costs of preventive measures. Such problems are non-convex and standard results need not to hold. We use a Dynamic Programming approach and prove some continuity properties of the value function of the associated optimization problem. We study the corresponding Hamilton–Jacobi–Bellman equation and show that the value function solves it in the viscosity sense. Finally, we discuss some optimality conditions. Our paper represents a first contribution towards a complete analysis of non-convex dynamic optimization problems, within a Dynamic Programming approach.

BACKGROUND During the initial phases of the vaccination campaign worldwide, Non-Pharmaceutical Interventions (NPIs) remained pivotal in the fight against the COVID-19 pandemic. In this context, it is important to understand how the arrival of vaccines affected the adoption of NPIs. Indeed, some individuals might have seen the start of mass vaccination campaigns as the end of the emergency and, as a result, have relaxed their COVID-safe behaviors, facilitating the spread of the virus in a delicate epidemic phase such as the initial rollout. OBJECTIVE Our study aims to collect information about the possible relaxation of behaviors following key events of the vaccination campaign in four countries and to analyse possible associations of these behavioral tendencies with socio-demographic characteristics of participants. METHODS We developed an online survey named “COVID-19 Prevention and Behavior Survey” that we conducted between November 26 and December 22, 2021. Participants were recruited using targeted ads on Facebook in four different countries: Italy, the United Kingdom, Brazil and South Africa. We measured the onset of relaxation of protective measures in response to key events of the vaccination campaign, namely personal vaccination and vaccination of the most vulnerable population. Through odds ratios and regression analysis we assessed the strength of association between compliance with NPIs and socio-demographic characteristics of participants. RESULTS We received 2263 questionnaires from the four countries. Participants reported the most significant changes in social activities, such as going to restaurant or cinema and visiting relatives and friends. This is in good agreement with validated psychological models of health-related behavioral change such as the Health Belief Model (HBM), according to which activities with higher costs and perceived barriers (e.g., the social activities) are more prone to early relaxation. Multivariate analysis using a Generalised Linear Model showed that the two main determinants of the drop of social NPIs are i) having previously tested positive for COVID-19 (after second dose: OR 2.46, 95% CI 1.73-3.49) and ii) living with people at risk (after second dose: OR 1.57, 95% CI 1.22-2.03). CONCLUSIONS This work shows that particular caution has to be taken during vaccination campaigns. Indeed, people might relax their safe behaviors regardless the dynamics of the epidemic. For this reason, it is crucial to keep high the compliance with NPIs to avoid hindering the beneficial effects of the vaccine. CLINICALTRIAL Ethical approval: Ethical approval was obtained from the bioethical committee of the University of Turin (Prot. n. 280342 del 8.5.2021).

The increase of brain dimensions and complexity has characterized the evolution of the genus Homo. According to the available fossil and genetic evidence, a crucial stage came before the divergence of Neanderthals, Denisovans and Homo sapiens, during the Middle Pleistocene. We consider a specimen of about 400 ka, whose phenotype is at the roots of this divergence: Ceprano calvarium (Italy). Here, we show a derived cerebrovascular organization with a mosaic of modern human and primitive features characteristics. Computed microtomography shows vascular variation and ontogenetic defects associated with ventricular and lymphatic involvement while phylogenetic analyzes highlight a dysregulation of the Tet1 gene that shows an accelerated mutation rate between 1.2 Ma and 466 ka, in contrast with the expected neutral evolution of the human genome. These results shed light on the dynamics of cranio-cerebral growth during the encephalization process and on the cerebral vascular and lymphatic system involved in this process. The results of this study could have implications for the research of many of the diseases of the central nervous system that have become predominant in an increasingly structured and long-lived brain system such as that of modern Homo sapiens. One-Sentence Summary: Genetic mutation, anatomical variations and glymphatic system in the process of encephalization towards Homo sapiens.

DNA damage repair systems are critical for genomic integrity. However, they must be coordinated with DNA replication and cell division to ensure accurate genomic transmission. In most bacteria, this coordination is mediated by the SOS response through LexA, which triggers a halt in cell division until repair is completed. Recently, an SOS-independent damage response system was revealed in Caulobacter crescentus. This pathway is controlled by the transcription activator, DriD, but how DriD senses and signals DNA damage is unknown. To address this question, we performed biochemical, cellular, and structural studies. We show that DriD binds a specific promoter DNA site via its N-terminal HTH domain to activate transcription of genes, including the cell division inhibitor didA. A structure of the C-terminal portion of DriD revealed a WYL motif domain linked to a WCX dimerization domain. Strikingly, we found that DriD binds ssDNA between the WYL and WCX domains. Comparison of apo and ssDNA-bound DriD structures reveals that ssDNA binding orders and orients the DriD domains, indicating a mechanism for ssDNA-mediated operator DNA binding activation. Biochemical and in vivo studies support the structural model. Our data thus reveal the molecular mechanism underpinning an SOS-independent DNA damage repair pathway.

This study will provide an overview and a description of the most promising alternatives to conventional thermal treatments for juice stabilization, as well as a review of the literature data on fruit and vegetable juice processing in terms of three key parameters in juice production, which are microbial reduction, enzyme inactivation, and nutrient-compound retention. The alternatives taken into consideration in this work can be divided, according to the action mechanism upon which these are based, in non-conventional thermal treatments, among which microwave heating (MWH) and ohmic heating (OH), and non-thermal treatments, among which electrical treatments, i.e., pulsed electric fields (PEF), high-pressure processing (HPP), radiation treatments such as ultraviolet light (UVL) and high-intensity pulsed light (PL), and sonication (HIUS) treatment, and inert-gas treatments, i.e., the pressure change technology (PCT) and supercritical carbon dioxide (SC-CO2) treatments. For each technology, a list of the main critical process parameters (CPP), advantages (PROS), and disadvantages (CONS) will be provided. In addition, for the non-thermal technologies, a summary of the most relevant published result of their application on fruit and vegetable juices will be presented. On top of that, a comparison of typical specific working energy costs for the main effective and considered technologies will be reported in terms of KJ per kilograms of processed product.

A energia solar é uma fonte viável em pequena e larga escala. A energia elétrica gerada por um sistema fotovoltaico pode ser usada para uma ampla gama de soluções. O Sistema de Rastreamento Solar é a tecnologia mais adequada para aumentar a eficiência das células solares rastreando o sol. Este artigo apresenta o design de hardware e implementação de um sistema que garante a posição do painel solar para ser sempre normal à radiação solar incidente a fim de extrair o máximo de energia que incide sobre eles, em comparação com um sistema de geração fixo. Os resultados experimentais de avaliação através das curvas de geração em KW apresentam um ganho superior a 30% de ganho nos meses de novembro e dezembro na cidade de Cascavel – PR, em relação ao um sistema fixo, confirmando que o sistema de rastreamento de eixo simples baseado em automação em comparação com o sistema de geração fixa melhora a eficiência e o desempenho geral de uma usina solar.

Autism Spectrum Disorder (ASD) is characterized by substantial, yet highly heterogeneous abnormalities in functional brain connectivity. However, the origin and significance of this phenomenon remain unclear. To unravel ASD connectopathy and relate it to underlying etiological heterogeneity, we carried out a bi-center cross-etiological investigation of fMRI-based connectivity in the mouse, in which specific ASD-relevant mutations can be isolated and modeled minimizing environmental contributions. By performing brain-wide connectivity mapping across 16 mouse mutants, we show that different ASD-associated etiologies cause a broad spectrum of connectional abnormalities in which diverse, often diverging, connectivity signatures are recognizable. Despite this heterogeneity, the identified connectivity alterations could be classified into four subtypes characterized by discrete signatures of network dysfunction. Our findings show that etiological variability is a key determinant of connectivity heterogeneity in ASD, hence reconciling conflicting findings in clinical populations. The identification of etiologically-relevant connectivity subtypes could improve diagnostic label accuracy in the non-syndromic ASD population and paves the way for personalized treatment approaches., Molecular Psychiatry, 26 (12), ISSN:1359-4184, ISSN:1476-5578

Background and Overview Severely molar-incisor hypomineralization (MIH)–affected teeth are prone to develop early posteruptive enamel breakdown (PEB) and caries. A novel conservative interim approach for the prevention of this complication is presented. Case Description A 6-year-old boy with strong hypersensitivity and extensive brown opacities in the partially erupted mandibular permanent first molars (PFMs) was diagnosed with MIH. Constant hygiene and dietary counseling were followed by the application of luted orthodontic bands and glass ionomer sealants to protect PFMs from caries and PEB until the complete eruption of the teeth. After 36 months, the PFMs were completely erupted, with no caries and PEB, and the cooperation of the child increased. Conclusions and Practical Implications Temporary strategies are useful to preserve MIH-affected PFMs. With the methodology described, the hypersensitivity decreased and the patient reached a good degree of cooperation, making possible definitive rehabilitative considerations.

Objective To evaluate the rate of progression towards specific autoimmune diseases (SADs) of a prospective, multi-centre cohort of patients classifiable as interstitial pneumonia with autoimmune features (IPAF). Methods IPAF patients were enrolled based on specific research criteria, and jointly followed by rheumatologists and pulmonologists for at least one year with clinical check-ups, serological exams including autoimmunity, capillaroscopy and high-resolution computed tomography (HRCT). Diagnostic assessment was repeated at least once a year, or earlier when deemed useful. Results We enrolled 191 IPAF patients through 95 different combinations of IPAF criteria. Of these, 24.1% progressed towards SAD, mainly in connective tissue diseases but also in microscopic polyangiitis. The IPAF patients who progressed were younger than stable IPAF patients (63±10 years vs. 68±9 years, p=0.002) and had a longer follow-up (36.9±18.7 vs. 29.3±15.7 months, p=0.007), but similar severity. No parameters were associated with overall progression, but some parameters were associated with the development of specific diagnoses: Sjögren’s syndrome with positivity for SSA (p=0.007, χ2 7.4); idiopathic inflammatory myopathy with mechanic’s hands (p=

Background PET with radiolabeled amino acids is used in the preoperative evaluation of patients with glial neoplasms. This study aimed to assess the role of [11C]methionine (MET) PET in assessing molecular features, tumor extent, and prognosis in newly diagnosed lower-grade gliomas (LGGs) surgically treated. Methods One hundred and fifty-three patients with a new diagnosis of grade 2/3 glioma who underwent surgery at our Institution and were imaged preoperatively using [11C]MET PET/CT were retrospectively included. [11C]MET PET images were qualitatively and semi-quantitatively analyzed using tumor-to-background ratio (TBR). Progression-free survival (PFS) rates were estimated using the Kaplan-Meier method and Cox proportional-hazards regression was used to test the association of clinicopathological and imaging data to PFS. Results Overall, 111 lesions (73%) were positive, while thirty-two (21%) and ten (6%) were isometabolic and hypometabolic at [11C]MET PET, respectively. [11C]MET uptake was more common in oligodendrogliomas than IDH-mutant astrocytomas (87% vs 50% of cases, respectively). Among [11C]MET-positive gliomas, grade 3 oligodendrogliomas had the highest median TBRmax (3.22). In 25% of patients, PET helped to better delineate tumor margins compared to MRI only. In IDH-mutant astrocytomas, higher TBRmax values at [11C]MET PET were independent predictors of shorter PFS. Conclusions This work highlights the role of preoperative [11C]MET PET in estimating the type of suspected LGGs, assessing tumor extent, and predicting biological behavior and prognosis of histologically confirmed LGGs. Our findings support the implementation of [11C]MET PET in routine clinical practice to better manage these neoplasms.

Type I toxin-antitoxin (TA) systems typically consist of a protein toxin that imbeds in the inner membrane where it can oligomerize and form pores that change membrane permeability, and an RNA antitoxin that interacts directly with toxin mRNA to inhibit its translation. In Escherichia coli, symE/symR is annotated as a type I TA system with a non-canonical toxin. SymE was initially suggested to be an endoribonuclease, but has predicted structural similarity to DNA binding proteins. To better understand SymE function, we used RNA-seq to examine cells ectopically producing it. Although SymE drives major changes in gene expression, we do not find strong evidence of endoribonucleolytic activity. Instead, our biochemical and cell biological studies indicate that SymE binds DNA. We demonstrate that the toxicity of symE overexpression likely stems from its ability to drive severe nucleoid condensation, which disrupts DNA and RNA synthesis and leads to DNA damage, similar to the effects of overproducing the nucleoid-associated protein H-NS. Collectively, our results suggest that SymE represents a new class of nucleoid-associated proteins that is widely distributed in bacteria.

How the emergent functional connectivity (FC) relates to the underlying anatomy (structural connectivity, SC) is one of the biggest questions of modern neuroscience. At the macro-scale level, no one-to-one correspondence between structural and functional links seems to exist. And we posit that to better understand their coupling, two key aspects should be taken into account: the directionality of the structural connectome and the limitations of describing network functions in terms of FC. Here, we employed an accurate directed SC of the mouse brain obtained by means of viral tracers, and related it with single-subject effective connectivity (EC) matrices computed by applying a recently developed DCM to whole-brain resting-state fMRI data. We analyzed how SC deviates from EC and quantified their couplings by conditioning both on the strongest SC links and EC links. We found that when conditioning on the strongest EC links, the obtained coupling follows the unimodal-transmodal functional hierarchy. Whereas the reverse is not true, as there are strong SC links within high-order cortical areas with no corresponding strong EC links. This mismatch is even more clear across networks. Only the connections within sensory motor networks align both in terms of effective and structural strength.

The formation of a robust long-term antigen (Ag)-specific memory, both humoral and cell-mediated, is created following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination. Here, by using polychromatic flow cytometry and complex data analyses, we deeply investigated the magnitude, phenotype, and functionality of SARS-CoV-2-specific immune memory in two groups of healthy subjects after heterologous vaccination compared to a group of subjects who recovered from SARS-CoV-2 infection. We find that coronavirus disease 2019 (COVID-19) recovered patients show different long-term immunological profiles compared to those of donors who had been vaccinated with three doses. Vaccinated individuals display a skewed T helper (Th)1 Ag-specific T cell polarization and a higher percentage of Ag-specific and activated memory B cells expressing immunoglobulin (Ig)G compared to those of patients who recovered from severe COVID-19. Different polyfunctional properties characterize the two groups: recovered individuals show higher percentages of CD4+ T cells producing one or two cytokines simultaneously, while the vaccinated are distinguished by highly polyfunctional populations able to release four molecules, namely, CD107a, interferon (IFN)-γ, tumor necrosis factor (TNF), and interleukin (IL)-2. These data suggest that functional and phenotypic properties of SARS-CoV-2 adaptive immunity differ in recovered COVID-19 individuals and vaccinated ones.

In this paper we propose a theoretical model including a susceptible-infected-recovered-dead (SIRD) model of epidemic in a dynamic macroeconomic general equilibrium framework with agents' mobility. The latter affect both their income (and consumption) and their probability of infecting and of being infected. Strategic complementarities among individual mobility choices drive the evolution of aggregate economic activity, while infection externalities caused by individual mobility affect disease diffusion. Rational expectations of forward looking agents on the dynamics of aggregate mobility and epidemic determine individual mobility decisions. The model allows to evaluate alternative scenarios of mobility restrictions, especially policies dependent on the state of epidemic. We prove the existence of an equilibrium and provide a recursive construction method for finding equilibrium(a), which also guides our numerical investigations. We calibrate the model by using Italian experience on COVID-19 epidemic in the period February 2020 - May 2021. We discuss how our economic SIRD (ESIRD) model produces a substantially different dynamics of economy and epidemic with respect to a SIRD model with constant agents' mobility. Finally, by numerical explorations we illustrate how the model can be used to design an efficient policy of state-of-epidemic-dependent mobility restrictions, which mitigates the epidemic peaks stressing health system, and allows for trading-off the economic losses due to reduced mobility with the lower death rate due to the lower spread of epidemic.

Pulcherrimin is an iron-binding reddish pigment produced by various bacterial and yeast species. In the soil bacterium Bacillus subtilis, this pigment is first synthesized intracellularly as the colorless pulcherriminic acid by using two molecules of tRNA-charged leucine as the substrate; pulcherriminic acid molecules are then secreted and bind to ferric iron extracellularly to form the red-colored pigment pulcherrimin. The biological importance of pulcherrimin is not well understood. A previous study showed that secretion of pulcherrimin caused iron depletion in the surroundings and growth arrest on cells located at the edge of a B. subtilis colony biofilm. In this study, we identified that pulcherrimin is primarily produced under biofilm conditions and provides protection to cells in the biofilm against oxidative stress. We presented molecular evidence on how pulcherrimin lowers the level of reactive oxygen species (ROS) and alleviates oxidative stress and DNA damage caused by ROS accumulation in a mature biofilm. We also performed global transcriptome profiling to identify differentially expressed genes in the pulcherrimin-deficient mutant compared to wild type, and further characterized the regulation of genes by pulcherrimin that are related to iron homeostasis, DNA damage response (DDR), and oxidative stress response. Based on our findings, we propose pulcherrimin as an important antioxidant as well as a signal modulating B. subtilis biofilm development.

Objective: Data are scarce regarding hospital infection control committees and compliance with infection prevention and control (IPC) recommendations in Brazil, a country of continental dimensions. We assessed the main characteristics of infection control committees (ICCs) on healthcare-associated infections (HAIs) in Brazilian hospitals. Methods: This cross-sectional study was conducted in ICCs of public and private hospitals distributed across all Brazilian regions. Data were collected directly from the ICC staff by completing an online questionnaire and during on-site visits through face-to-face interviews. Results: In total, 53 Brazilian hospitals were evaluated from October 2019 to December 2020. All hospitals had implemented the IPC core components in their programs. All centers had protocols for the prevention and control of ventilator-associated pneumonia as well as bloodstream, surgical site, and catheter-associated urinary tract infections. Most hospitals (80%) had no budget specifically allocated to the IPC program; 34% of the laundry staff had received specific IPC training; and only 7.5% of hospitals reported occupational infections in healthcare workers. Conclusions: In this sample, most ICCs complied with the minimum requirements for IPC programs. The main limitation regarding ICCs was the lack of financial support. The findings of this survey support the development of strategic plans to improve IPCs in Brazilian hospitals.

We study a family of stochastic control problems arising in typical applications (such as boundary control and control of delay equations with delay in the control) with the ultimate aim of finding solutions of the associated HJB equations, regular enough to find optimal feedback controls. These problems are difficult to treat since the underlying transition semigroups do not possess good smoothing properties nor the so-called "structure condition" which typically allows to apply the backward equations approach. In the papers [14], [15], and, more recently, [16] we studied such problems developing new partial smoothing techniques which allowed us to obtain the required regularity in the case when the cost functional is independent of the state variable. This is a somehow strong restriction which is not verified in most applications. In this paper (which can be considered a continuation of the research of the above papers) we develop a new approach to overcome this restriction. We extend the partial smoothing result to a wider class of functions which depend on the whole trajectory of the underlying semigroup and we use this as a key tool to improve our regularity result for the HJB equation. The fact that such class depends on trajectories requires a nontrivial technical work as we have to lift the original transition semigroup to a space of trajectories, defining a new "high-level" environment where our problems can be solved., Comment: arXiv admin note: text overlap with arXiv:2107.04305

To synthesize the evidence for factors impacting contraceptive access and use, and associated interventions among women with migratory experience in high-income countries in Europe, North America and Australasia.

SARS-CoV-2 triggers inflammasome-dependent release of pro-inflammatory cytokine IL-1β and pyroptosis, therefore contributes to the huge inflammatory response observed in severe COVID-19 patients. Less is known about the engagement of inflammasome in neutrophils, main players in tissue injury and severe infection. We studied the activation of the inflammasome in neutrophils from severe COVID-19 patients and assessed its consequence in term of cells contribution to disease pathogenesis. We demonstrated that NLRP3 inflammasome is dramatically activated in neutrophils from severe COVID-19 patients, and that the specific inhibition of NLRP3 reverts neutrophils' activation. Next, the stimulation of severe patients' neutrophils with common NLRP3 stimuli was not able to further activate the inflammasome, possibly due to exhaustion or increased percentage of circulating immature neutrophils. Collectively, our results demonstrate that the NLRP3 inflammasome is hyperactivated in severe COVID-19 neutrophils and its exhaustion may be responsible for the increased susceptibility to subsequent (and possibly lethal) infections. Our findings thus include a novel piece in the complex puzzle of COVID-19 pathogenesis.

The macroscale connectome is the network of physical, white-matter tracts between brain areas. The connections are generally weighted and their values interpreted as measures of communication efficacy. In most applications, weights are either assigned based on imaging features--e.g. diffusion parameters--or inferred using statistical models. In reality, the ground-truth weights are unknown, motivating the exploration of alternative edge weighting schemes. Here, we explore a multi-modal (combining diffusion and functional MRI data) regression-based, explanatory model that endows reconstructed fiber tracts with directed and signed weights. Benchmarking this method on Human Connectome Project data, we find that the model fits observed data well, outperforming a suite of null models. The estimated weights are subject-specific and highly reliable, even when fit using relatively few training samples. Next, we analyze the resulting network using graph-theoretic tools from network neuroscience, revealing bilaterally symmetric communities that span cerebral hemispheres. These communities exhibit a clear mapping onto known functional systems. We also study the shortest paths structure of this network, discovering that almost every edge participates in at least one shortest path. We also find evidence of robust asymmetries in edge weights, that the network reconfigures in response to naturalistic stimuli, and that estimated edge weights differ with age. In summary, we offer a simple framework for weighting connectome data, demonstrating both its ease of implementation while benchmarking its utility for typical connectome analyses, including graph theoretic modeling and brain-behavior associations.

Fungal pathogens are one of the most important agents affecting crop production and food safety, and agrochemical application is one of the main approaches to reduce phytopathogenic fungi contamination in agricultural products. However, excessive and inadequate use can cause environmental damage, human and animal hazard, and increased phytopathogen resistance to fungicides. Biological control using lactic acid bacteria (LAB) and Bacillus spp. is an environmentally friendly strategy for phytopathogenic fungi management. Several molecules produced by these bacteria indeed affect fungal growth and viability in different plant crops. In this article, the activity spectra are reviewed along with the antifungal effect and antifungal compounds produced by LAB (e.g. organic acids, peptides, cyclic dipeptides, fatty acids, and volatile compounds) and Bacillus spp. (e.g. peptides, enzymes, and volatile compounds).

Advanced echocardiographic and CMR features of patients with repaired Tetralogy of Fallot in the long-term follow-up. Anna Gozzi1, Jolanda Sabatino1, Elena Cuppini1, Irene Cattapan1, Alessia Basso1, Jennifer Fumanelli1, Angela Di Candia1, Martina Avesani1, Domenico Sirico1, Biagio Castaldi1, Elena Reffo1, Alessia Cerutti1, Roberta Biffanti1, Giovanni Di Salvo1 1Department for Women's and Children's Health, University Hospital of Padova, Pediatric and Congenital Cardiology Unit, Via Nicolo` Giustiniani, 2, 35128 Padova, Italy Background Tetralogy of Fallot (ToF) is the most common cyanotic congenital heart disease and the population of ToF repair survivors is growing rapidly. Children and, more frequently young adults, with repaired ToF develop late complications. Sudden cardiac death and life-threatening ventricular arrhythmia remain a concern in patients with repaired tetralogy of Fallot. The aim of this study was to describe and analyse advanced echocardiographic and CMR features of patients with repaired ToF in the long-term follow-up and to find non-invasive predictors of adverse prognosis. Methods This is a retrospective cohort study. Consecutive 200 patients with repaired ToF who did not undergo pulmonary valve replacement were included. Mean age of all patients was 19 ± 8. The electrocardiographic (ECG), cardiopulmonary exercise testing (CPET), echocardiographic and cardiac magnetic resonance (CMR) data were reviewed retrospectively. Right myocardial work index (RWI) was calculated as the area of the right ventricular pressure strain loops. From RWI, Right Constructive Work (RCW), Wasted Work (RWW) and Work Efficiency (RWE) were estimated. Patients were screened according the age at surgery (12 months) and the time since the repair (< 25 years and ≥ 25 years). A composite end-point of major adverse cardiovascular events (sudden cardiac death, sustained and non-sustained ventricular tachycardia, resuscitated sudden cardiac death, or syncope) was used. Results CPET values were not significantly different in patients with more than 25 years since the corrective surgery. Left ventricular ejection fraction measured either by CMR or echocardiography were slightly but significantly reduced in patients with more than 25 years since the corrective surgery. Patients with older age at surgery (>12 months) have significantly reduced V02max at CPET, larger RA and LA areas and larger RV basal diameter. During a median follow-up of 2.9 years, 1 patient died suddenly, 5 had documented ventricular tachycardia, and other 4 had syncope. On univariate analysis, echocardiographic left atrial area/BSA (P=0.044) and right ventricular longitudinal strain (P=0.010) were significantly related to the combined end point. Patients with reported VT at Holter ECG presented significantly reduced right ventricular function in terms of CMR-EF, echocardiographic FAC and RWI. Finally, TOF patients with borderline/impaired predicted VO2 max at CPET presented with significantly reduced RV freewall longitudinal strain and right ventricular myocardial work index. Conclusion Long-term survival and clinical condition after surgical correction of ToF in infancy is generally good and the late functional status in ToF - operated patients could be excellent up to 25 years after the repair. However, patients with older age at surgery have relative reduced functional status compared with those undergoing early repair. The echocardiographic and CMR evaluation of RV function are usually related to worse prognosis, recurrency of VT and reduced functional status in patients with repaired TOF. Right ventricular myocardial work index is feasible in patients with repaired TOF; disadvantageous right ventricular work may be a more sensitive indicator of right ventricular impairment compared with standard echocardiographic parameters, and is able to predict exercise capacity.

Background Clinical manifestations of children's coronavirus disease-2019 (COVID-19) were initially considered less severe compared with adult patients. However, there is now increasing evidence of a “long-tail” of COVID-19 related symptoms lasting for several months after recovery from the acute infection. Long COVID-19-related symptoms and mechanisms are poorly characterized and understood, with several phenotypes reported, often driven by long-term tissue damage (such as lung, heart and brain) and pathological inflammation due to viral persistence and/or immune deregulation. Purpose The objective of this study was to evaluate atrio-ventricular mechanics, by means of two-dimensional speckle-tracking echocardiography, in previously healthy children recovered from asymptomatic or mildly symptomatic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in a long-term follow-up. Methods We analysed a cohort of 157 paediatric patients, mean age 7 ± 4 years, who had a confirmed diagnosis of SARS-CoV-2 infection and were asymptomatic or mildly symptomatic for COVID-19. Patients underwent standard transthoracic echocardiogram and speckle tracking echocardiographic study 148 ± 68 days after diagnosis. One hundred seven age, sex, and body surface area comparable healthy subjects were used as control group. Results Left ventricular ejection fraction was within normal limits in postCOVID-19 cases and CTRL with no significant differences between the two groups (postCOVID-19: 65.6 ± 4% vs CTRL: 65.0 ± 5%, p = 0.182).Left ventricular (LV) global longitudinal strain (postCOVID-19: -20.5 ± 2.9%; CTRL: -21.8 ± 1.7%; p < 0.001) was significantly reduced in cases compared with CTRLs. An amount of 11 (7%) postCOVID-19 cases showed impaired GLS values < -17% and 95 subjects (60%) presented with a strain lower than -16% in more than 2 segments. These subjects did not show any difference regarding symptoms or serological findings. Moreover, GLS was significantly reduced in children with disease's onset during the second wave of COVID-19 pandemic, compared with those during the first wave (second wave: -20.2 ± 2.6%; first wave: -21.2 ± 3.4%; p = 0.048). Finally, peak left atrial systolic strain was within the normal range in the postCOVID-19 group with no significant differences compared to CTRL (postCOVID-19: 49.1 ± 12%; CTRL: 49.5 ± 18%). Conclusions SARS-CoV-2 infection may affect left ventricular deformation in children despite an asymptomatic or only mildly symptomatic acute illness. Our data show an amount of 60% of children, recovering from asymptomatic or mildly symptomatic COVID-19, with still mild subclinical systolic cardiac impairment in the mid- and long-term follow-up after the infection. This subtle impairment was seen to be worse in children recovering from the second wave of COVID-19 compared to the first one. A follow-up is needed to verify the reversibility of these alterations and their impact on long-term outcomes.

Background The objective of this study was to characterize frailty and resilience in people evaluated for Post-Acute COVID-19 Syndrome (PACS), in relation to quality of life (QoL) and Intrinsic Capacity (IC). Methods This cross-sectional, observational, study included consecutive people previously hospitalized for severe COVID-19 pneumonia attending Modena (Italy) PACS Clinic from July 2020 to April 2021. Four frailty-resilience phenotypes were built: “fit/resilient”, “fit/non-resilient”, “frail/resilient” and “frail/non-resilient”. Frailty and resilience were defined according to frailty phenotype and Connor Davidson resilience scale (CD-RISC-25) respectively. Study outcomes were: QoL assessed by means of Symptoms Short form health survey (SF-36) and health-related quality of life (EQ-5D-5L) and IC by means of a dedicated questionnaire. Their predictors including frailty-resilience phenotypes were explored in logistic regressions. Results 232 patients were evaluated, median age was 58.0 years. PACS was diagnosed in 173 (74.6%) patients. Scarce resilience was documented in 114 (49.1%) and frailty in 72 (31.0%) individuals. Table 1 shows demographic, anthropometric and clinical characteristics, comorbidities and patient-reported outcomes according to four frailty-resilience phenotypes. With regards to study outcomes, Figure 1 depicts in radar graphs, mean scores of each domain of SF-36 (1A), EQ-5D5L (1B) and IC (1C). Figures shows polygon areas for each frailty/resilience phenotypes. Progressive increase of mean scores of each domain are plotted in the vertices of polygons, from the lowest (near the center) in frail and non-resilient, to highest (towards periphery) in fit and resilient. Multivariate logistic analyses were used to identify predictors of the total scores of SF-36 (Figure 2A), EQ-5D5L (Figure 2B) and IC (Figure 2C). Conclusion Resilience is complementary to frailty in the identification of clinical phenotypes with different impact on wellness and QoL. Frailty and resilience should be evaluated in hospitalized COVID-19 patients to identify vulnerable individuals to prioritize urgent health interventions in people with PACS. Funding This study is supported by a Gilead Sciences Inc. unrestricted grant. Disclosures All Authors: No reported disclosures.

Background: Patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) may experience severe acute respiratory failure, even requiring ventilatory assistance. Physiological data on lung mechanics during these events are lacking. Methods: Patients with AE-IPF admitted to Respiratory Intensive Care Unit to receive non-invasive ventilation (NIV) were retrospectively analyzed. Esophageal pressure swing (ΔPes) and respiratory mechanics before and after 2 hours of NIV were collected as primary outcome. The correlation between positive end-expiratory pressure (PEEP) levels and changes of in dynamic compliance (dynCRS) and PaO2/FiO2 ratio was assessed. Further, an exploratory comparison with a historical cohort of ARDS patients matched 1:1 by age, sequential organ failure assessment score, body mass index and PaO2/FiO2 level was performed. Results: At baseline, AE-IPF patients presented a high respiratory drive activation with ΔPes = 27 (21-34) cmH2O, respiratory rate (RR) = 34 (30-39) bpm and minute ventilation (VE) = 21 (20-26) L/min. Two hours after NIV application, ΔPes, RR and VE values showed a significant reduction (16 [14-24] cmH2O, p

The D-aspartate oxidase (DDO) gene encodes the enzyme responsible for the catabolism of D-aspartate, an atypical amino acid enriched in the mammalian brain and acting as an endogenous NMDA receptor agonist. Considering the key role of NMDA receptors in neurodevelopmental disorders, recent findings suggest a link between D-aspartate dysmetabolism and schizophrenia. To clarify the role of D-aspartate on brain development and functioning, we used a mouse model with constitutive Ddo overexpression and D-aspartate depletion. In these mice, we found reduced number of BrdU-positive dorsal pallium neurons during corticogenesis, and decreased cortical and striatal gray matter volume at adulthood. Brain abnormalities were associated with social recognition memory deficit at juvenile phase, suggesting that early D-aspartate occurrence influences neurodevelopmental related phenotypes. We corroborated this hypothesis by reporting the first clinical case of a young patient with severe intellectual disability, thought disorders and autism spectrum disorder symptomatology, harboring a duplication of a chromosome 6 region, including the entire DDO gene.

The heterogeneity of response to SARS-CoV-2 infection is directly linked to the individual genetic background. Genetic variants of inflammasome-related genes have been pointed as risk factors for several inflammatory sterile and infectious disease. In the group of inflammasome receptors, NLRP1 stands out as a good novel candidate as severity factor for COVID-19 disease.To address this question, we performed an association study of NLRP1, DPP9, CARD8, IL1B, and IL18 single nucleotide variants (SNVs) in a cohort of 945 COVID-19 patients.The NLRP1 p.Leu155His in the linker region, target of viral protease, was significantly associated to COVID-19 severity, which could contribute to the excessive cytokine release reported in severe cases.Inflammasome genetic background contributes to individual response to SARS-CoV-2.

Access to COVID-19 vaccines on the global scale has been drastically impacted by structural socio-economic inequities. Here, we develop a data-driven, age-stratified epidemic model to evaluate the effects of COVID-19 vaccine inequities in twenty lower middle and low income countries (LMIC) sampled from all WHO regions. We focus on the first critical months of vaccine distribution and administration, exploring counterfactual scenarios where we assume the same per capita daily vaccination rate reported in selected high income countries. We estimate that, in this high vaccine availability scenario, more than 50% of deaths (min-max range: [56% − 99%]) that occurred in the analyzed countries could have been averted. We further consider a scenario where LMIC had similarly early access to vaccine doses as high income countries; even without increasing the number of doses, we estimate an important fraction of deaths (min-max range: [7% − 73%]) could have been averted. In the absence of equitable allocation, the model suggests that considerable additional non-pharmaceutical interventions would have been required to offset the lack of vaccines (min-max range: [15% − 75%]). Overall, our results quantify the negative impacts of vaccines inequities and call for amplified global efforts to provide better access to vaccine programs in low and lower middle income countries.

Many neurodevelopmental conditions, including autism, affect males more than females. Genomic mechanisms enhancing risk in males may contribute to this sex-bias. The ubiquitin protein ligase E3A gene (Ube3a) exerts pleiotropic effects on cellular homeostasis via control of protein turnover and by acting as transcriptional coactivator with steroid hormone receptors. Overdosage ofUbe3avia duplication or triplication of chromosomal region 15q11-13 causes 1-2% of autistic cases. Here, we test the hypothesis that increased dosage ofUbe3amay influence autism-relevant phenotypes in a sex-biased manner. We report robust sex-biasing effects on brain connectomics and repetitive behaviors in mice with extra copies of Ube3a. These effects were associated with a profound transcriptional dysregulation of several known autism-associated genes (e.g., FMR1, SCN2A, PTEN, MEF2C, SHANK3, TSC2) as well as differentially-expressed genes identified in human 15q duplication and in autistic patients. Notably, increased Ube3a dosage also affects multiple sex-relevant mechanisms, including genes on the X chromosome, genes influenced by sex steroid hormones, downstream targets of the androgen and estrogen receptors, or genes that are sex-differentially regulated by transcription factors. These results suggest thatUbe3aoverdosage can critically contribute to sex-bias in neurodevelopmental conditions via influence on sex-differential mechanisms.