Duration of the patient interval in breast cancer and factors associated with longer delays in low-and middle-income countries: A systematic review with meta-analysis.

OBJECTIVE: Breast cancer survival is lower in low- and middle-income countries (LMICs) partially due to many women being diagnosed with late-stage disease. The patient interval refers to the time elapsed between the detection of symptoms and the first consultation with a healthcare provider and is considered one of the core indicators for early diagnosis and treatment. The goal of the current research was to conduct a meta-analysis of the duration of the patient interval in LMICs and investigate the socio-demographic and socio-cultural factors related to longer delays in presentation. METHODS: We conducted a systematic review with meta-analysis (pre-registered protocol CRD42020200752). We searched seven information sources (2009-2022) and included 50 articles reporting the duration of patient intervals for 18,014 breast cancer patients residing in LMICs. RESULTS: The longest patient intervals were reported in studies from the Middle East (3-4 months), followed by South-East Asia (2 months), Africa (1-2 months), Latin America (1 month), and Eastern Europe (1 month). Older age, not being married, lower socio-economic status, illiteracy, low knowledge about cancer, disregarding symptoms or not attributing them to cancer, fear, negative beliefs about cancer, and low social support were related to longer delays across most regions. Longer delays were also related to use of alternative medicine in the Middle East, South-East Asia, and Africa and distrust in the healthcare system in Eastern Europe. CONCLUSIONS: There is large variation in the duration of patient intervals across LMICs in different geographical regions. Patient intervals should be reduced and, for this purpose, it is important to explore their determinants taking into account the social, cultural, and economic context.

Risk factors associated with early mortality after recovery from severe listeriosis: a multicentre 17-year longitudinal study.

BACKGROUND: Listeriosis presents high rates of mortality but prognostic factors for early prevention are not well established. The aim of this study was to analyse factors associated with in-hospital and early mortality of adults after recovery from severe infection caused by Listeria monocytogenes. METHODS: All cases of listeriosis notified in the province of Granada from January 2005 to December 2021, including 9 centres, were included. Only laboratory confirmed non-neonatal cases were considered. Follow-up was conducted by accessing medical records and epidemiological data. Bivariate and multivariate analyses were conducted to detect potential risk factors associated to in-hospital mortality, 1-year, and 5-year early death after recovery. Multivariate Cox regression models were performed. A total of 206 patients were identified. RESULTS: The mean age was 62.6 years (sd, 18.8). A high frequency of comorbidities (88.3%) was observed, and 42 patients (20.4%) died during hospitalisation. Of the patients who recovered from acute infection, 26 (15.9%) died during the following year and 47 (28.7%) died during the following 5 years. The main factors associated with early mortality after recovery were age (HR: 1.03; 95% CI 1.02-1.07), diabetes mellitus (HR 1.86, 95% CI 1.01-3.44), chronic kidney disease (HR 3.96, 95% CI 1.87-8.38), liver disease (HR 3.62, 95% CI 1.64-8.51), and cancer (HR 3.76, 95% CI 1.90-7.46). CONCLUSION: Listeriosis is associated with high early post-recovery mortality. Our study describes the main prognostic factors, which may help to improve preventive follow-up strategies of adults with severe listeriosis.

A ribonuclease III involved in virulence of Mucorales fungi has evolved to cut exclusively single-stranded RNA.

Members of the ribonuclease III (RNase III) family regulate gene expression by processing double-stranded RNA (dsRNA). This family includes eukaryotic Dicer and Drosha enzymes that generate small dsRNAs in the RNA interference (RNAi) pathway. The fungus Mucor lusitanicus, which causes the deadly infection mucormycosis, has a complex RNAi system encompassing a non-canonical RNAi pathway (NCRIP) that regulates virulence by degrading specific mRNAs. In this pathway, Dicer function is replaced by R3B2, an atypical class I RNase III, and small single-stranded RNAs (ssRNAs) are produced instead of small dsRNA as Dicer-dependent RNAi pathways. Here, we show that R3B2 forms a homodimer that binds to ssRNA and dsRNA molecules, but exclusively cuts ssRNA, in contrast to all known RNase III. The dsRNA cleavage inability stems from its unusual RNase III domain (RIIID) because its replacement by a canonical RIIID allows dsRNA processing. A crystal structure of R3B2 RIIID resembles canonical RIIIDs, despite the low sequence conservation. However, the groove that accommodates dsRNA in canonical RNases III is narrower in the R3B2 homodimer, suggesting that this feature could be responsible for the cleavage specificity for ssRNA. Conservation of this activity in R3B2 proteins from other mucormycosis-causing Mucorales fungi indicates an early evolutionary acquisition.

A non-canonical RNAi pathway controls virulence and genome stability in Mucorales.

Epimutations in fungal pathogens are emerging as novel phenomena that could explain the fast-developing resistance to antifungal drugs and other stresses. These epimutations are generated by RNA interference (RNAi) mechanisms that transiently silence specific genes to overcome stressful stimuli. The early-diverging fungus Mucor circinelloides exercises a fine control over two interacting RNAi pathways to produce epimutants: the canonical RNAi pathway and a new RNAi degradative pathway. The latter is considered a non-canonical RNAi pathway (NCRIP) because it relies on RNA-dependent RNA polymerases (RdRPs) and a novel ribonuclease III-like named R3B2 to degrade target transcripts. Here in this work, we uncovered the role of NCRIP in regulating virulence processes and transposon movements through key components of the pathway, RdRP1 and R3B2. Mutants in these genes are unable to launch a proper virulence response to macrophage phagocytosis, resulting in a decreased virulence potential. The transcriptomic profile of rdrp1Δ and r3b2Δ mutants revealed a pre-exposure adaptation to the stressful phagosomal environment even when the strains are not confronted by macrophages. These results suggest that NCRIP represses key targets during regular growth and releases its control when a stressful environment challenges the fungus. NCRIP interacts with the RNAi canonical core to protect genome stability by controlling the expression of centromeric retrotransposable elements. In the absence of NCRIP, these retrotransposons are robustly repressed by the canonical RNAi machinery; thus, supporting the antagonistic role of NCRIP in containing the epimutational pathway. Both interacting RNAi pathways might be essential to govern host-pathogen interactions through transient adaptations, contributing to the unique traits of the emerging infection mucormycosis.

Healthcare-associated infections by multidrug-resistant bacteria in Andalusia, Spain, 2014 to 2021.

BackgroundMultidrug-resistant (MDR) bacteria are among chief causes of healthcare-associated infections (HAIs). In Spain, studies addressing multidrug resistance based on epidemiological surveillance systems are lacking.AimIn this observational study, cases of HAIs by MDR bacteria notified to the epidemiological surveillance system of Andalusia, Spain, between 2014-2021, were investigated. Notified cases and their spatiotemporal distribution were described, with a focus on social determinants of health (SDoH).MethodsNew cases during the study period of HAIs caused by extended-spectrum ß-lactamase (ESBL)-/carbapenemase-producing Enterobacterales, MDR Acinectobacter baumannii, MDR Pseudomonas aeruginosa or meticillin resistant Staphylococcus aureus were considered. Among others, notification variables included sex and age, while socio-economic variables comprised several SDoH. Cases' spatial distribution across municipalities was assessed. The smooth standardised incidence ratio (sSIR) was obtained using a Bayesian spatial model. Association between municipalities' sSIR level and SDoH was evaluated by bivariate analysis.ResultsIn total, 6,389 cases with a median age of 68 years were notified; 61.4% were men (n = 3,921). The most frequent MDR bacteria were ESBL-producing Enterobacterales (2,812/6,389; 44.0%); the main agent was Klebsiella spp. (2,956/6,389; 46.3%). Between 2014 and 2021 case numbers appeared to increase. Overall, up to 15-fold differences in sSIR between municipalities were observed. In bivariate analysis, there appeared to be an association between municipalities' sSIR level and deprivation (p = 0.003).ConclusionThis study indicates that social factors should be considered when investigating HAIs by MDR bacteria. The case incidence heterogeneity between Andalusian municipalities might be explained by SDoH, but also possibly by under-notification. Automatising reporting may address the latter.

Oleanolic Acid Complexation with Cyclodextrins Improves Its Cell Bio-Availability and Biological Activities for Cell Migration.

Wound healing is a complex process to restore skin. Plant-derived bioactive compounds might be a source of substances for the treatment of wounds stalled in a non-resolving stage of wound healing. Oleanolic acid (OA), a pentacyclic triterpene, has shown favorable wound healing properties both in vitro and in vivo. Unfortunately, OA cannot be solubilized in aqueous media, and it needs to be helped by the use of dimethyl sulfoxide (DMSO). In this paper, we have shown that cyclodextrins (CDs) are a good alternative to DMSO as agents to deliver OA to cells, providing better features than DMSO. Cyclodextrins are natural macromolecules that show a unique tridimensional structure that can encapsulate a wide variety of hydrophobic compounds. We have studied the cyclodextrin-encapsulated form of OA with OA/DMSO, comparing their stability, biological properties for cell migration, and cell viability. In addition, detailed parameters related to cell migration and cytoskeletal reorganization have been measured and compared. Our results show that OA-encapsulateds compound exhibit several advantages when compared to non-encapsulated OA in terms of chemical stability, migration enhancement, and preservation of cell viability.

Amniotic Membrane Restores Chronic Wound Features to Normal in a Keratinocyte TGF-ß-Chronified Cell Model.

Unsuccessful wound closure in chronic wounds can be linked to altered keratinocyte activation and their inability to re-epithelize. Suggested mechanisms driving this impairment involve unbalanced cytokine signaling. However, the molecular events leading to these aberrant responses are poorly understood. Among cytokines affecting keratinocyte responses, Transforming Growth Factor-ß (TFG-ß) is thought to have a great impact. In this study, we have used a previously characterized skin epidermal in vitro model, HaCaT cells continuously exposed to TGF-ß1, to study the wound recovery capabilities of chronified/senescent keratinocytes. In this setting, chronified keratinocytes show decreased migration and reduced activation in response to injury. Amniotic membrane (AM) has been used successfully to manage unresponsive complicated wounds. In our in vitro setting, AM treatment of chronified keratinocytes re-enabled migration in the early stages of wound healing, also promoting proliferation at later stages. Interestingly, when checking the gene expression of markers known to be altered in TGF-ß chronified cells and involved in cell cycle regulation, early migratory responses, senescence, and chronic inflammation, we discovered that AM treatment seemed to reset back to keratinocyte status. The analysis of the evolution of both the levels of keratinocyte activation marker cytokeratin 17 and the spatial-temporal expression pattern of the proliferation marker Ki-67 in human in vivo biopsy samples suggests that responses to AM recorded in TGF-ß chronified HaCaT cells would be homologous to those of resident keratinocytes in chronic wounds. All these results provide further evidence that sustained TGF-ß might play a key role in wound chronification and postulate the validity of our TGF-ß chronified HaCaT in vitro model for the study of chronic wound physiology.

A high-density narrow-field inhibitory retinal interneuron with direct coupling to Müller glia.

Amacrine cells are interneurons composing the most diverse cell class in the mammalian retina. They help encode visual features such as edges or directed motion by mediating excitatory and inhibitory interactions between input (i.e. bipolar) and output (i.e. ganglion) neurons in the inner plexiform layer (IPL). Like other brain regions, the retina also contains glial cells that contribute to neurotransmitter uptake, metabolic regulation and neurovascular control. Here, we report that in mouse retina (of either sex), an abundant, though previously unstudied inhibitory amacrine cell is coupled directly to Müller glia. Electron microscopic reconstructions of this amacrine type revealed chemical synapses with known retinal cell types and extensive associations with Müller glia, the processes of which often completely ensheathe the neurites of this amacrine cell. Microinjecting small tracer molecules into the somas of these amacrine cells led to selective labelling of nearby Müller glia, leading us to suggest the name "Müller glia-coupled amacrine cell," or MAC. Our data also indicate that MACs release glycine at conventional chemical synapses, and viral retrograde transsynaptic tracing from the dorsal lateral geniculate nucleus (dLGN) showed selective connections between MACs and a subpopulation of RGC types. Visually-evoked responses revealed a strong preference for light increments; these "ON" responses were primarily mediated by excitatory chemical synaptic input and direct electrical coupling with other cells. This initial characterization of the MAC provides the first evidence for neuron-glia coupling in the mammalian retina and identifies the MAC as a potential link between inhibitory processing and glial function.Significance Statement:Gap junctions between pairs of neurons or glial cells are commonly found throughout the nervous system and play multiple roles, including electrical coupling and metabolic exchange. In contrast, gap junctions between neurons and glia cells have rarely been reported and are poorly understood. Here we report the first evidence for neuron-glia coupling in the mammalian retina, specifically between an abundant (but previously unstudied) inhibitory interneuron and Müller glia. Moreover, viral tracing, optogenetics and serial electron microscopy provide new information about the neuron's synaptic partners and physiological responses.

The patient, diagnostic, and treatment intervals in adult patients with cancer from high- and lower-income countries: A systematic review and meta-analysis.

BACKGROUND: Longer time intervals to diagnosis and treatment are associated with worse survival for various types of cancer. The patient, diagnostic, and treatment intervals are considered core indicators for early diagnosis and treatment. This review estimated the median duration of these intervals for various types of cancer and compared it across high- and lower-income countries. METHODS AND FINDINGS: We conducted a systematic review with meta-analysis (prospectively registered protocol CRD42020200752). Three databases (MEDLINE, Embase, and Web of Science) and information sources including grey literature (Google Scholar, OpenGrey, EThOS, ProQuest Dissertations & Theses) were searched. Eligible articles were published during 2009 to 2022 and reported the duration of the following intervals in adult patients diagnosed with primary symptomatic cancer: patient interval (from the onset of symptoms to first presentation to a healthcare professional), diagnostic interval (from first presentation to diagnosis), and treatment interval (from diagnosis to treatment start). Interval duration was recorded in days and study medians were combined in a pooled estimate with 95% confidence intervals (CIs). The methodological quality of studies was assessed using the Aarhus checklist. A total of 410 articles representing 68 countries and reporting on 5,537,594 patients were included. The majority of articles reported data from high-income countries (n = 294, 72%), with 116 (28%) reporting data from lower-income countries. Pooled meta-analytic estimates were possible for 38 types of cancer. The majority of studies were conducted on patients with breast, lung, colorectal, and head and neck cancer. In studies from high-income countries, pooled median patient intervals generally did not exceed a month for most cancers. However, in studies from lower-income countries, patient intervals were consistently 1.5 to 4 times longer for almost all cancer sites. The majority of data on the diagnostic and treatment intervals came from high-income countries. Across both high- and lower-income countries, the longest diagnostic intervals were observed for hematological (71 days [95% CI 52 to 85], e.g., myelomas (83 days [47 to 145])), genitourinary (58 days [50 to 77], e.g., prostate (85 days [57 to 112])), and digestive/gastrointestinal (57 days [45 to 67], e.g., colorectal (63 days [48 to 78])) cancers. Similarly, the longest treatment intervals were observed for genitourinary (57 days [45 to 66], e.g., prostate (75 days [61 to 87])) and gynecological (46 days [38 to 54], e.g., cervical (69 days [45 to 108]) cancers. In studies from high-income countries, the implementation of cancer-directed policies was associated with shorter patient and diagnostic intervals for several cancers. This review included a large number of studies conducted worldwide but is limited by survivor bias and the inherent complexity and many possible biases in the measurement of time points and intervals in the cancer treatment pathway. In addition, the subintervals that compose the diagnostic interval (e.g., primary care interval, referral to diagnosis interval) were not considered. CONCLUSIONS: These results identify the cancers where diagnosis and treatment initiation may take the longest and reveal the extent of global disparities in early diagnosis and treatment. Efforts should be made to reduce help-seeking times for cancer symptoms in lower-income countries. Estimates for the diagnostic and treatment intervals came mostly from high-income countries that have powerful health information systems in place to record such information.

Long COVID 12 months after discharge: persistent symptoms in patients hospitalised due to COVID-19 and patients hospitalised due to other causes-a multicentre cohort study.

BACKGROUND: Long-term-specific sequelae or persistent symptoms (SPS) after hospitalisation due to COVID-19 are not known. The aim of this study was to explore the presence of SPS 12 months after discharge in survivors hospitalised due to COVID-19 and compare it with survivors hospitalised due to other causes. METHODS: Prospective cohort study, the Andalusian Cohort of Hospitalised patients for COVID-19 (ANCOHVID study), conducted in 4 hospitals and 29 primary care centres in Andalusia, Spain. The sample was composed of 906 adult patients; 453 patients hospitalised due to COVID-19 (exposed) and 453 hospitalised due to other causes (non-exposed) from March 1 to April 15, 2020, and discharged alive. The main outcomes were (1) the prevalence of SPS at 12 months after discharge and (2) the incidence of SPS after discharge. Outcome data at 12 months were compared between the exposed and non-exposed cohorts. Risk ratios were calculated, and bivariate analyses were performed. RESULTS: A total of 163 (36.1%) and 160 (35.3%) patients of the exposed and non-exposed cohorts, respectively, showed at least one SPS at 12 months after discharge. The SPS with higher prevalence in the subgroup of patients hospitalised due to COVID-19 12 months after discharge were persistent pharyngeal symptoms (p<0.001), neurological SPS (p=0.049), confusion or memory loss (p=0.043), thrombotic events (p=0.025) and anxiety (p=0.046). The incidence of SPS was higher for the exposed cohort regarding pharyngeal symptoms (risk ratio, 8.00; 95% CI, 1.85 to 36.12), confusion or memory loss (risk ratio, 3.50; 95% CI, 1.16 to 10.55) and anxiety symptoms (risk ratio, 2.36; 95% CI, 1.28 to 4.34). CONCLUSIONS: There was a similar frequency of long-term SPS after discharge at 12 months, regardless of the cause of admission (COVID-19 or other causes). Nevertheless, some symptoms that were found to be more associated with COVID-19, such as memory loss or anxiety, merit further investigation. These results should guide future follow-up of COVID-19 patients after hospital discharge.

Listeriosis outbreak caused by contaminated stuffed pork, Andalusia, Spain, July to October 2019.

Between 1 July and 26 October 2019 in Andalusia, Spain, a large outbreak with 207 confirmed cases of listeriosis was identified. Confirmed cases had a median age of 44 years (range: 0-94) and 114 were women (55.1%). Most cases (n = 154) had mild gastroenteritis, 141 (68.1%) required hospitalisation and three died; five of 34 pregnant women had a miscarriage. The median incubation period was 1 day (range: 0-30), and was significantly shorter in cases presenting with gastroenteritis compared to those presenting without gastroenteritis (1 day vs. 3 days, respectively, p value < 0.001). Stuffed pork, a ready-to-eat product consumed unheated, from a single producer contaminated with Listeria monocytogenes ST388 was identified as the source of infection. The outbreak strain was identified in 189 human samples and 87 non-human (82 food and 5 environmental) samples. Notification of new cases declined abruptly after control measures were implemented. These included contaminated food recall, protocols for clinical management of suspected cases and for post-exposure prophylaxis in pregnant women and communication campaigns with concise messages to the population through social media. Given that there were 3,059 probable cases, this was the largest L. monocytogenes outbreak ever reported in Europe.

A Multirobot System in an Assisted Home Environment to Support the Elderly in Their Daily Lives.

The increasing isolation of the elderly both in their own homes and in care homes has made the problem of caring for elderly people who live alone an urgent priority. This article presents a proposed design for a heterogeneous multirobot system consisting of (i) a small mobile robot to monitor the well-being of elderly people who live alone and suggest activities to keep them positive and active and (ii) a domestic mobile manipulating robot that helps to perform household tasks. The entire system is integrated in an automated home environment (AAL), which also includes a set of low-cost automation sensors, a medical monitoring bracelet and an Android application to propose emotional coaching activities to the person who lives alone. The heterogeneous system uses ROS, IoT technologies, such as Node-RED, and the Home Assistant Platform. Both platforms with the home automation system have been tested over a long period of time and integrated in a real test environment, with good results. The semantic segmentation of the navigation and planning environment in the mobile manipulator for navigation and movement in the manipulation area facilitated the tasks of the later planners. Results about the interactions of users with the applications are presented and the use of artificial intelligence to predict mood is discussed. The experiments support the conclusion that the assistance robot correctly proposes activities, such as calling a relative, exercising, etc., during the day, according to the user's detected emotional state, making this is an innovative proposal aimed at empowering the elderly so that they can be autonomous in their homes and have a good quality of life.

Genetic Manipulation in Mucorales and New Developments to Study Mucormycosis.

The study of the Mucoralean fungi physiology is a neglected field that the lack of effective genetic tools has hampered in the past. However, the emerging fungal infection caused by these fungi, known as mucormycosis, has prompted many researchers to study the pathogenic potential of Mucorales. The main reasons for this current attraction to study mucormycosis are its high lethality, the lack of effective antifungal drugs, and its recent increased incidence. The most contemporary example of the emergence character of mucormycosis is the epidemics declared in several Asian countries as a direct consequence of the COVID-19 pandemic. Fortunately, this pressure to understand mucormycosis and develop new treatment strategies has encouraged the blossoming of new genetic techniques and methodologies. This review describes the history of genetic manipulation in Mucorales, highlighting the development of methods and how they allowed the main genetic studies in these fungi. Moreover, we have emphasized the recent development of new genetic models to study mucormycosis, a landmark in the field that will configure future research related to this disease.

Establishing the ground squirrel as a superb model for retinal ganglion cell disorders and optic neuropathies.

Retinal ganglion cell (RGC) death occurs after optic nerve injury due to acute trauma or chronic degenerative conditions such as optic neuropathies (e.g., glaucoma). Currently, there are no effective therapies to prevent permanent vision loss resulting from RGC death, underlining the need for research on the pathogenesis of RGC disorders. Modeling human RGC/optic nerve diseases in non-human primates is ideal because of their similarity to humans, but has practical limitations including high cost and ethical considerations. In addition, many retinal degenerative disorders are age-related making the study in primate models prohibitively slow. For these reasons, mice and rats are commonly used to model RGC injuries. However, as nocturnal mammals, these rodents have retinal structures that differ from primates - possessing less than one-tenth of the RGCs found in the primate retina. Here we report the diurnal thirteen-lined ground squirrel (TLGS) as an alternative model. Compared to other rodent models, the number and distribution of RGCs in the TLGS retina are closer to primates. The TLGS retina possesses ~600,000 RGCs with the highest density along the equatorial retina matching the location of the highest cone density (visual streak). TLGS and primate retinas also share a similar interlocking pattern between RGC axons and astrocyte processes in the retina nerve fiber layer (RNFL). In addition, using TLGS we establish a new partial optic nerve injury model that precisely controls the extent of injury while sparing a portion of the retina as an ideal internal control for investigating the pathophysiology of axon degeneration and RGC death. Moreover, in vivo optical coherence tomography (OCT) imaging and ex vivo microscopic examinations of the retina in optic nerve injured TLGS confirm RGC loss precedes proximal axon degeneration, recapitulating human pathology. Thus, the TLGS retina is an excellent model, for translational research in neurodegeneration and therapeutic neuroprotection.

Sequelae, persistent symptomatology and outcomes after COVID-19 hospitalization: the ANCOHVID multicentre 6-month follow-up study.

BACKGROUND: Long-term effects of COVID-19, also called Long COVID, affect more than 10% of patients. The most severe cases (i.e. those requiring hospitalization) present a higher frequency of sequelae, but detailed information on these effects is still lacking. The objective of this study is to identify and quantify the frequency and outcomes associated with the presence of sequelae or persistent symptomatology (SPS) during the 6 months after discharge for COVID-19. METHODS: Retrospective observational 6-month follow-up study conducted in four hospitals of Spain. A cohort of all 969 patients who were hospitalized with PCR-confirmed SARS-CoV-2 from March 1 to April 15, 2020, was included. We collected all the SPS during the 6 months after discharge reported by patients during follow-up from primary care records. Cluster analyses were performed to validate the measures. The main outcome measures were return to the Emergency Services, hospital readmission and post-discharge death. Surviving patients' outcomes were collected through clinical histories and primary care reports. Multiple logistic regression models were applied. RESULTS: The 797 (82.2%) patients who survived constituted the sample followed, while the rest died from COVID-19. The mean age was 63.0 years, 53.7% of them were men and 509 (63.9%) reported some sequelae during the first 6 months after discharge. These sequelae were very diverse, but the most frequent were respiratory (42.0%), systemic (36.1%), neurological (20.8%), mental health (12.2%) and infectious (7.9%) SPS, with some differences by sex. Women presented higher frequencies of headache and mental health SPS, among others. A total of 160 (20.1%) patients returned to the Emergency Services, 35 (4.4%) required hospital readmission and 8 (1.0%) died during follow-up. The main factors independently associated with the return to Emergency Services were persistent fever, dermatological SPS, arrythmia or palpitations, thoracic pain and pneumonia. CONCLUSIONS: COVID-19 cases requiring hospitalization during the first wave of the pandemic developed a significant range of mid- to long-term SPS. A detailed list of symptoms and outcomes is provided in this multicentre study. Identification of possible factors associated with these SPS could be useful to optimize preventive follow-up strategies in primary care for the coming months of the pandemic.

Robotic-Based Well-Being Monitoring and Coaching System for the Elderly in Their Daily Activities.

The increasingly ageing population and the tendency to live alone have led science and engineering researchers to search for health care solutions. In the COVID 19 pandemic, the elderly have been seriously affected in addition to suffering from isolation and its associated and psychological consequences. This paper provides an overview of the RobWell (Robotic-based Well-Being Monitoring and Coaching System for the Elderly in their Daily Activities) system. It is a system focused on the field of artificial intelligence for mood prediction and coaching. This paper presents a general overview of the initially proposed system as well as the preliminary results related to the home automation subsystem, autonomous robot navigation and mood estimation through machine learning prior to the final system integration, which will be discussed in future works. The main goal is to improve their mental well-being during their daily household activities. The system is composed of ambient intelligence with intelligent sensors, actuators and a robotic platform that interacts with the user. A test smart home system was set up in which the sensors, actuators and robotic platform were integrated and tested. For artificial intelligence applied to mood prediction, we used machine learning to classify several physiological signals into different moods. In robotics, it was concluded that the ROS autonomous navigation stack and its autodocking algorithm were not reliable enough for this task, while the robot's autonomy was sufficient. Semantic navigation, artificial intelligence and computer vision alternatives are being sought.

The RNAi Mechanism Regulates a New Exonuclease Gene Involved in the Virulence of Mucorales.

Mucormycosis is a lethal disease caused by Mucorales, which are emerging as human causes that explain the high mortality for this disease. Consequently, the research community is searching for virulence determinants that could be repurposed as targets to develop new treatments against mucormycosis. Our work explores an RNA interference (RNAi)-based approach to find targets involved in the virulence of Mucorales. A transcriptomewide analysis compared sRNAs and their target mRNAs in two Mucor lusitanicus different pathotypes, virulent and avirulent, generating a list of 75 loci selected by their differential sRNA accumulation in these strains. As a proof of concept and validity, an experimental approach characterized two loci showing opposite behavior, confirming that RNAi activity causes their differential expression in the two pathotypes. We generated deletion mutants for two loci and a knockin-strain overexpressing for one of these loci. Their functional analysis in murine virulence assays identified the gene wex1, a putative DEDDy exonuclease with RNase domains, as an essential factor for virulence. The identification of wex1 showed the potential of our approach to discover virulence factors not only in Mucorales but also in any other fungal model with an active RNAi machinery. More importantly, it adds a new layer to the biological processes controlled by RNAi in M. lusitanicus, confirming that the Dicer-dependent RNAi pathway can silence gene expression to promote virulence.

Antifungal drug resistance evoked via RNAi-dependent epimutations.

Microorganisms evolve via a range of mechanisms that may include or involve sexual/parasexual reproduction, mutators, aneuploidy, Hsp90 and even prions. Mechanisms that may seem detrimental can be repurposed to generate diversity. Here we show that the human fungal pathogen Mucor circinelloides develops spontaneous resistance to the antifungal drug FK506 (tacrolimus) via two distinct mechanisms. One involves Mendelian mutations that confer stable drug resistance; the other occurs via an epigenetic RNA interference (RNAi)-mediated pathway resulting in unstable drug resistance. The peptidylprolyl isomerase FKBP12 interacts with FK506 forming a complex that inhibits the protein phosphatase calcineurin. Calcineurin inhibition by FK506 blocks M. circinelloides transition to hyphae and enforces yeast growth. Mutations in the fkbA gene encoding FKBP12 or the calcineurin cnbR or cnaA genes confer FK506 resistance and restore hyphal growth. In parallel, RNAi is spontaneously triggered to silence the fkbA gene, giving rise to drug-resistant epimutants. FK506-resistant epimutants readily reverted to the drug-sensitive wild-type phenotype when grown without exposure to the drug. The establishment of these epimutants is accompanied by generation of abundant fkbA small RNAs and requires the RNAi pathway as well as other factors that constrain or reverse the epimutant state. Silencing involves the generation of a double-stranded RNA trigger intermediate using the fkbA mature mRNA as a template to produce antisense fkbA RNA. This study uncovers a novel epigenetic RNAi-based epimutation mechanism controlling phenotypic plasticity, with possible implications for antimicrobial drug resistance and RNAi-regulatory mechanisms in fungi and other eukaryotes.

Relationship between exposure to mixtures of persistent, bioaccumulative, and toxic chemicals and cancer risk: A systematic review.

Environmental risks are responsible for one in five of all deaths worldwide. Persistent, bioaccumulative, and toxic substances are chemicals that can subsist for decades in human tissues and the environment. They include heavy metals, organochlorines, polychlorinated biphenyls, organobromines, organofluorines, and polycyclic aromatic hydrocarbons among others. Although humans are often exposed to multiple pollutants simultaneously, their negative effects on health have generally been studied for each one separately. Among the most severe of these harmful effects is cancer. Here, to compile and analyze the available evidence on the relationship between exposure to mixtures of persistent, bioaccumulative, and toxic chemicals and the risk of developing cancer in the general population, we provide a systematic review based on the main databases (Cochrane, PubMed and Embase), together with complementary sources, using the general methodology of the PRISMA Statement. The articles analyzed were selected by two researchers working independently and their quality was evaluated by reference to the Newcastle-Ottawa scale. The initial search yielded 2379 results from the main sources of information and 22 from the complementary ones. After the article selection process, 22 were included in the final review (21 case-control studies and one cohort study). Analysis of the selected studies revealed that most of the mixtures analyzed were positively associated with risk of cancer, especially that of the breast, colon-rectum or testis, and more strongly so than each contaminant alone. In view of the possible stronger association observed with the development of cancer for some mixtures of pollutants than when each one is present separately, exposure to mixtures should also be monitored and measured, preferably in cohort designs, to complement the traditional approach to persistent, bioaccumulative, and toxic chemicals. The results presented should be taken into account in public health policies in order to strengthen the regulatory framework for cancer prevention and control.