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Abstract The orphan G protein-coupled receptor 37 (GPR37), widely associated with Parkinson’s disease (PD), undergoes proteolytic processing under physiological conditions. The N-terminus domain is proteolyzed by a disintegrin and metalloproteinase 10 (ADAM-10), which generates various membrane receptor forms and ectodomain shedding (ecto-GPR37) in the extracellular environment. We investigated the processing and density of GPR37 in several neurodegenerative conditions, including Lewy body disease (LBD), multiple system atrophy (MSA), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Alzheimer’s disease (AD). The presence of ecto-GPR37 peptides in the cerebrospinal fluid (CSF) of PD, MSA, CBD and PSP patients was assessed through an in-house nanoluciferase-based immunoassay. This study identified increased receptor processing in early-stage LBD within the PFC and striatum, key brain areas in neurodegeneration. In MSA only the 52 kDa form of GPR37 appeared in the striatum. This form was also significantly elevated in the striatum of AD necropsies. On the contrary, GPR37 processing remained unchanged in the brains of CBD and PSP patients. Furthermore, while CSF ecto-GPR37 increased in PD patients, its levels remained unchanged in MSA, CBD, and PSP subjects. Importantly, patients with PD with rapid progression of the disease did not have elevated ecto-GPR37 in the CSF, while those with slow progression showed a significant increase, suggesting a possible prognostic use of ecto-GPR37 in PD. This research underscores the distinctive processing and density patterns of GPR37 in neurodegenerative diseases, providing crucial insights into its potential role as an indicator of PD progression rates.

BackgroundFollowing the low incidence rates of non-SARS-CoV-2 respiratory viruses registered during the strict lockdown enforced in the pandemic, a resurgence of several endemic viruses in Catalonia (Spain) was noted during the early summer of 2021.ObjectivesIn this study, we investigated whether the circulation of non-SARS-CoV-2 respiratory viruses in Catalonia, assessed by Microbiological Reporting System of Catalonia (MRSC) and the Epidemiological Surveillance Network of Catalonia, was affected by the strict lockdown measures, as well as, the implication of the Coronavirus Disease 19 (COVID-19) de-escalation process in the late season outbreaks registered during the 2020-2021 season.Study designA retrospective comparison of epidemic patterns in the respiratory viruses' incidence, using regional public health surveillance data from MRSC, was performed between weeks 26/2016 to week 27/2021. Data were expressed as the weekly total number of test positivity for individual viruses. A segmented negative binomial regression model was conducted, with two parameters included (level and trend) for each segment of the time series (2020 pre-lockdown, 2020 post-lockdown and 2021). Results were reported as a unit changed in the strict lockdown.ResultsA total of 51588 confirmed cases of the different respiratory viruses were included in the analysis, the majority were influenza cases (63.7%). An immediate reduction in the weekly number of cases was observed in 2020 after the COVID-19 outbreak for human adenovirus virus (HAdV) (β2 = -2.606; P ConclusionsOur data not only provides evidence that occurrence of different respiratory virus infections was affected by the strict lockdown taken against SARS-CoV-2 but it also shows a late resurgence of seasonal respiratory viruses' cases during the 2020-2021 season following the relaxation of COVID-19-targeted non-pharmaceutical interventions.

Adenosine plays an important role in modulating immune cell function, particularly T cells and myeloid cells, such as macrophages and dendritic cells. Cell surface adenosine A2A receptors (A2AR) regulate the production of pro-inflammatory cytokines and chemokines, as well as the proliferation, differentiation, and migration of immune cells. In the present study, we expanded the A2AR interactome and provided evidence for the interaction between the receptor and the Niemann–Pick type C intracellular cholesterol transporter 1 (NPC1) protein. The NPC1 protein was identified to interact with the C-terminal tail of A2AR in RAW 264.7 and IPMФ cells by two independent and parallel proteomic approaches. The interaction between the NPC1 protein and the full-length A2AR was further validated in HEK-293 cells that permanently express the receptor and RAW264.7 cells that endogenously express A2AR. A2AR activation reduces the expression of NPC1 mRNA and protein density in LPS-activated mouse IPMФ cells. Additionally, stimulation of A2AR negatively regulates the cell surface expression of NPC1 in LPS-stimulated macrophages. Furthermore, stimulation of A2AR also altered the density of lysosome-associated membrane protein 2 (LAMP2) and early endosome antigen 1 (EEA1), two endosomal markers associated with the NPC1 protein. Collectively, these results suggested a putative A2AR-mediated regulation of NPC1 protein function in macrophages, potentially relevant for the Niemann–Pick type C disease when mutations in NPC1 protein result in the accumulation of cholesterol and other lipids in lysosomes.

Contact tracing outcome indicators, such as symptom development (SD) and secondary attack rate (SAR) among close contacts (CCs), are key to understanding SARS-CoV-2 transmission. This study analyses SD and SAR and estimates the incubation period (IP) from a cohort of 47,729 CCs from 17,679 SARS-CoV-2 cases diagnosed in Catalonia (Spain) from May to August 2020. Globally, 19.4% of the CCs reported symptoms, especially adult women living in urban areas. SAR was 24.5%, notably higher among infants (37.6%), and 45.9% of secondary cases (SCs) were asymptomatic. Household CCs had 98% (OR: 1.98, 95% CI: 1.81–2.18) and 138% (2.38, 2.19–2.58) increased risk of SD and becoming SCs compared to social settings. The IP was 3.42 days, being 4.10 days among social CCs, and only 15.4% and 4.8% of SCs developed symptoms after days 7 and 10 of quarantine, respectively. These results, notably the higher SAR among asymptomatic children, highlight the importance of diligent monitoring to inform SARS-CoV-2 control strategies.

We analyzed the effect of COVID-19 on healthcare demand and invasive pneumococcal disease in children in Catalonia, Spain. Compared with 2018–2019, we noted large reductions in healthcare activities and incidence of invasive pneumococcal disease in 2020. These changes likely resulted from nonpharmaceutical measures implemented during the COVID-19 pandemic.

Abstract Wastewater-based epidemiology has shown to be an efficient tool to track the circulation of SARS-CoV-2 in communities assisted by wastewater treatment plants (WWTPs). The challenge comes when this approach is employed to help Health authorities in their decision-making. Here, we describe the roadmap for the design and deployment of SARSAIGUA, the Catalan Surveillance Network of SARS-CoV-2 in Sewage. The network monitors, weekly or biweekly, 56 WWTPs evenly distributed across the territory and serving 6 M inhabitants (80% of the Catalan population). Each week, samples from 45 WWTPs are collected, analyzed, results reported to Health authorities, and finally published within less than 72 h in an online dashboard ( https://sarsaigua.icra.cat ). After 20 months of monitoring (July 20–March 22), the standardized viral load (gene copies/day) in all the WWTPs monitored fairly matched the cumulative number of COVID-19 cases along the successive pandemic waves, showing a good fit with the diagnosed cases in the served municipalities (Spearman Rho = 0.69). Here we describe the roadmap of the design and deployment of SARSAIGUA while providing several open-access tools for the management and visualization of the surveillance data.

Abstract Alzheimer’s disease (AD) is characterized by a reorganization of brain activity determining network hyperexcitability and loss of synaptic plasticity. Precisely, a dysfunction in metabotropic GABAB receptor signalling through G protein-gated inwardly rectifying K+ (GIRK or Kir3) channels on the hippocampus has been postulated. Thus, we determined the impact of amyloid-β (Aβ) pathology in GIRK channel density, subcellular distribution, and its association with GABAB receptors in hippocampal CA1 pyramidal neurons from the APP/PS1 mouse model using quantitative SDS-digested freeze-fracture replica labelling (SDS-FRL) and proximity ligation in situ assay (P-LISA). In wild type mice, single SDS-FRL detection revealed a similar dendritic gradient for GIRK1 and GIRK2 in CA1 pyramidal cells, with higher densities in spines, and GIRK3 showed a lower and uniform distribution. Double SDS-FRL showed a co-clustering of GIRK2 and GIRK1 in post- and presynaptic compartments, but not for GIRK2 and GIRK3. Likewise, double GABAB1 and GIRK2 SDS-FRL detection displayed a high degree of co-clustering in nanodomains (40–50 nm) mostly in spines and axon terminals. In APP/PS1 mice, the density of GIRK2 and GIRK1, but not for GIRK3, was significantly reduced along the neuronal surface of CA1 pyramidal cells and in axon terminals contacting them. Importantly, GABAB1 and GIRK2 co-clustering was not present in APP/PS1 mice. Similarly, P-LISA experiments revealed a significant reduction in GABAB1 and GIRK2 interaction on the hippocampus of this animal model. Overall, our results provide compelling evidence showing a significant reduction on the cell surface density of pre- and postsynaptic GIRK1 and GIRK2, but not GIRK3, and a decline in GABAB receptors and GIRK2 channels co-clustering in hippocampal pyramidal neurons from APP/PS1 mice, thus suggesting that a disruption in the GABAB receptor–GIRK channel membrane assembly causes dysregulation in the GABAB signalling via GIRK channels in this AD animal model.

Abstract Background Guidance on SARS-CoV-2 contact tracing indicators have been recently revised by international public health agencies. The aim of the study is to describe and analyse contact tracing indicators based on Catalonia’s (Spain) real data and proposing to update them according to recommendations. Methods Retrospective cohort analysis including Catalonia’s contact tracing dataset from 20 May until 31 December 2020. Descriptive statistics are performed including sociodemographic stratification by age, and differences are assessed over the study period. Results We analysed 923,072 contacts from 301,522 SARS-CoV-2 cases with identified contacts (67.1% contact tracing coverage). The average number of contacts per case was 4.6 (median 3, range 1–243). A total of 403,377 contacts accepted follow-up through three phone calls over a 14-day quarantine period (84.5% of contacts requiring follow-up). The percentage of new cases declared as contacts 14 days prior to diagnosis evolved from 33.9% in May to 57.9% in November. All indicators significantly improved towards the target over time (p

Background: Invasive pneumococcal disease (IPD) is the most important bacterial infection in young children, and the introduction of pneumococcal conjugate vaccines has changed its presentation. This study compared the incidence, characteristics and serotype distribution of IPD before and after the introduction of the pneumococcal conjugate vaccine (PCV13). Methods: Prospective enrolment of patients with IPD aged less than 60 months and admitted to either of 2 tertiary care hospitals between January 2007 and December 2009 (pre-PCV13 period) and January 2012 and June-2016 (PCV13 period). Results: We identified 493 cases, 319 in the pre-PCV13 period and 174 in the PCV13 period. The incidence of IPD decreased from 89.7 to 34.4 casos per 100 000 habitantes ( −62%; P

Resumen: Introducción: La enfermedad neumocócica invasiva (ENI) es la infección bacteriana más relevante en niños pequeños y la introducción de las vacunas antineumocócicas conjugadas (VNC) ha cambiado su presentación clínica. En este estudio se analizaron los cambios en la incidencia, características clínicas y distribución de serotipos en los casos de ENI antes y después de la disponibilidad de la VNC13. Métodos: Se incluyeron prospectivamente pacientes con ENI menores de 60 meses ingresados en 2 hospitales pediátricos terciarios desde enero de 2007 a diciembre de 2009 (período pre-VNC13) y de enero de 2012 a junio de 2016 (período VNC13). Resultados: Se identificaron 493 casos, 319 en el período pre-VNC13 y 174 en el período VNC13. La incidencia de ENI disminuyó de 89,7 a 34,4 casos por 100.000 habitantes (−62%, p

IntroductionThe protection of children is a major driver of behavior among those in charge of their care. We evaluated whether compliance with preventive measures against SARS-CoV-2 infection among adults living with children was different from that of those not living with them, in 2020.MethodsWe used the COSMO-SPAIN (N = 867) and the nationally representative ENE-COVID (N = 29,926) surveys to estimate prevalence of compliance (95% confidence interval). Logistic model based standardization methods were applied to estimate standardized prevalence differences (SPrD) to the overall distribution of age, sex, education, history of COVID-19, and residence of other >60 yrs in the household.ResultsWe observed that adults living with children more frequently avoided bars (SPrDENE−COVID: 4.2%; 95% CI: 2.3–6.1), crowded places (SPrDCOSMO: 8.0%; 95% CI: 0.6–15.1) and did not use public transportation (SPrDENE−COVID: 4.9%; 95% CI: 3.0–6.7). They were also more worried about work and family conciliation (SPrDCOSMO: 12.2%; 95% CI: 4.8–19.5) and about closure of education centers (SPrDCOSMO: 26.5%; 95% CI: 19.4–33.6).DiscussionIn general, adults living with children adopted slightly more frequently social distancing measures.

Objective: Assess the risk associated with COVID-19 in pregnant women on maternal and neonatal outcomes in Catalonia (Spain) in 2020, before the beginning of COVID-19 vaccination campaign. Method: Cross-sectional descriptive study with all pregnant women (41,560) and their live newborns (42,097) (1st March to 31st December 2020). Women were classified: positive and negative COVID-19 diagnosis during pregnancy. The outcomes analysed were complications during pregnancy, gestational age, admission of newborns to neonatal intensive care unit (NICU) and birth weight. Associations among positive COVID-19 and maternal and infant variables were measured with logistic regression models. Results were expressed as odds ratios and 95% confidence intervals. Models were adjusted for nationality, maternal age, socioeconomic status, type of pregnancy and type of centre where the delivery occurred (public or private management hospital). Results: A total of 696 women (1.7%) were diagnosed with COVID-19 during pregnancy. Women with COVID-19 were 4.37 times more likely to have complications during pregnancy (4.37; 3.52-5.40). A total of 713 newborns (1.7%) were from mothers with COVID-19. A positive diagnosis of COVID-19 increased the risk of preterm birth (1.41; 1.03-1.89), admission to NICU (1.40; 1.06-1.82) and low birth weight (1.35; 0.99-1.80) in babies. Conclusions: Pregnant women with COVID-19 had higher risk of developing complications during pregnancy and their newborns were more likely to be admitted to NICU and had prematurity. Resumen: Objetivo: Evaluar el riesgo asociado de COVID-19 y los resultados en mujeres embarazadas y sus recién nacidos en Cataluña (España) antes del inicio de la campaña de vacunación. Método: Estudio descriptivo transversal de mujeres gestantes (41.560) y sus recién nacidos (42.097) (del 1 de marzo al 31 de diciembre de 2020). Las gestantes fueron clasificadas según diagnóstico COVID-19 positivo o negativo durante el embarazo. Los resultados analizados fueron complicaciones gestacionales, semana gestacional, ingreso del recién nacido en la unidad de cuidados intensivos neonatales (UCIN) y bajo peso al nacer. Las asociaciones entre COVID-19 positivo y variables maternas y perinatales se midieron con regresión logística. Los resultados se expresaron con odds ratio e intervalo de confianza del 95%. Los modelos se ajustaron por nacionalidad, edad materna, nivel socioeconómico, tipo de embarazo y titularidad (pública o privada) del hospital donde se dio a luz. Resultados: Un total de 696 gestantes (1,7%) fueron diagnosticadas de COVID-19 durante el embarazo. Las gestantes con COVID-19 presentaron 4,37 veces mayor probabilidad de tener complicaciones durante el embarazo (4,37; 3,52-5,40). Hubo 713 recién nacidos (1,7%) de gestantes con COVID-19. El diagnóstico positivo de COVID-19 incrementó el riesgo de prematuridad (1,41; 1,03-1,89), ingreso en UCIN (1,40; 1,06-1,82) y bajo peso al nacer (1,35; 0,99-1,80) de los recién nacidos. Conclusiones: Las gestantes con COVID-19 presentaron mayor riesgo de desarrollar complicaciones durante el embarazo y sus hijos tuvieron mayor probabilidad de ingreso en la UCIN y de prematuridad.

The dopamine D4 receptor (D4R) is expressed in the retina, prefrontal cortex, and autonomic nervous system and has been implicated in attention deficit hyperactivity disorder (ADHD), substance use disorders, and erectile dysfunction. D4R has also been investigated as a target for antipsychotics due to its high affinity for clozapine. As opposed to the closely related dopamine D2 receptor (D2R), dopamine-induced arrestin recruitment and desensitization at the D4R have not been studied in detail. Indeed, some earlier investigations could not detect arrestin recruitment and desensitization of this receptor upon its activation by agonist. Here, we used a novel nanoluciferase complementation assay to study dopamine-induced recruitment of β-arrestin2 (βarr2; also known as arrestin3) and G protein-coupled receptor kinase-2 (GRK2) to the D4R in HEK293T cells. We also studied desensitization of D4R-evoked G protein-coupled inward rectifier potassium (GIRK; also known as Kir3) current responses in Xenopus oocytes. Furthermore, the effect of coexpression of GRK2 on βarr2 recruitment and GIRK response desensitization was examined. The results suggest that coexpression of GRK2 enhanced the potency of dopamine to induce βarr2 recruitment to the D4R and accelerated the rate of desensitization of D4R-evoked GIRK responses. The present study reveals new details about the regulation of arrestin recruitment to the D4R and thus increases our understanding of the signaling and desensitization of this receptor.

Incidence of invasive pneumococcal disease (IPD) decreased worldwide in 2020, coinciding with the implementation of measures to reduce COVID-19 transmission. We evaluated the impact of the COVID-19 pandemic on healthcare demand and IPD in children in 2021 compared to the pre-pandemic period (2018–2019) and the early pandemic period (2020) in a study carried out during 2018–2021 in Catalonia. Incidence rates were compared by calculating the incidence rate ratio (IRR), and expressing percentage changes in IRR as (1-IRR)x100. Compared to 2018–2019, emergency room (ER) visits declined by 21% in 2021 (p < 0.001), mainly in the first quarter (−39%), and compared to 2020, ER visits increased by 22% in 2021 (p < 0.001), except in the first quarter. IPD incidence overall was 11.0 in 2018–2019 and 4.6 in 2021 (−58%, p < 0.001); the reduction in incidence was similar in the 0–4 age group and was higher in the first quarters. Compared to 2020, in 2021, IPD incidence decreased during the first quarter (−86%, p < 0.001), but increased from 0.0 to 1.2 in the second quarter (p = 0.02) and from 0.6 to 2.1 (p=0.03) in the fourth quarter. The decreased IPD incidence observed in 2021 compared to 2018–2019 (most especially in the first quarter) was greater than the decrease in healthcare demand and PCR test requests. Compared to 2020, IPD incidence decreased in the first quarter when a second state of alarm was in force. In 2021, compared to 2018–2019, there was a greater reduction in PCV13 serotypes than in non-PCV13 serotypes.

Guanine-based purines (GBPs) exert numerous biological effects at the central nervous system through putative membrane receptors, the existence of which is still elusive. To shed light on this question, we screened orphan and poorly characterized G protein-coupled receptors (GPRs), selecting those that showed a high purinoreceptor similarity and were expressed in glioma cells, where GBPs exerted a powerful antiproliferative effect. Of the GPRs chosen, only the silencing of GPR23, also known as lysophosphatidic acid (LPA) 4 receptor, counteracted GBP-induced growth inhibition in U87 cells. Guanine (GUA) was the most potent compound behind the GPR23-mediated effect, acting as the endpoint effector of GBP antiproliferative effects. Accordingly, cells stably expressing GPR23 showed increased sensitivity to GUA. Furthermore, while GPR23 expression was low in a hypoxanthine-guanine phosphoribosyl-transferase (HGPRT)-mutated melanoma cell line showing poor sensitivity to GBPs, and in HGPRT-silenced glioma cells, GPR23-induced expression in both cell types rescued GUA-mediated cell growth inhibition. Finally, binding experiments using [3H]-GUA and U87 cell membranes revealed the existence of a selective GUA binding (KD = 29.44 ± 4.07 nM; Bmax 1.007 ± 0.035 pmol/mg prot) likely to GPR23. Overall, these data suggest GPR23 involvement in modulating responses to GUA in tumor cell lines, although further research needs to verify whether this receptor mediates other GUA effects.

The functional and pharmacological significance of the dopamine D4 receptor (D4R) has remained the least well understood of all the dopamine receptor subtypes. Even more enigmatic has been the role of the very prevalent human DRD4 gene polymorphisms in the region that encodes the third intracellular loop of the receptor. The most common polymorphisms encode a D4R with 4 or 7 repeats of a proline-rich sequence of 16 amino acids (D4.4R and D4.7R). DRD4 polymorphisms have been associated with individual differences linked to impulse control-related neuropsychiatric disorders, with the most consistent associations established between the gene encoding D4.7R and attention-deficit hyperactivity disorder (ADHD) and substance use disorders. The function of D4R and its polymorphic variants is being revealed by addressing the role of receptor heteromerization and the relatively avidity of norepinephrine for D4R. We review the evidence conveying a significant and differential role of D4.4R and D4.7R in the dopaminergic and noradrenergic modulation of the frontal cortico-striatal pyramidal neuron, with implications for the moderation of constructs of impulsivity as personality traits. This differential role depends on their ability to confer different properties to adrenergic α2A receptor (α2AR)-D4R heteromers and dopamine D2 receptor (D2R)-D4R heteromers, preferentially localized in the perisomatic region of the frontal cortical pyramidal neuron and its striatal terminals, respectively. We also review the evidence to support the D4R as a therapeutic target for ADHD and other impulse-control disorders, as well as for restless legs syndrome.

Abstract Objective α-Synuclein has been studied as a potential biomarker for Parkinson’s disease (PD) with no concluding results. Accordingly, there is an urgent need to find out reliable specific biomarkers for PD. GPR37 is an orphan G protein-coupled receptor that toxically accumulates in autosomal recessive juvenile parkinsonism. Here, we investigated whether GPR37 is upregulated in sporadic PD, and thus a suitable potential biomarker for PD. Methods GPR37 protein density and mRNA expression in postmortem substantia nigra (SN) from PD patients were analysed by immunoblot and RT-qPCR, respectively. The presence of peptides from the N-terminus-cleaved domain of GPR37 (i.e. ecto-GPR37) in human cerebrospinal fluid (CSF) was determined by liquid chromatography-mass spectrometric analysis. An engineered in-house nanoluciferase-based immunoassay was used to quantify ecto-GPR37 in CSF samples from neurological control (NC) subjects, PD patients and Alzheimer’s disease (AD) patients. Results GPR37 protein density and mRNA expression were significantly augmented in sporadic PD. Increased amounts of ecto-GPR37 peptides in the CSF samples from PD patients were identified by mass spectrometry and quantified by the in-house ELISA method. However, the CSF total α-synuclein level in PD patients did not differ from that in NC subjects. Similarly, the cortical GPR37 mRNA expression and CSF ecto-GPR37 levels in AD patients were also unaltered. Conclusion GPR37 expression is increased in SN of sporadic PD patients. The ecto-GPR37 peptides are significantly increased in the CSF of PD patients, but not in AD patients. These results open perspectives and encourage further clinical studies to confirm the validity and utility of ecto-GPR37 as a potential PD biomarker.

Resumen: Introducción: La enfermedad neumocócica invasora (ENI) puede requerir ingreso en la unidad de cuidados intensivos pediátricos (UCIP). El objetivo de este trabajo es analizar las características epidemiológicas, clínicas y microbiológicas asociadas a la ENI que predisponen el ingreso en la UCIP. Material y métodos: Estudio prospectivo de casos diagnosticados con ENI en tres hospitales pediátricos de Barcelona entre enero de 2012 y junio de 2016. Se analizaron las asociaciones entre el ingreso en la UCIP y las variables epidemiológicas, clínicas y microbiológicas. Resultados: Se incluyeron 263 casos con ENI. El 19% (n = 50) requirió ingreso en la UCIP. El 100% (7) de los pacientes con shock séptico, 84,2% (16) con meningitis y 15,2% (23) con neumonía complicada ingresaron en la UCIP. Las complicaciones más frecuentes fueron pulmonares (35,2%) y neurológicas (39,5%). La razón entre ingreso y no ingreso en la UCIP fue 4,17 veces mayor en los sujetos con enfermedad de base. Los serotipos asociados al ingreso en la UCIP fueron el 19A (23% del total de este serotipo), el 14 (20%), el 3 (17%) y el serotipo 1 (12,5%). Conclusiones: La ENI requiere ingreso en la UCIP en caso de shock séptico y meningitis, no así, de entrada, la neumonía complicada. El porcentaje de ingresos es mayor en los niños con enfermedad de base. El ingreso en la UCIP conlleva una estancia más prolongada, así como complicaciones durante la fase aguda y secuelas, sobre todo, neurológicas. Los serotipos de los pacientes que ingresaron en la UCIP fueron, predominantemente, serotipos vacunales. Abstract: Introduction: Patients with invasive pneumococcal disease (IPD) may require admission into paediatric intensive care units (PICU). The aim of this study is to analyse the epidemiological, clinical, and microbiological characteristics associated with IPD that may require admission to the PICU. Material and methods: A prospective study was conducted on cases of IPD diagnosed in three Paediatric Hospitals in Barcelona between January 2012 and June 2016. An analysis was made of the associations between the admission to PICU and the epidemiological, clinical, and microbiological variables. Results: A total of 263 cases with IPD were included, of which 19% (n = 50) required admission to PICU. Patients with septic shock (7; 100%), meningitis (16; 84.2%), and those with complicated pneumonia (23; 15.2%) were admitted to the PICU. The most frequent complications were pulmonary (35.2%) and neurological (39.5%). The ratio between admission and non-admission to PICU was 4.7 times higher in subjects with an underlying disease. The serotypes associated with PICU admission were 19A (23% of the total of this serotype), serotype 14 (20%), serotype 3 (17%), and serotype 1 (12.5%). Conclusions: IPD required PICU admission in cases of septic shock and meningitis, and less so with complicated pneumonia. The percentage of admissions is greater in children with an underlying disease. Admission into the PICU involves a longer stay, complications during the acute phase, as well as sequelae, particularly neurological ones. The serotypes of the patients that were admitted to PICU were predominantly vaccine serotypes.

Introduction: Patients with invasive pneumococcal disease (IPD) may require admission into paediatric intensive care units (PICU). The aim of this study is to analyse the epidemiological, clinical, and microbiological characteristics associated with IPD that may require admission to the PICU. Material and methods: A prospective study was conducted on cases of IPD diagnosed in three Paediatric Hospitals in Barcelona between January 2012 and June 2016. An analysis was made of the associations between the admission to PICU and the epidemiological, clinical, and microbiological variables. Results: A total of 263 cases with IPD were included, of which 19% (n = 50) required admission to PICU. Patients with septic shock (7; 100%), meningitis (16; 84.2%), and those with complicated pneumonia (23; 15.2%) were admitted to the PICU. The most frequent complications were pulmonary (35.2%) and neurological (39.5%). The ratio between admission and non-admission to PICU was 4.7 times higher in subjects with an underlying disease. The serotypes associated with PICU admission were 19A (23% of the total of this serotype), serotype 14 (20%), serotype 3 (17%), and serotype 1 (12.5%). Conclusions: IPD required PICU admission in cases of septic shock and meningitis, and less so with complicated pneumonia. The percentage of admissions is greater in children with an underlying disease. Admission into the PICU involves a longer stay, complications during the acute phase, as well as sequelae, particularly neurological ones. The serotypes of the patients that were admitted to PICU were predominantly vaccine serotypes. Resumen: Introducción: La enfermedad neumocócica invasora (ENI) puede requerir ingreso en la unidad de cuidados intensivos pediátricos (UCIP). El objetivo de este trabajo es analizar las características epidemiológicas, clínicas y microbiológicas asociadas a la ENI que predisponen el ingreso en la UCIP. Material y métodos: Estudio prospectivo de casos diagnosticados con ENI en tres hospitales pediátricos de Barcelona entre enero de 2012 y junio de 2016. Se analizaron las asociaciones entre el ingreso en la UCIP y las variables epidemiológicas, clínicas y microbiológicas. Resultados: Se incluyeron 263 casos con ENI. El 19% (n = 50) requirió ingreso en la UCIP. El 100% (7) de los pacientes con shock séptico, 84,2% (16) con meningitis y 15,2% (23) con neumonía complicada ingresaron en la UCIP. Las complicaciones más frecuentes fueron pulmonares (35,2%) y neurológicas (39,5%). La razón entre ingreso y no ingreso en la UCIP fue 4,17 veces mayor en los sujetos con enfermedad de base. Los serotipos asociados al ingreso en la UCIP fueron el 19A (23% del total de este serotipo), el 14 (20%), el 3 (17%) y el serotipo 1 (12,5%). Conclusiones: La ENI requiere ingreso en la UCIP en caso de shock séptico y meningitis, no así, de entrada, la neumonía complicada. El porcentaje de ingresos es mayor en los niños con enfermedad de base. El ingreso en la UCIP conlleva una estancia más prolongada, así como complicaciones durante la fase aguda y secuelas, sobre todo, neurológicas. Los serotipos de los pacientes que ingresaron en la UCIP fueron, predominantemente, serotipos vacunales.

Vaccination with the 13-valent conjugated pneumococcal disease (PCV13) has reduced invasive pneumococcal disease (IPD), but there have been reports of vaccine failures. We performed a prospective study in children aged 2–59 months who received diagnoses of IPD during January 2012–June 2016 in 3 pediatric hospitals in Catalonia, Spain, a region with a PCV13 vaccination coverage of 63%. We analyzed patients who had been age-appropriately vaccinated but who developed IPD caused by PCV13 serotypes. We detected 24 vaccine failure cases. The serotypes involved were 3 (16 cases); 19A (5 cases); and 1, 6B, and 14 (1 case each). Cases were associated with children without underlying conditions, with complicated pneumonia (OR 6.65, 95% CI 1.91–23.21), and with diagnosis by PCR (OR 5.18, 95% CI 1.84–14.59). Vaccination coverage should be increased to reduce the circulation of vaccine serotypes. Continuous surveillance of cases of IPD using both culture and PCR to characterize vaccine failures is necessary.

Abstract Background It has been hypothesized that heteromers of adenosine A2A receptors (A2AR) and cannabinoid CB1 receptors (CB1R) localized in glutamatergic nerve terminals mediate the integration of adenosine and endocannabinoid signaling involved in the modulation of striatal excitatory neurotransmission. Previous studies have demonstrated the existence of A2AR-CB1R heteromers in artificial cell systems. A dependence of A2AR signaling for the Gi protein-mediated CB1R signaling was described as one of its main biochemical characteristics. However, recent studies have questioned the localization of functionally significant A2AR-CB1R heteromers in striatal glutamatergic terminals. Results Using a peptide-interfering approach combined with biophysical and biochemical techniques in mammalian transfected cells and computational modeling, we could establish a tetrameric quaternary structure of the A2AR-CB1R heterotetramer. This quaternary structure was different to the also tetrameric structure of heteromers of A2AR with adenosine A1 receptors or dopamine D2 receptors, with different heteromeric or homomeric interfaces. The specific quaternary structure of the A2A-CB1R, which depended on intermolecular interactions involving the long C-terminus of the A2AR, determined a significant A2AR and Gs protein-mediated constitutive activation of adenylyl cyclase. Using heteromer-interfering peptides in experiments with striatal glutamatergic terminals, we could then demonstrate the presence of functionally significant A2AR-CB1R heteromers with the same biochemical characteristics of those studied in mammalian transfected cells. First, either an A2AR agonist or an A2AR antagonist allosterically counteracted Gi-mediated CB1R agonist-induced inhibition of depolarization-induced glutamate release. Second, co-application of both an A2AR agonist and an antagonist cancelled each other effects. Finally, a CB1R agonist inhibited glutamate release dependent on a constitutive activation of A2AR by a canonical Gs-Gi antagonistic interaction at the adenylyl cyclase level. Conclusions We demonstrate that the well-established cannabinoid-induced inhibition of striatal glutamate release can mostly be explained by a CB1R-mediated counteraction of the A2AR-mediated constitutive activation of adenylyl cyclase in the A2AR-CB1R heteromer.

Background In the context of COVID-19 pandemic in Catalonia (Spain), the present study analyses respiratory samples collected by the primary care network using Acute Respiratory Infections Sentinel Surveillance System (PIDIRAC) during the 2019–2020 season to complement the pandemic surveillance system in place to detect SARS-CoV-2. The aim of the study is to describe whether SARS-CoV-2 was circulating before the first confirmed case was detected in Catalonia, on February 25th, 2020. Methods The study sample was made up of all samples collected by the PIDIRAC primary care network as part of the Influenza and Acute Respiratory Infections (ARI) surveillance system activities. The study on respiratory virus included coronavirus using multiple RT-PCR assays. All positive samples for human coronavirus were subsequently typed for HKU1, OC43, NL63, 229E. Every respiratory sample was frozen at—80°C and retrospectively studied for SARS-CoV-2 detection. A descriptive study was performed, analysing significant differences among variables related to SARS-CoV- 2 cases comparing with rest of coronaviruses cases through a bivariate study with Chi-squared test and statistical significance at 95%. Results Between October 2019 and April 2020, 878 respiratory samples from patients with acute respiratory infection or influenza syndrome obtained by PIDIRAC were analysed. 51.9% tested positive for influenza virus, 48.1% for other respiratory viruses. SARS-CoV-2 was present in 6 samples. The first positive SARS-CoV-2 case had symptom onset on 2 March 2020. These 6 cases were 3 men and 3 women, aged between 25 and 50 years old. 67% had risk factors, none had previous travel history nor presented viral coinfection. All of them recovered favourably. Conclusion Sentinel Surveillance PIDIRAC enhances global epidemiological surveillance by allowing confirmation of viral circulation and describes the epidemiology of generalized community respiratory viruses’ transmission in Catalonia. The system can provide an alert signal when identification of a virus is not achieved in order to take adequate preparedness measures.

ABSTRACT The goal of this study was to investigate the distribution of serotypes and clonal composition of Streptococcus pneumoniae isolates causing invasive pneumococcal disease (IPD) in Catalonia, before and after systematic introduction of PCV13. Pneumococcal strains isolated from normally sterile sites obtained from patients of all ages with IPD received between 2013 and 2019 from 25 health centers of Catalonia were included. Two study periods were defined: presystematic vaccination period (2013 and 2015) and systematic vaccination period (SVP) (2017 to 2019). A total of 2,303 isolates were analyzed. In the SVP, there was a significant decrease in the incidence of IPD cases in children 5 to 17 years old (relative risk [RR] 0.61; 95% confidence interval [CI] 0.38 to 0.99), while there was a significant increase in the incidence of IPD cases in 18- to 64-year-old adults (RR 1.33; 95% CI 1.16 to 1.52) and adults over 65 years old (RR 1.23; 95% CI 1.09 to 1.38). Serotype 8 was the major emerging serotype in all age groups except in 5- to 17-year-old children. In children younger than 5 years old, the main serotypes in SVP were 24F, 15A, and 3, while in adults older than 65 years they were serotypes 3, 8, and 12F. A significant decrease in the proportions of clonal complexes CC156, CC191, and ST306 and an increase in those of CC180, CC53, and CC404 were observed. A steady decrease in the incidence of IPD caused by PCV13 serotypes indicates the importance and impact of systematic vaccination. The increase of non-PCV13 serotypes highlights the need to expand serotype coverage in future vaccines and rethink vaccination programs for older adults. IMPORTANCE We found that with the incorporation of the PCV13 vaccine, the numbers of IPD cases caused by serotypes included in this vaccine decreased in all of the age groups. Still, there was an unforeseen increase of the serotypes not included in this vaccine causing IPD, especially in the >65-year-old group. Moreover, a significant increase of serotype 3 included in the vaccine has been observed; this event has been reported by other researchers. These facts call for the incorporation of more serotypes in future vaccines and a more thorough surveillance of the dynamics of this microorganism.

Objectives: The study aimed to characterize the clonal spread of resistant bacteria and dissemination of resistance plasmids among carbapenem-resistant Enterobacterales at a tertiary hospital in Catalonia, Spain.Methods: Isolates were recovered from surveillance rectal swabs and diagnostic samples. Species identification was by matrix-assisted laser desorption ionization-time time of flight mass spectrometry (MALDI-TOF MS). Molecular typing was performed by pulsed-field gel electrophoresis (PFGE) and multi-locus sequence typing (MLST). Antimicrobial susceptibility was assessed by gradient-diffusion and carriage of bla genes was detected by PCR. Plasmid typing, conjugation assays, S1-PFGE studies and long-read sequencing were used to characterize resistance plasmids.Results: From July 2018 to February 2019, 125 Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales were recovered from 101 inpatients from surveillance (74.4%) or clinical samples (25.6%), in a tertiary hospital in Barcelona. Clonality studies identified a major clone of Klebsiella pneumoniae belonging to sequence type ST15 and additional isolates of K. pneumoniae, Escherichia coli and Enterobacter sp. from different STs. All isolates but one carried the blaKPC–2 allelic variant. The blaKPC–2 gene was located in an IncFIIk plasmid of circa 106 Kb in a non-classical Tn4401 element designated NTEKPC-pMC-2-1. Whole-genome sequencing revealed different rearrangements of the 106 Kb plasmid while the NTEKPC-pMC-2-1 module was highly conserved.Conclusion: We report a hospital outbreak caused by the clonal dissemination of KPC-producing ST15 K. pneumoniae but also the intra- and inter-species transmission of the blaKPC–2 gene associated with plasmid conjugation and/or transposon dissemination. To our knowledge, this is the first report of an outbreak caused by KPC-producing Enterobacterales isolated from human patients in Catalonia and highlights the relevance of surveillance studies in the early detection and control of antibiotic resistant high-risk clones.

We evaluated invasive pneumococcal disease (IPD) during 8 years of infant pneumococcal conjugate vaccine (PCV) programs using 10-valent (PCV10) and 13-valent (PCV13) vaccines in 10 countries in Europe. IPD incidence declined during 2011–2014 but increased during 2015–2018 in all age groups. From the 7-valent PCV period to 2018, IPD incidence declined by 42% in children 65 years of age; non-PCV13 serotype incidence increased by 111%, 63%, and 84%, respectively, for these groups. Trends were similar in countries using PCV13 or PCV10, despite different serotype distribution. Serotypes included in the 15-valent PCV represented one third of cases and those in the 20-valent PCVs two thirds of cases in children 65 years of age in 2018. Non-PCV13 serotype increases reduced the overall effect of childhood PCV10/PCV13 programs on IPD. New vaccines providing broader serotype protection are needed.

Objectives: The aim of this study was to assess the indirect effect of paediatric 13-valent pneumococcal conjugate vaccine (PCV13) vaccination on people ≥65 years of age with invasive pneumococcal disease (IPD) in Catalonia and to determine factors predictive of mortality. Methods: During 2014–2016, 1285 IPD cases were reported to the Public Health Agency of Catalonia. The indirect effect of paediatric PCV13 vaccination was calculated by comparing the incidence rate (IR) in 2016 (PCV13 year) with that in 2009 (pre-PCV13). Predictors of mortality were determined using multivariate logistic regression. Results: Comparing 2016 and 2009, IPD decreased by 19% (IR 40.1 and 32.5 per 100 000 person-years, respectively). PCV13 serotypes decreased by 57% (IR 23.7 and 10.1), while non-PCV13 serotypes increased by 36% (IR 16.4 and 22.4). During 2014–2016, the mortality rate was 17.5%, and mortality was associated with age ≥85 years (adjusted odds ratio (aOR) 2.91, 95% confidence interval (CI) 1.89, 4.48), meningitis (aOR 2.29, 95% CI 1.25, 4.19), non-focal bacteraemia (aOR 3.73, 95% CI 2.00, 6.94), and ≥1 high-risk condition (aOR 1.89, 95% CI 1.08, 3.32). PPV23non13 serotypes were associated with lower mortality than PCV13 serotypes (aOR 0.54, 95% CI 0.34, 0.86). Conclusions: The incidence of IPD in people ≥65 years of age decreased after the introduction of paediatric PCV13, and this was due to a reduction in PCV13 serotypes, although an increase in non-PCV13 serotypes was observed. Mortality was associated with age, meningitis, non-focal bacteraemia, ≥1 high-risk condition, and PCV13 serotypes. Keywords: Streptococcus pneumoniae, IPD, PCV13, Adults, Case fatality rate, Comorbidities, Mortality

Telework is presented as a model of work organisation that changes the paradigms of business culture in many organisations, reshaping established management and social systems. The COVID-19 pandemic and the restrictions applied to the mobility and concentration of people have accelerated the implementation of telework, generating an accelerated change in organisational models. Telework dynamics significantly transform many aspects of the business, social and personal environment. The research community has investigated: work performance; the environment; technology; social factors; and work–life balance, among other issues. However, it is necessary to know in greater depth what the most salient aspects related to telework are. To this end, a total of 539 publications from the Web of Science database between 1984 and 2021 were analysed using bibliometric techniques. The results obtained indicate an outstanding interest in this subject in the last two years. The research comes from many different areas of knowledge and mainly focused on issues related to worker–employer–family conflict, work–life balance and flexibility policies. There has been remarkable growth and dispersion in telework research, where, in addition to productivity-based approaches, the field of study has opened up to other issues such as worker health and satisfaction, professional isolation, the role of supervisors or the gender perspective, among others. The contribution of this research is broadening knowledge about the dynamics of telework in organisations and the issues that have been the most considered by the scientific community, so that it can serve as a point of support for future research.

Neuroblastoma arises from neural crest cell precursors failing to complete the process of differentiation. Thus, agents helping tumor cells to differentiate into normal cells can represent a valid therapeutic strategy. Here, we evaluated whether guanosine (GUO), a natural purine nucleoside, which is able to induce differentiation of many cell types, may cause the differentiation of human neuroblastoma SH-SY5Y cells and the molecular mechanisms involved. We found that GUO, added to the cell culture medium, promoted neuron-like cell differentiation in a time- and concentration-dependent manner. This effect was mainly due to an extracellular GUO action since nucleoside transporter inhibitors reduced but not abolished it. Importantly, GUO-mediated neuron-like cell differentiation was independent of adenosine receptor activation as it was not altered by the blockade of these receptors. Noteworthy, the neuritogenic activity of GUO was not affected by blocking the phosphoinositide 3-kinase pathway, while it was reduced by inhibitors of protein kinase C or soluble guanylate cyclase. Furthermore, the inhibitor of the enzyme heme oxygenase-1 but not that of nitric oxide synthase reduced GUO-induced neurite outgrowth. Interestingly, we found that GUO was largely metabolized into guanine by the purine nucleoside phosphorylase (PNP) enzyme released from cells. Taken together, our results suggest that GUO, promoting neuroblastoma cell differentiation, may represent a potential therapeutic agent; however, due to its spontaneous extracellular metabolism, the role played by the GUO-PNP-guanine system needs to be further investigated.