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Introduction The use of novel adjuvants in human vaccines continues to expand as their contribution to preventing disease in challenging populations and caused by complex pathogens is increasingly understood. AS01 is a family of liposome-based vaccine Adjuvant Systems containing two immunostimulants: 3-O-desacyl-4’-monophosphoryl lipid A and the saponin QS-21. AS01-containing vaccines have been approved and administered to millions of individuals worldwide.Areas covered Here, we report advances in our understanding of the mode of action of AS01 that contributed to the development of efficacious vaccines preventing disease due to malaria, herpes zoster, and respiratory syncytial virus. AS01 induces early innate immune activation that induces T cell-mediated and antibody-mediated responses with optimized functional characteristics and induction of immune memory. AS01-containing vaccines appear relatively impervious to baseline immune status translating into high efficacy across populations. Currently licensed AS01-containing vaccines have shown acceptable safety profiles in clinical trials and post-marketing settings.Expert opinion Initial expectations that adjuvantation with AS01 could support effective vaccine responses and contribute to disease control have been realized. Investigation of the utility of AS01 in vaccines to prevent other challenging diseases, such as tuberculosis, is ongoing, together with efforts to fully define its mechanisms of action in different vaccine settings.

Abstract Objective Biallelic titin truncating variants (TTNtv) have been associated with a wide phenotypic spectrum, ranging from complex prenatal muscle diseases with dysmorphic features to adult‐onset limb‐girdle muscular dystrophy, with or without cardiac involvement. Given the size and complexity of TTN, reaching an unequivocal molecular diagnosis and precise disease prognosis remains challenging. Methods In this case series, 12 unpublished cases and one already published case with biallelic TTNtv were collected from multiple international medical centers between November 2022 and September 2023. TTN mutations were detected through exome or genome sequencing. Information about familial and personal clinical history was collected in a standardized form. RNA‐sequencing and analysis of TTN exon usage were performed on an internal sample cohort including postnatal skeletal muscles, fetal skeletal muscles, postnatal heart muscles, and fetal heart muscles. In addition, publicly available RNA‐sequencing data was retrieved from ENCODE. Results We generated new RNA‐seq data on TTN exons and identified genotype–phenotype correlations with prognostic implications for each titinopathy patient (whether worsening or improving in prenatal and postnatal life) using percentage spliced in (PSI) data for the involved exons. Interestingly, thanks to exon usage, we were also able to rule out a titinopathy diagnosis in one prenatal case. Interpretation This study demonstrates that exon usage provides valuable insights for a more exhaustive clinical interpretation of TTNtv; additionally, it may serve as a model for implementing personalized medicine in many other genetic diseases, since most genes undergo alternative splicing.

Let $\Delta$ be a numerical semigroup. In this work we show that $\mathcal{J}(\Delta) =\{I\cup\nobreak\{0\} I is an ideal of \Delta\}$ is a distributive lattice, which in addition is a Frobenius restricted variety. We give an algorithm which allows us to compute the set $\mathcal{J}_a(\Delta)=\{S\in\mathcal{J}(\Delta) \max(\Delta\backslash S)=a\}$ for a given $a\in\Delta.$ As a consequence, we obtain another algorithm that computes all the elements of $\mathcal{J}(\Delta)$ with a fixed genus.

Abstract Aim The objective of this study was to assess the therapeutic effects of corticosteroids in adult patients hospitalized with viral community-acquired pneumonia. Methods This is a retrospective analysis of data collected prospectively from November 1996 to June 2024. All adult patients with viral community-acquired pneumonia were enrolled. The primary outcome was 30-day mortality. Secondary outcomes included all-cause in-hospital mortality, ICU admission, length of ICU and hospital stay, mechanical ventilation, and 1-year mortality. Propensity score matching (PSM) was used to obtain balance among the baseline variables in the two groups. Results Of the 524 patients with viral pneumonia, 30 (6%) received corticosteroids and 494 (94%) did not. Patients were primarily male (n = 299, 57%), with a median [Q1-Q3] age of 66.9 [55–81] years. The 3:1 propensity matching procedure identified 90 patients not treated with corticosteroid (CS-) as controls. After PSM, no difference in 30-day mortality was found [7% (95%CI 1 to 22%) vs. 4% (95%CI 1 to 11%), p = 0.639]. The risk of death at 30 days did not differ significantly in unmatched and matched cohorts [Hazard Ratio (HR) 1.33 (0.32–5.63), p = 0.695 vs. HR 1.51 (0.28–8.27), p = 0.632, respectively]. Nor were differences found in hospital length of stay, ICU admission and length of stay, or mechanical ventilation requirement and duration between matched and unmatched CS + and CS-. Conclusions There were no significant differences in the primary and secondary outcomes regarding the use of corticosteroids in patients with viral pneumonia.

Determining the number of cases of an epidemic is the first function of epidemiological surveillance. An important underreporting of cases was observed in many locations during the first wave of the COVID-19 pandemic. To estimate this underreporting in the COVID-19 outbreak of Borriana (Valencia Community, Spain) in March 2020, a cross-sectional study was performed in June 2020 querying the public health register. Logistic regression models were used. Of a total of 468 symptomatic COVID-19 cases diagnosed in the outbreak through anti-SARS-CoV-2 serology, 36 cases were reported (7.7%), resulting in an underreporting proportion of 92.3% (95% confidence interval [CI], 89.5–94.6%), with 13 unreported cases for every reported case. Only positive SARS-CoV-2 polymerase chain reaction cases were predominantly reported due to a limited testing capacity and following a national protocol. Significant factors associated with underreporting included no medical assistance for COVID-19 disease, with an adjusted odds ratio [aOR] of 10.83 (95% CI 2.49–47.11); no chronic illness, aOR = 2.81 (95% CI 1.28–6.17); middle and lower social classes, aOR = 3.12 (95% CI 1.42–6.85); younger age, aOR = 0.97 (95% CI 0.94–0.99); and a shorter duration of illness, aOR = 0.98 (95% CI 0.97–0.99). To improve the surveillance of future epidemics, new approaches are recommended.

Objectives: The prevalence and risk factors of SARS-CoV-2 infection among unvaccinated people living with HIV (PWH) are not well understood, and the protective role of tenofovir remains controversial. This study aimed to assess the SARS-CoV-2 prevalence and associated risk factors among unvaccinated PWH, and to evaluate the impact of tenofovir. Methods: We conducted as a cross-sectional study between November 2020 and May 2021. Plasma samples from 4,400 of 5,476 PWH were tested for total antibodies, IgG, IgM, and IgA. Results: Among the participants (median age 48 years, 84% male), 92% had undetectable HIV viral loads and 5% had syphilis. The prevalence of SARS-CoV-2 infection was 18% (95% CI 17-19), with 1,180 individuals showing antibodies (IgG 13%, IgA 10%, IgM 11%). Of those seropositive for SARS-CoV-2, 67.5% were asymptomatic, 29% had mild disease, and 3.5% had severe/critical conditions. Risk factors included younger age, being female, men who have sex with men (MSM) status, non-European origin, and a history of syphilis. Neither antiretrovirals nor tenofovir provided protection against SARS-CoV-2 infection or COVID-19 disease. Conclusion: Ongoing surveillance and tailored interventions are crucial for at-risk PWH amid evolving SARS-CoV-2 variants. Tenofovir did not prevent SARS-CoV-2 infection or COVID-19.

IntroductionThe interplay among sleep patterns, social habits and environmental cues is becoming increasingly more important for public health and wellbeing due to its connection to circadian desynchronization. This paper explores said connections in Spain (which has an official and solar time mismatch), introducing the “Three Times Score” ‒which is based on questions widely used in the field‒ as a complementary tool for exploring the interplay of daily rhythms.MethodsThe questionnaire covers sleep-related habits, social time, and environmental time. The study includes 9,947 participants (34.89 ± 12.15 y/o, mean ± SD; 5,561 women) from different Spanish regions. Sleep parameters were obtained for work and free days, as well as a modified version of the sleep-corrected midsleep on free days (MBFbc) and a parameter similar to social jet lag, both derived from bed time rather than sleep time. A number of indexes were computed to compare bed and work-related habits, together with natural light/dark cycle, along with the Three Times Score. Mixed-effect regression analysis was used to test whether the biological, social and environmental factors included in the study significantly predicted the sleep-related parameters: bedtime, wake-up time, time in bed and mid-bedtime.Results and discussionTemporal differences were found between work and free days, with waking-up occurring 2 h earlier on work days (7:10 ± 0:01) than on free days (9:15 ± 0:01). Bed times were 1 h earlier on work days (23:46 ± 0:01) than on free days (00:45 ± 0:01), whereas time in bed was over 1 h shorter on work (7 h 23 min) versus free (8 h 29 min) days. Strong correlations were found between work starting time and waking-up and bedtimes on workdays. Women went to bed earlier and woke up later, spending more time in bed. Differences in sleep habits were observed between work and free days across all age groups. The group of younger adults (18–30) reported going to bed later than older and younger groups, especially on free days. Adolescents and young adults also woke-up later than other age groups, especially on free days. Social jet lag (relative to bed time) and desynchronization indexes also varied with age, with younger adult participants exhibiting higher levels. Seasonal differences were limited, with minor variations between winter and summer. According to the multiple regression analysis, social (day type, work start time, alarm clock usage), biological (age, gender, in most cases related to sex) and environmental (sunset time) factors significantly contribute to predicting sleep/bed related schedules. This study provides insights into sleep habits in the Spanish population, introducing the Three Times Score as a complementary tool for exploring the interactions between sleep/bed-related habits, natural darkness and work-related schedules. Understanding this interplay is crucial for developing tailored interventions to improve sleep and wellbeing.

Abstract Introduction There is no reliable microbiological marker to guide responses to antiviral treatment in kidney transplant recipients (KTR) with COVID-19. We aimed to evaluate the dynamics of subgenomic RNA (sgRNA) RT-PCR before and after receiving treatment with remdesivir compared with genomic RNA (gRNA) RT-PCR and its use as a surrogate marker of viral replication. Methods We analyzed gRNA and sgRNA at baseline and after remdesivir treatment in KTR who received remdesivir for SARS-CoV-2 infection from November 2021 to February 2022. Results Thirty-four KTR received remdesivir for SARS-CoV-2 infection. The median time since transplantation was 80 months (IQR 3–321) and 75% of patients had previously received 3 doses of a mRNA SARS-CoV-2 vaccine. Three patients (8%) were classified with mild, 25 (73%) with moderate, and 6 (17%) with severe SARS-CoV-2 infection. Thirty-two (94%) patients received 5 doses of remdesivir and two patients received 2 doses. The median time between symptom onset to remdesivir treatment was 5 days (IQR 3–8.5). The median days of hospitalization were 6 (IQR 2–112). gRNA was positive in all patients at baseline and after remdesivir. Five (15%) patients had negative sgRNA at baseline and 20 (59%) after receiving remdesivir. Patients presenting with negative sgRNA at baseline were discharged from hospital in ≤ 6 days without complications. Moreover, those with negative sgRNA after remdesivir therapy did not require ICU admission and had favorable outcomes. Nevertheless, patients with positive sgRNA after antiviral treatment presented worse outcomes, with 47% requiring ICU admission and the three (9%) recorded deaths in the study were in this group. Conclusions Based on these data, we hypothesize that sgRNA may have clinical utility to help monitor virologic response more accurately than gRNA in KTR who receive remdesivir. Moreover, patients with negative sgRNA at baseline may not require antiviral treatment and others presenting positive sgRNA at day 5 could benefit from prolonged or combined therapies.

Diamond-Blackfan anemia syndrome (DBAS) is an inherited bone marrow failure disorder that typically presents in infancy as hypoplastic anemia and developmental abnormalities in approximately 50% of cases. DBAS is caused by haploinsufficiency in one of 24 ribosomal protein genes, with RPS19 mutations accounting for 25% of cases. We generated iPSC lines from two patients with different heterozygous RPS19 mutations (c.191T > C and c.184C > T) and isogenic lines in which the mutations were corrected by Cas9-mediated homology directed repair.

Abstract Background Mitochondrial diseases (MDs) are genetic disorders characterized by dysfunctions in mitochondria. Clinical data suggest that additional factors, beyond genetics, contribute to the onset and progression of this group of diseases, but these influencing factors remain largely unknown. Mounting evidence indicates that immune dysregulation or distress could play a role. Clinical observations have described the co-incidence of infection and the onset of the disease as well as the worsening of symptoms following infection. These findings highlight the complex interactions between MDs and immunity and underscore the need to better understand their underlying relationships. Results We used Ndufs4 KO mice, a well-established mouse model of Leigh syndrome (one of the most relevant MDs), to test whether chronic induction of a neuroinflammatory state in the central nervous system before the development of neurological symptoms would affect both the onset and progression of the disease in Ndufs4 KO mice. To this aim, we took advantage of the GFAP-IL6 mouse, which overexpresses interleukin-6 (IL-6) in astrocytes and produces chronic glial reactivity, by generating a mouse line with IL-6 overexpression and NDUFS4 deficiency. IL-6 overexpression aggravated the mortality of female Ndufs4 KO mice but did not alter the main motor and respiratory phenotypes measured in any sex. Interestingly, an abnormal region-dependent microglial response to IL-6 overexpression was observed in Ndufs4 KO mice compared to controls. Conclusion Overall, our data indicate that chronic neuroinflammation may worsen the disease in Ndufs4 KO female mice, but not in males, and uncovers an abnormal microglial response due to OXPHOS dysfunction, which may have implications for our understanding of the effect of OXPHOS dysfunction in microglia.

Background and Objectives: Oral rehabilitation seeks to enhance mastication, a vital component of oral function that is compromised by tooth loss. This study aimed to assess the degree of improvement of masticatory performance in partially edentulous patients rehabilitated with removable partial dentures (RPD) or fixed partial dental prosthesis (FPDP). Changes in the occlusal contact area (OCA) and satisfaction with their chewing ability during the adaptation period were also evaluated. Materials and Methods: in total, 34 partially edentulous participants (median age 65.3 years; 56% women) who received an RPD or FPDP were assessed using masticatory performance assay, OCA calculation, and a visual analog scale (VAS). Results: Masticatory performance improved by 20% (range from 17% to 25%, p < 0.05) depending on the edentulism and the rehabilitation types. The OCA improved by 4.7 mm2 (p < 0.05) and satisfaction with the masticatory function improved by 9% (p < 0.05) 3 months after prosthesis insertion. Conclusions: Conventional prostheses benefited partially edentulous individuals, improving masticatory performance by 20%. Treatment also increased the OCA in all types of partial edentulism, except in Kennedy class I patients rehabilitated with RPD. Patients’ satisfaction with their chewing ability only increased in Kennedy class III patients rehabilitated with RPD.

Pig production is one of the most important providers of high-quality proteins and amino acids (AAs) to human nutrition. In this sector, feeding has an important economic and environmental impact. A strategy to reduce production costs and negative sustainability effects is reducing dietary crude protein (CP) contents with or without AA supplementation. This review addresses the different aspects related to this strategy, particularly the effects on growth performance and pork traits in piglets and growing and finishing pigs, as well as the physiological molecular mechanisms’ underlying effects. Insight is also provided into the effects of dietary CP reduction on the productive performances of alternative pig production systems and breeding boars and sows. Finally, an overview is conducted on the effects of dietary CP reduction on ammonia, odor, and greenhouse gas emissions arising from pig production systems. Overall, CP reduction may lead to production losses, albeit they can be, to some extent, hindered by adequate AA supplementation. Losses are particularly relevant during the post-weaning phase, whereas in finishing pigs, it may bring additional benefits, such as high intramuscular fat contents in some markets or improved gut barrier function with benefits to the animals’ health and welfare, as well as decreased ammonia emissions to the environment.

Mediante este estudio de corte exploratorio se realiza una aproximación a la equidad centrada en el desarrollo de marcos y procedimientos pedagógicos desde la doble perspectiva de la educación activa y la satisfacción de las necesidades psicológicas básicas del alumnado. Dicho acercamiento se ha basado en la información proporcionada por un colectivo de docentes procedentes de centros de educación infantil y primaria con altas expectativas equitativas de la Región de Murcia. El objetivo principal es conocer y visibilizar algunos de estos marcos y procedimientos pedagógicos que los centros están desarrollando para garantizar una educación inclusiva y justa, especialmente, a través la educación activa y la satisfacción de las necesidades del alumnado. Entre sus principales propuestas pedagógicas se encuentran el paidocentrismo y la promoción de una educación que para materializarse como tal, ha de ser activa y respetuosa con las necesidades e intereses de los destinatarios. La información se ha recabado a través de entrevistas semiestructuradas individuales. Los informantes proceden de cinco centros docentes, tres públicos y dos privados, quedando la muestra compuesta por 15 docentes. Y entre las principales conclusiones destacan: la profundización en el sentido de la educación; El fortalecimiento de funciones docentes centradas en el acompañamiento emocional; La enseñanza y la evaluación enfocadas en la observación, seguimiento, guía, orientación y facilitación del aprendizaje. Y la organización y planificación colaborativa de entornos preparados para aprender.

BackgroundPatients with hematological malignancies receiving hematopoietic cell transplantation (HCT) or chimeric antigen receptor (CAR) T-cell therapy are at risk of developing serious clinical complications after discharge. ObjectiveThe aim of the TEL-HEMATO study was to improve our telehealth platform for the follow-up of patients undergoing HCT or CAR T-cell therapy during the first 3 months after discharge with the addition of wearable devices. MethodsEleven patients who received autologous (n=2) or allogeneic (n=5) HCT or CAR T-cell therapy (n=4) for hematological malignancies were screened from November 2022 to July 2023. Two patients discontinued the study after enrollment. The telehealth platform consisted of the daily collection of vital signs, physical symptoms, and quality of life assessment up to 3 months after hospital discharge. Each patient received a clinically validated smartwatch (ScanWatch) and a digital thermometer, and a dedicated smartphone app was used to collect these data. Daily revision of the data was performed through a web-based platform by a hematologist or a nurse specialized in HCT and CAR T-cell therapy. ResultsVital signs measured through ScanWatch were successfully collected with medium/high adherence: heart rate was recorded in 8/9 (89%) patients, oxygen saturation and daily steps were recorded in 9/9 (100%) patients, and sleeping hours were recorded in 7/9 (78%) patients. However, temperature recorded manually by the patients was associated with lower compliance, which was recorded in 5/9 (55%) patients. Overall, 5/9 (55%) patients reported clinical symptoms in the app. Quality of life assessment was completed by 8/9 (89%) patients at study enrollment, which decreased to 3/9 (33%) at the end of the third month. Usability was considered acceptable through ratings provided on the System Usability Scale. However, technological issues were reported by the patients. ConclusionsWhile the addition of wearable devices to a telehealth clinical platform could have potentially synergic benefits for HCT and CAR T-cell therapy patient monitoring, noncomplete automation of the platform and the absence of a dedicated telemedicine team still represent major limitations to be overcome. This is especially true in our real-life setting where the target population generally comprises patients of older age with a low digital education level.

The use of natural immunostimulants in aquaculture is intended to foster overall health and bolster resilience against diseases in farmed fish populations. It constitutes a crucial strategy that can contribute to securing the sustainability of the aquaculture industry, and it is an area that warrants ongoing exploration and development. Therefore, the aim of the present work was to evaluate the effect of dietary administration of olive pulp on growth rate, metabolic profile, serum antioxidant potential, and humoral and cellular innate immune parameters of gilthead seabream (Sparus aurata L.). For this, fish were fed control diet or olive pulp enriched diets (50, 100, and 200 mg kg feed−1) for 4 weeks. Our results demonstrated that the highest inclusion level improved the growth rates and the biological antioxidant potential in the serum of fish. However, after 4 weeks of feeding, most of the assayed metabolic parameters (Ca2+, TP, ALB, K+, and Na+) were increased in the serum of fish fed with a diet containing the lowest level of olive pulp (50 mg kg feed−1). Regarding the innate immune parameters, the IgM levels decreased in the serum of fish fed 50′s diet after 2 and 4 weeks of trial. However, the serum of fish fed with diets containing 100 and 200 showed an increase in hemolytic complement activity after 2 weeks whilst this increase was only sustained in the 200′s group after 4 weeks. After 2 weeks of feeding, the serum of the fish showed an increase in peroxidase activity due to the highest olive inclusion. Concerning cellular innate parameters, peroxidase activity, respiratory burst, and phagocytic ability were increased in head-kidney leucocytes of fish fed 100′s diet at 2 weeks compared to values from control fish. These results suggest that the administration of olive pulp-enriched diets can benefit fish growth, antioxidant, and immune status of gilthead seabream.

Mitofusins are large GTPases that trigger fusion of mitochondrial outer membranes. Similarly to the human mitofusin Mfn2, which also tethers mitochondria to the endoplasmic reticulum (ER), the yeast mitofusin Fzo1 stimulates contacts between Peroxisomes and Mitochondria when overexpressed. Yet, the physiological significance and function of these "PerMit" contacts remain unknown. Here, we demonstrate that Fzo1 naturally localizes to peroxisomes and promotes PerMit contacts in physiological conditions. These contacts are regulated through co-modulation of Fzo1 levels by the ubiquitin-proteasome system (UPS) and by the desaturation status of fatty acids (FAs). Contacts decrease under low FA desaturation but reach a maximum during high FA desaturation. High-throughput genetic screening combined with high-resolution cellular imaging reveal that Fzo1-mediated PerMit contacts favor the transit of peroxisomal citrate into mitochondria. In turn, citrate enters the TCA cycle to stimulate the mitochondrial membrane potential and maintain efficient mitochondrial fusion upon high FA desaturation. These findings thus unravel a mechanism by which inter-organelle contacts safeguard mitochondrial fusion.

Abstract Background Worms of the nematode genus Trichinella are zoonotic pathogens with a worldwide distribution. The first report of Trichinella on the Mediterranean island of Sardinia was for Trichinella britovi, one of the four species of this genus circulating in Europe, which was identified in 2005 following an outbreak of trichinellosis in humans due to the consumption of pork from pigs reared in the wild. Since then, T. britovi larvae have been repeatedly isolated from free-ranging pigs, foxes (Vulpes vulpes) and wild boars (Sus scrofa) sampled in the central-eastern region of the island (Orgosolo municipality), but have never been isolated from samples from other areas of the island. The aim of this study was to investigate the parasitological and serological prevalence of T. britovi infection in wild boars in Sardinia over space [eight wild boar hunting management units (HMUs)] and time (seven wild boar hunting seasons). Methods Muscle and serum samples of boars killed in the 2014–2015 to 2020–2121 hunting seasons were collected from eight HMUs of central and south-western Sardinia. Trichinella sp. larvae were detected by artificial digestion of predilection muscles. A total of 4111 serum samples of wild boar were collected from the investigated HMUs and tested by enzyme-linked immunosorbent assay as a screening test and by western blot as a confirmatory test using excretory/secretory antigens. Results Trichinella britovi muscle larvae were detected in six (0.03%) of the 17,786 wild boars tested. All of the Trichinella sp.-positive wild boars had been hunted in Orgosolo municipality (central-eastern area of the island), except for one, hunted in a neighboring municipality. An overall serological prevalence of 3.8% (95% confidence interval, 3.3–4.5) was detected by western blot. No statistical differences were detected between the HMUs where T. britovi larvae were detected in wild boars, foxes, and free-ranging pigs and those where wild boars, foxes and free-ranging pigs tested negative. Conclusions The serological prevalence did not vary between the wild boar populations in which the larval load was detectable by artificial digestion (Orgosolo municipality) and those in which the larval load was below the detection limit. Furthermore, the serological prevalence of anti-Trichinella immunoglobulin G in the wild boar populations remained constant during the study period, which covered seven wild boar hunting seasons. As the transmission events (i.e., the serological prevalence) are stable, the high biomass of the parasite in Orgosolo municipality can only have arisen as a consequence of factors independent of its natural cycle, i.e., the presence of a high number of free-ranging pigs, and the concomitant presence of African swine fever, due to illegal pig slaughtering in the field. This epidemiological situation suggests that the natural cycle of T. britovi may be influenced by inappropriate pig husbandry and slaughtering practices. Graphical Abstract

Abstract Background CPX‐351 is approved for the treatment of therapy related acute myeloid leukemia (t‐AML) and AML with myelodysplastic related changes (MRC‐AML). The benefits of this treatment over standard chemotherapy has not been addressed in well matched cohorts of real‐life patients. Methods Retrospective analysis of AML patients treated with CPX‐351 as per routine practice. A propensity score matching (PSM) was used to compare their main outcomes with those observed in a matched cohort among 765 historical patients receiving intensive chemotherapy (IC), all of them reported to the PETHEMA epidemiologic registry. Results Median age of 79 patients treated with CPX‐351 was 67 years old (interquartile range 62–71), 53 were MRC‐AML. The complete remission (CR) rate or CR without recovery (CRi) after 1 or 2 cycles of CPX‐351 was 52%, 60‐days mortality 18%, measurable residual disease

Introduction The European Environment Agency estimates that 75% of the European population lives in cities. Despite the many advantages of city life, the risks and challenges to health arising from urbanisation need to be addressed in order to tackle the growing burden of disease and health inequalities in cities. This study, Urban environment and health: a cross-sectional multiregional project based on population health surveys in Spain (DAS-EP project), aims to investigate the complex association between the urban environmental exposures (UrbEEs) and health.Methods and analysis DAS-EP is a Spanish multiregional cross-sectional project that combines population health surveys (PHS) and geographical information systems (GIS) allowing to collect rich individual-level data from 17 000 adult citizens participating in the PHS conducted in the autonomous regions of the Basque Country, Andalusia, and the Valencian Community, and the city of Barcelona in the years 2021–2023. This study focuses on the population living in cities or metropolitan areas with more than 100 000 inhabitants. UrbEEs are described by objective estimates at participants’ home addresses by GIS, and subjective indicators present in PHS. The health outcomes included in the PHS and selected for this study are self-perceived health (general and mental), prevalence of chronic mental disorders, health-related quality of life, consumption of medication for common mental disorders and sleep quality. We aim to further understand the direct and indirect effects between UrbEEs and health, as well as to estimate the impact at the population level, taking respondents’ sociodemographic and socioeconomic characteristics, and lifestyle into consideration.Ethics and dissemination The study was approved by the regional Research Ethics Committee of the Basque Country (Ethics Committee for Research Involving Medicinal Products in the Basque Country; PI2022138), Andalusia (Biomedical Research Ethics Committee of the Province of Granada; 2078-N-22), Barcelona (CEIC-PSMar; 2022/10667) and the Valencian Community (Ethics Committee for Clinical Research of the Directorate General of Public Health and Center for Advanced Research in Public Health; 20221125/04). The results will be communicated to the general population, health professionals, and institutions through conferences, reports and scientific articles.

The involvement of androgens in the regulation of energy metabolism has been demonstrated. The main objective of the present research was to study the involvement of androgens in both the programming of energy metabolism and the regulatory peptides associated with feeding. For this purpose, androgen receptors and the main metabolic pathways of testosterone were inhibited during the first five days of postnatal life in male and female Wistar rats. Pups received a daily s.c. injection from the day of birth, postnatal day (P) 1, to P5 of Flutamide (a competitive inhibitor of androgen receptors), Letrozole (an aromatase inhibitor), Finasteride (a 5-alpha-reductase inhibitor) or vehicle. Body weight, food intake and fat pads were measured. Moreover, hypothalamic Agouti-related peptide (AgRP), neuropeptide Y (NPY), orexin, and proopiomelanocortin (POMC) were analyzed by quantitative real-time polymerase chain reaction assay. The inhibition of androgenic activity during the first five days of life produced a significant decrease in body weight in females at P90 but did not affect this parameter in males. Moreover, the inhibition of aromatase decreased hypothalamic AgRP mRNA levels in males while the inhibition of 5α-reductase decreased hypothalamic AgRP and orexin mRNA levels in female rats. Finally, food intake and visceral fat, but not subcutaneous fat, were affected in both males and females depending on which testosterone metabolic pathway was inhibited. Our results highlight the differential involvement of androgens in the programming of energy metabolism as well as the AgRP and orexin systems during development in male and female rats.

IntroductionInitiation of antiretroviral treatment (ART) in patients early after HIV-infection and long-term suppression leads to low or undetectable levels of HIV RNA and cell-associated (CA) HIV DNA and RNA. Both CA-DNA and CA-RNA, overestimate the size of the HIV reservoir but CA-RNA as well as p24/cell-free viral RNA can be indicators of residual viral replication. This study describes HIV RNA amounts and levels of cytokines/soluble markers in 40 well-suppressed adolescents who initiated ART early in life and investigated which viral markers may be informative as endpoints in cure clinical trials within this population.MethodsForty adolescents perinatally infected with HIV on suppressive ART for >5 years were enrolled in the CARMA study. HIV DNA and total or unspliced CA-RNA in PBMCs were analyzed by qPCR/RT-qPCR and dPCR/RT-dPCR. Cell-free HIV was determined using an ultrasensitive viral load (US-VL) assay. Plasma markers and p24 were analyzed by digital ELISA and correlations between total and unspliced HIV RNA and clinical markers, including age at ART, Western Blot score, levels of cytokines/inflammation markers or HIV CA-DNA, were tested.ResultsCA-RNA was detected in two thirds of the participants and was comparable in RT-qPCR and RT-dPCR. Adolescents with undetectable CA-RNA showed significantly lower HIV DNA compared to individuals with detectable CA-RNA. Undetectable unspliced CA-RNA was positively associated with age at ART initiation and Western Blot score. We found that a higher concentration of TNF-α was predictive of higher CA-DNA and CA-RNA. Other clinical characteristics like US-VL, time to suppression, or percent CD4+ T-lymphocytes were not predictive of the CA-RNA in this cross-sectional study.ConclusionsLow CA-DNA after long-term suppressive ART is associated with lower CA-RNA, in concordance with other reports. Patients with low CA-RNA levels in combination with low CA-DNA and low Western Blot scores should be further investigated to characterize candidates for treatment interruption trials. Unspliced CA-RNA warrants further investigation as a marker that can be prioritized in paediatric clinical trials where the sample volume can be a significant limitation.

Background and Objectives: High-grade malignant neuroendocrine tumors (G3 NETs) and neuroendocrine carcinomas (NECs) are characterized by rapid proliferation, high metastatic capacity, and strong expression of somatostatin receptors (SSTRs). We aimed to analyze the presence of SSTRs in NET G3 and NEC, and to correlate their expression with the use of octreotide and pasireotide. Materials and Methods: For this purpose, we first performed a retrospective study of G3 NET and NEC patients, which included the determination of SSTR expression and response to octreotide treatment. Second, we selected the H69 small cell lung cancer cell line to determine the effect of octreotide and pasireotide. Results: Our results showed the traditional somatostatin analog (SSA) octreotide was ineffective in patients with NET G3 and NEC. On the other hand, RT-qPCR showed a high expression of SSTR2 and SSTR5 in H69 cells. Interestingly, while octreotide did not modify H69 cell proliferation, a strong inhibition of proliferation was detected with the use of pasireotide. Conclusions: In view of these results, a clinical trial in NET G3 and NEC patients using pasireotide is necessary to determine the usefulness of this drug in improving patient treatment.

Summary: Background: GBP510 vaccine contains self-assembling, recombinant nanoparticles displaying SARS-CoV-2 spike receptor-binding domains. We report interim phase 3 immunogenicity results for GBP510 adjuvanted with AS03 (GBP510/AS03) compared with ChAdOx1-S (Vaxzevria, AstraZeneca) in healthy adults aged ≥18 years, up to 6 months after the second dose. Methods: This was a randomised, active-controlled, observer-blinded, parallel group, phase 3 study, conducted at 38 sites across six countries (South Korea, Philippines, Thailand, Vietnam, Ukraine and New Zealand). Cohort 1 (no history of SARS-CoV-2 infection/COVID-19 vaccination) was randomised 2:1 to receive two doses of GBP510/AS03 or ChAdOx1-S (immunogenicity and safety), while Cohort 2 (regardless of baseline serostatus) was randomised 5:1 (safety). Primary objectives were to demonstrate superiority in geometric mean titre (GMT) and non-inferiority in seroconversion rate (SCR; ≥4-fold rise from baseline) of GBP510/AS03 vs. ChAdOx1-S for neutralising antibodies against the ancestral strain by live-virus neutralisation assay. Secondary objectives included assessment of safety and reactogenicity (long-term 6 months cut-off date: 09 August 2022). This study was registered on ClinicalTrials.gov (NCT05007951). Findings: Between 30 August 2021 and 11 January 2022, a total of 4913 participants were screened and 4036 participants (1956 in Cohort 1 and 2080 in Cohort 2) who met eligibility criteria were enrolled and randomised to receive 2 doses of GBP510/AS03 (n = 3039) or ChAdOx1-S (n = 997). Most participants were Southeast Asian (81.5%) and aged 18–64 years (94.7%). The primary objectives assessed in per-protocol set included 877 participants in GBP510/AS03 and 441 in ChAdOx1-S group: at 2 weeks after the second vaccination, the GMT ratio (GBP510/AS03/ChAdOx1-S) in per-protocol set was 2.93 (95% CI 2.63–3.27), demonstrating superiority (95% CI lower limit >1) of GBP510/AS03; the between-group SCR difference of 10.8% (95% CI 7.68–14.32) also satisfied the non-inferiority criterion (95% CI lower limit > −5%). Neutralizing antibody titres sustained higher for the GBP510/AS03 group compared to the ChAdOx1-S group through 6 months after the second vaccination. In Safety analysis (Cohort 1 & 2), the proportion of participants with adverse events (AEs) after any vaccination was higher with GBP510/AS03 vs. ChAdOx1-S for solicited local AEs (56.7% vs. 49.2%), but was similar for solicited systemic AEs (51.2% vs. 53.5%) and unsolicited AEs (13.3% vs. 14.6%) up to 28 days after the second vaccination. No safety concerns were identified during follow-up for 6 months after the second vaccination. Interpretation: Our interim findings suggested that GBP510/AS03 met the superiority criterion for neutralising antibodies and non-inferiority criterion for SCR compared with ChAdOx1-S, and showed a clinically acceptable safety profile. Funding: This work was supported, in whole or in part, by funding from CEPI and the Bill & Melinda Gates Foundation Investments INV-010680 and INV-006462. The Bill & Melinda Gates Foundation supported this project for the generation of IND-enabling data and CEPI supported this clinical study.

Abstract Background Distal first metatarsal osteotomy is used to correct mild or moderate hallux valgus (HV). We designed a cadaveric study to compare the resistance to axial load between two percutaneous distal first metatarsal osteotomies: Bösch osteotomy and percutaneous chevron. The first aim of this study was to develop a systematic technique for measuring the sagittal displacement on lateral foot X-rays. Our second objective was to measure the resistance to axial load for both of these osteotomies. Methods Ten pairs of freshly frozen cadaveric feet were randomly assigned to one of the two techniques investigated. Pre- and post-operative lateral X-rays were obtained. After surgery, the feet were placed under progressive axial loads up to 60 kg. Metaphyseo-diaphyseal angle (MDA) and the distance between bone fragments were measured, and the differences between the two techniques were statistically assessed. Results The MDA decreased in both surgical techniques. The mean plantar tilt was −6.90 degrees (SD = 10.251) for chevron osteotomy and −5.34 degrees (SD = 16.621) for Bösch osteotomy. There was no significant difference between the techniques (p = 0.41). Regarding the distance between the bone fragments, the Bösch osteotomy produced more plantar displacement than the chevron osteotomy, which was statistically significant for the 10 and 20 kg loads (p = 0.031 and 0.04, respectively). At loads ≥ 30 kg, the bone fragment distance did not differ significantly between the techniques (p = 0.114). Conclusions Although the chevron technique confers higher stability regarding fragment displacement during axial loading, both techniques increase the plantar angulation of the metatarsal head. Level of evidence Cadaveric study. Level V.

Abstract Background Research related to sustainable diets is is highly relevant to provide better understanding of the impact of dietary intake on the health and the environment. Aim To assess the association between the adherence to an energy-restricted Mediterranean diet and the amount of CO2 emitted in an older adult population. Design and population Using a cross-sectional design, the association between the adherence to an energy-reduced Mediterranean Diet (erMedDiet) score and dietary CO2 emissions in 6646 participants was assessed. Methods Food intake and adherence to the erMedDiet was assessed using validated food frequency questionnaire and 17-item Mediterranean questionnaire. Sociodemographic characteristics were documented. Environmental impact was calculated through greenhouse gas emissions estimations, specifically CO2 emissions of each participant diet per day, using a European database. Participants were distributed in quartiles according to their estimated CO2 emissions expressed in kg/day: Q1 (≤2.01 kg CO2), Q2 (2.02-2.34 kg CO2), Q3 (2.35-2.79 kg CO2) and Q4 (≥2.80 kg CO2). Results More men than women induced higher dietary levels of CO2 emissions. Participants reporting higher consumption of vegetables, fruits, legumes, nuts, whole cereals, preferring white meat, and having less consumption of red meat were mostly emitting less kg of CO2 through diet. Participants with higher adherence to the Mediterranean Diet showed lower odds for dietary CO2 emissions: Q2 (OR 0.87; 95%CI: 0.76-1.00), Q3 (OR 0.69; 95%CI: 0.69-0.79) and Q4 (OR 0.48; 95%CI: 0.42-0.55) vs Q1 (reference). Conclusions The Mediterranean diet can be environmentally protective since the higher the adherence to the Mediterranean diet, the lower total dietary CO2 emissions. Mediterranean Diet index may be used as a pollution level index.

Abstract Obesity and oestrogen containing contraceptive products are well‐known independent cardiovascular risk factors. However, a significant number of obese women continue to receive prescriptions of hormonal products that contain oestrogens for their contraception. We have conducted a narrative review to discuss the latest evidence, ongoing research, and controversial issues on the synergistic effect of obesity and contraceptive use, in terms of cardiovascular risk. There is compelling evidence of an interplay between obesity and contraception in increasing cardiovascular risk. Women who present both obesity and use of combined oral contraceptives (COCs) have a greater risk (between 12 and 24 times) to develop venous thromboembolism than non‐obese non‐COC users. Data here discussed offer new insights to increase clinicians' awareness on the cardiovascular risk in the clinical management of obese women. The synergistic effect of obesity and COCs on deep venous thrombosis risk must be considered when prescribing hormonal contraception. Progestin‐only products are a safer alternative to COCs in patients with overweight or obesity. Obese women taking contraceptives should be viewed as an ‘at risk’ population, and as such, they should receive advice to change their lifestyle, avoiding other cardiovascular risk factors, as a form of primary prevention. This indication should be extended to young women, as data show that COCs should be avoided in obese women of any age.

Abstract Introduction This observational retrospective matched cohort study evaluated the safety of a prenatal tetanus, diphtheria, acellular pertussis (Tdap) vaccination, Boostrix. We previously reported on the risk of maternal and neonatal outcomes; here we report on the risk of congenital anomalies in infants at birth through 6 months of age. Methods The study included pregnant Kaiser Permanente Southern California members. Women who received the Tdap vaccine on or after the 27th week of pregnancy between January 2018 and January 2019 were matched to women who were pregnant between January 2012 and December 2014 and were not vaccinated with Tdap during pregnancy. Unadjusted and adjusted relative risks (aRRs) with 95% confidence intervals were estimated by Poisson regression. Quantitative secular trend analyses, from 2011 to 2017, were conducted on congenital anomalies with a statistically significant aRR > 1. Results The analysis consisted of 16,350 and 16,088 live-born infants in the Tdap-exposed and unexposed cohorts, respectively. Of the 14 congenital anomaly body systems evaluated, 8 (eye, ear/face/neck, respiratory, upper gastrointestinal, genital, renal, musculoskeletal, integument) had statistically significant elevated aRRs, with point estimates ranging from 1.17 to 2.02. The observed elevated aRRs were consistent with their respective secular increases over time. Conclusion Cautious interpretation of these findings is warranted as these increases may have resulted from improved identification and diagnosis. Furthermore, the biological plausibility of an association between maternal vaccine exposure in the third trimester of pregnancy and birth defects is low. The overall study findings support the safety of maternal immunization with Boostrix during the third trimester of pregnancy. Trial Registration ClinicalTrials.gov identifier, NCT03463577.

Abstract The rapid spread of SARS-CoV-2 continues to impact humanity on a global scale with rising total morbidity and mortality. Despite the development of several effective vaccines, new products are needed to supply ongoing demand and to fight variants. We report herein a pre-specified interim analysis of the phase 2 portion of a Phase 2/3, randomized, placebo-controlled trial of a coronavirus virus-like particle (CoVLP) vaccine candidate, produced in plants that displays the SARS-CoV-2 spike glycoprotein, adjuvanted with AS03 (NCT04636697). A total of 753 participants were recruited between 25th November 2020 and 24th March 2021 into three groups: Healthy Adults (18–64 years: N = 306), Older Adults (≥65 years: N = 282) and Adults with Comorbidities (≥18 years: N = 165) and randomized 5:1 to receive two intramuscular doses of either vaccine (3.75 µg CoVLP/dose+AS03) or placebo, 21 days apart. This report presents safety, tolerability and immunogenicity data up to 6 months post-vaccination. The immune outcomes presented include neutralizing antibody (NAb) titres as measured by pseudovirion assay at days 21 and 42 as well as neutralizing antibody cross-reactivity to several variants of concern (VOCs): Alpha, Beta, Gamma, Delta, and Omicron (BA.1), up to 201 days post-immunization. Cellular (IFN-γ and IL-4 ELISpot) response data in day 21 and 42 peripheral blood are also presented. In this study, CoVLP+AS03 was well-tolerated and adverse events (AE) after each dose were generally mild to moderate and transient. Solicited AEs in Older Adults and Adults with Comorbidities were generally less frequent than in Healthy Adults and the reactogenicity was higher after the second dose. CoVLP+AS03 induced seroconversion in >35% of participants in each group after the first dose and in ~98% of participants, 21 days after the second dose. In all cohorts, 21-days after the second dose, NAb levels in sera against the vaccine strain were ~10-times those in a panel of convalescent sera. Cross-reactivity to Alpha, Beta and Delta variants was generally retained to day 201 (>80%) while cross-reactivity to the Gamma variant was reduced but still substantial at day 201 (73%). Cross-reactivity to the Omicron variant fell from 72% at day 42 to 20% at day 201. Almost all participants in all groups (>88%) had detectable cellular responses (IFN-γ, IL-4 or both) at 21 days after the second dose. A Th1-biased response was most evident after the first dose and was still present after the second dose. These data demonstrated that CoVLP+AS03 is well-tolerated and highly immunogenic, generating a durable (at least 6 months) immune response against different VOCs, in adults ≥18 years of age, with and without comorbidities.

Here, the authors report results from a Phase 1 trial with an AS03-adjuvanted, plant-based virus-like particle displaying the spike protein of the ancestral SARS-CoV-2. Six months post-second dose, they observe good neutralizing antibody titers and T cell responses to ancestral virus and variants of concern in participants.

Introduction Clostridioides difficile infection (CDI) is the most prevalent cause of nosocomial bacterial diarrhoea and it is strongly associated with antibiotic use. The recurrence of CDI is a growing medical problem. Data from real-life studies and one open label randomised clinical trial (RCT) suggest that secondary prophylaxis with oral vancomycin (SPV) during subsequent courses of systemic antibiotics is a promising approach for reducing the risk of CDI recurrence. Our aim is to confirm the role of SPV through a double-blind RCT.Methods and analysis We will perform a phase III, multicentre, placebo-controlled RCT (PREVAN trial) in a 2:1 ratio in favour of SPV (experimental treatment), in four tertiary care hospitals in Spain. Adult patients (≥18 years) with a previous history of CDI in the previous 180 days and with requirement for hospitalisation and systemic antibiotic therapy will be randomly allocated to receive either 125 mg of oral vancomycin or placebo every 6 hours for 10 days. Patients will be followed for 60 days after the end of treatment to verify a reduction in the rate of CDI recurrence in the experimental group. We assume a recurrence rate of 5% in the experimental group versus 25% in the placebo group. Accepting an alpha risk of 0.05 and a beta risk of 0.2 in a two-sided test, 104 subjects will be required in total (68 assigned to the SPV group and 34 to the placebo group).Ethics and dissemination Ethical approval has been obtained from the Ethic Committee for Research with medicinal products of the University Hospital ‘12 de Octubre’ (AC069/18) and from the Spanish Medicines and Healthcare Product Regulatory Agency (AEMPS, AC069/18), which is valid for all participating centres under existing Spanish legislation. The results will be presented at international meetings and will be made available to patients and funders.Trial registration number NCT05320068.

Summary: Background: In a parallel-group, international, phase 3 study (ClinicalTrials.gov NCT04762680), we evaluated prototype (D614) and Beta (B.1.351) variant recombinant spike protein booster vaccines with AS03-adjuvant (CoV2 preS dTM-AS03). Methods: Adults, previously primed with mRNA (BNT162b2, mRNA-1273), adenovirus-vectored (Ad26.CoV2.S, ChAdOx1nCoV-19) or protein (CoV2 preS dTM-AS03 [monovalent D614; MV(D614)]) vaccines were enrolled between 29 July 2021 and 22 February 2022. Participants were stratified by age (18–55 and ≥ 56 years) and received one of the following CoV2 preS dTM-AS03 booster formulations: MV(D614) (n = 1285), MV(B.1.351) (n = 707) or bivalent D614 + B.1.351 (BiV; n = 625). Unvaccinated adults who tested negative on a SARS-CoV-2 rapid diagnostic test (control group, n = 479) received two primary doses, 21 days apart, of MV(D614). Anti-D614G and anti-B.1.351 antibodies were evaluated using validated pseudovirus (lentivirus) neutralization (PsVN) assay 14 days post-booster (day [D]15) in 18–55-year-old BNT162b2-primed participants and compared with those pre-booster (D1) and on D36 in 18–55-year-old controls (primary immunogenicity endpoints). PsVN titers to Omicron BA.1, BA.2 and BA.4/5 subvariants were also evaluated. Safety was evaluated over a 12-month follow-up period. Planned interim analyses are presented up to 14 days post-last vaccination for immunogenicity and over a median duration of 5 months for safety. Findings: All three boosters elicited robust anti-D614G or -B.1.351 PsVN responses for mRNA, adenovirus-vectored and protein vaccine-primed groups. Among BNT162b2-primed adults (18–55 years), geometric means of the individual post-booster versus pre-booster titer ratio (95% confidence interval [CI]) were: for MV (D614), 23.37 (18.58–29.38) (anti-D614G); for MV(B.1.351), 35.41 (26.71–46.95) (anti-B.1.351); and for BiV, 14.39 (11.39–18.28) (anti-D614G) and 34.18 (25.84–45.22 (anti-B.1.351). GMT ratios (98.3% CI) versus post-primary vaccination GMTs in controls, were: for MV(D614) booster, 2.16 (1.69; 2.75) [anti-D614G]; for MV(B.1.351), 1.96 (1.54; 2.50) [anti-B.1.351]; and for BiV, 2.34 (1.84; 2.96) [anti-D614G] and 1.39 (1.09; 1.77) [anti-B.1.351]. All booster formulations elicited cross-neutralizing antibodies against Omicron BA.2 (across priming vaccine subgroups), Omicron BA.1 (BNT162b2-primed participants) and Omicron BA.4/5 (BNT162b2-primed participants and MV D614-primed participants). Similar patterns in antibody responses were observed for participants aged ≥56 years. Reactogenicity tended to be transient and mild-to-moderate severity in all booster groups. No safety concerns were identified. Interpretation: CoV2 preS dTM-AS03 boosters demonstrated acceptable safety and elicited robust neutralizing antibodies against multiple variants, regardless of priming vaccine. Funding: Sanofi and Biomedical Advanced Research and Development Authority (BARDA).

ABSTRACT Optimal coverage of Pseudomonas aeruginosa is challenging in febrile neutropenic patients due to a progressive increase in antibiotic resistance worldwide. We aimed to detail current rates of resistance to antibiotics recommended by international guidelines for P. aeruginosa isolated from bloodstream infections (BSI) in patients with hematologic malignancies. Secondarily, we aimed to describe how many patients received inappropriate empirical antibiotic treatment (IEAT) and its impact on mortality. We conducted a retrospective, multicenter cohort study of the last 20 BSI episodes caused by P. aeruginosa in patients with hematologic malignancies from across 14 university hospitals in Spain. Of the 280 patients with hematologic malignancies and BSI caused by P. aeruginosa, 101 (36%) had strains resistant to at least one of the β-lactam antibiotics recommended in international guidelines, namely, cefepime, piperacillin-tazobactam, and meropenem. Additionally, 21.1% and 11.4% of the strains met criteria for MDR and XDR P. aeruginosa, respectively. Even if international guidelines were followed in most cases, 47 (16.8%) patients received IEAT and 66 (23.6%) received inappropriate β-lactam empirical antibiotic treatment. Thirty-day mortality was 27.1%. In the multivariate analysis, pulmonary source (OR 2.22, 95% CI 1.14 to 4.34) and IEAT (OR 2.67, 95% CI 1.37 to 5.23) were factors independently associated with increased mortality. We concluded that P. aeruginosa-causing BSI in patients with hematologic malignancies is commonly resistant to antibiotics recommended in international guidelines, which is associated with frequent IEAT and higher mortality. New therapeutic strategies are needed. IMPORTANCE Bloodstream infection (BSI) caused by P. aeruginosa is related with an elevated morbidity and mortality in neutropenic patients. For this reason, optimal antipseudomonal coverage has been the basis of all historical recommendations in the empirical treatment of febrile neutropenia. However, in recent years the emergence of multiple types of antibiotic resistances has posed a challenge in treating infections caused by this microorganism. In our study we postulated that P. aeruginosa-causing BSI in patients with hematologic malignancies is commonly resistant to antibiotics recommended in international guidelines. This observation is associated with frequent IEAT and increased mortality. Consequently, there is a need for a new therapeutic strategy.

Introduction Congenital cytomegalovirus (cCMV) is the leading cause of non-genetic sensorineural hearing loss and one of the main causes of neurological disability. Despite this, no universal screening programme for cCMV has been implemented in Spain. A recent study has shown that early treatment with valaciclovir, initiated in the first trimester and before the onset of signs in the fetus, reduces the risk of fetal infection. This finding favours the implementation of a universal screening programme for cCMV.The aim of this study is to evaluate the performance of a universal screening programme for cCMV during the first trimester of pregnancy in a primary care setting.Methods and analysis This is an observational multicentre cohort study. The study will be conducted in four primary care settings from the Northern Metropolitan Barcelona area and three related hospitals and will last 3 years and will consist of a recruitment period of 18 months.In their first pregnancy visit, pregnant women will be offered to add a CMV serology test to the first trimester screening tests. Pregnant women with primary infection will be referred to the reference hospital, where they will continue treatment and follow-up according to the clinical protocol of the referral hospital, which includes treatment with valacyclovir. A CMV-PCR will be performed at birth on newborns of mothers with primary infection, and those who are infected will undergo neonatal follow-up for at least 12 months of life.For the analysis, the acceptance rate, the prevalence of primary CMV infections and the CMV seroprevalence in the first trimester of pregnancy will be studied.Ethics and dissemination Ethical approval was obtained from the University Institute Foundation for Primary Health Care Research Jordi Gol i Gurina Ethics Committee 22/097-P dated 27 April 2022.

Utilizamos a quimioterapia como tratamento inicial do carcinoma avançado do colo do útero em 40 pacientes, nos estádios lLa, llb e lllb a fim de aumentar a eficácia da radioterapia e torna-los operáveis. As drogas utilizadas foram cisplatina (80-100 mg/rrf/ciclo) e bleomicina (15 mg/ciclo), seguidas de radioterapia e cirurgia quando localmente possível. Foram operadas 21 pacientes (12 Wertheim-Meigs e nove pan-histerectomias). Em oito peças cirúrgicas (21,7%) não foi encontrada neoplasia residual. Quanto aos gânglios pélvicos, 83,3% dos casos submetidos a linfadenectomia não apresentavam metástases. Dos tumores operáveis, 85,7% eram exofíticos e três endofíticos (19,3%) e entre estes últimos houve dois óbitos e uma recidiva em cúpula vaginal. Nós concluímos que a associação da quimioterapia à radioterapia é efetiva em tornar operável mais da metade dos casos de tumores avançados do colo do útero. Os tumores exofíticos relacionam-se com melhor prognóstico em termos de resposta clínica e sobrevida livre de doença, e que possivelmente a quimioterapia diminui a porcentagem de pacientes com gânglios pélvicos metastáticos.

BackgroundCystic echinococcosis (CE), caused by Echinococcus granulosus sensu lato, is a neglected zoonosis. Its diagnosis relies on imaging, supported by serology, while only imaging is useful for staging and follow-up. Since diagnostic tools and expertise are not widely available, new accurate and easily implementable assays for the diagnosis and follow-up of CE are highly needed.Methodology/principal findingsWe aimed to identify new E. granulosus antigens through a bioinformatics selection applied to the parasite genome, followed by peptide microarray screening and validation in ELISA, using independent panels of sera from patients with hepatic CE and clinically relevant controls. From 950 proteins selected in silico, 2,379 peptides were evaluated by microarray for IgG reactivity and eight candidates selected for validation. Reactivity to one peptide was significantly higher in the CE group (p = 0.044), but had suboptimal diagnostic accuracy.Conclusions/significanceHere we performed bioinformatics analysis and peptide microarray for antigen discovery, useful for the diagnosis of CE. Eight candidates were selected and validated. Reactivity to one peptide associated to CE but had suboptimal diagnostic accuracy. Importantly, the database developed in this study may be used to identify other antigenic candidates for CE diagnosis and follow-up.

IntroductionNeurons are polarized cells, and their ability to change their morphology has a functional implication in the development and plasticity of the nervous system in order to establish new connections. Extracellular factors strongly influence neuronal shape and connectivity. For instance, the developmental actions of estradiol on hippocampal neurons are well characterized, and we have demonstrated in previous studies that Ngn3 mediates these actions. On the other hand, Kif21B regulates microtubule dynamics and carries out retrograde transport of the TrkB/brain-derived neurotrophic factor (BDNF) complex, essential for neuronal development.MethodsIn the present study, we assessed the involvement of kinesin Kif21B in the estradiol-dependent signaling mechanisms to regulate neuritogenesis through cultured mouse hippocampal neurons.ResultsWe show that estradiol treatment increases BDNF expression, and estradiol and BDNF modify neuron morphology through TrkB signaling. Treatment with K252a, a TrkB inhibitor, decreases dendrite branching without affecting axonal length, whereas. Combined with estradiol or BDNF, it blocks their effects on axons but not dendrites. Notably, the downregulation of Kif21B abolishes the actions of estradiol and BDNF in both the axon and dendrites. In addition, Kif21B silencing also decreases Ngn3 expression, and downregulation of Ngn3 blocks the effect of BDNF on neuron morphology.DiscussionThese results suggest that Kif21B is required for the effects of estradiol and BDNF on neuronal morphology, but phosphorylation-mediated activation of TrkB is essential only for axonal growth. Our results show that the Estradiol/BDNF/TrkB/Kif21B/Ngn3 is a new and essential pathway mediating hippocampal neuron development.

Background: Normative data for the effect of cardiopulmonary bypass (CPB) on coronary artery Doppler velocities by transesophageal echocardiography in paediatric patients with congenital heart disease (CHD) are lacking. The objective of the study was to prospectively examine the effects of CPB on coronary artery flow patterns by transesophageal echocardiography before and after CPB in children with CHD. Methods: All cases undergoing CHD surgery at the Hospital for Sick Children, Toronto, were eligible. The excluded cases included Norwood operation, heart transplantation, or weight

Abstract Some patients with COVID-19 pneumonia develop an associated cytokine storm syndrome that aggravates the pulmonary disease. These patients may benefit of anti-inflammatory treatment. The role of colchicine in hospitalized patients with COVID-19 pneumonia and established hyperinflammation remains unexplored. In a prospective, randomized controlled, observer-blinded endpoint, investigator-initiated trial, 240 hospitalized patients with COVID-19 pneumonia and established hyperinflammation were randomly allocated to receive oral colchicine or not. The primary efficacy outcome measure was a composite of non-invasive mechanical ventilation (CPAP or BiPAP), admission to the intensive care unit, invasive mechanical ventilation requirement or death. The composite primary outcome occurred in 19.3% of the total study population. The composite primary outcome was similar in the two arms (17% in colchicine group vs. 20.8% in the control group; p = 0.533) and the same applied to each of its individual components. Most patients received steroids (98%) and heparin (99%), with similar doses in both groups. In this trial, including adult patients with COVID-19 pneumonia and associated hyperinflammation, no clinical benefit was observed with short-course colchicine treatment beyond standard care regarding the combined outcome measurement of CPAP/BiPAP use, ICU admission, invasive mechanical ventilation or death (Funded by the Community of Madrid, EudraCT Number: 2020-001841-38; 26/04/2020).

Summary Ferritin proteins have an enormous capacity to store iron in cells. In search for the best conditions to accumulate and store bioavailable iron, we made use of a double mutant null for the monothiol glutaredoxins GRX3 and GRX4. The strain grx3grx4 accumulates high iron concentrations in the cytoplasm, making the metal easily available for ferritin chelation. Here, we perform a comparative study between human (L and H) and soya bean ferritins (H1 and H2) function in the eukaryotic system Saccharomyces cerevisiae. We demonstrate that the four human and soya bean ferritin chains are successfully expressed in our model system. Upon coexpression of either both human or soya bean ferritin chains, respiratory conditions along with iron supplementation led us to obtain the maximum yields of iron stored in yeast described to date. Human and soya bean ferritin chains are functional and present equivalent properties as promoters of cell survival in iron overload conditions. The best system revealed that the four human and soya bean ferritins possess a novel function as anti‐ageing proteins in conditions of iron excess. In this respect, both ferritin chains with oxidoreductase capacity (human‐H and soya bean‐H2) bear the highest capacity to extend life suggesting the possibility of an evolutionary conservation.

It is widely accepted that physical exercise can be used as a tool for the prevention and treatment of various diseases or disorders. In addition, in the recent years, exercise has also been successfully used to enhance people's cognition. There is a large amount of research that has supported the benefits of physical exercise on human cognition, both in children and adults. Among these studies, some have focused on the acute or transitory effects of exercise on cognition, while others have focused on the effects of regular physical exercise. However, the relation between exercise and cognition is complex and we still have limited knowledge about the moderators and mechanisms underlying this relation. Most of human studies have focused on the behavioral aspects of exercise-effects on cognition, while animal studies have deepened in its possible neuro-physiological mechanisms. Even so, thanks to advances in neuroimaging techniques, there is a growing body of evidence that provides valuable information regarding these mechanisms in the human population. This review aims to analyze the effects of regular and acute aerobic exercise on cognition. The exercise-cognition relationship will be reviewed both from the behavioral perspective and from the neurophysiological mechanisms. The effects of exercise on animals, adult humans, and infant humans will be analyzed separately. Finally, physical exercise intervention programs aiming to increase cognitive performance in scholar and workplace environments will be reviewed.