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Microenvironment contributes to follicular lymphoma (FL) pathogenesis and impacts survival with macrophages playing a controversial role. In the present study, using FL primary samples and HK follicular dendritic cells (FDC) to mimic the germinal center, together with mouse models, we have analyzed the three-way crosstalk of FL-FDC-macrophages and derived therapeutic opportunities. Ex vivo primary FL-FDC co-cultures ( n  = 19) and in vivo mouse co-xenografts demonstrated that FL-FDC crosstalk favors tumor growth and, via the secretion of CCL2 and CSF-1, promotes monocyte recruitment, differentiation, and polarization towards an M2-like protumoral phenotype. Moreover, FL-M2 co-cultures displayed enhanced angiogenesis, dissemination, and immunosuppression. Analysis of the CSF-1/CSF-1R pathway uncovered that CSF-1 was significantly higher in serum from grade 3A FL patients, and that high CSF-1R expression in FL biopsies correlated with grade 3A, reduced overall survival and risk of transformation. Furthermore, CSF-1R inhibition with pexidartinib (PLX3397) preferentially affected M2-macrophage viability and polarization program disrupting FL-M2 positive crosstalk. In vivo CSF1-R inhibition caused M2 reduction and repolarization towards M1 macrophages and antitumor effect cooperating with anti-CD20 rituximab. In summary, these results support the role of macrophages in FL pathogenesis and indicate that CSF-1R may be a relevant prognostic factor and a novel therapeutic target cooperating with anti-CD20 immunotherapy.

Cyclin D1 is an oncogene frequently overexpressed in human cancers that has a dual function as cell cycle and transcriptional regulator, although the latter is widely unexplored. Here, we investigated the transcriptional role of cyclin D1 in lymphoid tumor cells with cyclin D1 oncogenic overexpression. Cyclin D1 showed widespread binding to the promoters of most actively transcribed genes, and the promoter occupancy positively correlated with the transcriptional output of targeted genes. Despite this association, the overexpression of cyclin D1 in lymphoid cells led to a global transcriptional downmodulation that was proportional to cyclin D1 levels. This cyclin D1-dependent global transcriptional downregulation was associated with a reduced nascent transcription and an accumulation of promoter-proximal paused RNA polymerase II (Pol II) that colocalized with cyclin D1. Concordantly, cyclin D1 overexpression promoted an increase in the Poll II pausing index. This transcriptional impairment seems to be mediated by the interaction of cyclin D1 with the transcription machinery. In addition, cyclin D1 overexpression sensitized cells to transcription inhibitors, revealing a synthetic lethality interaction that was also observed in primary mantle cell lymphoma cases. This finding of global transcriptional dysregulation expands the known functions of oncogenic cyclin D1 and suggests the therapeutic potential of targeting the transcriptional machinery in cyclin D1-overexpressing tumors.

Background: Despite advances in the management of acute coronary syndrome (ACS), women continue to experience higher long-term mortality and lower access to secondary prevention compared with men. Objective: This study aimed to assess whether a universally inclusive, nurse-led secondary prevention program implemented at a University Hospital improved post-ACS outcomes and reduced gender disparities in risk factor control and mortality. Methods: This retrospective, observational study compared two cohorts of ACS survivors discharged from Bellvitge University Hospital: a pre-intervention cohort (2018) and a post-intervention cohort (2022). The nurse-led program included universal enrollment of all ACS patients, early follow-up, pharmacological optimization, therapeutic exercise, lifestyle counseling, and coordination with primary care. Outcomes included lipid and glycemic control and 18-month mortality, stratified by sex. Results: A total of 409 patients were included (2018: n = 200; 2022: n = 209), of whom 130 were women. Women were older and had more comorbidities. Post-program implementation, the proportion of patients without post-discharge blood testing dropped from >50% to <17% in both sexes. Lipid and glycemic control improved significantly at both early (1–4 months) and late (9–18 months) follow-up. Early differences favoring men disappeared by 18 months. Mortality decreased by 27.5% in men and 47.6% in women, representing a significantly greater relative reduction among women (p = 0.0001). Conclusions: A structured, nurse-led secondary prevention program with systematic inclusion improved clinical outcomes and significantly narrowed the gender gap in cardiovascular mortality. These findings demonstrate that equitable, protocolized care led by advanced practice nurses can reduce systemic inequities in cardiovascular health.

INTRODUCTION INTRODUCTIONIt is well known that Heart Failure (HF) is a very prevalent pathology and one of the main causes of the need for healthcare resources in our population, since clinical management is complex and often difficult to approach.It is for this reason that in recent decades, strategies have been sought, within the framework of the management of chronic diseases, to provide these patients with comprehensive and integrated care, achieving in these cases an improvement in clinical outcomes, such as mortality, readmissions and emergency room visits with the consequent impact on efficiency.However, assessing the impact of social determinants of health such as socioeconomic level (SES) on patients with Heart Failure is one of the challenges we have as a healthcare system and is what we are addressing in the following doctoral thesis.HYPOTHESIS HYPOTHESISIt is possible that low NSE negatively impacts the use of healthcare resources and clinical events in patients with CHF despite the universal access to healthcare that our healthcare system provides. However, it is possible that the effectiveness of comprehensive care programs for CHFis obtained independently of NSE but is partially attenuated by this factor.OBJECTIVES OBJECTIVESIn this project we propose as main objectives 1) to describe the association between NSE and clinical events in patients from the general population of Catalonia with CHF, 2) to evaluate the impact of NSE on the effectiveness of a comprehensive multidisciplinary program of transitional care for patients with CHF.We want to know the impact that these projects with territorial scope that integrate services and provide an integrated response can have and, at the same time, to be able to evaluate whether socioeconomic level (NSE) isone of the determining factors that can mean that these programs, which are difficultto implement and costly, work or not, since it could be thought that a low socioeconomic level is a vulnerability factor in these patients that implies having worse results and thatdepending on the socioeconomic level of the population treated, the deployment of the programs should be oriented differently.To answer this question of the impact of low socioeconomic status as a vulnerability factor and assess the management strategy in patients with heart failure, we proposed this thesis.RESULTS RESULTSIn the first work of the doctoral thesis, we carry out a descriptive study of the entire population with a diagnosis of HF in Catalonia during 2016, evaluating the NSE and analyzing the need for healthcare resources, such as urgent consultations, the need for hospital admission, and mortality.In the second work, we study patients with HF in the community reference area of ​​our hospital for 5 years, before, during, and after the implementation of a heart failure program that integrates hospital and primary care resources, with a transitional approach based on multidisciplinary and self-care. We evaluate the impact on health outcomes of this implementation by comparing ourselves with the rest of Catalonia both globally and stratified according to NSE.The data obtained suggest, on the one hand, that in patients with CHF, the NSE determines the evolution and use of healthcare resources, experiencing higher mortality, a decrease in life expectancy and with a greater use of unplanned urgent healthcare resources and a lower use of outpatient (preventive) healthcare resources. On the other hand, it is found that the benefit of the implementation of a community-based integrated care program for CHF, based on transitions of care and with case management as the driving force of the model, is obtained independently of the NSE of the patient, that is, the benefits of these programs are for all patients regardless of the NSE, especially in terms of mortality, but a gap does open, since the magnitude of the benefit seems to be slightly lower in the lower NSE strata in terms of the risk of hospitalizations. CONCLUSIONS CONCLUSIONSWith the data from the first study we can conclude that in patients with CHF with access to universal healthcare, lower income was independently associated with higher mortality and lower use of outpatient healthcare resources. The findings suggest that patients with CHF could benefit from a systematic assessment of their socioeconomic status and that this may help to identify vulnerable subgroups that can benefit from more personalized health education and management. On the other hand, the second study allows us to conclude that comprehensive multidisciplinary care programs for HF improve clinical outcomes, both in general and in all strata of NSE, although the effect of improvement in hospitalization in patients with CHF is partially attenuated in low or very low NSE strata.

Background Although hospital-based outpatient quick diagnosis units (QDU) are an increasingly recognized cost-effective alternative to hospitalization for the diagnosis of potentially serious diseases, patient perception of their quality of care has not been evaluated well enough. This cross-sectional study analyzed the perceived quality of care of a QDU of a public third-level university hospital in Barcelona. Methods One hundred sixty-two consecutive patients aged ≥ 18 years attending the QDU over a 9-month period were invited to participate. A validated questionnaire distributed by the QDU attending physician and completed at the end of the first and last QDU visit evaluated perceived quality of care using six subscales. Results Response rate was 98 %. Perceived care in all subscales was high. Waiting times were rated as ‘short’/’very short’ or ‘better’/’much better’ than expected by 69–89 % of respondents and physical environment as ‘better’/’much better’ than expected by 94–96 %. As to accessibility, only 3 % reported not finding the Unit easily and 7 % said that frequent travels to hospital for visits and investigations were uncomfortable. Perception of patient–physician encounter was high, with 90–94 % choosing the positive extreme ends of the clinical information and personal interaction subscales items. Mean score of willingness to recommend the Unit using an analogue scale where 0 was ‘never’ and 10 ‘without a doubt’ was 9.5 (0.70). On multivariate linear regression, age >65 years was an independent predictor of clinical information, personal interaction, and recommendation, while age 18–44 years was associated with lower scores in these subscales. No schooling predicted higher clinical information and recommendation scores, while university education had remarkable negative influence on them. Having ≥4 QDU visits was associated with lower time to diagnosis and recommendation scores and malignancy was a negative predictor of time to diagnosis, clinical information, and recommendation. Discussion It is worthy of note that the questionnaire evaluated patient perception and opinions of healthcare quality including recommendation rather than simply satisfaction. It has been argued that perception of quality of care is a more valuable approach than  satisfaction. In addition to embracing an affective dimension, satisfaction appears more dependent on patient expectations than is perception of quality. Conclusions While appreciating that completing the questionnaire immediately after the visit and its distribution by the QDU physician may have affected the results, scores of perceived quality of care including recommendation were high. There were, however, significant differences in several subscales associated with age, education, number of QDU visits, and diagnosis of malignant vs. benign condition.

With the surge of new SARS-CoV-2 variants, countries have begun offering COVID-19 vaccine booster doses to high-risk groups and, more recently, to the adult population in general. However, uncertainty remains over how long primary vaccination series remain effective, the ideal timing for booster doses, and the safety of heterologous booster regimens. We aimed to investigate COVID-19 primary vaccine series effectiveness and its waning, and the safety and effectiveness of booster doses, in a UK community setting. We used SARS-CoV-2 positivity rates in individuals from a longitudinal, prospective, community-based study (ZOE COVID Study), in which data were self-reported through an app, to assess the effectiveness of three COVID-19 vaccines (ChAdOx1 nCov19 [Oxford-AstraZeneca], BNT162b2 [Pfizer-BioNtech], and mRNA1273 [Moderna]) against infection in the 8 months after completion of primary vaccination series. In individuals receiving boosters, we investigated vaccine effectiveness and reactogenicity, by assessing 16 self-reported systemic and localised side-effects. We used multivariate Poisson regression models adjusting for confounders to estimate vaccine effectiveness. We included 620 793 participants who received two vaccine doses (204 731 [33·0%] received BNT162b2, 405 239 [65·3%] received ChAdOx1 nCoV-19, and 10 823 [1·7%] received mRNA-1273) and subsequently had a SARS-CoV-2 test result between May 23 (chosen to exclude the period of alpha [B.1.1.7] variant dominance) and Nov 23, 2021. 62 172 (10·0%) vaccinated individuals tested positive for SARS-CoV-2 and were compared with 40 345 unvaccinated controls (6726 [16·7%] of whom tested positive). Vaccine effectiveness waned after the second dose: at 5 months, BNT162b2 effectiveness was 82·1% (95% CI 81·3–82·9), ChAdOx1 nCoV-19 effectiveness was 75·7% (74·9–76·4), and mRNA-1273 effectiveness was 84·3% (81·2–86·9). Vaccine effectiveness decreased more among individuals aged 55 years or older and among those with comorbidities. 135 932 individuals aged 55 years or older received a booster (2123 [1·6%] of whom tested positive). Vaccine effectiveness for booster doses in 0–3 months after BNT162b2 primary vaccination was higher than 92·5%, and effectiveness for heterologous boosters after ChAdOx1 nCoV-19 was at least 88·8%. For the booster reactogenicity analysis, in 317 011 participants, the most common systemic symptom was fatigue (in 31 881 [10·1%] participants) and the most common local symptom was tenderness (in 187 767 [59·2%]). Systemic side-effects were more common for heterologous schedules (32 632 [17·9%] of 182 374) than for homologous schedules (17 707 [13·2%] of 134 637; odds ratio 1·5, 95% CI 1·5–1·6, p<0·0001). After 5 months, vaccine effectiveness remained high among individuals younger than 55 years. Booster doses restore vaccine effectiveness. Adverse reactions after booster doses were similar to those after the second dose. Homologous booster schedules had fewer reported systemic side-effects than heterologous boosters. Wellcome Trust, ZOE, National Institute for Health Research, Chronic Disease Research Foundation, National Institutes of Health, Medical Research Council

The Pfizer-BioNTech (BNT162b2) and the Oxford-AstraZeneca (ChAdOx1 nCoV-19) COVID-19 vaccines have shown excellent safety and efficacy in phase 3 trials. We aimed to investigate the safety and effectiveness of these vaccines in a UK community setting. In this prospective observational study, we examined the proportion and probability of self-reported systemic and local side-effects within 8 days of vaccination in individuals using the COVID Symptom Study app who received one or two doses of the BNT162b2 vaccine or one dose of the ChAdOx1 nCoV-19 vaccine. We also compared infection rates in a subset of vaccinated individuals subsequently tested for SARS-CoV-2 with PCR or lateral flow tests with infection rates in unvaccinated controls. All analyses were adjusted by age (≤55 years vs >55 years), sex, health-care worker status (binary variable), obesity (BMI <30 kg/m2vs ≥30 kg/m2), and comorbidities (binary variable, with or without comorbidities). Between Dec 8, and March 10, 2021, 627 383 individuals reported being vaccinated with 655 590 doses: 282 103 received one dose of BNT162b2, of whom 28 207 received a second dose, and 345 280 received one dose of ChAdOx1 nCoV-19. Systemic side-effects were reported by 13·5% (38 155 of 282 103) of individuals after the first dose of BNT162b2, by 22·0% (6216 of 28 207) after the second dose of BNT162b2, and by 33·7% (116 473 of 345 280) after the first dose of ChAdOx1 nCoV-19. Local side-effects were reported by 71·9% (150 023 of 208 767) of individuals after the first dose of BNT162b2, by 68·5% (9025 of 13 179) after the second dose of BNT162b2, and by 58·7% (104 282 of 177 655) after the first dose of ChAdOx1 nCoV-19. Systemic side-effects were more common (1·6 times after the first dose of ChAdOx1 nCoV-19 and 2·9 times after the first dose of BNT162b2) among individuals with previous SARS-CoV-2 infection than among those without known past infection. Local effects were similarly higher in individuals previously infected than in those without known past infection (1·4 times after the first dose of ChAdOx1 nCoV-19 and 1·2 times after the first dose of BNT162b2). 3106 of 103 622 vaccinated individuals and 50 340 of 464 356 unvaccinated controls tested positive for SARS-CoV-2 infection. Significant reductions in infection risk were seen starting at 12 days after the first dose, reaching 60% (95% CI 49–68) for ChAdOx1 nCoV-19 and 69% (66–72) for BNT162b2 at 21–44 days and 72% (63–79) for BNT162b2 after 45–59 days. Systemic and local side-effects after BNT162b2 and ChAdOx1 nCoV-19 vaccination occur at frequencies lower than reported in phase 3 trials. Both vaccines decrease the risk of SARS-CoV-2 infection after 12 days. ZOE Global, National Institute for Health Research, Chronic Disease Research Foundation, National Institutes of Health, UK Medical Research Council, Wellcome Trust, UK Research and Innovation, American Gastroenterological Association.

Reports of long-lasting coronavirus disease 2019 (COVID-19) symptoms, the so-called ‘long COVID’, are rising but little is known about prevalence, risk factors or whether it is possible to predict a protracted course early in the disease. We analyzed data from 4,182 incident cases of COVID-19 in which individuals self-reported their symptoms prospectively in the COVID Symptom Study app 1 . A total of 558 (13.3%) participants reported symptoms lasting ≥28 days, 189 (4.5%) for ≥8 weeks and 95 (2.3%) for ≥12 weeks. Long COVID was characterized by symptoms of fatigue, headache, dyspnea and anosmia and was more likely with increasing age and body mass index and female sex. Experiencing more than five symptoms during the first week of illness was associated with long COVID (odds ratio = 3.53 (2.76–4.50)). A simple model to distinguish between short COVID and long COVID at 7 days (total sample size, n  = 2,149) showed an area under the curve of the receiver operating characteristic curve of 76%, with replication in an independent sample of 2,472 individuals who were positive for severe acute respiratory syndrome coronavirus 2. This model could be used to identify individuals at risk of long COVID for trials of prevention or treatment and to plan education and rehabilitation services. Analysis of data from the COVID Symptom Study app reveals fatigue, headache, dyspnea and anosmia as key attributes of long COVID, with those experiencing five or more symptoms during the first week of being at increased risk of prolonged disease.

Recently, hesperidin, a flavonone mainly present in citrus fruits, has emerged as a new potential therapeutic agent able to modulate several cardiovascular diseases (CVDs) risk factors. Animal and in vitro studies demonstrate beneficial effects of hesperidin and its derived compounds on CVD risk factors. Thus, hesperidin has shown glucose-lowering and anti-inflammatory properties in diabetic models, dyslipidemia-, atherosclerosis-, and obesity-preventing effects in CVDs and obese models, and antihypertensive and antioxidant effects in hypertensive models. However, there is still controversy about whether hesperidin could contribute to ameliorate glucose homeostasis, lipid profile, adiposity, and blood pressure in humans, as evidenced by several clinical trials reporting no effects of treatments with this flavanone or with orange juice on these cardiovascular parameters. In this review, we focus on hesperidin’s beneficial effects on CVD risk factors, paying special attention to the high interindividual variability in response to hesperidin-based acute and chronic interventions, which can be partly attributed to differences in gut microbiota. Based on the current evidence, we suggest that some of hesperidin’s contradictory effects in human trials are partly due to the interindividual hesperidin variability in its bioavailability, which in turn is highly dependent on the α-rhamnosidase activity and gut microbiota composition.

Dispersal and recruitment are fundamental processes for population recovery following disturbances in sessile species. While both processes are well understood for many terrestrial species, they still remain poorly resolved for some macroalgal species. Here we experimentally investigated the effective dispersal and recruit survival of a mesophotic Mediterranean fucoid, Cystoseira zosteroides. In three isolated populations, four sets of settlement collectors were placed at increasing distances (from 0 to 10 m) and different orientations (North, South, East and West). We observed that effective dispersal was restricted to populations' vicinity, with an average of 6.43 m and not further than 13.33 m, following a Weibull distribution. During their first year of life, survival was up to 50%, but it was lower underneath the adult canopy, suggesting a negative density-dependence. To put our results in a broader context we compared the effective dispersal of other fucoid and kelp species reported in the literature, which confirmed the low dispersal ability of brown algae, in particular for fucoids, with an effective dispersal of few meters. Given the importance of recruitment for the persistence and recovery of populations after disturbances, these results underline the vulnerability of C. zosteroides and other fucoid species to escalating threats.