Abstract
T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally ...exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy.
On 11 March 2020 the SARS-CoV-2 virus was officially declared a pandemic and measures were set up in various countries to avoid its spread among the population. This paper aims to analyse the ...perception of risk of COVID-19 infection in the Spanish population. A cross-sectional, descriptive observational study was conducted with a total of 16,372 Spanish participants. An online survey was used to gather data for 5 consecutive days over the compulsory lockdown period which was established after the state of emergency was declared. There is an association between socio-demographic variables and risk perception, and a very strong relationship between this perception and contact and direct experience with the virus in a family, social or professional setting. We also found that compared to working from home, working outside the home increased the perception of risk of infection and the perception of worsening health. Understanding the public perception of the risk of COVID-19 infection is fundamental for establishing effective prevention measures.
Objective To investigate the effect of parenteral administration of vitamin C on neutrophil apoptosis by determining Fas receptor expression and caspase-3, poly (ADP-ribose) polymerase (PARP), and ...Bcl-2 levels in neutrophils from septic abdominal surgery patients. Study design Twenty septic abdominal surgery patients were studied in a prospective, randomized, double-blinded clinical trial. A group of healthy volunteers ( n = 10) constituted a reference group for baseline parameter values. The patients were randomly assigned to a vitamin C-treated ( n = 10) or placebo-treated ( n = 10) group. For a 6-d period from 12 h post-surgery, the vitamin C group received 450 mg/d of the vitamin in 3 doses and the placebo group an identical administration of 5% dextrose. Early-morning peripheral blood samples were obtained daily from 24 h after vitamin C administration until d 6 post-surgery (T1d-T6d). Results Vitamin C group showed a nonsignificant reduction in Fas (CD95) expression on CD15-positive peripheral blood neutrophils, significantly decreased caspase-3, and PARP levels (caspase-3: T4d: P < 0.05, T5d: P < 0.05, T6d P < 0.01; and PARP: T3d: P < 0.05, T4d: P < 0.05, T6d: P < 0.05), and significantly increased Bcl-2 levels (T3d: P = 0.001) versus placebo group. Conclusions Postoperative vitamin C treatment of septic abdominal surgery patients exerts an antiapoptotic effect on peripheral blood neutrophils, reducing caspase-3 and PARP levels, and increasing Bcl-2 levels. However, these antiapoptotic effects are not maintained at all time points.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Nonsyndromic orofacial clefts are a common complex birth defect caused by genetic and environmental factors and/or their interactions. A previous genome-wide linkage scan discovered a novel locus for ...cleft lip with or without cleft palate (CL/P) at 9q22–q33. To identify the etiologic gene, we undertook an iterative and complementary fine mapping strategy using family-based CL/P samples from Colombia, USA and the Philippines. Candidate genes within 9q22–q33 were sequenced, revealing 32 new variants. Concurrently, 397 SNPs spanning the 9q22–q33 2-LOD-unit interval were tested for association. Significant SNP and haplotype association signals (P = 1.45E − 08) narrowed the interval to a 200 kb region containing: FOXE1, C9ORF156 and HEMGN. Association results were replicated in CL/P families of European descent and when all populations were combined the two most associated SNPs, rs3758249 (P = 5.01E − 13) and rs4460498 (P = 6.51E − 12), were located inside a 70 kb high linkage disequilibrium block containing FOXE1. Association signals for Caucasians and Asians clustered 5′ and 3′ of FOXE1, respectively. Isolated cleft palate (CP) was also associated, indicating that FOXE1 plays a role in two phenotypes thought to be genetically distinct. Foxe1 expression was found in the epithelium undergoing fusion between the medial nasal and maxillary processes. Mutation screens of FOXE1 identified two family-specific missense mutations at highly conserved amino acids. These data indicate that FOXE1 is a major gene for CL/P and provides new insights for improved counseling and genetic interaction studies.
Abstract
Aims
To describe the prevalence and characteristics of pain in adult hospitalised patients, as well as to analyse the concordance between patient‐reported and recorded pain and its impact on ...analgesic management.
Design
A cross sectional study.
Methods
The study was performed on a sample of 611 patients, from October to December 2017. Data were obtained from patient interviews, review of medical and nursing records and review of electronic prescribing.
Results
The prevalence of pain at the time of the interview was 36.7%. The median VAS score was 4. 90% of the patients had their pain assessed within the last 24 h; however, concordance between patient‐reported pain and recorded pain in the nursing record was slight.
Conclusion
Pain is still often documented inadequately. Despite the wide use of analgesics, half of the patients with moderate to severe pain do not have adequate pain management. A systematic assessment and recording of pain promotes appropriate analgesic prescription.
Implications for the profession and patient care
The findings of our study provide insight into the main gaps in the correct management of pain in hospitalised patients. A systematic assessment and recording of the pain suffered by the patient facilitates its control and allows a better management of the analgesic prescription by the physician. This information could help hospital managers to develop training programmes on pain assessment and on the importance of doctor–nurse collaboration to improve pain management, increasing the quality of care and reducing hospital costs.
Reporting method
The study has adhered to the relevant EQUATOR guidelines, according to The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK, VSZLJ
Global crop production is limited by water, nitrogen, and phosphorous availability. Reclaimed water and organic fertilizers, such as crop residues, animal manure, and biosolids, can mitigate these ...needs. However, these materials may contain different pollutants arising from, among others, human and veterinarian health care, industry, cleaning media, or leakages from plastics or textiles. The European PRIMA-DSWAP project deals with the risks derived from these practices in relation to the presence of the so-called contaminants of emerging concern, or CECs, while exploring possible technical and mitigation measures to minimize those impacts. Risk assessment analyses of the CEC presence in soils and water bodies have been mainly focused in their consequences for human and environmental health, but very little has been studied about their potential negative effects on crop performance and quality. Here we review the current knowledge on macroscopic and molecular plant responses to the presence of several CECs known to abound in reclaimed waters, manure, and biosolids, with particular emphasis on crop plants, when available. With this information, and with the analysis of the potential implications of scaling these effects to the commercial agricultural level, we intend to contribute to the ongoing debate on the water reuse and biosolid application in agriculture in the context of circular economy.
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•Use of reclaimed water and biosolids is becoming widespread in agriculture.•The potential impact of this practice on crop performance is still poorly known.•Current data on CEC plant toxicity indicates a potentially significant impact.•Legal limitations for CECs levels in reclaimed water and amendments are proposed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This book not only provides unique and in-depth information to understand the language of architecture and civil engineering, it is also helpful for students and professionals who need to improve ...their linguistic skills. The LACE book includes plenty of.
Throughout the pandemic, national and international health authorities have called on the population to collaborate and contribute with their behavior to control the problem. The aim of this study is ...to analyze the implementation of the protective measures against COVID-19 and to determine the factors involved in their compliance. To respond to the objectives, a cross-sectional study was performed involving a total of 5560 individuals. An ad hoc online questionnaire was created and shared through social networks, scientific societies, and various health institutions. The probability of high or total compliance with the protective measures was higher in women (OR = 1.401) and as age increases, with an OR = 2.524 in the interval between 31 and 64 years old and an OR = 2.896 in the oldest interval (65 and over). This study shows the characteristics of the population that considers it more likely to be infected by SARS-CoV-2, thus adopting greater adherence to prevention measures. Knowing which factors are associated with adherence to protective measures is essential for establishing effective pandemic control measures. Our findings may be useful for designing future awareness campaigns adapted to different socio-demographic characteristics in settings affected by COVID-19.
Current clinical guidelines establish Pulmonary Vein (PV) isolation as the indicated treatment for Atrial Fibrillation (AF). However, AF can also be triggered or sustained due to atrial drivers ...located elsewhere in the atria. We designed a new simulation workflow based on personalized computer simulations to characterize AF complexity of patients undergoing PV ablation, validated with non-invasive electrocardiographic imaging and evaluated at one year after ablation. We included 30 patients using atrial anatomies segmented from MRI and simulated an automata model for the electrical modelling, consisting of three states (resting, excited and refractory). In total, 100 different scenarios were simulated per anatomy varying rotor number and location. The 3 states were calibrated with Koivumaki action potential, entropy maps were obtained from the electrograms and compared with ECGi for each patient to analyze PV isolation outcome. The completion of the workflow indicated that successful AF ablation occurred in patients with rotors mainly located at the PV antrum, while unsuccessful procedures presented greater number of driving sites outside the PV area. The number of rotors attached to the PV was significantly higher in patients with favorable long-term ablation outcome (1-year freedom from AF: 1.61 ± 0.21 vs. AF recurrence: 1.40 ± 0.20; p-value = 0.018). The presented workflow could improve patient stratification for PV ablation by screening the complexity of the atria.
Abstract Objectives The aim of this study was to describe grandmothers’ experiences of taking care of their grandchildren in terms of their care-giving tasks, motivations and emotions. Methods A ...qualitative phenomenological study was conducted. Purposive sampling was used, based on the relevance of the research question. Seventeen participants were included, women ≥ 65 years old, grandmothers who care for their grandchildren at least 10 h per week and who attended the Nursing units of the Primary Care Health Centers (Madrid Public Health Service). Seventeen in-depth interviews were conducted. The interviews were audio-recorded, transcribed verbatim and thematic analysis was carried out from the perspective of hermeneutic phenomenology. For the analysis, the Excel program was used to organize and share the coding process. Also, we followed COREQ guidelines. Results Four main themes were identified: (a) Care out of obligation, where participants feel an obligation to help their children by caring for grandchildren, regardless of their number, and prefer to do so voluntarily; (b) Care out of responsibility, where grandmothers see their role as a responsibility that includes saving costs by caring for grandchildren and facilitating their children’s work life balance; (c) Care as a social duty, reflecting a moral commitment inherited from their mothers to help future generations; and (d) Construction of care from a gender perspective, where grandmothers, as women, primarily assume the care and upbringing of grandchildren. Discussion Our results contribute to increase knowledge about childcare provided by grandmothers to their grandchildren. Grandmothers become fundamental pillars of families by helping their children balance family and work. Behind this care there is a strong sense of obligation, duty and generational responsibility. Grandmothers’ help presents differences in the distribution of tasks and care by sex. Identifying factors that motivate grandmothers to care for their grandchildren helps nurses to perform higher quality comprehensive care.
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IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, UL, UM, UPUK, VSZLJ
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