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Very few data exist on when a particular thrombopoietin-receptor agonist (TPO-RA) is favored in clinical practice for the treatment of patients with immune thrombocytopenia (ITP), about novel risk factors for vascular events (VE) with these drugs, nor about predictive factors for therapy free responses (TFR). We conducted an observational, retrospective, long-term follow-up multicenter study from November 2016 to January 2018 of 121 adult ITP patients initiating TPO-RA between January 2012 to December 2014. Data reflected that a platelet count ≤25 × 10 9 /l at the time when the TPO-RA was initiated was associated with a 2.8 higher probability of receiving romiplostim vs . eltrombopag ( P  = 0.010). VE on TPO-RA was related to previous neoplasia in patients over 65 years (50% vs . 2.2%, P  < 0.001), and to previous splenectomy in younger patients (100% vs . 33%, P  = 0.001). Receiving romiplostim as first TPO-RA with no subsequent TPO-RA switching was associated with a 50% likelihood of TFR after 2.9 years of therapy (3.3 years in chronic ITP patients). These real-world data help deciphering some areas of uncertainty, and offer insight into some of the most relevant challenges of ITP which may help clinicians make appropriate treatment decisions in the management of adult ITP patients with TPO-RA.

[This corrects the article DOI: 10.1371/journal.pone.0288348.].

Aims To find out whether the information that the nursing process provides (functional patterns and the NANDA-NIC-NOC taxonomy), presented through clinical histories, influences predictions of total healthcare costs. Background The nursing process, is not included in the systems that calculate expenditure in the Spanish healthcare system. Such an omission can result in suboptimal resource allocation. Methods Analytical and retrospective observational study of a population of 1,691,075 people over the age of 15. The explanatory variables were age, sex and nursing process data, with total healthcare cost as the outcome variable. A bivariate analysis and a multiple regression were performed for the multivariate analysis. To improve prediction accuracy and account for non-linear relationships, the analysis was completed using two machine learning models. Results 58% ( n  = 980,437) of the population presented some data from the nursing process, for individuals with an assessed pattern, the average cost was €2304.17 compared with €950.93 for those who had none; with a nursing diagnosis, the average cost was €1,666 versus €840 without it. Having created the best model for the analysis using neural networks and XGBOOST, an average coefficient of determination of R 2  = 21.45% was obtained. Conclusions The variability in total healthcare costs can be explained in more than 21% of cases by the model created, including sex, age, and the information related to the nursing process. Implications for health policy: Demonstrating the influence of nursing care on total patient costs will facilitate its inclusion in management programs, promoting the use of nursing data in risk adjustment models and healthcare planning.

The complexity of palliative care means that the emotional distress and burden that primary family caregivers suffer under can be particularly high. The objective of this study was to determine the level of burden endured by these primary family caregivers and to identify the variables that predict it in the caregiving relatives of people who require home-based palliative care. A descriptive-correlational cross-sectional study was conducted. Socio-demographic and clinical data were collected from caregivers through a self-administered questionnaire that included questions from the 12-Item Short Form Health Survey (SF-12), Zarit Caregiver Burden Interview (ZBI), Hospital Anxiety and Depression Scale (HADS), Brief Resilient Coping Scale (BRCS), Post Traumatic Growth Inventory (PTGI), and Fatigue Assessment Scale (FAS). A total of 77 caregivers participated; 66.2% were women, and the mean age was 61.5 years. Most (62.3%) were providing care to cancer patients. From among these data, the presence of anxiety as a clinical problem (48.1%), a high average fatigue score (FAS) of 23.0 (SD = 8.5), and the prevalence of intense overload (41.6%) stood out. We found statistically significant correlations between the variables of burden, fatigue, post-traumatic growth, anxiety, and depression, with the latter two being the main predictive variables of burden. In addition, caregiver burden was associated with a worsening of health. Identifying the factors that influence the appearance of overburden will allow the specific needs of careers to be assessed in order to offer them emotional support within the healthcare environment.

CRISPR/Cas ability to target several loci simultaneously (multiplexing) is a game-changer in plant breeding. Multiplexing not only accelerates trait pyramiding but also can unveil traits hidden by functional redundancy. Furthermore, multiplexing enhances dCas-based programmable gene expression and enables cascade-like gene regulation. However, the design and assembly of multiplex constructs comprising tandemly arrayed guide RNAs (gRNAs) requires scarless cloning and is still troublesome due to the presence of repetitive sequences, thus hampering a more widespread use. Here we present a comprehensive extension of the software-assisted cloning platform GoldenBraid (GB), in which, on top of its multigene cloning software, we integrate new tools for the Type IIS-based easy and rapid assembly of up to six tandemly-arrayed gRNAs with both Cas9 and Cas12a, using the gRNA-tRNA-spaced and the crRNA unspaced approaches, respectively. As stress tests for the new tools, we assembled and used for Agrobacterium-mediated stable transformation a 17 Cas9-gRNAs construct targeting a subset of the Squamosa-Promoter Binding Protein-Like (SPL) gene family in Nicotiana tabacum . The 14 selected genes are targets of miR156, thus potentially playing an important role in juvenile-to-adult and vegetative-to-reproductive phase transitions. With the 17 gRNAs construct we generated a collection of Cas9-free SPL edited T 1 plants harboring up to 9 biallelic mutations and showing leaf juvenility and more branching. The functionality of GB-assembled dCas9 and dCas12a-based CRISPR/Cas activators and repressors using single and multiplexing gRNAs was validated using a Luciferase reporter with the Solanum lycopersicum Mtb promoter or the Agrobacterium tumefaciens nopaline synthase promoter in transient expression in Nicotiana benthamiana . With the incorporation of the new web-based tools and the accompanying collection of DNA parts, the GB4.0 genome edition turns an all-in-one open platform for plant genome engineering.

Background: Tofacitinib is effective for refractory ulcerative colitis (UC), a chronic inflammatory disease of the colonic mucosa. However, its use has been associated with an increased risk of thromboembolic events, prompting regulatory restrictions. Understanding the pathophysiological mechanisms contributing to these potential risks is critical for patient safety. We aim to evaluate and compare ex vivo the effects of tofacitinib and anti-TNF on coagulation parameters and platelet function. Methods: Whole blood and platelet-rich plasma from 10 active UC (aUC) and 10 quiescent UC (qUC) patients and 10 healthy controls (HC) were spiked ex vivo with tofacitinib, anti-TNF (as comparator), or a sterile solution. Coagulation kinetics were measured by rotational thromboelastometry (ROTEM), platelet aggregation by aggregometry, and platelet activation by flow cytometry. The study was conducted at Hospital Universitario de La Princesa. Results: Flow cytometry showed increased expression of activation markers CD62P and CD63 and higher PAC-1 binding in platelets from both aUC and qUC patients incubated with either tofacitinib or anti-TNF versus no drug. No differences were found between the drugs. CD63 expression also increased in HC after drug exposure, with no differences between anti-TNF or tofacitinib. Platelet aggregation and coagulation parameters did not differ between tofacitinib, anti-TNF, and no drug in aUC, qUC, and HC. Conclusions: Tofacitinib does not alter platelet function or coagulation in UC patients under ex vivo conditions compared to anti-TNF. The increased thromboembolic risk observed in some populations treated with tofacitinib cannot be attributed to these factors in UC patients.

A promising new class of SynBio tools that could play this function are the synthetic transcriptional activators based on CRISPR/Cas9 architecture, which combine autonomous transcriptional activation domains (TADs) capable of recruiting the cellular transcription machinery, with the easily customizable DNA‐binding activity of nuclease‐inactivated Cas9 protein (dCas9), creating so‐called programmable transcriptional activators (PTAs). During the cloning of the gRNA2.0 scaffold employed in the scRNA design, a spontaneous mutation occurred consisting in the insertion of an adenine in the loop of the first aptamer (Figure c). Since this aptamer variant had not been studied earlier, we decided to include it in the comparison analysis (labelled as gRNA2.1). In a further optimization step, we tested the scRNA2.1 design with new TAD combinations covering different types of autonomous TADs, namely two plant transcriptional factors (TFs; EDLL, ERF2), two viral TFs (VP64, VP192), a chromatin modifier (P300) and two combined domain fusions (VPR, TV; Chavez et al., ; Li et al., ). The promoter of the SlDFR gene (dihydroflavonol‐4‐reductase) from Solanum lycopersicum (pSlDFR, catalogued as GB1160) has very low basal expression levels (RTA < 0.04 RPUs), but it is strongly induced by the presence of ‘natural’ Myb TF (e.g. SlANT1). [...]pSlDFR was used as model promoter to test the activation range of dCasEV2.1 induction.

The COVID-19 pandemic generated a global health crisis that significantly impacted healthcare systems and professionals. Healthcare workers were exposed to high levels of psychological distress, including posttraumatic stress symptomatology (PTSS). Analyse the evolution of PTSS among Spanish healthcare workers during the COVID-19 pandemic, and to identify associated factors. A multicenter prospective cohort study with a 12-month follow-up was conducted. PTSS was the primary outcome. Secondary variables included sociodemographic, occupational, psychological, and coping-related factors. Statistical analyses comprised bivariate comparisons and multivariate modelling, such as generalized linear models and linear mixed models. Of the 428 participants, 180 completed the 12-month follow-up. At baseline, changes in work posts, negative family-work relations, avoidant coping, burnout symptoms, and emotional intelligence were associated with PTSS levels. Linear mixed models showed a significant decrease in PTSS over the 12-month period, regardless of gender, age, household type, occupational role, contract type, job title, level of care or type of service (p < 0.001). The generalised linear model explained 25.5% of the variance in PTSS levels at baseline, highlighting the role of psychological and coping factors over sociodemographic or occupational characteristics. This study highlights the need for early identification and intervention focused on psychological and coping mechanisms. Promoting emotional regulation, reducing burnout, and addressing maladaptive coping may help mitigate long-term psychological effects among healthcare workers during public health crises.

Breast cancer is currently the most diagnosed type of cancer in the world, with a five-year survival rate of 90%. Survivors develop genitourinary dysfunction symptoms due to cancer treatment, which implies that they have to endure physical and psychological sequelae, with a negative impact on their quality of life. We present a study protocol to verify the effect of radiofrequency (RF) and pelvic floor muscle training (PFMT) for the treatment of genitourinary dysfunction in breast cancer survivors. This is a double-blind, three-arm, randomised clinical trial (Registration: NCT06694519). Participants from two breast cancer associations from Alicante (Spain) will be randomly assigned to one of the three intervention groups (RF, PFMT, RF + PFMT). It will include survivors aged ≥ 18 years who present pelvic dysfunction assessed by the Pelvic Floor Distress Inventory questionnaire (PFDI20) ≥ 100. Pelvic muscle strength, pelvic function, vaginal symptoms, sexual function, self-esteem and quality of life will be evaluated before the intervention, with follow-up at 15 days, 6 months and 1 year after the intervention. RF could offer additional benefits to PFMT due to its proven effectiveness in the treatment of vaginal dryness and dyspareunia. The expected results will have a positive impact on the health and well-being of women with breast cancer, reducing the symptomatology associated with the disease and its treatment, and improving their quality of life, as well as providing value for the development of more effective treatment protocols. ClinicalTrials.gov NCT06694519.