Search Results (207)

Background: For infants, withholding or withdrawal of feeding is ethically permissible when the child is imminently dying or chronically and irreversibly comatose. It can also be appropriate in cases of medical futility with a low chance of survival. However, there is much contention in situations where the medical prognosis is uncertain. Case presentation: Annie is a 6-week-old neonate with antenatally acquired cystic encephalomalacia, a chronic non-progressive neurological condition. Her future neurological outcome is uncertain. She is putting on weight in the NICU with stable cardiorespiratory status on room air and tolerates full nasogastric tube feeding but requires frequent oropharyngeal suctioning. Her parents ask to stop tube feeding and allow Annie to die. They deem she has a poor quality of life and is experiencing tremendous suffering. Discussion: Parents’ perceptions of “best interest” and “physical suffering” are explored, alongside those of the healthcare team. Concomitant issues like feeding withdrawal and moral distress are examined in context—that of a newborn where developmental outcomes and disease trajectory are unclear. Conceptual frameworks, empirical evidence and consensus-based ethics guidelines informed a rich and multi-dimensional exposition of a difficult and value-laden decision. Conclusions: While instinctively legitimate, enteral feeding in an infant, in this case with severe neurological impairment, is ultimately still a medical intervention. In contrast to prevailing conventions within adult medicine, the careful and nuanced consideration of benefits and burdens from different stakeholders’ perspectives is critical before any deliberate withdrawal to allow natural death. Full article

Diabetic retinopathy is the most common diabetic complication of the microvasculature and one of the leading causes of acquired vision loss worldwide. Yet, the current treatments for this blinding disease are futile to many diabetics. Accordingly, new biomarkers and therapeutics for diabetic retinopathy are needed. We discovered that STEAP4 (Six-Transmembrane Epithelial Antigen of the Prostate 4) is significantly increased in peripheral blood mononuclear cells of diabetics. STEAP4 expression was gradiently increased from low levels in diabetics without retinopathy to successively higher levels in diabetics with more severe disease. Although the role of STEAP4 in the diabetic retina is unclear, these results provide strong evidence that this metabolic enzyme could be a potential biomarker for diabetic retinopathy progression. Thus, the central goal of this study was to evaluate if this potential biomarker impacts the intrinsic pathologies that lead to the development of diabetic retinopathy. In diabetic mice, STEAP4 was significantly increased and co-localized with 4-Hydroxy-2-nonenal in the Müller glia and photoreceptor layers of the retina. STEAP4 inhibition significantly decreased reactive oxygen species in murine photoreceptor cells, human Müller glia, and retinas of diabetic mice. Administering an intravitreal injection of anti-STEAP4 to diabetic mice halted Occludin degradation in the retinal vasculature. Similarly, anti-STEAP4 treatment of human retina endothelial cells halted cell death mediated by diabetic donor sera. Collectively, our findings provide strong evidence that STEAP4 impacts the intrinsic pathologies that initiate the development of diabetic retinopathy. Suggesting that STEAP4 could be a novel biomarker and clinically relevant therapeutic target for this diabetic complication and blinding disease. Full article

Biliary atresia (BA) is an obliterative disease of the bile ducts affecting between 1 in 10,000–20,000 infants with a predominance in Asian countries. It is clinically heterogeneous with a number of distinct variants (e.g., isolated, Biliary Atresia Splenic Malformation syndrome, Cat-eye syndrome, cystic BA, and CMV-associated BA). Facts about its aetiology are hard to encounter but might include genetic, developmental, exposure to an environmental toxin, or perinatal virus infection. However, the cholestatic injury triggers an intrahepatic fibrotic process beginning at birth and culminating in cirrhosis some months later. Affected infants present with a triad of conjugated jaundice, pale stools, and dark urine and may have hepatosplenomegaly upon examination, with later ascites coincident with the onset of progressive liver disease. Rapid, efficient, and expeditious diagnosis is essential with the initial treatment being surgical, typically with an attempt to restore the bile flow (Kasai portoenterostomy (KPE)) or primary liver transplantation (<5%) if considered futile. Failure to restore bile drainage or the onset of complications such as recurrent cholangitis, treatment-resistant varices, ascites, hepatopulmonary syndrome, and occasionally malignant change are usually managed by secondary liver transplantation. This issue summarises recent advances in the disease and points a way to future improvements in its treatment. Full article

Background: A significant proportion of elderly patients referred to transcatheter aortic valve replacement (TAVR) do not experience an improvement of their symptoms. New tools are needed to better select candidates and avoid futile procedures. The objective of this study was to evaluate the impact of a new echocardiographic classification which assesses the consequences of chronic elevation of afterload on mortality and hospitalizations for heart failure (HF) in patients with severe AS undergoing TAVR. Methods: This study included 130 high-risk, elderly patients with severe AS who underwent TAVR between January 2018 and December 2019. The patients were classified into three groups according to anatomical and functional features based on transthoracic echocardiography (TTE). The combined end point was death from all causes and HF admissions. Results: Echocardiographic staging was significantly associated with increased rates of death and HF hospitalizations. After multivariate adjustment, the patients with severe cardiac damage exhibited a significant increase in hospitalizations for HF and all-cause mortality (HR 4.79; 95% CI 2.00–11.05; p = 0.000), whereas the moderate cardiac damage group did not (HR 1.84; 95% CI 0.88–3.84; p = 0.104). Conclusions: Echocardiographic staging of severe AS could be a useful tool for predicting HF hospitalizations and all-cause mortality after TAVR in elderly, high-risk patients. Evaluating cardiac damage with this new score may be a promising strategy to better select patients and improve outcomes following TAVR. Full article

Universities and journals increasingly rely on software tools for detecting textual overlap of a scientific text with the previously published literature to detect potential plagiarism. Although software outputs need to be carefully reviewed by competent humans to verify the existence of plagiarism, university and journal staff, for various reasons, often erroneously interpret the degree of plagiarism based on the percentage of textual overlap shown in the similarity report. This is often accompanied by explicit recommendations to the author(s) to paraphrase the text to achieve an “acceptable” percentage of overlap. Here, based on the available literature and real-world examples from similarity reports, we provide a classification with extensive examples of phrases that falsely inflate the similarity index and argue the futility and dangers of rephrasing such statements just for the sake of reducing the similarity index. The examples provided in this paper call for a more reasonable assessment of text similarity. To fully endorse the principles of academic integrity and prevent loss of clarity of the scientific literature, we believe it is important to shift from pure bureaucratic and quantificational view on the originality of scientific texts to human-centered qualitative assessment of the manuscripts, including the software outputs. Full article

Background: Elderly patients with severe aortic stenosis (AS) need individualized decision-making in their management in order to benefit in terms of survival and improvement of quality of life. Frailty, a common condition in elderly patients, needs to be considered when weighing treatment options. Aim: We aimed to evaluate outcomes including survival and functional parameters according to disability criteria at six years of follow-up in an older population treated for severe AS using a frailty-based management. Methods: We evaluated data derived from a pilot clinical project involving elderly patients with severe AS referred to a tailored management based on classification by Fried’s score into pre-frail, early frail, and frail and a multidimensional geriatric assessment. A Frailty, Inflammation, Malnutrition, and Sarcopenia (FIMS) score was used to predict the risk of mortality at six years of follow-up. Functional status was evaluated by telephonic interview. Results: At six years of follow-up, we found a survival rate of 40%. It was higher in the pre-frail patients (long rank < 0.001) and in the patients who underwent TAVR treatment (long rank < 0.001). The cut-off FIMS score value of ≥1.28 was an independent determinant associated with a higher risk of mortality at six years of follow-up (HR 2.91; CI 95% 1.7–5.1; p-value 0.001). We found a moderate increase of disability levels, malnutrition status, comorbidities, and number of drugs, but none of them self-reported advanced NYHA class III–IV heart failure. Conclusion: An accurate clinical–instrumental and functional geriatric evaluation in an elderly population with AS is required for a non-futile interventional treatment in terms of survival and functional status even in long-term follow-up. Full article

Background: Targeted therapies (e.g., ibrutinib) have markedly improved chronic lymphocytic leukemia (CLL) management; however, ~20% of patients experience disease relapse, suggesting the inadequate depth and durability of these front-line strategies. Moreover, immunotherapeutic success in CLL has been stifled by its pro-tumor microenvironment milieu and low mutational burden, cultivating poor antigenicity and limited ability to generate anti-tumor immunity through adaptive immune cell engagement. Previously, we have demonstrated how a three-carbon-linker spirocyclic dimer (SpiD3) promotes futile activation of the unfolded protein response (UPR) in CLL cells through immense misfolded-protein mimicry, culminating in insurmountable ER stress and programmed CLL cell death. Method: Herein, we used flow cytometry and cell-based assays to capture the kinetics and magnitude of SpiD3-induced damage-associated molecular patterns (DAMPs) in CLL cell lines and primary samples. Result: SpiD3 treatment, in vitro and in vivo, demonstrated the capacity to propagate immunogenic cell death through emissions of classically immunogenic DAMPs (CALR, ATP, HMGB1) and establish a chemotactic gradient for bone marrow-derived dendritic cells. Conclusions: Thus, this study supports future investigation into the relationship between novel therapeutics, manners of cancer cell death, and their contributions to adaptive immune cell engagement as a means for improving anti-cancer therapy in CLL. Full article

Phosphatases are enzymes that catalyze the hydrolysis of phosphate esters. They play critical roles in diverse biological processes such as extracellular nucleotide homeostasis, transport of molecules across membranes, intracellular signaling pathways, or vertebrate mineralization. Among them, tissue-nonspecific alkaline phosphatase (TNAP) is today increasingly studied, due to its ubiquitous expression and its ability to dephosphorylate a very broad range of substrates and participate in several different biological functions. For instance, TNAP hydrolyzes inorganic pyrophosphate (PP_i) to allow skeletal and dental mineralization. Additionally, TNAP hydrolyzes pyridoxal phosphate to allow cellular pyridoxal uptake, and stimulate vitamin B6-dependent reactions. Furthermore, TNAP has been identified as a key enzyme in non-shivering adaptive thermogenesis, by dephosphorylating phosphocreatine in the mitochondrial creatine futile cycle. This latter recent discovery and others suggest that the list of substrates and functions of TNAP may be much longer than previously thought. In the present review, we sought to examine TNAP within the alkaline phosphatase (AP) superfamily, comparing its sequence, structure, and evolutionary trajectory. The AP superfamily, characterized by a conserved central folding motif of a mixed beta-sheet flanked by alpha-helices, includes six subfamilies: AP, arylsulfatases (ARS), ectonucleotide pyrophosphatases/phosphodiesterases (ENPP), phosphoglycerate mutases (PGM), phosphonoacetate hydrolases, and phosphopentomutases. Interestingly, TNAP and several ENPP family members appear to participate in the same metabolic pathways and functions. For instance, extra-skeletal mineralization in vertebrates is inhibited by ENPP1-mediated ATP hydrolysis into the mineralization inhibitor PP_i, which is hydrolyzed by TNAP expressed in the skeleton. Better understanding how TNAP and other AP family members differ structurally will be very useful to clarify their complementary functions. Structurally, TNAP shares the conserved catalytic core with other AP superfamily members but has unique features affecting substrate specificity and activity. The review also aims to highlight the importance of oligomerization in enzyme stability and function, and the role of conserved metal ion coordination, particularly magnesium, in APs. By exploring the structural and functional diversity within the AP superfamily, and discussing to which extent its members exert redundant, complementary, or specific functions, this review illuminates the evolutionary pressures shaping these enzymes and their broad physiological roles, offering insights into TNAP’s multifunctionality and its implications for health and disease. Full article

In a hyperproductive interactive environment, where speed and cost-effectiveness often overshadow accuracy, the media’s role is increasingly shifting towards an educational function, beyond its traditional informative and entertaining roles. This shift, particularly through the promotion of science and education, aims to bridge the gap between educational institutions and the labor market. In this context, the importance of 21st-century competencies—encompassing a broad range of knowledge and skills—becomes increasingly clear. Educational institutions are now expected to equip students with relevant, universally applicable, and market-competitive competencies. This paper proposes using a combination of principal component analysis (PCA) and fuzzy analytic hierarchy process (FAHP) to rank 21st-century competencies developed throughout the educational process to improve the system. The highest-ranked competency identified is the ability to manage information—specifically, gathering and analyzing information from diverse sources. It has been shown that respondents who developed “soft skills” and media literacy during their studies are better able to critically assess content on social networks and distinguish between credible and false information. The significance of this work lies in its focus on the damaged credibility of online media caused by user-generated content and the rapid spread of unverified and fake news. Denying such discourse or erasing digital traces is therefore futile. Developing a critical approach to information is essential for consistently identifying fake news, doctored images, and recordings taken out of context, as well as preventing their spread. Full article

Application of the FOLFOX scheme to colorectal cancer (CRC) patients often results in the development of chemo-resistance, leading to therapy failure. This study aimed to develop a functional and easy-to-use algorithm to predict patients’ response to FOLFOX treatment. Transcriptomic data of CRC patient’s samples treated with FOLFOX were downloaded from the Gene Expression Omnibus database (GSE83129, GSE28702, GSE69657, GSE19860 and GSE41568). Comparing the expression of top up- and downregulated genes in FOLFOX responder and non-responder patients’ groups, we selected 30 potential markers that were used to create a step-by-step eliminative procedure based on modified radial data visualization, which depicts the interplay between the expression level of chosen attributes (genes) to locate data points in low-dimensional space. Our analysis proved that FOLFOX-resistant CRC samples are predominantly characterized by upregulated expression levels of TMEM182 and MCM9 and downregulated LRRFIP1. Additionally, the procedure developed based on expression levels of TMEM182, MCM9, LRRFIP1, LAMP1, FAM161A, KLHL36, ETV5, RNF168, SRSF11, NCKAP5, CRTAP, VAMP2, ZBTB49 and RIMBP2 proved to be capable in predicting FOLFOX therapy response. In conclusion, our approach can give a unique insight into clinical decision-making regarding therapy scheme administration, potentially increasing patients’ survival and, consequently, medical futility due to incorrect therapy application. Full article

Atrial fibrillation (AF) is a common arrhythmia in clinical practice, and oral anticoagulation is the cornerstone of stroke prevention in AF. Direct oral anticoagulants (DOAC) significantly reduce the incidence of intracerebral hemorrhage with preserved efficacy for preventing stroke compared to vitamin K antagonists (VKA). However, the pivotal randomized controlled trials (RCTs) of DOAC excluded patients with valvular heart disease, especially mitral stenosis, which remains an exclusion criterion for DOAC use. The INVICTUS study was a large multicenter global RCT aimed at evaluating the role of DOAC compared to VKA in stroke prevention among patients with rheumatic valvular AF. In this study, rivaroxaban failed to prove superiority over VKA in preventing the composite primary efficacy endpoints of stroke, systemic embolism, myocardial infarction, and death. Unfortunately, the bleeding rates were not lower with rivaroxaban either. The death and drug discontinuation rates were higher in the DOAC arm. Close to the heels of the dismal results of INVICTUS, an apixaban trial in prosthetic heart valves, PROACT-Xa, was also prematurely terminated due to futility. Hence, for AF complicating moderate-to-severe mitral stenosis or prosthetic valve VKA remains the standard of care. However, DOAC can be used in patients with surgical bioprosthetic valve implantation, TAVR, and other native valve diseases with AF, except for moderate-to-severe mitral stenosis. Factor XI inhibitors represent a breakthrough in anticoagulation as they aim to dissociate thrombosis from hemostasis, thereby indicating a potential to cut down bleeding further. Multiple agents (monoclonal antibodies—e.g., osocimab, anti-sense oligonucleotides—e.g., fesomersen, and small molecule inhibitors—e.g., milvexian) have garnered positive data from phase II studies, and many have entered the phase III studies in AF/Venous thromboembolism. Future studies on conventional DOAC and new-generation DOAC will shed further light on whether DOAC can dethrone VKA in valvular heart disease. Full article

Background: Current treatments for inflammatory bowel disease (IBD) are relatively futile and the extended use of drugs may reduce effectiveness. Several probiotic strains have shown promise in relieving/treating IBD symptoms. Objectives: The current study investigated the impact of fermented soymilk with a mixture of probiotic starter cultures containing Lactobacillus rhamnosus, L. casei, L. plantarum, L. acidophilus, Bifidobacterium longum, and B. animalis subsp. lactis in rats with dextran sulfate sodium (DSS)-induced colitis compared to control. Methods: Rats were randomly assigned to five groups (5 rats/group; n = 25): G1: negative normal control; G2: positive control (DSS); G3: DSS with sulfasalazine (DSS-Z); G4: DSS with soymilk (DSS-SM), and G5: DSS with fermented soymilk (DSS-FSM). Parameters monitored included the following: the disease activity index (DAI), macroscopic and histological assessments of colitis, and a fecal microbial analysis performed to assess the severity of inflammation and ulceration. Results: The DSS-FSM rats group exhibited lower DAI scores (p < 0.05) than other treated groups during the induction period. A macroscopical examination revealed no ulceration or swelling in the intestinal mucosa of rats in the DSS-FSM-treated group, resembling the findings in the negative control group. In the positive control (DSS group), the colon tissue showed increased inflammation (p < 0.05), whereas those in the DSS-SM- and DSS-FSM-treated rats groups did not show significant macroscopic scores of colitis. The positive DSS control and DSS-Z groups had crypt erosion and ulceration areas, severe crypt damage, and epithelial surface erosion, which were absent in the negative control and DSS-FSM groups. The counts of Lactobacillus spp. and Bifidobacterium spp. remained stable in both G1 and G5 over 4 weeks. The consumption of fermented soymilk with a mixture of probiotics could minimize the severity of DSS-induced colitis in rats. Conclusion, it was found that fermented soymilk containing Lactobacilli and Bifidobacterium might be an effective vehicle for reducing the severity of DSS-induced colitis in rats. Full article

Diagnosis and treatment of acute coronary syndrome (ACS) pose particular challenges in elderly patients. When high troponin levels are detected, the distinction between non-ischemic myocardial injury (NIMI), type 1, and type 2 myocardial infarction (MI) is the necessary first step to guide further care. However, the assessment of signs of ischemia is hindered in older patients, and no simple clinical or laboratory tool proved useful in this discrimination task. Current evidence suggests a benefit of an invasive vs. conservative approach in terms of recurrence of MI, with no significant impact on mortality. In patients with multivessel disease in which the culprit lesion has been treated, a physiology-guided complete percutaneous revascularization significantly reduced major events. The management of ACS in elderly patients is an example of the actual need for a multimodal, thorough clinical approach, coupled with shared decision-making, in order to ensure the best treatment and avoid futility. Such a need will likely grow throughout the next decades, with the aging of the world population. In this narrative review, we address pivotal yet common questions arising in clinical practice while caring for elderly patients with ACS. Full article

Antibiotic misuse in Romania has exacerbated the issue of antibiotic resistance, as patients often use antibiotics without proper medical consultation. This study aimed to assess the resistance of prevalent bacteria to different antibiotics. In this observational study conducted over six months, we analyzed 31 pediatric patients aged from 12 days to 13 years using the disk diffusion method. We identified 31 bacterial isolates, including 8 Gram-negative and 8 Gram-positive strains, with the most common being Pseudomonas aeruginosa, Escherichia coli, Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, Streptococcus species, and Elizabethkingia meningoseptica. Our findings revealed that the most effective antibiotics were linezolid, ertapenem, and teicoplanin. In contrast, nearly all tested bacteria exhibited resistance to penicillin, followed by oxacillin and ampicillin. Resistance to cephalosporins varied with generation, showing higher resistance to lower-generation cephalosporins. The study highlights significant antibiotic resistance among common bacterial pathogens in Romanian pediatric patients, emphasizing the urgent need for controlled antibiotic use and alternative treatment strategies to combat this growing issue. Effective antibiotics such as linezolid and ertapenem offer potential solutions, whereas reliance on penicillin and lower-generation cephalosporins is increasingly futile. Full article

Background/Objectives: The change in critically ill patients makes limitation of therapeutic effort (LTE) a widespread practice when therapeutic goals cannot be achieved. We aimed to describe the application of LTE in a post-surgical Intensive Care Unit (ICU), analyze the measures used, the characteristics of the patients, and their evolution. Methods: Retrospective observational study, including all patients to whom LTE was applied in a postsurgical ICU between January 2021 and December 2022. The LTE defined were brain death, withdrawal of measures, and withholding. Withholding limitations included orders for no cardiopulmonary resuscitation, no orotracheal intubation, no reintubation, no tracheostomy, no renal replacement therapies, and no vasoactive support. Patient and ICU admission data were related to the applied LTE. Results: Of the 2056 admitted, LTE protocols were applied to 106 patients. The prevalence of LTE in the ICU was 5.1%. Data were analyzed in 80 patients. A total of 91.2% of patients had been admitted in an emergency situation, and 56.2% had been admitted after surgery. The most widespread limitation was treatment withholding (83.8%) compared to withdrawal (13.8%). No differences were found regarding who made the decision and the type of limitation employed. However, patients with the limitation of no intubation had a longer stay (p = 0.025). Additionally, the order of not starting or increasing vasopressor support resulted in a longer hospital stay (p = 0.007) and a significantly longer stay until death (p = 0.044). Conclusions: LTE is a frequent measure in critically ill patient management and is less common in the postoperative setting. The most widespread measure was withholding, with the do-not-resuscitate order being the most common. The decision was made mainly by the medical team and the family, respecting the wishes of the patients. A joint patient-centered approach should be made in these decisions to avoid futile treatment and ensure end-of-life comfort. Full article