Glutathione S-transferases (GSTs) are an important part of the cellular detoxification system and, perhaps, evolved to protect cells against reactive oxygen metabolites. Theta is considered the most ...ancient among the GSTs and theta-like GSTs are found in mammals, fish, insects, plants, unicellular algae, and bacteria. It is thought that an ancestral theta-gene underwent an early duplication before the divergence of fungi and animals and further duplications generated the variety of the other classes of GSTs (alpha, mu, phi, etc.). The comparison of the aminoacidic homologies among mammals suggests that a duplication of an ancient GST theta occurred before the speciation of mammals and resulted in the subunits GSTT1 and GSTT2. The ancestral GST theta has a dehalogenase activity towards several halogenated compounds, such as the dichloromethane. In fact, some aerobic and anaerobic methylotrophic bacteria can use these molecules as the sole carbon and energy source. The mammalian GST theta cannot sustain the growth of bacteria but still retains the dehalogenating activity. Therefore, although mammalian GST theta behaves as a scavenger towards electrophiles, such as epoxides, it acts also as metabolic activator for halogenated compounds, producing a variety of intermediates potentially dangerous for DNA and cells. For example, mice exposed to dichloromethane show a dose-dependent incidence of cancer via the GSTT1-1 pathway. Because GSTT1-1 is polymorphic in humans, with about 20% of Caucasians and 80% of Asians lacking the enzyme, the relationship between the phenotype and the incidence of cancer has been investigated extensively in order to detect GSTT1-1-associated differential susceptibility towards endogenous or exogenous carcinogens. The lack of the enzyme is related to a slightly increased risk of cancer of the bladder, gastro-intestinal tract, and for tobacco-related tumors (lung or oral cavity). More pronounced risks were found in males with the GSTT1-null genotype for brain diseases and skin basal cell carcinomas not related to sunlight exposures. Moreover, there was an increased risk of kidney and liver tumors in humans with the GSTT1-1 positive genotype following exposures to halogenated solvents. Interestingly, the liver and kidney are two organs that express the highest level of GST theta in the human body. Thus, the GSTT1-1 genotype is suspected to confer decreased or increased risk of cancer in relation to the source of exposure; in vitro studies, mostly conducted on metabolites of butadiene, confirm the protective action of GSTT1-1, whereas, thus far, experimental studies prove that the increasing risk is limited.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Correction to: BMC Health Services Research (2024) 24:46 https://doi.org/10.1186/s12913-023-10461-3 In this article, the statement in the Funding section was incomplete. Verify currency and ...authenticity via CrossMark Cite this article Landi, S., Panella, M.M. & Leardini, C. Correction: Disentangling organizational levers and economic benefits in transitional care programs: a systematic review and configurational analysis. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative Correction Open access Published:27 February 2024 Correction: Disentangling organizational levers and economic benefits in transitional care programs: a systematic review and configurational analysis Stefano Landi 1, Maria Martina Panella2 & Chiara Leardini1 BMC Health Services Research volume 24, Article number: 248 (2024) Cite this article 137 Accesses 1 Altmetric Metrics details The Original Article was published on 09 January 2024 Correction to: BMC Health Services Research (2024) 24:46 https://doi.org/10.1186/s12913-023-10461-3 In this article, the statement in the Funding section was incomplete.
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CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Promoting safe and efficient transitions of care is critical to reducing readmission rates and associated costs and improving the quality of patient care. A growing body of literature suggests that ...transitional care (TC) programs are effective in improving quality of life and reducing unplanned readmissions for several patient groups. TC programs are highly complex and multidimensional, requiring evidence on how specific practices and system characteristics influence their effectiveness in patient care, readmission reduction and costs.
Using a systematic review and a configurational approach, the study examines the role played by system characteristics (size, ownership, professional skills, technology used), the organizational components implemented, analyzing their combinations, and the potential economic impact of TC programs.
The more organizational components are implemented, the greater the likelihood that a TC program will be successful in reducing readmission rates. Not all components have the same effect. The results show that certain components, 'post-discharge symptom monitoring and management' and 'discharge planning', are necessary but not sufficient to achieve the outcome. The results indicate the existence of two different combinations of components that can be considered sufficient for the reduction of readmissions. Furthermore, while system characteristics are underexplored, the study shows different ways of incorporating the skill mix of professionals and their mode of coordination in TC programs. Four organizational models emerge: the health-based monocentric, the social-based monocentric, the multidisciplinary team and the mono-specialist team. The economic impact of the programs is generally positive. Despite an increase in patient management costs, there is an overall reduction in all post-intervention costs, particularly those related to readmissions.
The results underline the importance of examining in depth the role of system characteristics and organizational factors in facilitating the creation of a successful TC program. The work gives preliminary insights into how to systematize organizational practices and different coordination modes for facilitating decision-makers' choices in TC implementation. While there is evidence that TC programs also have economic benefits, the quality of economic evaluations is relatively low and needs further study.
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CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Functional motor disorders (FMDs) are prevalent and highly disabling conditions in young adults that can result in reduced independence. Despite advances in diagnosis and treatment, the economic ...burden of FMDs is largely unknown.
This pilot retrospective study provides a real-world overview of the economic costs related to delayed diagnosis of FMDs from a cohort of patients of a specialized clinic in Italy, based on Italian healthcare costs.
Sociodemographic data, clinical history, healthcare service utilization, and associated direct costs were collected for a period of up to 5 years before a definite diagnosis of FMDs in 40 patients.
The mean time lag between the onset of FMDs symptoms and diagnosis was 6.63 years (±8.57). The mean annual use of recourses per patient was three specialist visits (95% CI 2.4-3.4) and three diagnostic examinations (95% CI 2.2-3.6) that made up a total of six investigations and over seven (95% CI 5.5-9.7) rehabilitation contacts per year per patient were used before a diagnosis of FMDs was established. In more than 50% of the cases, patients had been hospitalized or made an ER visit at least once before receiving the correct diagnosis. The average annual costs for delayed diagnosis, taking into account only direct healthcare costs (without medications), was about €2,302 (CI 95% €1,570-2,830) per patient €1,524 covered by the NHS (CI 95% €1,214-1,834) and € 778 by the patient (CI 95% €606-960). Hospitalization accounted for €916 (CI 95% €670-1,160) per patient per year, followed by rehabilitation €493 (CI 95% €345-641) and diagnostic tests € 387 (CI 95% €314-460).
These preliminary results shed some light on the high healthcare services volume and direct healthcare costs from clinic to clinic for visits, unnecessary tests, and prescribed treatments in a real-world overview from a cohort of patients of a specialized clinic in Italy. It may represent a starting point for future studies to statistically test and quantify cost reduction after implementing appropriate healthcare pathways.
Malignant pleural mesothelioma (MPM) is a fatal tumor lacking effective therapies. The characterization of overexpressed genes could constitute a strategy for identifying drivers of tumor progression ...as targets for novel therapies. Thus, we performed an integrated gene-expression analysis on RNAseq data of 85 MPM patients from TCGA dataset and reference samples from the GEO. The gene list was further refined by using published studies, a functional enrichment analysis, and the correlation between expression and patients' overall survival. Three molecular signatures defined by 15 genes were detected. Seven genes were involved in cell adhesion and extracellular matrix organization, with the others in control of the mitotic cell division or apoptosis inhibition. Using Western blot analyses, we found that ADAMTS1, PODXL, CIT, KIF23, MAD2L1, TNNT1, and TRAF2 were overexpressed in a limited number of cell lines. On the other hand, interestingly, CTHRC1, E-selectin, SPARC, UHRF1, PRSS23, BAG2, and MDK were abundantly expressed in over 50% of the six MPM cell lines analyzed. Thus, these proteins are candidates as drivers for sustaining the tumorigenic process. More studies with small-molecule inhibitors or silencing RNAs are fully justified and need to be undertaken to better evaluate the cancer-driving role of the targets herewith identified.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Health inequalities exist between nations, regions, and even smaller units. In societies where social and economic structures change rapidly and continuously, analysis of health socioeconomic ...determinants plays a fundamental role to provide proper policy answers. This study aims to measure accurately two different conceptions of deprivation by developing two different indexes using non-compensatory among sub-indicators aggregation methods. The proposed indicators are compared with premature mortality to verify deprivation's effect on health status. The results show that materially deprived areas are not necessarily socially deprived and vice versa. Material deprivation has a positive statistical co-graduation with premature mortality, while social deprivation has no association with premature mortality.
Reduced DNA repair capacity and DNA damage accumulation may lead to cancer development. Regulation of and coordination between genes involved in DNA repair pathways is fundamental for maintaining ...genome stability, and post-transcriptional gene regulation by microRNAs (miRNAs) may therefore be of particular relevance. In this context, the presence of single nucleotide polymorphisms (SNPs) within the 3'untranslated regions of target DNA repair genes could alter the binding with specific miRNAs, modulating gene expression and ultimately affecting cancer susceptibility. In this study, we investigated the role of genetic variations in miRNA-binding sites of nucleotide excision repair (NER) genes in association with colorectal cancer (CRC) risk. From 28 NER genes, we screened among SNPs residing in their 3'untranslated regions and simultaneously located in miRNA-binding sites, with an in silico approach. Through the calculation of different binding free energy according to both alleles of identified SNPs, and with global binding free energies median providing a threshold, we selected nine NER gene variants. We tested those SNPs in 1098 colorectal cancer cases and 1469 healthy controls from the Czech Republic. Rs7356 in RPA2 and rs4596 in GTF2H1 were associated with colorectal cancer risk. After stratification for tumor location, the association of both SNPs was significant only for rectal cancer (rs7356: OR 1.52, 95% CI 1.02-2.26, P = 0.04 and rs4596: OR 0.69, 95% CI 0.50-0.94, P = 0.02; results not adjusted for multiple testing). Variation in miRNA target binding sites in the 3'untranslated region of NER genes may be important for modulating colorectal cancer risk, with a different relevance according to tumor location.
Decades of research have shown that mutations in the p53 stress response pathway affect the incidence of diverse cancers more than mutations in other pathways. However, most evidence is limited to ...somatic mutations and rare inherited mutations. Using newly abundant genomic data, we demonstrate that commonly inherited genetic variants in the p53 pathway also affect the incidence of a broad range of cancers more than variants in other pathways. The cancer-associated single nucleotide polymorphisms (SNPs) of the p53 pathway have strikingly similar genetic characteristics to well-studied p53 pathway cancer-causing somatic mutations. Our results enable insights into p53-mediated tumour suppression in humans and into p53 pathway-based cancer surveillance and treatment strategies.
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IJS, NUK, SBMB, UL, UM, UPUK
BACKGROUND AND OBJECTIVEPortal vein thrombosis (PVT) is a common complication in cirrhosis, and when complete, it increases morbidity and mortality in liver transplant candidates. The aim of the ...study was to assess the hemostatic status, as well as clinical characteristics of thrombus and patients, as predictors of therapeutic efficacy of anticoagulation for the treatment of PVT in cirrhotics.
PATIENTS AND METHODSPatients with cirrhosis consecutively treated for PVT with enoxaparin were enrolled. All patients underwent evaluation of coagulation status and thrombophilia screening. Thrombus characteristics and extension were evaluated at baseline and during follow-up. Anticoagulation was continued until recanalization or up to 12 months. Variables correlated with the response to anticoagulation were used to create a predictive score that was validated in an external multicenter cohort.
RESULTSA total of 65 patients were included and had partial PVT in most cases (72%). Treatment with enoxaparin resulted in an overall response rate of 66% (43/65) after a median time of 4.4 months and 76% (33/43) within the first 6 months. At multivariate analysis, efficacy of anticoagulation correlated with the severity of liver disease, complete verus partial PVT, age of the thrombus, and time interval from treatment start (<6 months). The areas under the curve of the statistical model for predicting the response to anticoagulation were 0.84 and 0.76 for the training (n=65) and validation (n=60) cohorts, respectively.
CONCLUSIONEarly diagnosis and early treatment are key factors for the successful management of PVT in cirrhosis, so that screening of PVT and prompt start of anticoagulant treatment should be mandatory.
Recent studies indicate the existence of a complex microbiome in the meconium of newborns that plays a key role in regulating many host health-related conditions. However, a high variability between ...studies has been observed so far. In the present study, the meconium microbiome composition and the predicted microbial metabolic pathways were analysed in a consecutive cohort of 96 full-term newborns. The effect of maternal epidemiological variables on meconium diversity was analysed using regression analysis and PERMANOVA. Meconium microbiome composition mainly included Proteobacteria (30.95%), Bacteroidetes (23.17%) and Firmicutes (17.13%), while for predicted metabolic pathways, the most abundant genes belonged to the class "metabolism". We observed a significant effect of maternal Rh factor on Shannon and Inverse Simpson indexes (p = 0.045 and p = 0.049 respectively) and a significant effect of delivery mode and maternal antibiotic exposure on Jaccard and Bray-Curtis dissimilarities (p = 0.001 and 0.002 respectively), while gestational age was associated with observed richness and Shannon indexes (p = 0.018 and 0.037 respectively), and Jaccard and Bray-Curtis dissimilarities (p = 0.014 and 0.013 respectively). The association involving maternal Rh phenotype suggests a role for host genetics in shaping meconium microbiome prior to the exposition to the most well-known environmental variables, which will influence microbiome maturation in the newborn.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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