Tag: pubmed

Pharmacotherapy. 2024 Apr 30. doi: 10.1002/phar.2923. Online ahead of print.

ABSTRACT

BACKGROUND: Major bleeding occurs annually in 1%-3% of patients on vitamin K antagonists (VKAs), despite close monitoring. Genetic variants in proteins involved in VKA response may affect this risk.

AIM: To determine the association of genetic variants (cytochrome P450 enzymes 2C9 [CYP2C9] and 4F2 [CYP4F2], gamma-glutamyl carboxylase [GGCX]) with major bleeding in VKA users, separately and combined, including vitamin K epoxide reductase complex subunit-1 (VKORC1).

METHODS: A case-cohort study was established within the BLEEDS cohort, which includes 16,570 patients who initiated VKAs between 2012 and 2014. We selected all 326 major bleeding cases that occurred during 17,613 years of follow-up and a random subcohort of 978 patients. We determined variants in CYP2C9, CYP4F2, GGCX, VKORC1 and evaluated the interaction between variant genotypes. Hazard ratios for major bleeding with 95% confidence intervals (95% CI) were estimated by weighted Cox regression.

RESULTS: Genotype was determined in 256 cases and 783 subcohort members. Phenprocoumon was the most prescribed VKA for both cases and the subcohort (78% and 75%, respectively). Patients with major bleeding were slightly older than subcohort patients. CYP4F2-TT carriership was associated with a 1.6-fold (95% CI 0.9-2.8) increased risk of major bleeding compared with CC-alleles, albeit not statistically significant. For the CYP2C9 and GGCX variants instead, the major bleeding risk was around unity. Carrying at least two variant genotypes in CYP2C9 (poor metabolizer), CYP4F2-TT, and VKORC1-AA was associated with a 4.0-fold (95%CI 1.4-11.4) increased risk, while carriers of both CYP4F2-TT and VKORC1-AA had a particularly increased major bleeding risk (hazard ratio 6.7, 95% CI 1.5-29.8) compared with carriers of CC alleles in CYP4F2 and GG in VKORC1. However, the number of major bleeding cases in carriers of multiple variants was few (8 and 5 patients, respectively).

CONCLUSIONS: CYP4F2 polymorphism was associated with major bleeding, especially in combination with VKORC1 genetic variants. These variants could be considered to further personalize anticoagulant treatment.

PMID:38686648 | DOI:10.1002/phar.2923

Acta Anaesthesiol Scand. 2024 Apr 30. doi: 10.1111/aas.14429. Online ahead of print.

ABSTRACT

BACKGROUND: The European Society of Anesthesiology and Intensive Care recommends the use of neuromuscular blocking agents (NMBA) in adults, to facilitate tracheal intubation and reduce its associated complications. Children who undergo tracheal intubation may suffer some of the same complications, however, no consensus exists regarding the use of NMBA for tracheal intubation in the pediatric population. We will explore the existing evidence assessing the effects of avoidance versus the use of NMBA for the facilitation of tracheal intubation in children and infants.

METHODS: This protocol follows the preferred reporting items for systematic reviews and meta-analyses protocols recommendations. We will include all randomized controlled clinical trials assessing the effects of avoidance versus the use of NMBA for facilitation of tracheal intubation (oral or nasal) using direct laryngoscopy or video laryngoscopy in pediatric participants (<18 years). Our primary outcome is incidence of difficult tracheal intubation. Secondary outcomes include incidence of serious adverse events, failed intubation, events of upper airway discomfort or injury, and difficult laryngoscopy. We will conduct a thorough database search to identify relevant trials, including CENTRAL, MEDLINE, EMBASE, BIOSIS, Web of Science, CINAHL, and trial registries. Two review authors will independently handle the screening of literature and data extraction. Each trial will be evaluated for major sources of bias with the “classic risk of bias tool” used in the Cochrane Collaboration tool from 2011. We will use Review manager (RevMan) or R with the meta package to perform the meta-analysis. We will perform a trial sequential analysis on the meta-analysis of our primary outcome, providing an estimate of statistical reliability. Two review authors will independently assess the quality of the body of evidence using the grading of recommendations assessment, development, and evaluation (GRADE) approach. We will use GRADEpro software to conduct the GRADE assessments and to create “Summary of the findings” tables.

PMID:38686634 | DOI:10.1111/aas.14429

Cancer Med. 2024 May;13(9):e7207. doi: 10.1002/cam4.7207.

ABSTRACT

BACKGROUND: Most high-risk neuroblastoma patients who relapse succumb to disease despite the existing therapy. We recently reported increased event-free and overall survival in neuroblastoma patients receiving difluoromethylornithine (DFMO) during maintenance therapy. The effect of DFMO on cellular processes associated with neuroblastoma tumorigenesis needs further elucidation. Previous studies have shown cytotoxicity with IC50 values >5-15 mM, these doses are physiologically unattainable in patients, prompting further mechanistic studies at therapeutic doses.

METHODS: We characterized the effect of DFMO on cell viability, cell cycle, apoptosis, neurosphere formation, and protein expression in vitro using five established neuroblastoma cell lines (BE2C, CHLA-90, SHSY5Y, SMS-KCNR, and NGP) at clinically relevant doses of 0, 50, 100, 500, 1000, and 2500 μM. Limiting Dilution studies of tumor formation in murine models were performed. Statistical analysis was done using GraphPad and the level of significance set at p = 0.05.

RESULTS: There was not a significant loss of cell viability or gain of apoptotic activity in the in vitro assays (p > 0.05). DFMO treatment initiated G1 to S phase cell cycle arrest. There was a dose-dependent decrease in frequency and size of neurospheres and a dose-dependent increase in beta-galactosidase activity in all cell lines. Tumor formation was decreased in xenografts both with DFMO-pretreated cells and in mice treated with DFMO.

CONCLUSION: DFMO treatment is cytostatic at physiologically relevant doses and inhibits tumor initiation and progression in mice. This study suggests that DFMO, inhibits neuroblastoma by targeting cellular processes integral to neuroblastoma tumorigenesis at clinically relevant doses.

PMID:38686627 | DOI:10.1002/cam4.7207

J Gastroenterol Hepatol. 2024 Apr 30. doi: 10.1111/jgh.16589. Online ahead of print.

ABSTRACT

BACKGROUND AND AIM: To identify individuals with metabolic dysfunction-associated steatohepatitis (MASH) or “at-risk” MASH among patients with metabolic dysfunction-associated steatotic liver disease (MASLD), three noninvasive models are available with satisfactory efficiency, which include magnetic resonance imaging [MRI]- AST (MAST), FibroScan-AST (FAST score), and magnetic resonance elastography [MRE] plus FIB-4 (MEFIB). We aimed to evaluate the most accurate approach for diagnosing MASH or “at-risk” MASH.

METHODS: We included 108 biopsy-proven MASLD patients who underwent simultaneous assessment of MRE, MRI proton density fat fraction (MRI-PDFF), and FibroScan scans. Compared with the histological diagnosis, we analyzed the AUC of each model and assessed the accuracy.

RESULTS: Our study cohort consisted of 64.8% of MASH and 25.9% of “at-risk” MASH. When analyzing the performance of each model for the diagnostic accuracy of MASH, we found that the AUC [95% CI] of MAST was comparable to FAST (0.803 [0.719-0.886] vs 0.799 [0.707-0.891], P = 0.930) and better than MEFIB (0.671 [0.571-0.772], P = 0.005). Similar findings were observed in the “at-risk” MASH patients. The AUCs [95% CI] for MAST, FAST, and MEFIB were 0.810 [0.719-0.900], 0.782 [0.689-0.874], and 0.729 [0.619-0.838], respectively. The models of MAST and FAST had comparable AUCs (P = 0.347), which were statistically significantly higher than that of MEFIB (P = 0.041). Additionally, the cutoffs for diagnosis of MASH were lower than “at-risk” MASH.

CONCLUSION: MAST and FAST performed better than MEFIB in diagnosing “at-risk” MASH and MASH using lower cutoff values. Our findings provided evidence for selecting the most accurate noninvasive model to identify patients with MASH or at-risk MASH.

PMID:38686620 | DOI:10.1111/jgh.16589

Genet Epidemiol. 2024 Apr 30. doi: 10.1002/gepi.22565. Online ahead of print.

ABSTRACT

Numerous studies over the past generation have identified germline variants that increase specific cancer risks. Simultaneously, a revolution in sequencing technology has permitted high-throughput annotations of somatic genomes characterizing individual tumors. However, examining the relationship between germline variants and somatic alteration patterns is hugely challenged by the large numbers of variants in a typical tumor, the rarity of most individual variants, and the heterogeneity of tumor somatic fingerprints. In this article, we propose statistical methodology that frames the investigation of germline-somatic relationships in an interpretable manner. The method uses meta-features embodying biological contexts of individual somatic alterations to implicitly group rare mutations. Our team has used this technique previously through a multilevel regression model to diagnose with high accuracy tumor site of origin. Herein, we further leverage topic models from computational linguistics to achieve interpretable lower-dimensional embeddings of the meta-features. We demonstrate how the method can identify distinctive somatic profiles linked to specific germline variants or environmental risk factors. We illustrate the method using The Cancer Genome Atlas whole-exome sequencing data to characterize somatic tumor fingerprints in breast cancer patients with germline BRCA1/2 mutations and in head and neck cancer patients exposed to human papillomavirus.

PMID:38686586 | DOI:10.1002/gepi.22565

Med Lav. 2024 Apr 24;115(2):e2024016. doi: 10.23749/mdl.v115i2.14649.

ABSTRACT

BACKGROUND: Recent studies supported the association between occupational exposure to asbestos and risk of cholangiocarcinoma (CC). Aim of the present study is to investigate this association using an update of mortality data from the Italian pooled asbestos cohort study and to test record linkage to Cancer Registries to distinguish between hepatocellular carcinoma (HCC) and intrahepatic/extrahepatic forms of CC.

METHODS: The update of a large cohort study pooling 52 Italian industrial cohorts of workers formerly exposed to asbestos was carried out. Causes of death were coded according to ICD. Linkage was carried out for those subjects who died for liver or bile duct cancer with data on histological subtype provided by Cancer Registries.

RESULTS: 47 cohorts took part in the study (57,227 subjects). We identified 639 causes of death for liver and bile duct cancer in the 44 cohorts covered by Cancer Registry. Of these 639, 240 cases were linked to Cancer Registry, namely 14 CC, 83 HCC, 117 cases with unspecified histology, 25 other carcinomas, and one case of cirrhosis (likely precancerous condition). Of the 14 CC, 12 occurred in 2010-2019, two in 2000-2009, and none before 2000.

CONCLUSION: Further studies are needed to explore the association between occupational exposure to asbestos and CC. Record linkage was hampered due to incomplete coverage of the study areas and periods by Cancer Registries. The identification of CC among unspecific histology cases is fundamental to establish more effective and targeted liver cancer screening strategies.

PMID:38686579 | DOI:10.23749/mdl.v115i2.14649

Med Lav. 2024 Apr 24;115(2):e2024009. doi: 10.23749/mdl.v115i2.15168.

ABSTRACT

BACKGROUND: The high incidence rates, treatment difficulties, and tendency to become chronic, which subsequently affects personal and occupational functioning, make mental health disorders among the most important public health concerns. In this context, healthcare university students (HS) appear to be more vulnerable to psychological distress than others.

OBJECTIVE: Investigate the prevalence of diagnosed mental illness among different groups of HS to detect students who may be psychologically vulnerable and determine whether the implementation of support interventions is necessary.

METHODS: All HS who had a clinical examination performed by an occupational physician at our occupational health unit between 2021 and 2022 were included in our case series. Data were collected and analyzed as part of the occupational physicians’ health surveillance program.

RESULTS: out of 679 HS (507 females, 172 males, aged 22.2±3.9 mean±s.d) undergone clinical examination at our Occupational Health Unit, 36 (5.3%) reported a diagnosed psychiatric illness, and 20 were receiving pharmacological therapy at the time of the visit. A higher prevalence of psychological disorders has been highlighted in females (6.1% vs 2.9% in males) and students of the mental health sector (11.1%) when compared with others. A fit-to-work judgment with prescription was necessary for 16.7% of students with mental diseases. The presence of psychiatric disorders was associated with underweight (27.8%) and higher smoking habit (44.4%).

CONCLUSIONS: These results underline the necessity of improving the current health surveillance protocols, which should also evaluate students’ psychological fragility and implement effective intervention strategies to promote their health and wellbeing.

PMID:38686578 | DOI:10.23749/mdl.v115i2.15168

Cancer Med. 2024 May;13(9):e7180. doi: 10.1002/cam4.7180.

ABSTRACT

BACKGROUND: The risks of cardiovascular disease (CVD) and CVD mortality are prevalent among cancer survivors (CS) population. The 2022 ESC Guidelines on cardio-oncology have recommended that modifying cardiovascular risk factors (CVRF) could potentially improve long-term outcomes in CS.

OBJECTIVES: To identify the independent and joint chronic kidney disease (CKD) associations of hyperuricemia with the incidence of CVD and mortality outcomes among CS.

METHODS: Utilizing data from the US National Health and Nutrition Examination Survey spanning 2005-2018, we assessed the risk of CVD through weighted multivariable logistic regression and restricted cubic spline (RCS) regression. Additionally, all-cause and CVD-related mortality were evaluated using weighted multivariable Cox regression and Kaplan-Meier analysis. Subgroup analysis was conducted to further elucidate the interplay between hyperuricemia, CKD, and mortality within the CS population.

RESULTS: A total of 3276 CS participants were enrolled in this study. Results showed that hyperuricemia was positively related to the incidence of CVD (OR [95% CI] = 1.86 [1.24, 2.81], p = 0.004). RCS analysis further demonstrated that uric acid levels ≥345 μmol/L positively correlated with CVD incidence (p value for nonlinearity = 0.0013). However, the association between hyperuricemia and CVD mortality, as well as all-cause mortality did not reach statistical significance in the fully adjusted model (HR = 1.48, 95% CI: 0.92-2.39, p = 0.11; HR = 1.11, 95% CI:0.92, 1.34, p = 0.28, respectively). Among CS participants with CKD, hyperuricemia could increase risks of all-cause (HR [95% CI] = 1.39 [1.08, 1.11], p = 0.02) and CVD mortality (HR [95% CI] =2.17 [1.29, 3.66], p = 0.004) after adjusting for sex, age, and ethnicity.

CONCLUSIONS: In the CS population, hyperuricemia was positively associated with the incidence of CVD. In addition, CKD might be an intermediate variable among the CS population that mediated the effects of hyperuricemia on mortality.

PMID:38686569 | DOI:10.1002/cam4.7180

ESC Heart Fail. 2024 Apr 30. doi: 10.1002/ehf2.14808. Online ahead of print.

ABSTRACT

AIMS: Interleukin-16 (IL-16) has been reported to mediate left ventricular myocardial fibrosis and stiffening in patients with heart failure with preserved ejection fraction (HFpEF). We sought to elucidate whether IL-16 has a distinct impact on pathophysiology and prognosis across different subphenotypes of acute HFpEF.

METHODS AND RESULTS: We analysed 211 patients enrolled in a prospective multicentre registry of acute decompensated HFpEF for whom serum IL-16 levels after stabilization were available (53% female, median age 81 [interquartile range 75-85] years). We divided this sub-cohort into four phenogroups using our established clustering algorithm. The study endpoint was all-cause death. Patients were subclassified into phenogroup 1 (‘rhythm trouble’ [n = 69]), phenogroup 2 (‘ventricular-arterial uncoupling’ [n = 49]), phenogroup 3 (‘low output and systemic congestion’ [n = 41]), and phenogroup 4 (‘systemic failure’ [n = 52]). After a median follow-up of 640 days, 38 patients had died. Among the four phenogroups, phenogroup 2 had the highest IL-16 level. The IL-16 level showed significant associations with indices of cardiac hypertrophy, diastolic dysfunction, and congestion only in phenogroup 2. Furthermore, the IL-16 level had a significant predictive value for all-cause death only in phenogroup 2 (C-statistic 0.750, 95% confidence interval 0.606-0.863, P = 0.017), while there was no association between the IL-16 level and the endpoint in the other phenogroups.

CONCLUSIONS: Our results indicated that the serum IL-16 level had a significant association with indices that reflect the pathophysiology and prognosis of HFpEF in a specific phenogroup in acute HFpEF.

PMID:38686566 | DOI:10.1002/ehf2.14808

Knee Surg Sports Traumatol Arthrosc. 2024 Apr 30. doi: 10.1002/ksa.12214. Online ahead of print.

ABSTRACT

PURPOSE: Osteochondritis dissecans (OCD) is a common cause of knee pain. Management for adult-onset OCD (AOCD) usually involves surgery. Surgical treatments include palliative, reparative and reconstructive techniques. The aim of this systematic review and meta-analysis is to evaluate the efficacy of reconstructive techniques for the treatment of OCD in skeletally mature knees.

METHODS: A systematic search was carried out on four databases up to November 2023 (Medline, Embase, Cochrane Library, Web of Science). The study was registered on international prospective register of systematic reviews and performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Clinical studies on skeletally mature patients were included, which utilised reconstructive techniques such as autologous chondrocyte implantation (ACI), matrix-induced autologous chondrocyte implantation, osteochondral allograft transplantation surgery or bone marrow-derived cellular transplantation. Demographical data, patient-reported outcome measures and postoperative complications were recorded. Quantitative outcome measures that were comparable across studies were pooled for meta-analysis. A random effects model was used. Heterogeneity was assessed using the I² statistic and Cochran’s Q test. Statistical significance was set at p < 0.05. Risk of bias was assessed using the risk of bias in non-randomised studies – of interventions tool for nonrandomised studies.

RESULTS: Sixteen studies were included with 458 OCD lesions in 432 patients. The average age was 24.9, and 62.6% were male. The mean follow-up time was 61.5 months. At 36 months follow-up, International Knee Documentation Committee (IKDC) subjective, Tegner and EuroQol-visual analogue scale (EQ-VAS) scores improved from 42.4 to 78.6 (standard mean difference [SMD]: 2.47; p < 0.001), 2.27-4.99 (SMD: 2.363; p = 0.002) and 30.4-57.5 (SMD: 2.390; p < 0.001), respectively. Overall complication rate was 8.9%. Smaller OCD lesion sizes resulted in a greater improvement in IKDC subjective (SMD: 2.64 vs. 2.01; p = 0.038), EQ-VAS (SMD: 3.16 vs. 0.95; p = 0.046) and Tegner scores (SMD: 3.13 vs. 1.05; p = 0.007) and had a lower complication rate (p = 0.008). Males showed a larger improvement in IKDC subjective scores than females (SMD: 2.56 vs. 1.56; p = 0.029), while younger patients had a larger improvement in IKDC subjective scores (SMD: 2.71 vs. 2.12; p = 0.045) and fewer complications than older patients (p = 0.003). There were no significant differences between cohorts treated with ACI and those treated with non-ACI reconstructive techniques. Publication bias was not detected (n.s.).

CONCLUSION: Reconstructive techniques used to treat OCD in the skeletally mature knee resulted in significant improvements in clinical and functional outcomes, with a low overall complication rate. Since a younger age leads to a greater improvement in IKDC subjective score and a lower complication rate, surgical intervention should not be delayed, especially in AOCD lesions which are more likely to follow a progressive and unremitting clinical course.

LEVEL OF EVIDENCE: Level III.

PMID:38686565 | DOI:10.1002/ksa.12214