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Mechanical heart valve (MHV) replacement requires long-life anticoagulation due to the risk of Prosthetic Valve Dysfunction (PVD) and cardioembolism. We report data from a prospective observational study conducted on MHV patients in the Khartoum Salam Centre for Cardiac Surgery built by 'Emergency,' an Italian Non-Governmental Organization, to evaluate the occurrence of PVD and associated risk factors. We prospectively followed 3647 patients, and 38 patients (rate 1.04 × 100 pt-years) had PVD during follow-up. The time in therapeutic range (TTR) among patients without PVD was 53 % (IQR 37–67), and it was 43 % (IQR 19–58) among patients with PVD (p = 0.04). Twenty-three over 38 patients (60.5 %) were symptomatic, 18 (47.4 %) had obstructive valvular stenosis, 24 patients (63.2 %) had INR <2.0 at diagnosis, and 21 patients (55.3 %) had been off warfarin for a long time: 3 patients for 1 week, 1 patient for 2 weeks, and 17 patients for >4 weeks (6 patients were off warfarin from 3 to 12 months). Ten were uncompliant to treatment, and 8 were pregnant women. Ten patients (26.3 %) with PVD had had a previous episode of PVD, and 14 patients (36.8 %) had 2 or more associated risk factors. Only in 6 cases were no associate risk factors found. Among MHV patients on warfarin treatment with a sub-optimal quality of anticoagulation, the rate of PVD is 1.04 % pt-years, and the most frequent associated risk factor for PVD occurrence is warfarin withdrawal lasting more than one week. [Display omitted] • MHV requires long-life anticoagulation due to the risk of valvular thrombosis (VT) • Among Sub-Saharian MHV patients, VT occurs with a rate of 1.04 × 100 pt-yrs • The principal risk factor for VT is warfarin withdrawal lasting more than one week [ABSTRACT FROM AUTHOR]

Rheumatic heart disease with mechanical heart valve (MHV) replacement is common in Africa. However, MHV requires long-life anticoagulation and managing this can be challenging. We report data of a prospective observational study conducted between August 2018 and September 2019 in MHV patients in the Salam Centre for Cardiac Surgery built in Khartoum, by Emergency, an Italian Non-Governmental Organization, to evaluate the quality of anticoagulation control and the risk of thrombotic complications. We studied 3647 patients (median age 25.1 years; 53.9 % female). Median Time in Therapeutic Range (TTR) was 53 % (interquartile range 37 % to 67 %) and 70 thrombotic events (rate 1.8 × 100 pt-years [95 % CI 1.38–2.23]) were recorded. Among patients in the first quartile of TTR (≤37 %), we recorded 34/70 (48.6 %) of all thrombotic events (rate 3.7 × 100 pt-years [95 % CI 2.5–5.1]), with a high mortality rate (2.2 × 100 pt-years [95 % CI 1.3–3.3]). In patients with guideline-recommended TTR (≥65 %) the event rate was 0.8 × 100 pt-years for thrombotic events [95 % CI 0.3–1.5] and 0.4 × 100 pt-years for mortality [95 % CI 0.1–0.9]. Multivariable analysis showed that having a TTR in the lowest quartile (≤37 %) and being noncompliant are significantly associated with increased thrombotic risk. Aspirin use or different valve type did not influence the thrombotic risk. Almost 40 % of all thromboembolic complications could have been potentially prevented by further improving VKA management to obtain a TTR > 37 %. The thrombotic risk of MHV patients on VKAs living in a low-income country like Sudan is associated with low quality of anticoagulation control. Efforts should be made to decrease the number of non-compliant patients and to reach a guideline-recommended TTR of ≥65 %. [ABSTRACT FROM AUTHOR]

• DOAC treatment in patients with atrial fibrillation is performed with two doses (standard and reduced) selected according to recommended criteria. • The MAS trial demonstrated that the use of either dose, especially the reduced dose, did not prevent too low or too high DOAC blood levels in some patients because of the very high interpatient DOAC variability. • In this sub-analysis of the MAS study, we evaluated whether the use of the age-adjusted Charlson Comorbidity Index would have led to significant differences in DOAC dosing compared with the standard criteria. • We did not observe a potential benefit of using the Charlson index. Frailty influences the effectiveness and safety of anticoagulant therapy in patients with atrial fibrillation (AF). The age-weighted Charlson comorbidity index may offer a valuable tool to assess the risk of adverse events in AF patients treated with direct oral anticoagulants (DOACs). This sub-analysis of MAS trial data aimed to assess whether using the Charlson index, instead of the standard criteria, would have led to different dosing and improved adverse event occurrence during treatment. The MAS study looked for a relationship between DOAC levels assessed at baseline and adverse events during follow-up. The study is described in detail elsewhere. Among the 1,657 patients studied, 832 (50.2 %) had a relatively low Charlson index (up to 6, general median class), of whom 132 (15.9 %) were treated with reduced doses. Conversely, among the 825 patients with a high Charlson index (≥7), 257 (31.1 %) received standard doses. A weak but statistically significant positive correlation (r = 0.1413, p < 0.0001 by ANOVA) was observed between increasing Charlson classes and DOAC levels standardized to allow comparability among drug results. However, no significant differences were found in the incidence or number of adverse events during follow-up, or in other parameters, between patients with low and high Charlson's scores. Utilizing the Charlson index would have led to notable differences in DOAC dosing compared to standard criteria. However, we found no evidence that its use would have improved the prediction of adverse events in AF patients enrolled in the MAS study. [ABSTRACT FROM AUTHOR]

D-dimer testing may help deciding the duration of anticoagulation in subjects at high risk of venous thromboembolism (VTE) recurrence. Two management studies on this issue have been published (DULCIS in 2014 and APIDULCIS in 2022). They had similar designs but had important different results. Aim of this article is to compare their results. Both studies were finalized to extend anticoagulation [with vitamin K anticoagulants (VKAs) in DULCIS or apixaban 2.5 mg BID (kindly provided by BMS-Pfizer Collaboration) in APIDULCIS] only in patients with positive D-dimer results. More D-dimer assays resulted positive in APIDULCIS than in DULCIS (61.1 % vs 47.7 %, respectively; p < 0.0001). While only 4 (0.5 %) refused low dose apixaban in APIDULCIS, the 22.6 % of patients with positive D-dimer refused to resume VKAs in DULCIS; their rates of recurrence were 187 and 8.8 per 100 person-years, respectively (incidence rate ratio [IRR]: 21.2). The incidence of bleeding was low in those receiving apixaban vs those who resumed VKAs (0.4 vs 2.3 per 100 person-years, respectively; IRR 0.17;). While the recurrence rate was low and similar in the studies in subjects who resumed anticoagulation, it was significantly higher in APIDULCIS than in DULCIS in those who stopped anticoagulation for negative D-dimer (5.6 vs 3.0 per 100 person-years, respectively; IRR 1.9). The low dose Apixaban for extended VTE treatment is effective and safe, and well accepted by patients. Why subjects who stopped anticoagulation for negative D-dimer had a higher recurrence rate in APIDULCIS than in DULCIS remains to be explained. • D-dimer testing is used to stratify patients for the risk of VTE recurrence. • We performed 2 studies, at 10-year distance, with similar designs/authors. • Significantly more positive D-dimer results were recorded in APIDULCIS. • More recurrences after anticoagulation was stopped for negative D-dimer results in APIDULCIS. • Low-dose Apixaban was effective and safe in patients with positive results in APIDULCIS. [ABSTRACT FROM AUTHOR]

Continued growth of tourism has led to concerns about direct and indirect impacts on the ecology of coral reefs and ultimate sustainability of these environments under such pressure. This research assessed impacts of reef walking by tourists on a relatively pristine reef flat community associated with an ‘ecoresort’ on the Great Barrier Reef, Australia. Heavily walked areas had lower abundances of live hard coral but greater amounts of dead coral and sediment. Abundances of macroalgae were not affected between sites. Coral-associated butterflyfish were less abundant and less diverse in more trampled sites. A manipulative experiment showed handling holothurians on reef walks had lasting negative impacts. This is the first study to show potential impacts of such handling on holothurians. Ecological impacts of reef walking are weighed against sociocultural benefits of a first hand experience in nature. [ABSTRACT FROM AUTHOR]

Abstract: Background: Accurate measurement of von Willebrand factor (VWF) is a critical requirement for the diagnosis of von Willebrand disease (VWD). Aim of the study: To evaluate the diagnostic efficiency of a rapid quantitative test for the measurement of VWF antigen (VWF:Ag) in type 1 VWD. Patients and methods: VWF:Ag was measured with an ELISA in a robotic instrument, as a reference method, and with a fully automated latex-immunoassay (LIA) on an ACL 9000 analyser in 1,716 subjects enrolled within the Molecular and Clinical Markers for Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD) Study. Among these subjects, 1,049 were healthy controls, 281 healthy family members and 386 affected members from 127 European families with type 1 VWD. Results: The assay linearity range was 10-125IU/dL for LIA (R2 =0.99) and 5-133IU/dL for ELISA (R2 =0.99). The inter-assay CV for low VWF levels (∼30IU/dL) was 2% for the LIA test and 8.7 % for ELISA. The sensitivity for detection of type 1 VWD affected members was 86% and the specificity 91% for LIA, 87% and 90% for ELISA. A receiver-operator (ROC) analysis disclosed only a marginal difference between the two tests, LIA having a slightly greater area under the curve (0.94 vs. 0.93, p=0.03). Conclusion: VWF:Ag LIA compared well to standard ELISA in this large population of patients and controls, showing better CV. However the lower detection limit for the VWF:Ag LIA compared to the VWF:Ag ELISA means that the LIA assay is less good at discriminating between type 3 VWD and moderate type 1 VWD. [ABSTRACT FROM AUTHOR]

Abstract: Topoisomerase IIα is a nuclear enzyme that regulates the tertiary structure of DNA. The influence of topoisomerase IIα gene (TOP2A) or protein alterations on disease progression and treatment response in colorectal cancer (CRC) is unknown. The study investigated the clinical relevance of topoisomerase IIα in CRC using in vivo and in vitro models. Differentially expressed genes in early and late-stage CRC were identified by array comparative genomic hybridization (CGH). Cellular location of gene amplifications was determined by fluorescence in situ hybridization (FISH). Topoisomerase IIα levels, proliferation index, and HER2 expression were examined in 228 colorectal tumors by immunohistochemistry. Overexpression of topoisomerase IIα in vitro was achieved by liposome-based transfection. Cell growth inhibition and apoptosis were quantified using the crystal violet assay and flow cytometry, respectively, in response to drug treatment. Amplification of TOP2A was identified in 3 (7.7%) tumors using array CGH and confirmed using FISH. At the protein level, topoisomerase IIα staining was observed in 157 (69%) tumors, and both staining and intensity levels were associated with an aggressive tumor phenotype (p values 0.04 and 0.005, respectively). Using logistic regression analysis, topoisomerase IIα remained significantly associated with advanced tumor stage when corrected for tumor proliferation (p =0.007) and differentiation (p =0.001). No association was identified between topoisomerase IIα and HER2. In vitro, overexpression of topoisomerase IIα was associated with resistance to irinotecan (p =0.001) and etoposide chemotherapy (p =0.03), an effect mediated by inhibition of apoptosis. Topoisomerase IIα overexpression is significantly associated with alterations in tumor behavior and response to drug treatment in CRC. Our results suggest that gene amplification may represent an important mechanism underlying these changes. [Copyright &y& Elsevier]

Summary: Quantification of the bleeding severity in von Willebrand disease (VWD) by use of a bleeding score (BS) could be a useful tool toward a more objective diagnosis. The BS is computed as the sum of arbitrary grades of bleeding severity for several hemorrhagic symptoms, and in normal subjects is nearly always lower than 3. In the diagnosis of type 1 VWD, the use of the BS provided a high specificity (99.1%) and a satisfactory sensitivity (64.2%) in a multicenter, retrospective study. The BS is strongly related to all available measurements of von Willebrand factor activity, including the PFA-100 closure time. The BS could be used to assess the influence on bleeding symptoms of other biological factors in VWD. Therefore, BS represent a promising clinical tool for the analysis of bleeding in VWD, although further validation is warranted before an extensive use in clinical practice could be purported. [Copyright &y& Elsevier]

Abstract: Understanding external factors that determine cellular phenotypic responses is of key interest in the field of biomaterials. Currently, material surface characteristics, protein adsorption and cellular phenotypic responses are all considered to be interrelated and ultimately determine the biocompatibility of materials. The exact nature of the relationship between these distinct, yet related, phenomena still remains to be elucidated. Through the use of a series of thermoresponsive N-isopropylacrylamide-based co-polymer films, we aimed to shed light on the relationship between surface hydrophobicity, protein adsorption and subsequent cellular response. Despite changes in co-polymer hydrophobicity mediated by altered ratios of constituent monomers, differential cellular response was only apparent in the presence of serum. Co-polymer films displayed alterations with respect to the amount of protein adsorbed on the surface, with individual serum proteins (albumin and fibronectin) displaying contrasting adsorption characteristics. Changes in protein adsorption corresponded to changes in cell adhesion, cytoskeletal organisation and cell morphology, as well as to changes in cell movement and intracellular signalling events. Examination of focal adhesion kinase (FAK), and extracellular signal-regulated kinase (ERK 1/2), important mediators of adhesion and growth factor-related signalling events, revealed a comparative reduction in phosphorylation of these signalling proteins in cells grown on co-polymers in comparison to those cultured on tissue culture polystyrene (TCP; used as a control surface). We also associated surface-mediated phenotypic alterations of cells grown on TCP and co-polymer films with particular changes in gene expression. These results indicate that cellular response to interaction with our series of co-polymer films is determined by the surface-adsorbed protein layer, which in turn is determined by the changing surface chemistry as the ratio of the co-monomers is altered. [Copyright &y& Elsevier]

Background: Potassium and magnesium deficiency prolong the QT interval on a standard electrocardiogram and predispose the patient to dangerous cardiac arrhythmias. No information is available on QT interval in patients diagnosed with Gitelman disease.Methods: The QT interval was assessed on lead II in 27 patients with biochemically and genetically defined Gitelman disease, who had discontinued medical treatment for at least four weeks. They included 15 female and 12 male subjects, aged 6.7 to 40 years old, median 20 years old. The corrected QT interval was calculated from the measured QT interval and heart rate using the Bazett formula.Results: The corrected QT interval was normal (between 391 and 433 msec) in 16 and prolonged in the remaining 11 patients (between 444 and 504 msec). Patients with prolonged and patients with normal QT interval did not significantly differ with respect to female to male ratio, plasma potassium, plasma total magnesium, and plasma ionized calcium. Plasma sodium and chloride values were slightly but significantly lower and bicarbonate levels higher in patients with a prolonged than in those with a normal QT interval.Conclusions: The corrected QT interval is often pathologically prolonged in patients with Gitelman disease, suggesting that there is an increased risk for development of dangerous arrhythmias. Further investigations are required in patients with a prolonged QT interval to assess the true hazard of dangerous arrhythmias. [ABSTRACT FROM AUTHOR]

Summary This video provides a case report of a 16-year-old male patient who underwent bladder enlargement with a catheterized conduit under Macedo's technique. This technique involves the use of a segment of the distal ileum with a flap that is used for confection of the conduit. Key points include: 1) skin incision planning; 2) bladder release to allow a tension-free anastomosis; 3) reservoir and a conduit creation with a distal ileum; and 4) creation of a continence mechanism. [ABSTRACT FROM AUTHOR]

Abstract: The optimal management of bleeding or its prophylaxis in patients with disorders of platelet count or function is controversial. The bleeding diathesis of these patients is usually mild to moderate: therefore, transfusion of platelet concentrates may be inappropriate, as potential adverse effects might outweigh its benefit. The availability of several anti-hemorrhagic drugs further compounds this problem, mainly because the efficacy/suitability of the various treatment options in different clinical manifestations is not well defined. In these guidelines, promoted by the Italian Society for Studies on Haemostasis and Thrombosis (Società Italiana per lo Studio dell''Emostasi e della Trombosi [SISET]), we aim at offering the best available evidence to help the physicians involved in the management of patients with disorders of platelet count or function. Literature review and appraisal of available evidence are discussed for different clinical settings and for different available treatments, including platelet concentrates (PC), recombinant activated factor VII, desmopressin, antifibrinolytics, aprotinin and local hemostatic agents. [Copyright &y& Elsevier]

Highlights: [•] Pt/C catalyzed nitrobenzene hydrogenation to 4-aminophenol in a single liquid phase. [•] CF3COOH–H2O–CH3CN easily reusable solvent acid system. [•] Activity and selectivity of several catalysts have been studied under different conditions. [•] Comparison of nitrobenzene, nitrosobenzene and phenylhydroxylamine reactivity. [•] On the base of reagent and intermediates reactivity a likely reaction path have been proposed. [ABSTRACT FROM AUTHOR]

• rIX-FP can be used effectively for surgical management in hemophilia B patients • Most surgeries can be well managed using a single pre-operative dose of rIX-FP • Surgical procedures can be performed with low FIX consumption using rIX-FP • No inhibitors or adverse events related to treatment were reported [ABSTRACT FROM AUTHOR]

Presents a letter to the editor in response to the article about the validity of housekeeping genes commonly used in quantitative messenger RNA analysis.

Abstract: Introduction: Splanchnic vein thrombosis (SVT) is a serious complication in patients with paroxysmal nocturnal hemoglobinuria (PNH). Mutant PNH clones can be associated with an increased risk of SVT even in the absence of overt disease, but their prevalence in non-selected SVT patients remains unknown. Materials and Methods: Patients with objective diagnosis of SVT and without known PNH were tested for the presence of PNH clone using high-sensitivity flow cytometric analysis. Results: A total of 202 SVT patients were eligible, 58.4% were males, mean age was 54.6years (range 17–94), site of thrombosis was portal in 103 patients, mesenteric in 67, splenic in 37, and supra-hepatic in 10. SVT was associated with JAK2 V6167F in 28 of 126 (22.2%) screened patients, liver cirrhosis in 15.3% patients, recent surgery in 10.9%, and myeloproliferative neoplasm in 10.6%, whereas in 34.6% of patients neither permanent nor transient risk factors were detected. None of the patients had a clearly demonstrable PNH clone, but in two patients (0.99%, 95% CI 0.17-3.91) we observed very small PNH clones (size 0.014% and 0.16%) confirmed in two independent samples. One patient had portal vein thrombosis and no associated risk factors, the second had superior mesenteric vein thrombosis and inflammatory bowel disease. Conclusions: Very small PNH clones can be detected in patients with SVT and no clinical manifestations of disease. Future studies are needed to explore the potential role of this finding in the pathogenesis of SVT. [Copyright &y& Elsevier]

Abstract: Objective: Common carotid artery (CCA) intima-media thickness (IMT), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), but not triglyceride levels, are markers of future cardiovascular events. The relationship between these three factors is, however, unclear. Methods: We included six large observational studies that used the same harmonized, B-mode ultrasound protocol, the same software for IMT measurement by automatic edge detection on CCA in a plaque-free region, following the Mannheim consensus, and certification of all sonographers. Using the best view of the CCA, the sonographer had to confirm that the quality index was ≥0.5 on a measurement performed on 10-mm length. We used individual data meta-analysis to estimate the cross-sectional associations of lipids with CCA-IMT. Results: Overall, 21,587 patients with complete information on lipids and CCA-IMT were available. Age- and sex-adjusted CCA-IMT differed by −7.8 μm (95% CI −9.1 to −6.5 μm, P < 0.001) per 1 SD higher HDL-C level. After further adjustment for other atherosclerosis risk factors, the relationship was attenuated, but remained significant (regression coefficient, −3.7 μm; P < 0.001). This was found regardless of LDL-C levels (P for heterogeneity = 0.70). After adjustment for age and sex, triglycerides were positively associated with CCA-IMT, overall and in each LDL-C subgroup, but not after further adjustments for other risk factors. Conclusions: Relationships between HDL-C and triglyceride levels and CCA-IMT were consistent with that previously observed with clinical events by the Emergency Risk Collaboration group, including at low LDL-C levels. This reinforces the need to verify whether raising HDL-C levels decreases both CCA-IMT and future clinical events. [Copyright &y& Elsevier]

Objective: We compared the performance of aggregate data (AD)ebased and individual patient data (IPD)ebased meta-analyses to synthesize evidence on the ability of D-dimer to distinguish recurrence risk in patients with unprovoked venous thromboembolism (VTE) who stopped anticoagulation. Study Design and Setting: We compared the results of the published AD-based rate ratio of VTE recurrence for positive vs. negative D-dimer, estimated by a mixed-effect Poisson model, with those of the IPD-based hazard ratio obtained by a Cox regression stratified by trial. We performed three additional analyses to investigate the methodological reasons for differences between the two approaches, comparing the IPD Cox regression with AD generated from IPD Poisson regression (to control for differences in population on study), AD timeto- event meta-analysis, and AD generated from IPD meta-regression. Results: Published analyses agreed in direction and statistical significance when estimating the prognostic value of D-dimer even if IPD estimates suggested a stronger effect. The additional analyses suggested that differences in study populations might explain this slight difference. Poor reporting in published studies precluded a true comparison of AD- and IPD-based assessments of heterogeneity sources. Conclusion: AD and IPD meta-analyses yielded similar estimates of D-dimer effect to distinguish risk for recurrent VTE. The IPD approach was justified by the need to investigate sources of heterogeneity. [ABSTRACT FROM AUTHOR]

Abstract: A dimorphism in PROS1 gene (c.A2001G, p.Pro667Pro) has been associated with significantly reduced levels of both free and total protein S in carriers of the GG genotype. It is not known how the GG genotype could influence PS levels in normals, whether it could influence the levels of protein S in carriers of mutations in PROS1 gene and whether this genotype acts as an isolated or additive risk factor for venous thrombosis. With this as background, we evaluated the association of p.Pro667Pro dimorphism with free and total protein S centrally measured in a panel of 119 normal controls, 222 individuals with low protein S and 137 individuals with normal PS levels belonging to 76 families with protein S deficiency enrolled in the ProSIT study. Transient expression of recombinant wild type protein S and p.Pro667Pro protein S was performed to evaluate the role of the A to G transition at position 2001 in vitro. The p.Pro667Pro polymorphism was also expressed together with a p.Glu67Ala variant to assess a possible influence on protein S levels in protein S deficient subjects. Free and total protein S levels were significantly lower in normal women. In normal women only was the GG genotype associated with significantly lower free protein S levels in comparison to AA and AG genotypes (P =0.032). No significant influence of GG genotype was observed in patients, either with known mutations or with low protein S levels. These data were confirmed by in vitro transient expression, showing no difference in secretion levels of the p.Pro667Pro variant (even in association with the p.Glu67Ala mutation), compared to the wild type protein S. The genotype in itself was neither a significant risk factor for venous thrombosis nor a risk modifier in patients with known mutations. [Copyright &y& Elsevier]

Abstract: A current goal of the Italian Society for Thrombosis and Haemostasis (SISET) is the production of guidelines for clinical conditions related to haemostasis and thrombosis. In 2006, the Executive Committee of SISET adopted a new program for the production of methodologically and scientifically sound guidelines aimed at both addressing clinical practice and stimulating new research. The first major step for this program was to train methodologists to manage working groups that compose the guidelines, and to create a reference document that describes the development of the program. The aim of the present paper is to report a short version of this methodological document, for those who wish to follow SISET guidelines. We start by giving a brief outline of the SISET mission, then present the SISET guideline development process, which includes: project funding, selection of guidelines topics, multidisciplinary group composition, definition of clinical questions, literature search, evidence appraisal, grading recommendations, guideline implementation, external peer review, and guideline updating. [Copyright &y& Elsevier]