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Abstract Maintaining tissue perfusion in sepsis depends on vascular integrity provided by the endothelial glycocalyx, the critical layer covering the luminal surface of blood vessels. The glycocalyx is composed of proteoglycans, glycosaminoglycans, and functional plasma proteins that are critical for antithrombogenicity, regulating tone, controlling permeability, and reducing endothelial interactions with leukocytes and platelets. Degradation of the glycocalyx in sepsis is substantial due to thromboinflammation, and treatments for sepsis and septic shock may exacerbate endotheliopathy via additional glycocalyx injury. As a result, therapeutic strategies aimed at preserving glycocalyx integrity should be considered, including modifications in fluid volume resuscitation, minimizing catecholamine use, controlling hyperglycemia, and potential use of corticosteroids and anticoagulants. In this review, we explore treatment strategies aligned with the recommendations outlined in the Surviving Sepsis Campaign Guidelines 2021 with a special emphasis on evidence regarding glycocalyx protection.

Abstract Background Patients with acute myeloid leukemia (AML) are at increased risk of venous thromboembolic events (VTE). However, thromboprophylaxis is largely underused. Objectives This study aimed to determine possible VTE development risk factors and to develop a novel predictive model. Methods We conducted a retrospective cohort study of adult patients with newly diagnosed AML. We used univariate and multivariable logistic regression to estimate binary outcomes and identify potential predictors. Based on our final model, a dynamic nomogram was constructed with the goal of facilitating VTE probability calculation. Results Out of 626 eligible patients with AML, 72 (11.5%) developed VTE during 6 months of follow-up. Six parameters were independent predictors: male sex (odds ratio [OR] 1.82, 95% confidence interval [CI]: 1.077–2.065), prior history of thrombotic events (OR 2.27, 95% CI: 1.4–4.96), international normalized ratio (OR 0.21, 95% CI: 0.05–0.95), Eastern Cooperative Oncology Group performance status (OR 0.71, 95% CI: 0.53–0.94), and intensive therapy (OR 2.05, 95% CI: 1.07–3.91). The C statistics for the model was 0.68. The model was adequately calibrated and internally validated. The decision-curve analysis suggested the use of thromboprophylaxis in patients with VTE risks between 8 and 20%. Conclusion We developed a novel and convenient tool that may assist clinicians in identifying patients whose VTE risk is high enough to warrant thromboprophylaxis.

Cardiovascular diseases (CVDs) are the leading cause of mortality globally while also contributing to excess health system costs. Significant advancements have been made in the understanding and prevention of deaths from CVD. In addition to risk factor modifications, one of the key developments in this area is the appropriate prescribing of antiplatelet medications for secondary prevention of CVD. With the advent of vascular devices, there has been an increased use of potent antiplatelet agents to mitigate thrombosis risk. A well-recognized, albeit rare complication of antiplatelet drugs is the heightened risk of bleeding. This adverse effect is particularly relevant when a patient receiving these medications may require an urgent surgery. In addition, for elective surgeries, although these drugs can be withheld, there may be some situations when interruption of antiplatelet agents, even for short duration, may lead to thrombotic events. There are no robust guidelines on how to manage these clinical scenarios, although there have been some important studies published recently in this area. In this review, we provide our approach to patients on antiplatelet drugs who may require urgent surgeries or surgical interventions.

Coagulopathy continues to be a major challenge in the management of patients with acute promyelocytic leukemia (APL). Novel differentiating agents have led to improved survival in these patients, but perturbations in coagulation continue to have an impact on their prognosis. The most worrisome of coagulation disturbances is bleeding, which is not an uncommon cause of early death in APL. Despite this, there are no consistent predictors of this high risk of fatal hemorrhage in APL. In this context, the fibrinolytic system has been identified as a crucial role player in APL coagulopathy. However, the current guidelines for the management of APL give little regard to tests that measure the fibrinolytic system while giving more importance to close monitoring of conventional coagulation tests and platelet counts to identify the coagulopathy. More recently, viscoelastic tests have come to usefulness in determining global hemostasis and have been widely used for “diagnosing” hyperfibrinolysis in selected clinical settings. In this review, we attempt to describe risk assessment models for diagnosing APL coagulopathy, describe the possible application of viscoelastic tests in this setting, and persuade clinicians to reconsider the use of antifibrinolytics to improve survival of APL patients.

Background & Aims: Despite several recent international guidelines, no consensus exists on the bleeding risk nor haemostatic parameter thresholds that define the safety of invasive procedures in patients with cirrhosis. The aim of this study was to establish a position paper on the bleeding risk associated with invasive procedures in patients with cirrhosis among the experts involved in various guidelines. Methods: All experts involved in recent guidelines on the management of invasive procedures in patients with cirrhosis were invited to classify 80 procedures as ''high risk'' or ''low risk'' with respect to bleeding. Procedures were considered high risk when the estimated risk of major bleeding was 1.5% or more, or when even minor bleeding might lead to significant morbidity or death. The experts were also asked to choose safety thresholds for laboratory test values at which elective invasive procedures could be safely performed. The predetermined threshold considered as “consensus” was ≥75% agreement. Results: Fifty-two experts participated in the study. Out of 80 procedures, a consensus opinion was reached for 52 procedures (65%): 17 procedures were classified as “high risk”, primarily interventional endoscopic procedures, percutaneous organ biopsies, or procedures involving the central nervous system; and 35 as “low risk”, primarily “diagnostic” procedures. The lowest platelet counts at which performance of a low-risk procedure or a high-risk procedure/surgery were deemed acceptable were 30 × 109/L and 50 × 109/L, respectively. Experts did not believe that international normalised ratio should be considered before performing low-risk procedures; 71% also indicated that it should not be considered before performing high-risk procedures. Conclusions: This experience-based classification may be helpful to refine future study designs and to guide clinical decision making regarding invasive procedures in patients with cirrhosis. Impact and implications: Several risk classifications and management guidelines for invasive procedures in patients with cirrhosis have been proposed, but with conflicting recommendations. By providing a position paper, based on the opinion of a broad panel of experts, on the bleeding risk associated with 52 invasive procedures in patients with cirrhosis, this survey will help to provide a framework for future study design. The consensus on platelet count, international normalised ratio, fibrinogen and activated partial thromboplastin time identified in this survey will inform physicians regarding the laboratory test values considered acceptable by the experts prior to the performance of an elective invasive procedure in patients with cirrhosis.

Clostridial dermatitis (CD), caused by Clostridium septicum, is an emerging disease of increasing economic importance in turkeys. Currently, there are no effective vaccines for CD control. Here, two non-toxic domains of C. septicum alpha toxin, namely ntATX-D1 and ntATX-D2, were identified, cloned, and expressed in Escherichia coli as recombinant subunit proteins to investigate their use as potential vaccine candidates. Experimental groups consisted of a Negative control (NCx) that did not receive C. septicum challenge, while the adjuvant-only Positive control (PCx), ntATX-D1 immunization (D1) and ntATX-D2 immunization (D2) groups received C. septicum challenge. Turkeys were immunized subcutaneously with 100 μg of protein at 7, 8 and 9 weeks of age along with an oil-in-water nano-emulsion adjuvant, followed by C. septicum challenge at 11 weeks of age. Results showed that while 46.2% of birds in the PCx group died post-challenge, the rate of mortality in D1- or D2-immunization groups was 13.3%. The gross and histopathological lesions in the skin, muscle and spleen showed that the disease severity was highest in PCx group, while the D2-immunized birds had significantly lower lesion scores when compared to PCx. Gene expression analysis revealed that PCx birds had significantly higher expression of pro-inflammatory cytokine genes in the skin, muscle and spleen than the NCx group, while the D2 group had significantly lower expression of these genes compared to PCx. Peripheral blood cellular analysis showed increased frequencies of activated CD4+ and/or CD8+ cells in the D1 and D2-immunized groups. Additionally, the immunized turkeys developed antigen-specific serum IgY antibodies. Collectively, these findings indicate that ntATX proteins, specifically the ntATX-D2 can be a promising vaccine candidate for protecting turkeys against CD and that the protection mechanisms may include downregulation of C. septicum-induced inflammation and increased CD4+ and CD8+ cellular activation.

Background In facial reanimation, dual-innervated gracilis free functional muscle transfers (FFMTs) may have amalgamated increases in tone, excursion, synchroneity, and potentially spontaneity when compared with single innervation. The ideal staging of dual-innervated gracilis FFMTs has not been investigated. We aim to compare objective long-term outcomes following one- and two-stage dual-innervated gracilis FFMTs. Methods Included were adult patients with facial paralysis who underwent either one- (one-stage group) or two-stage (two-stage group) dual-innervated gracilis FFMT with ≥1 year of postoperative follow-up. Facial measurements were obtained from standardized photographs of patients in repose, closed-mouth smile, and open-mouth smile taken preoperatively, 1 year postoperatively, and 3 years postoperatively. Symmetry was calculated from the absolute difference between the paralyzed and healthy hemiface; a lower value indicates greater symmetry. Results Of 553 facial paralysis patients, 14 were included. Five and nine patients were in the one- and two-stage groups, with mean follow-up time, respectively, being 2.5 and 2.6 years. Within-group analysis of both groups, most paralyzed-side and symmetry measurements significantly improved over time with maintained significance at 3 years postoperatively in closed and open-mouth smile (all p ≤ 0.05). However, only the two-stage group had maintained significance in improvements at 3 years postoperatively in paralyzed-side and symmetry measurements in repose with commissure position (median change [interquartile range, IQR], 7.62 [6.00–10.56] mm), commissure angle (median change [IQR], 8.92 [6.18–13.69] degrees), commissure position symmetry (median change [IQR], −5.18 [−10.48 to −1.80] mm), commissure angle symmetry (median change [IQR], −9.78 [−11.73 to −7.32] degrees), and commissure height deviation (median change [IQR], −5.70 [−7.19 to −1.64] mm; all p ≤ 0.05). In the between-group analysis, all measurements were comparable in repose, closed-mouth smile, and open-mouth smile (all p > 0.05). Conclusion Long-term outcomes demonstrate that both one- and two-stage dual-innervated gracilis FFMTs significantly improve excursion, but only two-stage reconstruction significantly improves resting tone. [ABSTRACT FROM AUTHOR]

Clostridial dermatitis (CD), caused by Clostridium septicum, is an emerging disease of increasing economic importance in turkeys. Currently, there are no effective vaccines for CD control. Here, two non-toxic domains of C. septicum alpha toxin, namely ntATX-D1 and ntATX-D2, were identified, cloned, and expressed in Escherichia coli as recombinant subunit proteins to investigate their use as potential vaccine candidates. Experimental groups consisted of a Negative control (NCx) that did not receive C. septicum challenge, while the adjuvant-only Positive control (PCx), ntATX-D1 immunization (D1) and ntATX-D2 immunization (D2) groups received C. septicum challenge. Turkeys were immunized subcutaneously with 100 μg of protein at 7, 8 and 9 weeks of age along with an oil-in-water nano-emulsion adjuvant, followed by C. septicum challenge at 11 weeks of age. Results showed that while 46.2% of birds in the PCx group died post-challenge, the rate of mortality in D1- or D2-immunization groups was 13.3%. The gross and histopathological lesions in the skin, muscle and spleen showed that the disease severity was highest in PCx group, while the D2-immunized birds had significantly lower lesion scores when compared to PCx. Gene expression analysis revealed that PCx birds had significantly higher expression of pro-inflammatory cytokine genes in the skin, muscle and spleen than the NCx group, while the D2 group had significantly lower expression of these genes compared to PCx. Peripheral blood cellular analysis showed increased frequencies of activated CD4+ and/or CD8+ cells in the D1 and D2-immunized groups. Additionally, the immunized turkeys developed antigen-specific serum IgY antibodies. Collectively, these findings indicate that ntATX proteins, specifically the ntATX-D2 can be a promising vaccine candidate for protecting turkeys against CD and that the protection mechanisms may include downregulation of C. septicum-induced inflammation and increased CD4+ and CD8+ cellular activation. [ABSTRACT FROM AUTHOR]

Maintaining tissue perfusion in sepsis depends on vascular integrity provided by the endothelial glycocalyx, the critical layer covering the luminal surface of blood vessels. The glycocalyx is composed of proteoglycans, glycosaminoglycans, and functional plasma proteins that are critical for antithrombogenicity, regulating tone, controlling permeability, and reducing endothelial interactions with leukocytes and platelets. Degradation of the glycocalyx in sepsis is substantial due to thromboinflammation, and treatments for sepsis and septic shock may exacerbate endotheliopathy via additional glycocalyx injury. As a result, therapeutic strategies aimed at preserving glycocalyx integrity should be considered, including modifications in fluid volume resuscitation, minimizing catecholamine use, controlling hyperglycemia, and potential use of corticosteroids and anticoagulants. In this review, we explore treatment strategies aligned with the recommendations outlined in the Surviving Sepsis Campaign Guidelines 2021 with a special emphasis on evidence regarding glycocalyx protection. [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE), particularly portal vein thrombosis, is common in patients with cirrhosis. Misconceptions around the increased bleeding risk in this patient group may lead to delayed and/or inadequate anticoagulation. This nutshell review focusses on the approach to management including the role of direct oral anticoagulants in the treatment of VTE in patients with cirrhosis. [ABSTRACT FROM AUTHOR]

Antiphospholipid syndrome (APS) is a hypercoagulable state caused by antiphospholipid antibodies (aPL). APS clinically manifests with arterial or venous or microvascular thrombi and/or pregnancy complications. It is well-known that the development of aPL can be a transient phenomenon and thus the current diagnostic criterion for APS requires repeat laboratory testing several weeks apart before a definitive diagnosis is made. However, transient presence of aPL may also be pathogenic. In this article, we attempt to give historical and clinical evidence for the importance of these antibodies, even when transient, and call for further research into mechanisms by which these antibodies may promote thrombosis and pregnancy morbidities. [ABSTRACT FROM AUTHOR]

Background: Concerns about COVID-19-associated coagulopathy (CAC) in pregnant individuals were raised in early pandemic. Methods: An ISTH-sponsored COVID-19 coagulopathy in pregnancy (COV-PREG-COAG) international registry was developed to describe incidence of coagulopathy, VTE, and anticoagulation in this group. Results: All pregnant patients with COVID-19 from participating centers were entered, providing 430 pregnancies for the first pandemic wave. Isolated abnormal coagulation parameters were seen in 20%; more often with moderate/severe disease than asymptomatic/mild disease (49% vs 15%; p < 0.0001). No one met the ISTH criteria for disseminated intravascular coagulopathy (DIC), though 5/21 (24%) met the pregnancy DIC score. There was no difference in antepartum hemorrhage (APH) with asymptomatic/mild disease versus moderate/severe disease (3.4% vs 7.7%; p = 0.135). More individuals with moderate/severe disease experienced postpartum hemorrhage (PPH) (22.4% vs 9.3%; p = 0.006). There were no arterial thrombotic events. Only one COVID-associated venous thromboembolism (VTE) was reported. Conclusions: Low rates of coagulopathy, bleeding, and thrombosis were observed among pregnant people in the first pandemic wave. [ABSTRACT FROM AUTHOR]

This article provides guidelines for the diagnosis and management of heparin-induced thrombocytopenia (HIT), a condition characterized by low platelet count caused by an immune response to heparin. It discusses different types of HIT, the incidence of the condition, and the presentation and assessment of HIT. The article also provides recommendations for platelet monitoring and laboratory diagnosis of HIT, as well as management strategies including the use of alternative anticoagulants and therapies such as intravenous immunoglobulin and plasma exchange. The recommendations are evidence-based and aim to assist healthcare professionals in managing HIT. [Extracted from the article]

Russell Viper Venom (RVV) is widely used as a diagnostic test for antiphospholipid syndrome (APS). But the history of how this venom came to be discovered is well known. Dr Patrick Russell is responsible for the identification of the venom during his work on snake bites in India while Dr Robert Macfarlane used it to staunch bleeding in persons with haemophilia. The ability to directly activate factor X led RVV to the laboratory diagnosis of APS. More recently, it has come back to clinical world with a potential for an engineered factor X activator from RVV to be used in the treatment of haemophilia. [ABSTRACT FROM AUTHOR]

Background Masses in the heart and valves have a broad differential diagnosis including infective and rheumatic causes as well as primary or metastatic tumours. Diagnosis involves delineating the location, shape, and origin of the mass/masses and considering the clinical context. This case outlines the work-up and approach to diagnosing a cardiac mass along with imaging findings of a unique secondary metastatic mass in the left ventricle (LV). Case summary A 69-year-old female with past medical history of metastatic lung cancer treated with radiotherapy and breast cancer treated with mastectomy presented with dyspnoea and fever. Due to concern for infective endocarditis, transthoracic echocardiogram (TTE) was performed revealing 2 cm × 0.72 cm finger-like, echo-lucent, mobile mass, appearing to originate from LV lateral wall, protruding into the LV cavity, along with valvular masses on mitral and tricuspid valves. Initial differential diagnosis included benign pathologies, but due to the clinical suspicion of malignancy, cardiac MRI was performed which revealed a broad-based mass with invasion into the LV lateral wall and delayed gadolinium enhancement, suggestive of metastatic tumour. The patient was given Aspirin to prevent embolization and eventually underwent hospice care. Discussion Atypical appearing cardiac masses can be seen on TTE. Cardiac magnetic resonance imaging (MRI) should be used for definite diagnosis in cases where clinical features do not match the echocardiographic findings. [ABSTRACT FROM AUTHOR]

Radiation-induced normal tissue toxicity is a common acute and chronic outcome of radiotherapy (RT) for prostate cancer (PCa). There are currently no existing pre-assessments before treatment to predict acute and late RT-induced toxicity. Novel predictive blood biomarkers in radiation oncology may improve treatment decision-making and therapeutic monitoring for patients with PCa. A comprehensive systematic search of microRNA (miRNA/miR) profiling studies published in PubMed, Science Direct and Google Scholar was performed. The present systematic review, supported by meta-analysis, summarises key findings and discusses the results of prospective clinical studies investigating miRNA expression levels and their association with RT-induced toxicity in PCa. Out of seven clinical studies, six highlighted levels of 10 miRNAs changing in plasma, serum or peripheral blood mononuclear cells during RT. The post-RT expression levels of miRNA-132-5p, miRNA-1-3p, miRNA-410 and miRNA-221 were increased, and miRNA-23a-3p expression was decreased among patients with low-grade RT-induced toxicity. Furthermore, in patients with high-grade RT toxicity, miRNA-197-3p, miRNA-151a-5p, miRNA-18b-5p, miRNA-99a and miRNA-21 expression was increased, while miRNA-132-5p expression was decreased. The present miRNA meta-analysis could be the focus of future studies to identify their potential clinical value as PCa biomarkers and therapeutic mediators in RT-induced toxicity. The variations in miRNA levels post-RT could be used as predictive biomarkers of RT-induced toxicity. However, further extensive validation is required to establish the relationship between miRNA expression levels and RT-induced toxicity in PCa and to confirm their predictive value. [ABSTRACT FROM AUTHOR]

The healthcare systems are a prime target for cyber-attacks due to the sensitive nature of the information combined with the essential need for continuity of care. Medical laboratories are particularly vulnerable to cyber-attacks for a number of reasons, including the high level of information technology (IT), computerization and digitization. Based on reliable and widespread evidence that medical laboratories may be inadequately prepared for cyber-terrorism, a panel of experts of the Task Force Preparation of Labs for Emergencies (TF-PLE) of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) has recognized the need to provide some general guidance that could help medical laboratories to be less vulnerable and better prepared for the dramatic circumstance of a disruptive cyber-attack, issuing a number of consensus recommendations, which are summarized and described in this opinion paper. [ABSTRACT FROM AUTHOR]

This article discusses the increasing prevalence of cyber-attacks in healthcare and the specific vulnerability of clinical laboratories to these attacks. The EFLM Task Force Preparation of Labs for Emergencies (TF-PLE) conducted a survey to assess the current state of cyber-attacks in laboratory medicine in Europe. The survey revealed that a significant percentage of respondents were unfamiliar with cyber-attacks and had not received cybersecurity instructions from their institutions. The results highlight the need for increased cybersecurity training for laboratory staff and the importance of incident response planning in hospitals and clinical laboratories. [Extracted from the article]