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The reduced availability and the increasing prices of calf rennet, coupled to the growing global demand of cheese has led, worldwide, to explore alternative clotting enzymes, capable to replace traditional rennet, during the cheesemaking. In addition, religious factors and others related to the vegetarianism of some consumers, have led to alternative rennet substitutes. Nowadays, several plant-derived milk-clotting enzymes are available for cheesemaking technology. Many efforts have also been made to compare their effects on rheological and sensory properties of cheese to those arising from animal rennet. However, vegetable clotting enzymes are still partially suitable for cheesemaking, due to excessive proteolytic activity, which contribute to bitter flavor development. This review provides a literature overview of the most used vegetable clotting enzymes in cheese technology, classified according to their protease class. Finally, clotting and proteolytic activities are discussed in relation to their application on the different cheesemaking products.

The use of crude aqueous extracts of Cynara cardunculus flowers as coagulants in the production of high-quality sheep and goat cheeses—as are the cases of several Portuguese and Spanish cheese varieties with Protected Designation of Origin status—has been maintained since ancient times. The unique rheological attributes and sensory properties characteristic of these cheeses have always suggested that this plant coagulant (and, therefore, its isolated milk-clotting proteases) could be used as alternative rennet in the dairy industry, particularly suited for the production of sheep and goat cheeses. However, the lack of standardization of C. cardunculus crude flower extracts, whose quality and performance depends on numerous factors, has always hampered the application of this plant rennet in industrial production scales. To overcome these limitations, and to aim at developing more effective solutions with potential for scalability of production and commercial application, several strategies have been undertaken in more recent years to establish new cardoon-based rennets. This review provides an overview on these developments and on the currently available solutions, which range from producing standardized formulations of native cardoon enzymes, to the optimization of the heterologous production of cardosins and cyprosins to generate synthetic versions of these milk-clotting enzymes. Challenges and emerging opportunities are also discussed.

Cheese-making involves milk coagulation as a crucial step where calf rennet has been used traditionally as the milk-clotting enzyme in the cheese industry. This study investigated milk-clotting enzymes from seven species of seaweed and evaluated the parameters for their isolation and partial purification including post-harvest processing, extraction and purification methods. The saturation degree of ammonium sulphate and the precipitation stages were evaluated to obtain optimal purification conditions, and three desalting methods, namely dialysis, desalting column and the combination of dialysis and desalting column, were investigated to determine the most suitable method for ammonium sulphate removal. Protein extracts of all seven species of seaweeds exhibited some caseinolytic activity, but the extract of unprocessed (whole) dried samples had higher protein yields and stronger caseinolytic activities. The extract from one species, Gracilaria edulis, demonstrated the ability to clot milk. The evaluation of the purification method for G. edulis extract revealed an optimum single step of 50% saturation and ammonium sulphate precipitation with dialysis as the desalting method.

In this case series, investigators report a very rare but life-threatening sequela of ChAdOx1 nCoV-19 vaccination. Beginning 5 to 16 days after a first injection, some patients had symptoms consistent with thrombocytopenia, disseminated intravascular coagulation, and thromboses, including cerebral venous sinus thrombosis with catastrophic outcome. An anti–PF4 antibody capable of platelet activation appears to be the cause. Intravenous immune globulin may be therapeutic.

Long COVID is the patient-coined term for the disease entity whereby persistent symptoms ensue in a significant proportion of those who have had COVID-19, whether asymptomatic, mild or severe. Estimated numbers vary but the assumption is that, of all those who had COVID-19 globally, at least 10% have long COVID. The disease burden spans from mild symptoms to profound disability, the scale making this a huge, new health-care challenge. Long COVID will likely be stratified into several more or less discrete entities with potentially distinct pathogenic pathways. The evolving symptom list is extensive, multi-organ, multisystem and relapsing–remitting, including fatigue, breathlessness, neurocognitive effects and dysautonomia. A range of radiological abnormalities in the olfactory bulb, brain, heart, lung and other sites have been observed in individuals with long COVID. Some body sites indicate the presence of microclots; these and other blood markers of hypercoagulation implicate a likely role of endothelial activation and clotting abnormalities. Diverse auto-antibody (AAB) specificities have been found, as yet without a clear consensus or correlation with symptom clusters. There is support for a role of persistent SARS-CoV-2 reservoirs and/or an effect of Epstein–Barr virus reactivation, and evidence from immune subset changes for broad immune perturbation. Thus, the current picture is one of convergence towards a map of an immunopathogenic aetiology of long COVID, though as yet with insufficient data for a mechanistic synthesis or to fully inform therapeutic pathways.SARS-CoV-2 infection can lead to a diverse array of chronic symptoms, collectively termed ‘long COVID’. In this Review, Altmann and colleagues explore current thinking about the pathophysiology of long COVID and discuss potential immunological mechanisms.

IntroductionIn August 2023 NHSE published the ERCP Network and Service Recommendations. These advise that all patients undergo preassessment and a two-stage consent process. Care should be tailored to each specific patient.MethodIn Gloucestershire we undertake 350 ERCP procedures per year, but were not meeting these recommendations.• There was no formal process for the pre-assessment of day case patients.• There was difficulty managing day case patients with disordered clotting results.• Patients were consented on the day of their test.• Inpatients were poorly informed prior to their procedure.Change was needed to comply with the recommendations, so we developed a 2-year fixed term band 6 ERCP nurse specialist (ERCPNS) post to• Undertake preadmission clinics.• Take stage 1 consent.• Pre-assess inpatients.• Manage co-morbidity.• Train staff.• Assist in audit.ResultsThe ERCPNS has been in post for ten months:• Over 300 patients have been pre-assessed in outpatient clinic and on the wards.• Documentation has been developed that provides a standardised record.• Stage 1 consent taken.• PGD for administering Vitamin K.• Post procedure phone call the following day.ConclusionsThe ERCPNS has revolutionised our service:• There is patient centred care tailored to the individual with in-depth preprocedural information and two stage consent.• The service is safer with patients’ co-morbidity and clotting addressed, plus the safety net of postprocedural telephone follow-up.• Funding has been secured to make the post permanent.

Numerous clinical trials of mesenchymal stromal/stem cells (MSCs) as a new treatment for coronavirus-induced disease (COVID-19) have been registered recently, most of them based on intravenous (IV) infusion. There is no approved effective therapy for COVID-19, but MSC therapies have shown first promise in the treatment of acute respiratory distress syndrome (ARDS) pneumonia, inflammation, and sepsis, which are among the leading causes of mortality in COVID-19 patients. Many of the critically ill COVID-19 patients are in a hypercoagulable procoagulant state and at high risk for disseminated intravascular coagulation, thromboembolism, and thrombotic multi-organ failure, another cause of high fatality. It is not yet clear whether IV infusion is a safe and effective route of MSC delivery in COVID-19, since MSC-based products express variable levels of highly procoagulant tissue factor (TF/CD142), compromising the cells' hemocompatibility and safety profile. Of concern, IV infusions of poorly characterized MSC products with unchecked (high) TF/CD142 expression could trigger blood clotting in COVID-19 and other vulnerable patient populations and further promote the risk for thromboembolism. In contrast, well-characterized products with robust manufacturing procedures and optimized modes of clinical delivery hold great promise for ameliorating COVID-19 by exerting their beneficial immunomodulatory effects, inducing tissue repair and organ protection. While the need for MSC therapy in COVID-19 is apparent, integrating both innate and adaptive immune compatibility testing into the current guidelines for cell, tissue, and organ transplantation is critical for safe and effective therapies. It is paramount to only use well-characterized, safe MSCs even in the most urgent and experimental treatments. We here propose three steps to mitigate the risk for these vulnerable patients: (1) updated clinical guidelines for cell and tissue transplantation, (2) updated minimal criteria for characterization of cellular therapeutics, and (3) updated cell therapy routines reflecting specific patient needs.

Endothelial cells form a monolayer, which lines blood vessels. They are crucially involved in maintaining blood fluidity and providing controlled vascular hemostasis at sites of injury. Thereby endothelial cells facilitate multiple mechanisms, including both procoagulant and anticoagulant, which must be kept in balance. Under physiological conditions, endothelial cells constitute a nonadhesive surface preventing activation of platelets and the coagulation cascade. Multiple fibrinolytic and antithrombotic properties act on their cell surface contributing to the maintenance of blood fluidity. These include platelet inhibition, the heparin-antithrombin III system, tissue factor pathway inhibition, thrombomodulin/protein C system, and fibrinolytic qualities. At sites of vascular damage, platelets react immediately by adhering to the exposed extracellular matrix, followed by platelet-platelet interactions to form a clot that effectively seals the injured vessel wall to prevent excessive blood loss. For solid thrombus formation, functional platelets are essential. In this process, endothelial cells serve as a support surface for formation of procoagulant complexes and clotting. This review gives an overview about the central role of the endothelium as a dynamic lining which controls the complex interplay of the coagulation system with the surrounding cells.