Since the inception of rituximab in the 1990s, anti-CD20 monoclonal antibodies have revolutionised the treatment of B cell hematological malignancies and have become a cornerstone of modern gold-standard practice. Additionally, the potent efficacy of these agents in depleting the B cell compartment has been used in the management of a broad array of autoimmune diseases. Multiple iterations of these agents have been investigated and are routinely used in clinical practice. In this review, we will discuss the physiology of CD20 and its attractiveness as a therapeutic target, as well as the pharmacology, pre-clinical and clinical data for the major anti-CD20 monoclonal antibodies: rituximab, obinutuzumab and ofatumumab.
The recent dramatic appearance of variants of concern of SARS-coronavirus-2 (SARS-CoV-2) highlights the need for innovative approaches that simultaneously suppress viral replication and circumvent viral escape from host immunity and antiviral therapeutics. Here, we employ genome-wide computational prediction and single-nucleotide resolution screening to reprogram CRISPR-Cas13b against SARS-CoV-2 genomic and subgenomic RNAs. Reprogrammed Cas13b effectors targeting accessible regions of Spike and Nucleocapsid transcripts achieved >98% silencing efficiency in virus-free models. Further, optimized and multiplexed Cas13b CRISPR RNAs (crRNAs) suppress viral replication in mammalian cells infected with replication-competent SARS-CoV-2, including the recently emerging dominant variant of concern B.1.1.7. The comprehensive mutagenesis of guide-target interaction demonstrated that single-nucleotide mismatches does not impair the capacity of a potent single crRNA to simultaneously suppress ancestral and mutated SARS-CoV-2 strains in infected mammalian cells, including the Spike D614G mutant. The specificity, efficiency and rapid deployment properties of reprogrammed Cas13b described here provide a molecular blueprint for antiviral drug development to suppress and prevent a wide range of SARS-CoV-2 mutants, and is readily adaptable to other emerging pathogenic viruses.
The role of cytarabine-based induction and autologous stem cell transplantation (ASCT) in front-line treatment of younger patients with mantle cell lymphoma (MCL) is well established, however the utility of intensive approaches in older patients remains unclear. This retrospective study compared first line treatment outcomes in patients aged 60 years or more, treated at six tertiary centres between 2000–2015. 70 patients included had a median age of 69 (60–91) and most (94%) demonstrated advanced stage disease. Treatment regimens included: R-CHOP-like (n = 39), alternating R-CHOP/R-DHAC (n = 10), R-HyperCVAD/R-MA (n = 7), R-CHOP/Cytarabine (Nordic Protocol) (n = 10) and other (n = 4). 16 patients underwent an ASCT. The median follow-up for surviving patients was 37 months. Compared to R-CHOP-like therapies, cytarabine-based regimens were associated with an improved overall response rate (ORR) of 70% vs 33% (p < 0.001) and overall survival (OS) (HR 0.541, [0.292–1.001], p = 0.05). No difference in efficacy between different cytarabine-based regimens was detected, but R-HyperCVAD/R-MA was associated with increased hospitalisation and transfusion requirements. Patients undergoing ASCT demonstrated an improved median OS (HR 0.108 [0.015–0.796], p = 0.029) but were significantly younger. These results reaffirm the use of cytarabine in MCL for selected patients aged over 60. Such regimens should be strongly considered for this population in frontline therapy.
This meta-analysis suggests that noninvasive cBP estimation is device/technique-dependent. Consequently, caution is advisable in applying these devices and techniques across clinical studies.
What ' s known on the subject? and What does the study add? Urologists are increasingly involved in the management of patients taking oral anticoagulation ( OA ) who present with haematuria. It is accepted practice that haematuria in the presence of concurrent anticoagulation requires a full diagnostic evaluation, as it is frequently precipitated by a signifi cant pathological lesion. However, there is limited data on the impact of anticoagulation on the initial inpatient management of these patients. Much of the current evidence is either based around perioperative management of elective patients or, for emergency presentations, is focused on bleeding associated with high morbidity and mortality, such as in the neurosurgical population.In the present study, about half of all admissions with haematuria were for patients on some form of OA . The use of OA strongly predicted for the need for admission for bladder irrigation, regardless of the type of agent or combination of agents used. The use of dual antiplatelet therapy had the strongest association with the need for bladder irrigation, probably due to the well-described synergistic effect between aspirin and clopidogrel. The results of the present study emphasise the importance of early intervention in the management of patients on OA presenting with haematuria. Objective• To examine the effect of oral anticoagulation ( OA ) on the prevalence and inpatient management of haematuria in a contemporary Australian patient cohort. Patients and methods• Patients across all inpatient units who had diagnosis-related group ( DRG ) coding for haematuria were identifi ed from April 2010 to September 2011.• A retrospective chart review was performed to identify the type of anticoagulation (if any), requirement for bladder irrigation or blood transfusion, length of stay ( LOS ) and cause of haematuria.• Patients for whom the anticoagulation status was uncertain were excluded from analysis.• Statistical signifi cance was determined by Pearson ' s chi-square tests and Student ' s t -tests. Results• In all, 335 admissions with DRG coding for haematuria were identifi ed from hospital records, of which 268 admissions had clear documentation of anticoagulation. There were 118 emergency admissions and 150 elective admissions for day case cystoscopy. The mean age of the patients was 66 years and the male:female ratio was 5:1. In all, 123 admissions were for patients on some form of anticoagulation (46%).• Patients were on anticoagulation in 53% of the 118 emergency admissions for gross haematuria. These comprised patients on aspirin (28%), clopidogrel (4%), warfarin (10%), combined aspirin and warfarin (1%) and combined aspirin and clopidogrel (10%).• The use of OA was a signifi cant predictor of the need for intervention among the 118 emergency admissions (86% vs 62%, P = 0.003).• In particular, dual antiplatelet therapy in the form of aspirin and clopidogrel was associated with an increased requirement for bladder irrigation (92%) when compared with patients on other forms of ant...
As treatment options in modern medicine continue to expand, physicians globally have witnessed a veritable explosion in the utility of therapeutic devices. Particularly within the spheres of cardiology and critical care medicine, a plethora of devices are now available with an ever-increasing range of clinical indications. Additionally, the advent of transcatheter-mounted devices has enabled patients unsuitable for more invasive procedures to benefit from intervention, thereby greatly expanding the cohort of device-eligible patients. However, despite advances in design and materials, as well as pharmacological prophylaxis, hemostatic complications continue to plague device recipients, contributing to morbidity and mortality. Elucidating the complex interplay between components of the hemostatic system and cardiac devices has been the subject of much recent research, with greater focus on the coagulation cascade and device-induced perturbations. However, less is known about impact of mechanical surfaces on platelets and the resultant clinical complications, both hemorrhagic and thrombotic. This review will focus on exploring the pathobiology of platelet-surface interactions, contextualized within the wider hemostatic system, with a focus on the increasingly utilized technologies of transcatheter aortic-valve implantation, ventricular assist devices, and extracorporeal membrane oxygenation.
Background Lymphoma is a malignancy of lymphocytes and lymphoid tissues comprising a heterogeneous group of diseases, with up to 80 entities now described. Lymphoma is the 6th most common cancer in Australia, affecting patients of all ages, with rising incidence rates. With the proliferation of efficacious novel agents, therapeutic strategies are increasingly diverse and survival is improving. There is a clear need for contemporary robust and detailed data on diagnostic, investigational and management strategies for this disease in Australia, New Zealand and worldwide, to inform and benchmark local and international standards of care. Clinical quality registries can provide these data, and support development of strategies to address variations in management, including serving as platforms for clinical trials and research. The Lymphoma and Related Diseases Registry (LaRDR) was developed to capture details of patient demographics, disease characteristics, and management throughout their disease course and therapy and to develop outcome benchmarks nationally and internationally for lymphoma. This report describes the aims, development and implementation of the LaRDR, as well as challenges addressed in the process.Methods The LaRDR was established in 2016 as a multicentre, collaborative project at sites across Australia with a secure online database which collects prospective data on patients with a new diagnosis of lymphoma or chronic lymphocytic leukaemia (CLL). LaRDR development required multidisciplinary participation including specialist haematology, information technology, and biostatistical support, as well as secure funding. Here we describe the database development, data entry, ethics approval process, registry governance and support for participating sites and the coordinating centre.Results To date more than 4,700 patients have been enrolled from 27 sites. Multiple challenges arose during the development, which we describe, along with approaches used to overcome them. Several confirmed international collaborations are now in place, and the registry is providing valuable data for clinicians, researchers, industry and government, including through presentations of results at major national and international conferences.Conclusion Challenges in establishing the LaRDR have been successfully overcome and the registry is now a valuable resource for lymphoma clinicians, researchers, health economists and others in Australia and globally.
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