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Non-vitamin K antagonist oral anticoagulants (NOACs) include thrombin inhibitor dabigatran and coagulation factor Xa inhibitors rivaroxaban, apixaban, edoxaban, and betrixaban. NOACs have several benefits over warfarin, including faster time to the achieve effect, rapid onset of action, fewer documented food and drug interactions, lack of need for routine INR monitoring, and improved patient satisfaction. Local hemostatic measures, supportive care, and withholding the next NOAC dose are usually sufficient to achieve hemostasis among patients presenting with minor bleeding. The administration of reversal agents should be considered in patients on NOAC's with major bleeding manifestations (life-threatening bleeding, or major uncontrolled bleeding), or those who require rapid anticoagulant reversal for an emergent surgical procedure. The Food and Drug Administration (FDA) has approved two reversal agents for NOACs: idarucizumab for dabigatran and andexanet alfa for apixaban and rivaroxaban. The American College of Cardiology (ACC), American Heart Association (AHA), and Heart Rhythm Society (HRS) have released an updated guideline for the management of patients with atrial fibrillation that provides indications for the use of these reversal agents. In addition, the final results of the ANNEXA-4 study that evaluated the efficacy and safety of andexanet alfa were recently published. Several agents are in different phases of clinical trials, and among them, ciraparantag has shown promising results. However, their higher cost and limited availability remains a concern. Here, we provide a brief review of the available reversal agents for NOACs (nonspecific and specific), recent updates on reversal strategies, lab parameters (including point-of-care tests), NOAC resumption, and agents in development.

Bone marrow necrosis (BMN) is a rare pathological diagnosis, with an incidence of 0.3% to 2%. It is most often associated with hematological malignancies and less commonly due to solid tumors, infections, medications, sickle cell disease, chemotherapy, radiotherapy, or idiopathic causes. We reviewed bone marrow biopsies performed in our institution from 2009 to 2019 and found three cases of BMN. Two cases were secondary to neoplastic causes, while the third one was possibly from alcohol abuse.Bone marrow necrosis (BMN) is a rare pathological diagnosis, with an incidence of 0.3% to 2%. It is most often associated with hematological malignancies and less commonly due to solid tumors, infections, medications, sickle cell disease, chemotherapy, radiotherapy, or idiopathic causes. We reviewed bone marrow biopsies performed in our institution from 2009 to 2019 and found three cases of BMN. Two cases were secondary to neoplastic causes, while the third one was possibly from alcohol abuse.

Hyperprogression associated with immunotherapy has been reported previously with melanoma, non-small cell lung cancer (NSCLC), renal, and urothelial cancers but not with sarcoma. A 63-year old man with a biopsy-proven, localized 13 cm high-grade myxoid/round cell liposarcoma of the thigh was treated with concurrent, neoadjuvant checkpoint inhibitor immunotherapy and radiotherapy. After his subsequent wide surgical resection, he developed small hepatic lesions that rapidly progressed and caused his death, raising the possibility of hyperprogression in this entity.

Bacteria frequently encounter selection by both antibiotics and lytic bacteriophages. However, the evolutionary interactions between antibiotics and phages remain unclear, in particular, whether and when phages can drive evolutionary trade-offs with antibiotic resistance. Here, we describe Escherichia coli phage U136B, showing it relies on two host factors involved in different antibiotic resistance mechanisms: 1) the efflux pump protein TolC and 2) the structural barrier molecule lipopolysaccharide (LPS). Since TolC and LPS contribute to antibiotic resistance, phage U136B should select for their loss or modification, thereby driving a trade-off between phage resistance and either of the antibiotic resistance mechanisms. To test this hypothesis, we used fluctuation experiments and experimental evolution to obtain phage-resistant mutants. Using these mutants, we compared the accessibility of specific mutations (revealed in the fluctuation experiments) to their actual success during ecological competition and coevolution (revealed in the evolution experiments). Both tolC and LPS-related mutants arise readily during fluctuation assays, with tolC mutations becoming more common during the evolution experiments. In support of the trade-off hypothesis, phage resistance via tolC mutations occurs with a corresponding reduction in antibiotic resistance in many cases. However, contrary to the hypothesis, some phage resistance mutations pleiotropically confer increased antibiotic resistance. We discuss the molecular mechanisms underlying this surprising pleiotropic result, consideration for applied phage biology, and the importance of ecology in evolution of phage resistance. We envision that phages may be useful for the reversal of antibiotic resistance, but such applications will need to account for unexpected pleiotropy and evolutionary context.

Rabies is a fatal disease where post-exposure prophylaxis (PEP) is crucial in preventing infection. However, deaths even after appropriate PEP, have been reported. The PIKA Rabies vaccine adjuvant is a TLR3 agonist that activates B and T cells leading to a robust immune response. We conducted a phase I, open label, randomized study in healthy adults to assess the safety and immunogenicity of the PIKA Rabies vaccine and an accelerated vaccine regimen. Thirty-seven subjects were randomized into 3 groups: control vaccine classic regimen, PIKA vaccine classic regimen and PIKA vaccine accelerated regimen. Subjects were followed up for safety, rabies virus neutralizing antibodies (RVNA) and T cell responses. Both the control and PIKA Rabies vaccine were well tolerated. All adverse events (AEs) were mild and self-limiting. Seventy-five percent of subjects in the PIKA accelerated regimen achieved a RVNA titer ⩾0.5IU/mL on day 7, compared to 53.9% in the PIKA classic regimen (p=0.411) and 16.7% in control vaccine classic regimen (p=0.012). The PIKA rabies vaccine elicited multi-specific rabies CD4 mediated T cell response already detectable ex vivo at day 7 after vaccination and that was maintained at day 42. The investigational PIKA rabies vaccine was well tolerated and more immunogenic than the commercially available vaccine in healthy adults. Clinical trial registry: The study was registered with clinicaltrials.gov NCT02657161.

How tumor cells genetically lose antigenicity and evade immune checkpoints remains largely elusive. We report that tissue-specific expression of the human long noncoding RNA LINK-A in mouse mammary glands initiates metastatic mammary gland tumors, which phenotypically resemble human triple-negative breast cancer (TNBC). LINK-A expression facilitated crosstalk between phosphatidylinositol-(3,4,5)-trisphosphate and inhibitory G-protein-coupled receptor (GPCR) pathways, attenuating protein kinase A-mediated phosphorylation of the E3 ubiquitin ligase TRIM71. Consequently, LINK-A expression enhanced K48-polyubiquitination-mediated degradation of the antigen peptide-loading complex (PLC) and intrinsic tumor suppressors Rb and p53. Treatment with LINK-A locked nucleic acids or GPCR antagonists stabilized the PLC components, Rb and p53, and sensitized mammary gland tumors to immune checkpoint blockers. Patients with programmed ccll death protein-1(PD-1) blockade-resistant TNBC exhibited elevated LINK-A levels and downregulated PLC components. Hence we demonstrate lncRNA-dependent downregulation of antigenicity and intrinsic tumor suppression, which provides the basis for developing combinational immunotherapy treatment regimens and early TNBC prevention. Many tumors evade immunosurveillance by down-modulating expression of antigen-processing machinery and MHC molecules. Yang et al. report triple-negative tumor cell expression of the lncRNA LINK-A enhances degradation of antigen peptide-loading complex molecules and intrinsic tumor suppressors, which contribute to tumor persistence.

•Phase II study conducted comparing PIKA rabies vaccine accelerated regimen with standard rabies vaccine.•PIKA rabies vaccine is safe and well-tolerated.•PIKA rabies vaccine accelerated regimen is able to elicit protective immune response as early as Day 7.•All subjects in the PIKA group achieved protective RVNA titer by Day 14.•Immunogenicity of PIKA vaccine accelerated regimen is comparable to standard rabies vaccine. Human Rabies infection continues to be potentially fatal despite the availability of post-exposure prophylaxis with rabies vaccine. The PIKA Rabies vaccine adjuvant is a TLR3 agonist and has been shown to be safe and immunogenic in clinical phase I studies. We conducted a phase II, open label, randomized study in healthy adults to assess the safety and immunogenicity of the PIKA rabies vaccine under an accelerated regimen. 126 subjects were randomized into two groups: control vaccine classic regimen (“control-classic”) and PIKA vaccine accelerated regimen (“PIKA-accelerated”). Subjects were followed up for safety and rabies virus neutralizing antibodies (RVNA). Both the control and PIKA vaccines were generally well tolerated. 57.6% of subjects in the PIKA vaccine group, compared with 43.8% of subjects in the control-classic group, achieved the target RVNA titer of ≥0.5 IU/mL by Day 7. All subjects achieved the target RVNA titer by Day 14. The RVNA geometric mean titer at Day 7 was 0.60 IU/ml in the PIKA vaccine group and 0.39 IU/ml in the control-classic group. At Day 14, the RVNA geometric mean titer was 18.25 IU/ml in the PIKA-accelerated group and 19.24 IU/ml in the control-classic group. The median time taken to reach the target RVNA titer level of ≥0.5 IU/mL was 7.0 days (95% CI: 7.0–42.0 days) in the PIKA-accelerated group and 14.0 days (95% CI: 7.0–42.0 days) in the control-classic group. The accelerated regimen using the investigational PIKA Rabies vaccine was well-tolerated and demonstrated non-inferior immunogenicity compared to the classic regimen using the commercially available vaccine in healthy adults. Clinical trial registry: The study was registered with clinicaltrials.gov (NCT02956421).

Strongyloides stercoralis is a soil-transmitted helminth that is mainly found in the tropical and subtropical regions and affects approximately 600 million people globally. The medical importance of strongyloidiasis lies in its capacity to remain asymptomatic and chronically unnoticed until the host is immunocompromised. Additionally, in severe strongyloidiasis, hyperinfection syndrome and larva dissemination to various organs can occur. Parasitological techniques such as Baermann-Moraes and agar plate culture to detect larvae in stool samples are the current gold standard. However, the sensitivity might be inadequate, especially with reduced worm burden. Complementing parasitological techniques, immunological techniques including immunoblot and immunosorbent assays are employed, with higher sensitivity. However, cross-reactivity to other parasites may occur, hampering the assay’s specificity. Recently, advances in molecular techniques such as polymerase chain reaction and next-generation sequencing technology have provided the opportunity to detect parasite DNA in stool, blood, and environmental samples. Molecular techniques, known for their high sensitivity and specificity, have the potential to circumvent some of the challenges associated with chronicity and intermittent larval output for increased detection. Here, as S. stercoralis was recently included by the World Health Organization as another soil-transmitted helminth targeted for control from 2021 to 2030, we aimed to present a review of the current molecular techniques for detecting and diagnosing S. stercoralis in a bid to consolidate the molecular studies that have been performed. Upcoming molecular trends, especially next-generation sequencing technologies, are also discussed to increase the awareness of its potential for diagnosis and detection. Improved and novel detection methods can aid in making accurate and informed choices, especially in this era where infectious and non-infectious diseases are increasingly commonplace. Graphical Abstract

Background Parasitic helminths exhibit significant diversity, complicating both morphological and molecular species identification. Moreover, no helminth-specific tool is currently available to aid in species identification of helminths using molecular data. To address this, we developed and validated a straightforward, user-friendly application named Applying Taxonomic Boundaries for Species Identification of Helminths (ABIapp) using R and the Shiny framework. Serving as a preliminary step in species identification, ABIapp is designed to assist in visualizing taxonomic boundaries for nematodes, trematodes, and cestodes. ABIapp employs a database of genetic distance cut-offs determined by the K-means algorithm to establish taxonomic boundaries for ten genetic markers. Validation of ABIapp was performed both in silico and with actual specimens to determine its classification accuracy. The in silico validation involved 591 genetic distances sourced from 117 publications, while the validation with actual specimens utilized ten specimens. ABIapp’s accuracy was also compared with other online platforms to ensure its robustness to assist in helminth identification. Results ABIapp achieved an overall classification accuracy of 76% for in silico validation and 75% for actual specimens. Additionally, compared to other platforms, the classification accuracy of ABIapp was superior, proving its effectiveness to determine helminth taxonomic boundaries. With its user-friendly interface, minimal data input requirements, and precise classification capabilities, ABIapp offers multiple benefits for helminth researchers and can aid in identification. Conclusions Built on a helminth-specific database, ABIapp serves as a pioneering tool for helminth researchers, offering an invaluable resource for determining species boundaries and aiding in species identification of helminths. The availability of ABIapp to the community of helminth researchers may further enhance research in the field of helminthology. To enhance ABIapp’s accuracy and utility, the database will be updated annually.

Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. Here, within a phase 2 window clinical trial, RIO trial (EudraCT 2014-003319-12), we investigate the activity of PARP inhibitors in 43 patients with untreated TNBC. The primary end point, decreased Ki67, occured in 12% of TNBC. In secondary end point analyses, HR deficiency was identified in 69% of TNBC with the mutational-signature-based HRDetect assay. Cancers with HRDetect mutational signatures of HR deficiency had a functional defect in HR, assessed by impaired RAD51 foci formation on end of treatment biopsy. Following rucaparib treatment there was no association of Ki67 change with HR deficiency. In contrast, early circulating tumor DNA dynamics identified activity of rucaparib, with end of treatment ctDNA levels suppressed by rucaparib in mutation-signature HR-deficient cancers. In ad hoc analysis, rucaparib induced expression of interferon response genes in HR-deficient cancers. The majority of TNBCs have a defect in DNA repair, identifiable by mutational signature analysis, that may be targetable with PARP inhibitors. Defects in homologous recombination (HR) are found in some triple negative breast cancers, suggesting they may be sensitive to PARP inhibitors. In this phase II clinical trial of the PARP inhibitor rucaparib, changes in Ki67 levels did not correlate with markers of HR deficiency but HR deficiency was detected in 69% of tumours, indicating that PARP inhibitors may be a useful treatment.