Impact of the gut-lung axis on tuberculosis susceptibility and progression

Tuberculosis (TB) has remained at the forefront of the global infectious disease burden for centuries. Concerted global efforts to eliminate TB have been hindered by the complexity of Mycobacterium tuberculosis (Mtb), the emergence of antibiotic resistant Mtb strains and the recent impact of the ongoing pandemic of coronavirus disease 2019 (COVID19). Examination of the immunomodulatory role of gastrointestinal microbiota presents a new direction for TB research. The gut microbiome is well-established as a critical modulator of early immune development and inflammatory responses in humans. Recent studies in animal models have further substantiated the existence of the ‘gut-lung axis’, where distal gastrointestinal commensals modulate lung immune function. This gut microbiome-lung immune crosstalk is postulated to have an important correlation with the pathophysiology of TB. Further evaluation of this gut immunomodulation in TB may provide a novel avenue for the exploration of therapeutic targets. This mini-review assesses the proposed mechanisms by which the gut-lung axis impacts TB susceptibility and progression. It also examines the impact of current anti-TB therapy on the gut microbiome and the effects of gut dysbiosis on treatment outcomes. Finally, it investigates new therapeutic targets, particularly the use of probiotics in treatment of antibiotic resistant TB and informs future developments in the field

Detection of Cyber Attacks in Renewable-rich Microgrids Using Dynamic Watermarking

This paper presents the first demonstration of using an active mechanism to defend renewable-rich microgrids against cyber attacks. Cyber vulnerability of the renewable-rich microgrids is identified. The defense mechanism based on dynamic watermarking is proposed for detecting cyber anomalies in microgrids. The proposed mechanism is easily implementable and it has theoretically provable performance in term of detecting cyber attacks. The effectiveness of the proposed mechanism is tested and validated in a renewable-rich microgrid.Comment: This is a paper appeared at IEEE PES General Meeting 202

Acquired Factor X Deficiency in Light Chain Amyloidosis: A Report of 2 Korean Cases

Amyloidosis is a heterogeneous group of diseases in which misfolding of extracellular proteins is the pathogenic factor. Light chain amyloidosis (AL) is the most common form of amyloidosis, and the causative proteins in AL are the immunoglobulin light chains produced by clonal plasma cells. Hemorrhagic events, ranging from mild subcutaneous hemorrhage to life-threatening bleeding, account for a significant proportion of morbidities and mortality in AL patients. Deficiency of factor X from deposition into amyloid fibrils has been reported to be the most common acquired factor deficiency in AL. We herein report 2 patients with acquired factor X deficiency in AL. A 55-yr-old woman with AL had a prolonged prothrombin time (PT) and an activated partial thromboplastin time (aPTT) of 2.51 International Normalized Ratio (INR) and 75.1 sec, respectively, which were corrected on mixing with normal plasma. Factor X activity was markedly decreased at 5%. The other patient was a 67-yr-old man with AL with a PT of 1.63 INR and an aPTT of 50.3 sec, which were corrected on mixing with normal plasma. Factor X activity was decreased at 17%. Neither of the patients had apparent hemorrhagic manifestations. Identification of acquired factor deficiency and timely coagulation tests are needed in the diagnostic workup and management in AL

A Review of Current Research Trends in Power-Electronic Innovations in Cyber-Physical Systems.

In this paper, a broad overview of the current research trends in power-electronic innovations in cyber-physical systems (CPSs) is presented. The recent advances in semiconductor device technologies, control architectures, and communication methodologies have enabled researchers to develop integrated smart CPSs that can cater to the emerging requirements of smart grids, renewable energy, electric vehicles, trains, ships, internet of things (IoTs), etc. The topics presented in this paper include novel power-distribution architectures, protection techniques considering large renewable integration in smart grids, wireless charging in electric vehicles, simultaneous power and information transmission, multi-hop network-based coordination, power technologies for renewable energy and smart transformer, CPS reliability, transactive smart railway grid, and real-time simulation of shipboard power systems. It is anticipated that the research trends presented in this paper will provide a timely and useful overview to the power-electronics researchers with broad applications in CPSs.post-print2.019 K

A longitudinal evaluation of performance of automated BCR-ABL1 quantitation using cartridge-based detection system

An automated cartridge-based detection system (GeneXpert; Cepheid) is being widely adopted in low throughput laboratories for monitoring BCR-ABL1 transcript in chronic myelogenous leukaemia. This Australian study evaluated the longitudinal performance specific characteristics of the automated system.The automated cartridge-based system was compared prospectively with the manual qRT-PCR-based reference method at SA Pathology, Adelaide, over a period of 2.5 years. A conversion factor determination was followed by four re-validations. Peripheral blood samples (n = 129) with international scale (IS) values within detectable range were selected for assessment. The mean bias, proportion of results within specified fold difference (2-, 3- and 5-fold), the concordance rate of major molecular remission (MMR) and concordance across a range of IS values on paired samples were evaluated.The initial conversion factor for the automated system was determined as 0.43. Except for the second re-validation, where a negative bias of 1.9-fold was detected, all other biases fell within desirable limits. A cartridge-specific conversion factor and efficiency value was introduced and the conversion factor was confirmed to be stable in subsequent re-validation cycles. Concordance with the reference method/laboratory at >0.1-≤10 IS was 78.2% and at ≤0.001 was 80%, compared to 86.8% in the >0.01-≤0.1 IS range. The overall and MMR concordance were 85.7% and 94% respectively, for samples that fell within ± 5-fold of the reference laboratory value over the entire period of study.Conversion factor and performance specific characteristics for the automated system were longitudinally stable in the clinically relevant range, following introduction by the manufacturer of lot specific efficiency values.Anoop Enjeti, Neil Granter, Asma Ashraf, Linda Fletcher, Susan Branford, Philip Rowlings, Susan Doole

Shwachman-Bodian-Diamond syndrome (SBDS) protein is a direct inhibitor of protein phosphatase 2A (PP2A) activity and overexpressed in acute myeloid leukaemia.

Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase inactivated in many cancers including acute myeloid leukaemia (AML). Activation of PP2A is emerging as a therapeutic strategy, however the mechanisms underpinning PP2A inhibition are not well understood. Using myeloid progenitor cells harbouring oncogenic mutant c-KIT and characterised by PP2A inhibition, we have identified the ribosome biogenesis protein SBDS, as a target of the PP2A activating drugs FTY720 and AAL(S). We show SBDS binds to PP2A complexes comprised of the B55α regulatory subunit of PP2A. shRNA mediated knockdown of SBDS increased PP2A activity and induced apoptosis. At diagnosis, AML patients expressed significantly more SBDS mRNA than healthy controls, with relapsed patients expressing significantly more SBDS mRNA than both healthy controls and patients at diagnosis. Together, our data presents a role for SBDS in the dysregulation of PP2A in AML

Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a Phase Ib/II study

Purpose: Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. An international phase Ib/II study evaluated the safety and preliminary efficacy of venetoclax, a selective B-cell leukemia/lymphoma-2 inhibitor, together with low-dose cytarabine (LDAC) in older adults with AML. Patients and Methods: Adults 60 years or older with previously untreated AML ineligible for intensive chemotherapy were enrolled. Prior treatment of myelodysplastic syndrome, including hypomethylating agents (HMA), was permitted. Eighty-two patients were treated at the recommended phase II dose: venetoclax 600 mg per day orally in 28-day cycles, with LDAC (20 mg/m2 per day) administered subcutaneously on days 1 to 10. Key end points were tolerability, safety, response rates, duration of response (DOR), and overall survival (OS). Results: Median age was 74 years (range, 63 to 90 years), 49% had secondary AML, 29% had prior HMA treatment, and 32% had poor-risk cytogenetic features. Common grade 3 or greater adverse events were febrile neutropenia (42%), thrombocytopenia (38%), and WBC count decreased (34%). Early (30-day) mortality was 6%. Fifty-four percent achieved complete remission (CR)/CR with incomplete blood count recovery (median time to first response, 1.4 months). The median OS was 10.1 months (95% CI, 5.7 to 14.2), and median DOR was 8.1 months (95% CI, 5.3 to 14.9 months). Among patients without prior HMA exposure, CR/CR with incomplete blood count recovery was achieved in 62%, median DOR was 14.8 months (95% CI, 5.5 months to not reached), and median OS was 13.5 months (95% CI, 7.0 to 18.4 months). Conclusion: Venetoclax plus LDAC has a manageable safety profile, producing rapid and durable remissions in older adults with AML ineligible for intensive chemotherapy. High remission rate and low early mortality combined with rapid and durable remission make venetoclax and LDAC an attractive and novel treatment for older adults not suitable for intensive chemotherapy.Andrew H. Wei, Stephen A. Strickland Jr, Jing-Zhou Hou, Walter Fiedler, Tara L. Lin, Roland B. Walter, Anoop Enjeti, Ing Soo Tiong, Michael Savona, Sangmin Lee, Brenda Chyla, Relja Popovic, Ahmed Hamed Salem, Suresh Agarwal, Tu Xu, Kaffa M. Fakouhi, Rod Humerickhouse, Wan-Jen Hong, John Hayslip and Gail J. Robo