Grid-free algorithms for direction-of-arrival trajectory localization.

Direction-of-arrival (DOA) estimation algorithms are crucial in localizing acoustic sources. Traditional localization methods rely on block-level processing to extract the directional information from multiple measurements processed together. However, these methods assume that DOA remains constant throughout the block, which may not be true in practical scenarios. Also, the performance of localization methods is limited when the true parameters do not lie on the parameter search grid. In this paper, two trajectory models are proposed, namely the polynomial and harmonic trajectory models, to capture the DOA dynamics. To estimate trajectory parameters, two gridless algorithms are adopted: (i) Sliding Frank-Wolfe (SFW), which solves the Beurling LASSO problem, and (ii) Newtonized orthogonal matching pursuit (NOMP), which is improved over orthogonal matching pursuit (OMP) using cyclic refinement. Furthermore, our analysis is extended to include multi-frequency processing. The proposed models and algorithms are validated using both simulated and real-world data. The results indicate that the proposed trajectory localization algorithms exhibit improved performance compared to grid-based methods in terms of resolution, robustness to noise, and computational efficiency.

Comparison of Effect of Non-invasive Ventilation Delivered by Helmet vs Face Mask in Patients with COVID-19 Infection: A Randomized Control Study.

Background and aims: We compared the effectiveness of non-invasive ventilation (NIV) provided by helmet mask vs face mask in patients with COVID-19. Methods and materials: Between March and May 2021, a single-center, prospective, open-label randomized controlled research was undertaken. Sixty patients were randomly assigned to one of two groups based on the NIV delivery interface. In group I (n = 30) helmet mask was used and in group II (n = 30) face mask was used for delivery of NIV. The proportion of patients in each group who required endotracheal intubation was the primary outcome. The duration of NIV, length of stay in the intensive care unit (ICU), hospital mortality, ratio of partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2), respiratory rate, patient comfort, and complications were all documented as secondary outcomes. Results: In both groups, demographics, clinical characteristics, and treatment received were comparable. Around 10% of patients in the helmet mask group were intubated, while 43.3% of patients in the face mask group were intubated (p = 0.004). The two groups demonstrated similar hemodynamic patterns. The use of a helmet mask, on the other hand, resulted in enhanced oxygenation (263.57 ± 31.562 vs 209.33 ± 20.531, p = 0.00), higher patient satisfaction (p = 0.001), a lower risk of complications, and a shorter NIV and ICU stay (p = 0.001) (4.53 ± 0.776 vs 7.60 ± 1.354, p = 0.00 and 6.37 ± 0.556 vs 11.57 ± 2.161, p = 0.00). Conclusion: Helmet mask could be a reliable interface for delivery of NIV in COVID-19 and results in a lower rate of endotracheal intubation, better oxygenation with greater patient comfort and shorter ICU stay as compared to face mask used for NIV. How to cite this article: Saxena A, Nazir N, Pandey R, Gupta S. Comparison of Effect of Non-invasive Ventilation Delivered by Helmet vs Face Mask in Patients with COVID-19 Infection: A Randomized Control Study. Indian J Crit Care Med 2022;26(3):282-287.

Role of SHP2 in hematopoiesis and leukemogenesis.

PURPOSE OF REVIEW: SH2 domain-containing tyrosine phosphatase 2 (SHP2), encoded by PTPN11 plays an important role in regulating signaling from cell surface receptor tyrosine kinases during normal development as well as oncogenesis. Herein we review recently discovered roles of SHP2 in normal and aberrant hematopoiesis along with novel strategies to target it. RECENT FINDINGS: Cell autonomous role of SHP2 in normal hematopoiesis and leukemogenesis has long been recognized. The review will discuss the newly discovered role of SHP2 in lineage specific differentiation. Recently, a noncell autonomous role of oncogenic SHP2 has been reported in which activated SHP2 was shown to alter the bone marrow microenvironment resulting in transformation of donor derived normal hematopoietic cells and development of myeloid malignancy. From being considered as an 'undruggable' target, recent development of allosteric inhibitor has made it possible to specifically target SHP2 in receptor tyrosine kinase driven malignancies. SUMMARY: SHP2 has emerged as an attractive target for therapeutic targeting in hematological malignancies for its cell autonomous and microenvironmental effects. However a better understanding of the role of SHP2 in different hematopoietic lineages and its crosstalk with signaling pathways activated by other genetic lesions is required before the promise is realized in the clinic.

Emergence of Ceftolozane-Tazobactam-Resistant Pseudomonas aeruginosa during Treatment Is Mediated by a Single AmpC Structural Mutation.

Ceftolozane-tazobactam is a cephalosporin-ß-lactamase inhibitor combination that exhibits potent in vitro activity against Pseudomonas aeruginosa, including strains that are resistant to other ß-lactams. The emergence of ceftolozane-tazobactam resistance among clinical isolates of P. aeruginosa has rarely been described. Here we characterized ceftolozane-tazobactam-resistant P. aeruginosa strains recovered from a patient who was treated with this agent for 6 weeks for a recurrent wound infection. The results showed that the resistance was mediated by a single AmpC structural mutation.

Emergence of Ceftazidime-Avibactam Resistance Due to Plasmid-Borne blaKPC-3 Mutations during Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections.

Ceftazidime-avibactam is a novel ß-lactam/ß-lactamase inhibitor with activity against carbapenem-resistant Enterobacteriaceae (CRE) that produce Klebsiella pneumoniae carbapenemase (KPC). We report the first cases of ceftazidime-avibactam resistance to develop during treatment of CRE infections and identify resistance mechanisms. Ceftazidime-avibactam-resistant K. pneumoniae emerged in three patients after ceftazidime-avibactam treatment for 10 to 19 days. Whole-genome sequencing (WGS) of longitudinal ceftazidime-avibactam-susceptible and -resistant K. pneumoniae isolates was used to identify potential resistance mechanisms. WGS identified mutations in plasmid-borne blaKPC-3, which were not present in baseline isolates. blaKPC-3 mutations emerged independently in isolates of a novel sequence type 258 sublineage and resulted in variant KPC-3 enzymes. The mutations were validated as resistance determinants by measuring MICs of ceftazidime-avibactam and other agents following targeted gene disruption in K. pneumoniae, plasmid transfer, and blaKPC cloning into competent Escherichia coli In rank order, the impact of KPC-3 variants on ceftazidime-avibactam MICs was as follows: D179Y/T243M double substitution > D179Y > V240G. Remarkably, mutations reduced meropenem MICs ≥4-fold from baseline, restoring susceptibility in K. pneumoniae from two patients. Cefepime and ceftriaxone MICs were also reduced ≥4-fold against D179Y/T243M and D179Y variant isolates, but susceptibility was not restored. Reverse transcription-PCR revealed that expression of blaKPC-3 encoding D179Y/T243M and D179Y variants was diminished compared to blaKPC-3 expression in baseline isolates. In conclusion, the development of resistance-conferring blaKPC-3 mutations in K. pneumoniae within 10 to 19 days of ceftazidime-avibactam exposure is troubling, but clinical impact may be ameliorated if carbapenem susceptibility is restored in certain isolates.

Symptom Development in Response to Combined Infection of In Vitro-grown Lilium longiflorum with Pratylenchus penetrans and Soilborne Fungi Collected from Diseased Roots of Field-grown Lilies.

Eight fungal isolates (ELRF 1 to 8) were recovered from necrotic roots of Easter lilies, Lilium longiflorum cv. Nellie White, grown in a field in the U.S. Pacific Northwest. The eight fungal isolates were identified by sequencing and molecular phylogenetic analyses based on their ITS rDNA region. Five isolates were identified as Fusarium oxysporum, two as F. tricinctum, and one as Rhizoctonia sp. AG-I. This constitutes the first report of Rhizoctonia sp. AG-I infecting lilies worldwide and the first report of F. tricinctum infecting lilies in the United States. To study and validate their pathogenicity, pure cultures of each isolate were used to infect the roots of Easter lily plants growing in vitro. In addition, Easter lily plants growing in vitro were infected either with or without Pratylenchus penetrans, the root lesion nematode, prior to placing a culture plug of fungus 1 cm from a lily root. Pratylenchus penetrans is a nematode species commonly found in the sampled fields. The presence of both nematode and Rhizoctonia sp. AG-I isolate ELRF 3 in infected lilies was evaluated by molecular analyses, confirming the infection of roots 3 days after inoculation, prior to development of disease symptoms. Necrosis and root rot developed more rapidly with all eight fungal isolates when there had been prior infection with P. penetrans, the major nematode parasitizing Easter lily roots in the field in Oregon.

MntR(Rv2788): a transcriptional regulator that controls manganese homeostasis in Mycobacterium tuberculosis.

The pathogenic mycobacterium Mycobacterium tuberculosis encodes two members of the DtxR/MntR family of metalloregulators, IdeR and SirR. IdeR represses gene expression in response to ferrous iron, and we here demonstrate that SirR (Rv2788), although also annotated as an iron-dependent repressor, functions instead as a manganese-dependent transcriptional repressor and is therefore renamed MntR. MntR regulates transporters that promote manganese import and genes that respond to metal ion deficiency such as the esx3 system. Repression of manganese import by MntR is essential for survival of M. tuberculosis under conditions of high manganese availability, but mntR is dispensable during infection. In contrast, manganese import by MntH and MntABCD was found to be indispensable for replication of M. tuberculosis in macrophages. These results suggest that manganese is limiting in the host and that interfering with import of this essential metal may be an effective strategy to attenuate M. tuberculosis.

Genomic Characterization of Enterobacter cloacae Isolates from China That Coproduce KPC-3 and NDM-1 Carbapenemases.

Here, we report twoEnterobacter cloacaesequence type 231 isolates coproducing KPC-3 and NDM-1 that have caused lethal infections in a tertiary hospital in China. TheblaNDM-1-harboring plasmids carry IncA/C2and IncR replicons, showing a mosaic plasmid structure, and theblaNDM-1is harbored on a novel class I integron-like element.blaKPC-3is located on a Tn3-ΔblaTEM-1-blaKPC-3-ΔTn1722element, flanked by two 9-bp direct-repeat sequences and harbored on an IncX6 plasmid.

Targeting phosphatidylinositol-3-kinase pathway for the treatment of Philadelphia-negative myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPN) are a diverse group of chronic hematological disorders that involve unregulated clonal proliferation of white blood cells. Sevearl of them are associated with mutations in receptor tyrosine kinases or cytokine receptor associated tyrosine kinases rendering them independent of cytokine-mediated regulation. Classically they have been broadly divided into BCR-ABL1 fusion + ve (Ph + ve) or -ve (Ph-ve) MPNs. Identification of BCR-ABL1 tyrosine kinase as a driver of chronic myeloid leukemia (CML) and successful application of small molecule inhibitors of the tyrosine kinases in the clinic have triggered the search for kinase dependent pathways in other Ph-ve MPNs. In the past few years, identification of mutations in JAK2 associated with a majority of MPNs raised the hopes for similar success with specific targeting of JAK2. However, targeting JAK2 kinase activity has met with limited success. Subsequently, mutations in genes other than JAK2 have been identified. These mutations specifically associate with certain MPNs and can drive cytokine independent growth. Therefore, targeting alternate molecules and pathways may be more successful in management of MPNs. Among other pathways, phosphatidylinositol -3 kinase (PI3K) has emerged as a promising target as different cell surface receptor induced signaling pathways converge on the PI3K signaling axis to regulate cell metabolism, growth, proliferation, and survival. Herein, we will review the clinically relevant inhibitors of the PI3K pathway that have been evaluated or hold promise for the treatment of Ph-ve MPNs.

IdeR is required for iron homeostasis and virulence in Mycobacterium tuberculosis.

Iron is an essential but potentially harmful nutrient, poorly soluble in aerobic conditions, and not freely available in the human host. To acquire iron, bacteria have evolved high affinity iron acquisition systems that are expressed under iron limitation often in conjunction with virulence determinants. Because excess iron can be dangerous, intracellular iron must be tightly controlled. In mycobacteria, IdeR functions as a global iron dependent transcriptional regulator, but because inactivation of ideR is lethal for Mycobacterium tuberculosis, it has not been possible to use genetics to fully characterize this protein's function or examine the requirement of iron regulation during tuberculosis infection. In this work, a conditional M. tuberculosis ideR mutant was generated and used to study the basis of IdeR's essentiality. This investigation uncovered positive regulation of iron storage as a critical aspect of IdeR's function in regular culture and a prominent factor for survival under stresses associated with life in macrophages. Moreover, this study demonstrates that IdeR is indispensable in the mouse model of tuberculosis, thereby linking iron homeostasis to virulence in M. tuberculosis.

SMAC Mimetics for the Treatment of Lung Carcinoma: Present Development and Future Prospects.

BACKGROUND: Uncontrolled cell growth and proliferation, which originate from lung tissue often lead to lung carcinoma and are more likely due to smoking as well as inhaled environmental toxins. It is widely recognized that tumour cells evade the ability of natural programmed death (apoptosis) and facilitates tumour progression and metastasis. Therefore investigating and targeting the apoptosis pathway is being utilized as one of the best approaches for decades. OBJECTIVE: This review describes the emergence of SMAC mimetic drugs as a treatment approach, its possibilities to synergize the response along with current limitations as well as future perspective therapy for lung cancer. METHOD: Articles were analysed using search engines and databases namely Pubmed and Scopus. RESULT: Under cancerous circumstances, the level of Inhibitor of Apoptosis Proteins (IAPs) gets elevated, which suppresses the pathway of programmed cell death, plus supports the proliferation of lung cancer. As it is a major apoptosis regulator, natural drugs that imitate the IAP antagonistic response like SMAC mimetic agents/Diablo have been identified to trigger cell death. SMAC i.e. second mitochondria activators of caspases is a molecule produced by mitochondria, stimulates apoptosis by neutralizing/inhibiting IAP and prevents its potential responsible for the activation of caspases. Various preclinical data have proven that these agents elicit the death of lung tumour cells. Apart from inducing apoptosis, these also sensitize the cancer cells toward other effective anticancer approaches like chemo, radio, or immunotherapies. There are many SMAC mimetic agents such as birinapant, BV-6, LCL161, and JP 1201, which have been identified for diagnosis as well as treatment purposes in lung cancer and are also under clinical investigation. CONCLUSION: SMAC mimetics acts in a restorative way in the prevention of lung cancer.

Alkynyl nicotinamides show antileukemic activity in drug-resistant acute myeloid leukemia.

Activating mutations of FLT3 contribute to deregulated hematopoietic stem and progenitor cell (HSC/Ps) growth and survival in patients with acute myeloid leukemia (AML), leading to poor overall survival. AML patients treated with investigational drugs targeting mutant FLT3, including Quizartinib and Crenolanib, develop resistance to these drugs. Development of resistance is largely due to acquisition of cooccurring mutations and activation of additional survival pathways, as well as emergence of additional FLT3 mutations. Despite the high prevalence of FLT3 mutations and their clinical significance in AML, there are few targeted therapeutic options available. We have identified 2 novel nicotinamide-based FLT3 inhibitors (HSN608 and HSN748) that target FLT3 mutations at subnanomolar concentrations and are potently effective against drug-resistant secondary mutations of FLT3. These compounds show antileukemic activity against FLT3ITD in drug-resistant AML, relapsed/refractory AML, and in AML bearing a combination of epigenetic mutations of TET2 along with FLT3ITD. We demonstrate that HSN748 outperformed the FDA-approved FLT3 inhibitor Gilteritinib in terms of inhibitory activity against FLT3ITD in vivo.

IgA Levels among Type 2 Diabetic and Non-Diabetic Patients with Periodontitis: A Prospective Clinical Study.

OBJECTIVES: To estimate gingival crevicular immunoglobulin A(IgA) using enzyme-linked immunosorbent assay (ELISA) among type II diabetic patients with periodontitis. MATERIALS AND METHODS: A non-randomized study was done of 40 periodontitis subjects with a mean age of 50 years and were recruited into two groups, Group A (Type II controlled diabetics with HbA1c < 7%) and Group B (non-diabetics with HbA1c between 4 and 6%). Both the groups underwent nonsurgical periodontal therapy (NSPT). The clinical parameters were recorded at baseline, 1, and 3 months. GCF sample was collected for the estimation of crevicular IgA at baseline and at 3 months. STATISTICAL ANALYSIS: Results were analyzed using parametric tests paired t-test and Student's t-test for every assessment point. The level of significance was set at p < 0.05. RESULTS: Difference in IgA levels and clinical parameters was seen between diabetic and non-diabetic groups, which was statistically significant. CONCLUSION: Changes in crevicular IgA levels in patients with diabetic periodontitis can be used as a novel biomarker in assessing the inflammatory status.

Association of Serum Ferritin Level in Early Second Trimester of Pregnancy with Development of Gestational Diabetes Mellitus: A Prospective Observational Study.

Background: Gestational diabetes mellitus (GDM) is associated with various maternal and perinatal morbidities. Serum ferritin is a major storage protein of iron and also acts as acute phase reactant which is increased in inflammatory conditions. GDM is a state of insulin resistance and associated with inflammation. The aim of this study was to find the correlation between serum ferritin and development of GDM. Objectives: To determine the serum ferritin concentration in nonanemic pregnant women and its correlation with subsequent development of GDM. Methodology: In this prospective observational study, 302 nonanemic pregnant women with singleton gestation between 14 and 20 weeks, attending antenatal OPD, were enrolled. Serum ferritin was measured at the time of enrolment, and they were followed till 24-28 weeks of gestation and subjected to blood glucose test by DIPSI method. A total of 92 women had blood glucose level ≥ 140 mg/dl and were labeled as GDM, and 210 pregnant women with blood glucose level < 140 mg/dl were labeled as non-GDM. Result: Mean serum ferritin level of women with GDM (56.44 ± 19.19 ng/ml) was found to be higher as compared to non-GDM (27.62 ± 12.11 ng/ml), and this difference was found to be statistically significant (p < 0.001). The cutoff value of serum ferritin > 37.55 ng/ml was found to be 85.9% sensitive and 81.9% specific. Conclusion: We can infer that serum ferritin is associated with development of GDM. Based on the findings of the current study, serum ferritin level can be used a predictive marker for the development of GDM.

Tumor-associated macrophages employ immunoediting mechanisms in colorectal tumor progression: Current research in Macrophage repolarization immunotherapy.

Tumor-associated macrophages (TAMs) constitute the most prolific resident of the tumor microenvironment (TME) that regulate its TME into tumor suppressive or progressive milieu by utilizing immunoediting machinery. Here, the tumor cells construct an immunosuppressive microenvironment that educates TAMs to polarize from anti-tumor TAM-M1 to pro-tumor TAM-M2 phenotype consequently contributing to tumor progression. In colorectal cancer (CRC), the TME displays a prominent pro-tumorigenic immune profile with elevated expression of immune-checkpoint molecules notably PD-1, CTLA4, etc., in both MSI and ultra-mutated MSS tumors. This authenticated immune-checkpoint inhibition (ICI) immunotherapy as a pre-requisite for clinical benefit in CRC. However, in response to ICI, specifically, the MSIhi tumors evolved to produce novel immune escape variants thus undermining ICI. Lately, TAM-directed therapies extending from macrophage depletion to repolarization have enabled TME alteration. While TAM accrual implicates clinical benefit in CRC, sustained inflammatory insult may program TAMs to shift from M1 to M2 phenotype. Their ability to oscillate on both facets of the spectrum represents macrophage repolarization immunotherapy as an effective approach to treating CRC. In this review, we briefly discuss the differentiation heterogeneity of colonic macrophages that partake in macrophage-directed immunoediting mechanisms in CRC progression and its employment in macrophage re-polarization immunotherapy.

Therapeutic approaches for the treatment of Interstitial Lung Disease: An exploratory review on molecular mechanisms.

BACKGROUND: Interstitial Lung Diseases (ILDs) are characterized by shortness of breath caused by alveolar wall inflammation and/or fibrosis. OBJECTIVE: Our review aims to study the depth of various variants of ILD, diagnostic procedures, pathophysiology, molecular dysfunction and regulation, subject and objective assessment techniques, pharmacological intervention, exercise training and various modes of delivery for rehabilitation. METHOD: Articles are reviewed from PubMed and Scopus and search engines. RESULTS: ILD is a rapidly progressing disease with a high mortality rate. Each variant has its own set of causal agents and expression patterns. Patients often find it challenging to self-manage due to persistent symptoms and a rapid rate of worsening. The present review elaborated on the pathophysiology, risk factors, molecular mechanisms, diagnostics, and therapeutic approaches for ILD will guide future requirements in the quest for innovative and tailored ILD therapies at the molecular and cellular levels. CONCLUSION: The review highlights the rationale for conventional and novel therapeutic approaches for better management of ILD.

A ferritin mutant of Mycobacterium tuberculosis is highly susceptible to killing by antibiotics and is unable to establish a chronic infection in mice.

Iron is an essential, elusive, and potentially toxic nutrient for most pathogens, including Mycobacterium tuberculosis. Due to the poor solubility of ferric iron under aerobic conditions, free iron is not found in the host. M. tuberculosis requires specialized iron acquisition systems to replicate and cause disease. It also depends on a strict control of iron metabolism and intracellular iron levels to prevent iron-mediated toxicity. Under conditions of iron sufficiency, M. tuberculosis represses iron acquisition and induces iron storage, suggesting an important role for iron storage proteins in iron homeostasis. M. tuberculosis synthesizes two iron storage proteins, a ferritin (BfrB) and a bacterioferritin (BfrA). The individual contributions of these proteins to the adaptive response of M. tuberculosis to changes in iron availability are not clear. By generating individual knockout strains of bfrA and bfrB, the contribution of each one of these proteins to the maintenance of iron homeostasis was determined. The effect of altered iron homeostasis, resulting from impaired iron storage, on the resistance of M. tuberculosis to in vitro and in vivo stresses was examined. The results show that ferritin is required to maintain iron homeostasis, whereas bacterioferritin seems to be dispensable for this function. M. tuberculosis lacking ferritin suffers from iron-mediated toxicity, is unable to persist in mice, and, most importantly, is highly susceptible to killing by antibiotics, showing that endogenous oxidative stress can enhance the antibiotic killing of this important pathogen. These results are relevant for the design of new therapeutic strategies against M. tuberculosis.

Role of PARP Inhibitors in Glioblastoma and Perceiving Challenges as Well as Strategies for Successful Clinical Development.

Glioblastoma multiform is the most aggressive primary type of brain tumor, representing 54% of all gliomas. The average life span for glioblastoma multiform is around 14-15 months instead of treatment. The current treatment for glioblastoma multiform includes surgical removal of the tumor followed by radiation therapy and temozolomide chemotherapy for 6.5 months, followed by another 6 months of maintenance therapy with temozolomide chemotherapy (5 days every month). However, resistance to temozolomide is frequently one of the limiting factors in effective treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors have recently been investigated as sensitizing drugs to enhance temozolomide potency. However, clinical use of PARP inhibitors in glioblastoma multiform is difficult due to a number of factors such as limited blood-brain barrier penetration of PARP inhibitors, inducing resistance due to frequent use of PARP inhibitors, and overlapping hematologic toxicities of PARP inhibitors when co-administered with glioblastoma multiform standard treatment (radiation therapy and temozolomide). This review elucidates the role of PARP inhibitors in temozolomide resistance, multiple factors that make development of these PARP inhibitor drugs challenging, and the strategies such as the development of targeted drug therapies and combination therapy to combat the resistance of PARP inhibitors that can be adopted to overcome these challenges.