Publications by authors named "Ramandeep Singh"

295 Publications

Artificial intelligence-based vessel suppression for detection of sub-solid nodules in lung cancer screening computed tomography.

Quant Imaging Med Surg 2021 Apr;11(4):1134-1143

Division of Thoracic Imaging and Intervention, Massachusetts General Hospital, Boston, MA, USA.

Background: Lung cancer screening (LCS) with low-dose computed tomography (LDCT) helps early lung cancer detection, commonly presenting as small pulmonary nodules. Artificial intelligence (AI)-based vessel suppression (AI-VS) and automatic detection (AI-AD) algorithm can improve detection of subsolid nodules (SSNs) on LDCT. We assessed the impact of AI-VS and AI-AD in detection and classification of SSNs [ground-glass nodules (GGNs) and part-solid nodules (PSNs)], on LDCT performed for LCS.

Methods: Following regulatory approval, 123 LDCT examinations with sub-solid pulmonary nodules (average diameter ≥6 mm) were processed to generate three image series for each examination-unprocessed, AI-VS, and AI-AD series with annotated lung nodules. Two thoracic radiologists in consensus formed the standard of reference (SOR) for this study. Two other thoracic radiologists (R1 and R2; 5 and 10 years of experience in thoracic CT image interpretation) independently assessed the unprocessed images alone, then together with AI-VS series, and finally with AI-AD for detecting all ≥6 mm GGN and PSN. We performed receiver operator characteristics (ROC) and Cohen's Kappa analyses for statistical analyses.

Results: On unprocessed images, R1 and R2 detected 232/310 nodules (R1: 114 GGN, 118 PSN) and 255/310 nodules (R2: 122 GGN, 133 PSN), respectively (P>0.05). On AI-VS images, they detected 249/310 nodules (119 GGN, 130 PSN) and 277/310 nodules (128 GGN, 149 PSN), respectively (P≥0.12). When compared to the SOR, accuracy (AUC) for detection of PSN on the AI-VS images (AUC 0.80-0.81) was greater than on the unprocessed images (AUC 0.70-0.76). AI-VS images enabled detection of solid components in five nodules deemed as GGN on the unprocessed images. Accuracy of AI-AD was lower than both the radiologists (AUC 0.60-0.72).

Conclusions: AI-VS improved the detection and classification of SSN into GGN and PSN on LDCT of the chest for the two radiologist (R1 and R2) readers.
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http://dx.doi.org/10.21037/qims-20-630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930659PMC
April 2021

Monocarbonyl curcuminoids as antituberculosis agents with their moderate in-vitro metabolic stability on human liver microsomes.

J Biochem Mol Toxicol 2021 Mar 10:e22754. Epub 2021 Mar 10.

Department of Chemistry, University of Delhi, New Delhi, India.

Tuberculosis, an airborne infectious disease, results in a high morbidity and mortality rate. The continuous emergence of TB resistance strains including MDR (multidrug-resistant tuberculosis), XDR (extensive drug-resistant tuberculosis), and especially TDR (totally drug-resistant tuberculosis) is a major public health threat and has intensified the need to develop new antitubercular agents. A natural product, curcumin, possesses diverse biological activities but suffers due to a lack of water solubility and bioavailability. To overcome these limitations, a series of 17 water-soluble monocarbonyl curcuminoids was synthesized and evaluated for antimycobacterial activity. All compounds exhibited good to moderate anti-TB activity with MIC in the range of 3.12-25.0 µM, out of which 7c and 7p were found the most potent compounds with MIC in the range of 3.12-6.25 µM. Furthermore, these compounds were observed to be nonhaemolytic, nontoxic, and stable under both physiological as well as reducing conditions. In-vitro metabolic stability data of the representative compound 7p with the human liver microsome revealed that these compounds possess a moderate metabolism with a half-life of 1.2 h and an intrinsic clearance of 1.12 ml/h/mg.
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http://dx.doi.org/10.1002/jbt.22754DOI Listing
March 2021

Ultra-wide field retinal imaging: A wider clinical perspective.

Indian J Ophthalmol 2021 Apr;69(4):824-835

RP Centre, AIIMS, New Delhi, India.

The peripheral retina is affected in a variety of retinal disorders. Traditional fundus cameras capture only a part of the fundus even when montaging techniques are used. Ultra-wide field imaging enables us to delve into the retinal periphery in greater detail. It not only facilitates assessing color images of the fundus, but also fluorescein angiography, indocyanine green angiography, fundus autofluorescence, and red and green free images. In this review, a literature search using the keywords "ultra-widefield imaging", "widefield imaging", and "peripheral retinal imaging" in English and non-English languages was done and the relevant articles were included. Ultra-wide field imaging has made new observations in the normal population as well as in eyes with retinal disorders including vascular diseases, degenerative diseases, uveitis, age-related macular degeneration, retinal and choroidal tumors and hereditary retinal dystrophies. This review aims to describe the utility of ultra-wide field imaging in various retinal disorders.
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http://dx.doi.org/10.4103/ijo.IJO_1403_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012972PMC
April 2021

Sensitivity and specificity of neuroimaging signs in patients with idiopathic intracranial hypertension.

Neuroradiol J 2021 Mar 8:19714009211000623. Epub 2021 Mar 8.

Department of Neurology, Postgraduate Institute of Medical Education and Research (PGIMER), India.

Background: The primary role of neuroimaging in idiopathic intracranial hypertension (IIH) is to exclude secondary causes of raised intracranial pressure. Recently, a few imaging markers have been described which may suggest diagnosis of IIH in atypical cases. We carried out this study to assess the prevalence and accuracy of these neuroimaging signs in predicting the diagnosis of IIH.

Methods: Eighty treatment-naive patients with IIH and 30 controls were recruited as per a predefined criterion. Magnetic resonance imaging (MRI) brain with detailed sella imaging was done in all patients.

Results: The most common abnormality noted was optic nerve tortuosity in 82.5% of patients, followed by posterior scleral flattening in 80%, perioptic subarachnoid space (SAS) dilatation in 73.8% and partial empty sella in 68.8% of patients. The presence of optic nerve tortuosity was the most sensitive sign on neuroimaging, though the highest specificity was seen for posterior scleral flattening and perioptic SAS dilatation. The presence of more than three neuroimaging features correlated with severity of vision loss.

Conclusion: In suggestive clinical scenarios, posterior scleral flattening, perioptic SAS dilatation and optic nerve tortuosity are highly sensitive and specific signs in IIH. This study also highlights the utility of MRI as a valuable tool for prognosis of visual outcome in patients with IIH.
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http://dx.doi.org/10.1177/19714009211000623DOI Listing
March 2021

Multimodal imaging to aid in diagnosis of uveal effusion syndrome type 3.

BMJ Case Rep 2021 Mar 2;14(3). Epub 2021 Mar 2.

Advanced eye centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India

A 47-year-old man presented to our retina clinic with gradual onset diminution of vision in his right eye for the last 3 months. Anterior segment evaluation was normal in both eyes. Fundus evaluation showed the presence of leopard spot appearance in the right eye with inferior exudative retinal detachment. Multimodal imaging was done to evaluate retinal pigment epithelium function, choroidal thickness, choroidal vascularity and scleral thickness. Multimodal imaging showed increased choroidal thickness, choroidal congestion on indocyanine green angiography and peripheral choroidal detachment with normal sclera thickness in our patient, thus pointing towards a diagnosis of uveal effusion syndrome type 3.
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http://dx.doi.org/10.1136/bcr-2020-239556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929847PMC
March 2021

Corrigendum to Deciphering the genes involved in pathogenesis of Mycobacterium tuberculosis [Tuberculosis 85/5-6 325-335].

Tuberculosis (Edinb) 2021 Mar 19;127:102042. Epub 2021 Feb 19.

Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi, 110021, India. Electronic address:

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http://dx.doi.org/10.1016/j.tube.2020.102042DOI Listing
March 2021

TA-AAV: Are the visual outcomes different from GCA?

Arthritis Rheumatol 2021 Feb 18. Epub 2021 Feb 18.

Clinical Immunology and Rheumatology Unit, Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

The article by Delaval et al. beautifully highlighted the differences between clinical manifestations and temporal artery biopsy (TAB) in TA-AAV and GCA patients [1]. However, the differences in visual outcomes, if any, were not reported. Since visual outcomes in GCA are generally poor and can progress despite treatment, it would be interesting to know the visual outcomes in these patients[2, 3]. Two of our patients with early TA-AAV had good visual outcomes with treatment.
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http://dx.doi.org/10.1002/art.41698DOI Listing
February 2021

Outcomes of 25-gauge pars plana vitrectomy with encircling scleral band for acute retinal necrosis-related rhegmatogenous retinal detachment.

Indian J Ophthalmol 2021 Mar;69(3):635-640

Department of Ophthalmology, Advanced Eye Centre; This Study was Conducted at Advanced Eye Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

Purpose: The aim of this study was to evaluate the anatomic and functional outcomes of 25-gauge pars plana vitrectomy (25G PPV) with encircling scleral band (ESB) in patients with acute retinal necrosis (ARN)-related rhegmatogenous retinal detachment (RRD).

Methods: Single-center retrospective interventional case series of patients who underwent 25G PPV with ESB for ARN-related RRD. Complete anatomic success was defined as the complete attachment of retina after primary PPV. Functional success was measured by the final best-corrected visual acuity (BCVA) ≥20/400. Intraoperative and postoperative complications were also noted.

Results: 14 eyes of 13 patients were included in the study. Six patients (46.1%) were immunocompromised. The mean follow-up was 23.64 ± 9.95 (range 6-42) months. Silicone oil was used as tamponade in 13 eyes and CFgas in one eye. After the primary PPV, complete anatomical success was seen in all eyes (100%), however, one eye developed phthisis bulbi after silicone oil removal (SOR). Statistically significant improvement of BCVA was seen, from LogMAR 2.03 ± 0.29 preoperatively to LogMAR 1.57 ± 0.63 postoperatively (p-value 0.014). Six eyes (42.9%) had functional success. Nine eyes (64.3%) had improvement in vision while 4 eyes (28.6%) maintained preoperative vision. 10 eyes (71.4%) underwent cataract surgery, nine eyes (64.3%) underwent SOR while 2 eyes (14.3%) had epiretinal membrane (ERM) under oil during follow-up.

Conclusion: 25G PPV combines the advantages of minimally invasive vitrectomy surgery while offering improved anatomic outcomes in patients with ARN-related RRD. The functional outcome varies depending on the status of the optic disc and macula.
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http://dx.doi.org/10.4103/ijo.IJO_1353_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942078PMC
March 2021

Computer-assisted Reporting and Decision Support Increases Compliance with Follow-up Imaging and Hormonal Screening of Adrenal Incidentalomas.

Acad Radiol 2021 Feb 12. Epub 2021 Feb 12.

MGH & BWH Center for Clinical Data Science, Suite 1303, 100 Cambridge St, Boston, MA 02114 (R.R.A., B.C.B., K.P.A., T.K.A.); Radiology Department, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114 (B.C.B., R.S., T.K.A.). Electronic address:

Objective: To assess the impact of using a computer-assisted reporting and decision support (CAR/DS) tool at the radiologist point-of-care on ordering provider compliance with recommendations for adrenal incidentaloma workup.

Method: Abdominal CT reports describing adrenal incidentalomas (2014 - 2016) were retrospectively extracted from the radiology database. Exclusion criteria were history of cancer, suspected functioning adrenal tumor, dominant nodule size < 1 cm or ≥ 4 cm, myelolipomas, cysts, and hematomas. Multivariable logistic regression models were employed to predict follow-up imaging (FUI) and hormonal screening orders as a function of patient age and sex, nodule size, and CAR/DS use. CAR/DS reports were compared to conventional reports regarding ordering provider compliance with, frequency, and completeness of, guideline-warranted recommendations for FUI and hormonal screening of adrenal incidentalomas using Chi-square test.

Result: Of 174 patients (mean age 62.4; 51.1% women) with adrenal incidentalomas, 62% (108/174) received CAR/DS-based recommendations versus 38% (66/174) unassisted recommendations. CAR/DS use was an independent predictor of provider compliance both with FUI (Odds Ratio [OR]=2.47, p = 0.02) and hormonal screening (OR=2.38, p = 0.04). CAR/DS reports recommended FUI (97.2%,105/108) and hormonal screening (87.0%,94/108) more often than conventional reports (respectively, 69.7% [46/66], 3.0% [2/66], both p <0.0001). CAR/DS recommendations more frequently included instructions for FUI time, protocol, and modality than conventional reports (all p <0.001).

Conclusion: Ordering providers were at least twice as likely to comply with report recommendations for FUI and hormonal evaluation of adrenal incidentalomas generated using CAR/DS versus unassisted reporting. CAR/DS-directed recommendations were more adherent to guidelines than those generated without.
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http://dx.doi.org/10.1016/j.acra.2021.01.019DOI Listing
February 2021

COVID-19: Current knowledge in clinical features, immunological responses, and vaccine development.

FASEB J 2021 03;35(3):e21409

McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Medicine, McMaster University, Hamilton, ON, Canada.

The COVID-19 pandemic has unfolded to be the most challenging global health crisis in a century. In 11 months since its first emergence, according to WHO, the causative infectious agent SARS-CoV-2 has infected more than 100 million people and claimed more than 2.15 million lives worldwide. Moreover, the world has raced to understand the virus and natural immunity and to develop vaccines. Thus, within a short 11 months a number of highly promising COVID-19 vaccines were developed at an unprecedented speed and are now being deployed via emergency use authorization for immunization. Although a considerable number of review contributions are being published, all of them attempt to capture only a specific aspect of COVID-19 or its therapeutic approaches based on ever-expanding information. Here, we provide a comprehensive overview to conceptually thread together the latest information on global epidemiology and mitigation strategies, clinical features, viral pathogenesis and immune responses, and the current state of vaccine development.
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http://dx.doi.org/10.1096/fj.202002662RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898934PMC
March 2021

Streptomycin sulphate loaded solid lipid nanoparticles show enhanced uptake in macrophage, lower MIC in Mycobacterium and improved oral bioavailability.

Eur J Pharm Biopharm 2021 Mar 23;160:100-124. Epub 2021 Jan 23.

University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study, Panjab University, Chandigarh 160014, India. Electronic address:

Present study addresses the challenge of incorporating hydrophilic streptomycin sulphate (STRS; log P -6.4) with high dose (1 g/day) into a lipid matrix of SLNs. Cold high-pressure homogenization technique used for SLN preparation achieved 30% drug loading and 51.17 ± 0.95% entrapment efficiency. Polyethylene glycol 600 as a supporting-surfactant assigned small size (218.1 ± 15.46 nm) and mucus-penetrating property. It was conceived to administer STRS-SLNs orally rather than intramuscularly. STRS-SLNs remained stable on incubation for varying times in SGF or SIF. STRS-SLNs were extensively characterised for microscopic (TEM and AFM), thermal (DSC), diffraction (XRD) and spectroscopic (NMR and FTIR) properties and showed zero-order controlled release. Enhanced (60 times) intracellular uptake was observed in THP-1 and Pgp expressing LoVo and DLD-1 cell lines, using fluorescein-SLNs. Presence of SLNs in LoVo cells was also revealed by TEM studies. STRS-SLNs showed 3 times reduction in MIC against Mycobacterium tuberculosis H37RV (256182) in comparison to free STRS. It also showed better activity against both M. bovis BCG and Mycobacterium tuberculosis H37RV (272994) in comparison to free STRS. Cytotoxicity and acute toxicity studies (OECD 425 guidelines) confirmed in vitro and in vivo safety of STRS-SLNs. Single-dose oral pharmacokinetic studies in rat plasma using validated LCMS/MS technique or the microbioassay showed significant oral absorption and bioavailability (160% - 710% increase than free drug).
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http://dx.doi.org/10.1016/j.ejpb.2021.01.009DOI Listing
March 2021

Magnetic resonance imaging (MRI) versus computed tomographic scan (CT scan) of brain in evaluation of suspected cavernous sinus syndrome.

Neuroradiol J 2020 Dec;33(6):501-507

Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

Background And Purpose: The cavernous sinus is a unique region owing to anatomical factors and the pathologies affecting it. The diagnosis of cavernous sinus syndrome (CSS) predominantly relies on clinicoradiological correlation. We studied the utility of computed tomographic (CT) scan versus magnetic resonance imaging (MRI) in the diagnosis of CSS.

Methods: A prospective observational study was conducted in a tertiary care center in north India. All patients presenting with a clinical syndrome of cavernous sinus involvement with radiologically confirmed lesions were enrolled in the study. MRI and CT scan with cavernous sinus cuts were done and reviewed by experienced neuroradiologists for cavernous sinus lesions and compared with the final diagnosis. Sensitivity and specificity were calculated.

Results: We included 48 patients in our study. A final diagnosis was achieved in 41 out of 48 (85.6%) patients. Fungal infections (16 (33.3%)) constituted the commonest cause of CSS, followed by neoplastic involvement (13 (27.1%)) and Tolosa-Hunt syndrome (12 (25%)). Vascular involvement was seen in three (6.3%) patients. Other rare causes were seen in four (8.3%) patients. CT scan had an overall sensitivity of 14.6% in achieving a final diagnosis, whereas MRI had an overall sensitivity of 70.7%, with a statistically significant difference ( < 0.001).

Conclusions: Although CT scan is a relatively cheap and accessible resource, its role in CSS diagnosis and management is limited because of poor yield. Hence, it is prudent to do an MRI as an initial investigation in cases of CSS.
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http://dx.doi.org/10.1177/1971400920970921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788673PMC
December 2020

Paracentral Acute Middle Maculopathy in Bartonella Henselae Neuroretinitis.

Ophthalmol Retina 2020 Dec;4(12):1201

Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

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http://dx.doi.org/10.1016/j.oret.2020.06.004DOI Listing
December 2020

Quantifying and leveraging predictive uncertainty for medical image assessment.

Med Image Anal 2021 02 14;68:101855. Epub 2020 Oct 14.

Siemens Healthineers, Digital Technology and Innovation, Princeton, NJ, USA.

The interpretation of medical images is a challenging task, often complicated by the presence of artifacts, occlusions, limited contrast and more. Most notable is the case of chest radiography, where there is a high inter-rater variability in the detection and classification of abnormalities. This is largely due to inconclusive evidence in the data or subjective definitions of disease appearance. An additional example is the classification of anatomical views based on 2D Ultrasound images. Often, the anatomical context captured in a frame is not sufficient to recognize the underlying anatomy. Current machine learning solutions for these problems are typically limited to providing probabilistic predictions, relying on the capacity of underlying models to adapt to limited information and the high degree of label noise. In practice, however, this leads to overconfident systems with poor generalization on unseen data. To account for this, we propose a system that learns not only the probabilistic estimate for classification, but also an explicit uncertainty measure which captures the confidence of the system in the predicted output. We argue that this approach is essential to account for the inherent ambiguity characteristic of medical images from different radiologic exams including computed radiography, ultrasonography and magnetic resonance imaging. In our experiments we demonstrate that sample rejection based on the predicted uncertainty can significantly improve the ROC-AUC for various tasks, e.g., by 8% to 0.91 with an expected rejection rate of under 25% for the classification of different abnormalities in chest radiographs. In addition, we show that using uncertainty-driven bootstrapping to filter the training data, one can achieve a significant increase in robustness and accuracy. Finally, we present a multi-reader study showing that the predictive uncertainty is indicative of reader errors.
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http://dx.doi.org/10.1016/j.media.2020.101855DOI Listing
February 2021

Soybean lectin induces autophagy through P2RX7 dependent activation of NF-κB-ROS pathway to kill intracellular mycobacteria.

Biochim Biophys Acta Gen Subj 2021 02 28;1865(2):129806. Epub 2020 Nov 28.

Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India. Electronic address:

Background: Host-directed therapy is considered a novel anti-tuberculosis strategy in tackling the tuberculosis burden through autophagy induction by various inducers to curtail the growth of intracellular Mycobacterium tuberculosis.

Methods: In this study, we investigated the anti-tubercular role of soybean lectin, a lectin isolated from Glycine max (Soybean). Effect of SBL on intracellular mycobacterial viability through autophagy and the mechanism involved in differentiated THP-1 cells was studied using different experimental approaches.

Results: We initially performed a time kinetic experiment with the non-cytotoxic dose of SBL (20 μg/ml) and observed autophagy induction after 24 h of treatment. Abrogation of autophagy in the presence of 3-MA and an increase in LC3 puncta formation upon Baf-A1 addition elucidated the specific effect on autophagy and autophagic flux. SBL treatment also led to autophagy induction in mycobacteria infected macrophages that restricted the intracellular mycobacterial growth, thus emphasizing the host defensive role of SBL induced autophagy. Mechanistic studies revealed an increase in P2RX7 expression, NF-κB activation and reactive oxygen species generation upon SBL treatment. Inhibition of P2RX7 expression suppressed NF-κB dependent ROS level in SBL treated cells. Moreover, SBL induced autophagy was abrogated in the presence of either different inhibitors or P2RX7 siRNA, leading to the reduced killing of intracellular mycobacteria.

Conclusion: Taken together, these results conclude that SBL induced autophagy exerts an anti-mycobacterial effect in P2RX7-NF-κB dependent manner through the generation of ROS.

General Significance: This study has provided a novel anti-mycobacterial role of SBL, which may play an important role in devising new therapeutic interventions.
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http://dx.doi.org/10.1016/j.bbagen.2020.129806DOI Listing
February 2021

Artificial intelligence in image reconstruction: The change is here.

Phys Med 2020 Nov 24;79:113-125. Epub 2020 Nov 24.

Department of Radiology, Division of Thoracic Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:

Innovations in CT have been impressive among imaging and medical technologies in both the hardware and software domain. The range and speed of CT scanning improved from the introduction of multidetector-row CT scanners with wide-array detectors and faster gantry rotation speeds. To tackle concerns over rising radiation doses from its increasing use and to improve image quality, CT reconstruction techniques evolved from filtered back projection to commercial release of iterative reconstruction techniques, and recently, of deep learning (DL)-based image reconstruction. These newer reconstruction techniques enable improved or retained image quality versus filtered back projection at lower radiation doses. DL can aid in image reconstruction with training data without total reliance on the physical model of the imaging process, unique artifacts of PCD-CT due to charge sharing, K-escape, fluorescence x-ray emission, and pulse pileups can be handled in the data-driven fashion. With sufficiently reconstructed images, a well-designed network can be trained to upgrade image quality over a practical/clinical threshold or define new/killer applications. Besides, the much smaller detector pixel for PCD-CT can lead to huge computational costs with traditional model-based iterative reconstruction methods whereas deep networks can be much faster with training and validation. In this review, we present techniques, applications, uses, and limitations of deep learning-based image reconstruction methods in CT.
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http://dx.doi.org/10.1016/j.ejmp.2020.11.012DOI Listing
November 2020

Correction for Singh et al., "The Three RelE Homologs of Mycobacterium tuberculosis Have Individual, Drug-Specific Effects on Bacterial Antibiotic Tolerance".

J Bacteriol 2020 Nov 19;202(24). Epub 2020 Nov 19.

Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892

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http://dx.doi.org/10.1128/JB.00554-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685548PMC
November 2020

The Collaborative Ocular Tuberculosis Study (COTS)-1: A Multinational Review of 447 Patients with Tubercular Intermediate Uveitis and Panuveitis.

Ocul Immunol Inflamm 2020 Nov 17:1-11. Epub 2020 Nov 17.

Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER) , Chandigarh, India.

Tubercular intermediate uveitis (TIU) and panuveitis (TBP) are difficult to manage because of limitations in diagnostic tools and lack of evidence-based treatment guidelines. The Collaborative Ocular Tuberculosis Study (COTS) analyzed treatment regimens and therapeutic outcomes in patients with TIU and TBP. Multicentre retrospective analysis. A total of 138 TIU and 309 TBP patients were included. A total of 382 subjects received antitubercular therapy (ATT) (n = 382/447; 85.4%) and 382 received corticosteroids (n = 382/447; 85.4%). Treatment failure was observed in 78 individuals (n = 78/447; 17.4%), occurring less frequently in patients receiving ATT (n = 66/382; 17.2%) compared to those who did not (n = 12/65; 18.5%). The study did not show any statistically significant therapeutic effect of ATT in patients with TIU and TBP. Taking into account the limitations of the retrospective, non-randomized study design, resultant reliance on reported data records, and unequal size of the samples, the current study cannot provide conclusive evidence on the therapeutic benefit of ATT in TIU and TBP.
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http://dx.doi.org/10.1080/09273948.2020.1808226DOI Listing
November 2020

Corrigendum: CitE Enzymes Are Essential for to Establish Infection in Macrophages and Guinea Pigs.

Front Cell Infect Microbiol 2020 30;10:587907. Epub 2020 Oct 30.

Tuberculosis Research Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, Faridabad, India.

[This corrects the article DOI: 10.3389/fcimb.2018.00385.].
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http://dx.doi.org/10.3389/fcimb.2020.587907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662888PMC
October 2020

Corrigendum to 'Elicitation of efficient, protective immune responses by using DNA vaccines against tuberculosis' [Vaccine 23 (2005) 5655-5665].

Vaccine 2020 Nov 23;38(49):7874-7875. Epub 2020 Oct 23.

Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi 110021, India. Electronic address:

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http://dx.doi.org/10.1016/j.vaccine.2020.10.011DOI Listing
November 2020

Design of a highly thermotolerant, immunogenic SARS-CoV-2 spike fragment.

J Biol Chem 2020 Nov 5. Epub 2020 Nov 5.

Molecular Biophysics Unit (MBU), Indian Institute of Science, Bangalore, India.

Virtually all SARS-CoV-2 vaccines currently in clinical testing are stored in a refrigerated or frozen state prior to use. This is a major impediment to deployment in resource-poor settings. Furthermore, several of them use viral vectors or mRNA. In contrast to protein subunit vaccines, there is limited manufacturing expertise for these nucleic acid-based modalities, especially in the developing world. Neutralizing antibodies, the clearest known correlate of protection against SARS-CoV-2, are primarily directed against the Receptor Binding Domain (RBD) of the viral spike protein, suggesting that a suitable RBD construct might serve as a more accessible vaccine ingredient. We describe a monomeric, glycan engineered RBD protein fragment that is expressed at a purified yield of 214 mg/L in unoptimized, mammalian cell culture and, in contrast to a stabilized spike ectodomain, is tolerant of exposure to temperatures as high as 100 °C when lyophilized, up to 70 °C in solution and stable for over four weeks at 37 °C. In prime:boost guinea pig immunizations, when formulated with the MF59-like adjuvant AddaVax™, the RBD derivative elicited neutralizing antibodies with an endpoint geometric mean titer of ~415 against replicative virus, comparing favourably with several vaccine formulations currently in the clinic. These features of high yield, extreme thermotolerance and satisfactory immunogenicity suggest that such RBD subunit vaccine formulations hold great promise to combat COVID-19.
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http://dx.doi.org/10.1074/jbc.RA120.016284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832000PMC
November 2020

Endogenous endophthalmitis due to in a lactating woman.

Indian J Ophthalmol 2020 11;68(11):2595-2597

Department of Ophthalmology, Advanced Eye Centre, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.

Endogenous endophthalmitis (EE) is a rare but fulminant intraocular infection that needs prompt recognition and management. Bacteria are the commonest causative organisms and they may colonize the eye secondary to hematogenous spread from a focus anywhere in the body. EE in the peripartum period is an infrequent occurrence with no cases reported to occur secondary to a peurperal mastitis. We report a case of EE due to Staphylococcus aureous in a lactating female and describe its clinical presentation and management.
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http://dx.doi.org/10.4103/ijo.IJO_740_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774152PMC
November 2020

High-resolution computed tomography (HRCT) in pediatric and adult patients with unsafe chronic suppurative otitis media (CSOM) and its surgical correlation.

J Family Med Prim Care 2020 Aug 25;9(8):4067-4073. Epub 2020 Aug 25.

Department of Radiology, University of Alabama at Birmingham, Birmingham, United States of America.

Background And Aim: Atticoantral, alias unsafe type of CSOM affects the posterosuperior part of the middle ear cleft and is frequently coupled with complications and bony erosions. This study aimed to correlate the high-resolution computed tomography (HRCT) temporal bone and intraoperative findings in the patients with the unsafe type of CSOM.

Methods: This prospective study included 50 patients (28 males: 22 females; mean age 24 ± 14 years) who presented with clinically suspected unsafe CSOM. All patients underwent HRCT of the temporal bone and subsequent surgical procedure. The intraoperative and histopathological findings were compared with HRCT findings. Descriptive statistics, sensitivity, specificity, and positive and negative predictive value for HRCT were calculated. Student's -test and Chi-square test were performed.

Results: Out of 50 patients, left, right, and bilateral ear involvement were seen in 42% (21/50), 38% (19/50), and 20% (10/50) patients, respectively. Ear discharge was the most common symptom (100%) followed by earache (66%), vertigo (16%), and tinnitus (14%), respectively. Cholesteatoma was reported in 82% (49/60) of ears on HRCT while histopathological and intraoperative evaluation confirmed the diagnosis in 40 out of 49 ears. In 18% (11/60) ears, the cholesteatoma was not diagnosed on HRCT evaluation; however, the intraoperative and histopathological assessment revealed cholesteatoma in six patients while the rest had granulation tissue. For detection of ossicular erosions, tegmen erosions, erosions of facial nerve canal, erosions of sigmoid sinus plate, and erosions of lateral/posterior semicircular canals; HRCT had high sensitivity (86.44%-100%) and specificity (93.33%-100%).

Conclusion: HRCT has a superb correlation with intraoperative findings and is a valuable tool for preoperative assessment of temporal bone pathologies.
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http://dx.doi.org/10.4103/jfmpc.jfmpc_455_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586635PMC
August 2020

Low contrast volume dual-energy CT of the chest: Quantitative and qualitative assessment.

Clin Imaging 2021 Jan 6;69:305-310. Epub 2020 Oct 6.

Division of Thoracic Imaging and Intervention, Massachusetts General Hospital, Boston, MA, United States of America; Harvard Medical School, Boston, MA, United States of America.

Purpose: To evaluate the image quality of chest CT performed on dual-energy scanners using low contrast volume for routine chest (DECT-R) and pulmonary angiography (DECTPA) protocols.

Materials And Methods: This retrospective study included dual-energy CT scans of chest performed with low contrast volume in 84 adults (34M:50F; Age 69 ± 16 years: Weight 71 ± 16kg). There were 42 patients with DECT-R and 42 patients with DECT-PA protocols. Images were reviewed by two thoracic radiologists. Qualitative assessment was done on a four-point scale, for subjective assessment of contrast enhancement and artifacts (1 = Excellent, 2 = optimal, 3 = suboptimal, and 4 = Limited) in the pulmonary arteries and thoracic aorta, on virtual monoenergetic and material decomposition iodine (MDI) images. Quantitative assessment was performed by measuring the CT (Hounsfield) units in aorta and pulmonary arteries. The estimated glomerular filtration rate (eGFR) was calculated before and after CT scans. Two tailed student's t-test was performed to assess the significance of findings, and strength of correlation between readers was determined by Cohen's kappa test.

Results: DECT-PA and DECT-R demonstrated excellent/adequate contrast density within the pulmonary arteries (up to segmental branch), and aorta. There was no suboptimal or limited examination. There was strong interobserver agreement for arterial enhancement in pulmonary arteries (kappa = 0.62-0.89) and for thoracic aorta (kappa = 0.62-0.94). Pulmonary emboli were seen in 3/42(7%) in DECT-R and in 5/42(12%) in DECT-PA. There was no significant change in eGFR before and after IV contrast injection (p = 0.46-0.52).

Conclusion: DECT-R and DECT-PA performed with low contrast volume provide diagnostic quality opacification of the pulmonary vessels and aorta vessels.
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http://dx.doi.org/10.1016/j.clinimag.2020.10.006DOI Listing
January 2021

VapC21 Toxin Contributes to Drug-Tolerance and Interacts With Non-cognate VapB32 Antitoxin in .

Front Microbiol 2020 11;11:2037. Epub 2020 Sep 11.

Tuberculosis Research Laboratory, Translational Health Science and Technology Institute, Faridabad, India.

The prokaryotic ubiquitous Toxin-antitoxin (TA) modules encodes for a stable toxin and an unstable antitoxin. VapBC subfamily is the most abundant Type II TA system in genome. However, the exact physiological role for most of these Type II TA systems are still unknown. Here, we have comprehensively characterized the VapBC21 TA locus from . The overexpression of VapC21 inhibited mycobacterial growth in a bacteriostatic manner and as expected, growth inhibition was abrogated upon co-expression of the cognate antitoxin, VapB21. We observed that the deletion of had no noticeable influence on the and growth of . Using co-expression and biophysical studies, we observed that in addition to VapB21, VapC21 is also able to interact with non-cognate antitoxin, VapB32. The strength of interaction varied between the cognate and non-cognate TA pairs. The overexpression of VapC21 resulted in differential expression of approximately 435 transcripts in The transcriptional profiles obtained upon ectopic expression of VapC21 was similar to those reported in upon exposure to stress conditions such as nutrient starvation and enduring hypoxic response. Further, VapC21 overexpression also led to increased expression of WhiB7 regulon and bacterial tolerance to aminoglycosides and ethambutol. Taken together, these results indicate that a complex network of interactions exists between non-cognate TA pairs and VapC21 contributes to drug tolerance .
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http://dx.doi.org/10.3389/fmicb.2020.02037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517352PMC
September 2020

Corrigendum to: System-Wide Analysis Unravels the Differential Regulation and In Vivo Essentiality of Virulence-Associated Proteins B and C Toxin-Antitoxin Systems of Mycobacterium tuberculosis.

J Infect Dis 2021 Feb;223(4):733

Tuberculosis Research Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, Faridabad, Haryana.

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http://dx.doi.org/10.1093/infdis/jiaa556DOI Listing
February 2021

Non-Arteritic Anterior Ischaemic Optic Neuropathy - Myths and Misconceptions: Experience from a Tertiary Care Centre in North India.

Neuroophthalmology 2020 12;44(4):246-254. Epub 2019 Dec 12.

Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

We prospectively evaluated 22 consecutive patients (24 eyes) suffering from non-arteritic anterior ischaemic optic neuropathy (NAION) at a tertiary care centre in Northern India. The mean age was 51.7 years. Visual loss on awakening was noticed only in three (12.5%) eyes. Six (27.3%) patients had headache while three (9.7%) patients had retro-orbital pain at the onset of visual loss. Peripapillary haemorrhages were seen in two (8.3%) eyes. At follow up, only one eye showed improvement in visual acuity. The results of our study suggest that NAION may not always present with the classic clinical picture. Accordingly, a high index of suspicion remains the key to correct diagnosis.
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http://dx.doi.org/10.1080/01658107.2019.1688356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518334PMC
December 2019

2.09 Å Resolution structure of E. coli HigBA toxin-antitoxin complex reveals an ordered DNA-binding domain and intrinsic dynamics in antitoxin.

Biochem J 2020 10;477(20):4001-4019

Molecular Biophysics Unit, Indian Institute of Science, Bengaluru 560012, India.

The toxin-antitoxin (TA) systems are small operon systems that are involved in important physiological processes in bacteria such as stress response and persister cell formation. Escherichia coli HigBA complex belongs to the type II TA systems and consists of a protein toxin called HigB and a protein antitoxin called HigA. The toxin HigB is a ribosome-dependent endoribonuclease that cleaves the translating mRNAs at the ribosome A site. The antitoxin HigA directly binds the toxin HigB, rendering the HigBA complex catalytically inactive. The existing biochemical and structural studies had revealed that the HigBA complex forms a heterotetrameric assembly via dimerization of HigA antitoxin. Here, we report a high-resolution crystal structure of E. coli HigBA complex that revealed a well-ordered DNA binding domain in HigA antitoxin. Using SEC-MALS and ITC methods, we have determined the stoichiometry of complex formation between HigBA and a 33 bp DNA and report that HigBA complex as well as HigA homodimer bind to the palindromic DNA sequence with nano molar affinity. Using E. coli growth assays, we have probed the roles of key, putative active site residues in HigB. Spectroscopic methods (CD and NMR) and molecular dynamics simulations study revealed intrinsic dynamic in antitoxin in HigBA complex, which may explain the large conformational changes in HigA homodimer in free and HigBA complexes observed previously. We also report a truncated, heterodimeric form of HigBA complex that revealed possible cleavage sites in HigBA complex, which can have implications for its cellular functions.
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http://dx.doi.org/10.1042/BCJ20200363DOI Listing
October 2020

Biochemical characterization of ClpB protein from Mycobacterium tuberculosis and identification of its small-molecule inhibitors.

Int J Biol Macromol 2020 Dec 25;165(Pt A):375-387. Epub 2020 Sep 25.

Council of Scientific and Industrial Research-Institute of Microbial Technology, India. Electronic address:

Tuberculosis, caused by pathogenic M. tuberculosis, remains a global health concern among various infectious diseases. Studies show that ClpB, a major disaggregase, protects the pathogen from various stresses encountered in the host environment. In the present study we have performed a detailed biophysical characterization of M. tuberculosis ClpB followed by a high throughput screening to identify small molecule inhibitors. The sedimentation velocity studies reveal that ClpB oligomerization varies with its concentration and presence of nucleotides. Further, using high throughput malachite green-based screening assay, we identified potential novel inhibitors of ClpB ATPase activity. The enzyme kinetics revealed that the lead molecule inhibits ClpB activity in a competitive manner. These drugs were also able to inhibit ATPase activity associated with E. coli ClpB and yeast Hsp104. The identified drugs inhibited the growth of intracellular bacteria in macrophages. Small angle X-ray scattering based modeling shows that ATP, and not its non-hydrolyzable analogs induce large scale conformational rearrangements in ClpB. Remarkably, the identified small molecules inhibited these ATP inducible conformational changes, suggesting that nucleotide induced shape changes are crucial for ClpB activity. The study broadens our understanding of M. tuberculosis chaperone machinery and provides the basis for designing more potent inhibitors against ClpB chaperone.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.09.131DOI Listing
December 2020