Publications by authors named "Vivek Kumar"

546 Publications

Correction to: The impact of unilateral diaphragmatic paralysis on sleepdisordered breathing: a scoping review.

Can J Anaesth 2021 Apr 7. Epub 2021 Apr 7.

Department of Anesthesiology and Pain Management, Women's College Hospital, Toronto, ON, Canada.

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http://dx.doi.org/10.1007/s12630-021-01981-9DOI Listing
April 2021

Elicitation of potent serum neutralizing antibody responses in rabbits by immunization with an HIV-1 clade C trimeric Env derived from an Indian elite neutralizer.

PLoS Pathog 2021 Apr 7;17(4):e1008977. Epub 2021 Apr 7.

Translational Health Science & Technology Institute, NCR Biotech Science Cluster, Faridabad, India.

Evaluating the structure-function relationship of viral envelope (Env) evolution and the development of broadly cross-neutralizing antibodies (bnAbs) in natural infection can inform rational immunogen design. In the present study, we examined the magnitude and specificity of autologous neutralizing antibodies induced in rabbits by a novel HIV-1 clade C Env protein (1PGE-THIVC) vis-à-vis those developed in an elite neutralizer from whom the env sequence was obtained that was used to prepare the soluble Env protein. The novel 1PGE-THIVC Env trimer displayed a native like pre-fusion closed conformation in solution as determined by small angle X-ray scattering (SAXS) and negative stain electron microscopy (EM). This closed spike conformation of 1PGE-THIVC Env trimers was correlated with weak or undetectable binding of non-neutralizing monoclonal antibodies (mAbs) compared to neutralizing mAbs. Furthermore, 1PGE-THIVC SOSIP induced potent neutralizing antibodies in rabbits to autologous virus variants. The autologous neutralizing antibody specificity induced in rabbits by 1PGE-THIVC was mapped to the C3/V4 region (T362/P401) of viral Env. This observation agreed with electron microscopy polyclonal epitope mapping (EMPEM) of the Env trimer complexed with IgG Fab prepared from the immunized rabbit sera. Our study demonstrated neutralization of sequence matched and unmatched autologous viruses by serum antibodies induced in rabbits by 1PGE-THIVC and also highlighted a comparable specificity for the 1PGE-THIVC SOSIP trimer with that seen with polyclonal antibodies elicited in the elite neutralizer by negative-stain electron microscopy polyclonal epitope (ns-EMPEM) mapping.
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http://dx.doi.org/10.1371/journal.ppat.1008977DOI Listing
April 2021

Clinical course and outcome among patients with acute pancreatitis and COVID-19.

Eur J Gastroenterol Hepatol 2021 05;33(5):695-700

Division of Gastroenterology, Hepatology, and Endoscopy, Center for Pancreatic and Disease, Brigham and Women's Hospital.

Background: The data on clinical course and outcome of acute pancreatitis among patients with coronavirus disease 2019 (COVID-19) are sparse. In this study, we analyzed the clinical profiles of patients with COVID 19 and acute pancreatitis.

Methods: This retrospective study was conducted on Research Patient Data Registry data which was pooled from five Mass General Brigham Healthcare Network hospitals. We extracted data on demographics, symptoms, ICU transfer, mechanical ventilation, laboratories' profiles, imaging findings, and patient outcomes.

Result: Of 985 screened adult patients, 17 were eligible for the study, 9 (52.9%) were admitted primarily for respiratory failure and developed acute pancreatitis after a median of 22.5 days (13-76 days) from the onset of COVID-19 symptoms. On contrary, eight patients presented with typical symptoms and were diagnosed with acute pancreatitis, the majority with mild severity (62.5%) on admission. Patients who were admitted primarily with severe COVID-19 illness were younger (median age 57 vs. 63 years), females (55.6 vs. 25%), of Hispanic ethnicity (55.6 vs. 25%), and obese (88.9 vs. 37.5%). The median peak lipase, C reactive protein, ferritin, lactate dehydrogenase, D-dimer were higher among patients who developed acute pancreatitis later during hospitalization. Patients who developed acute pancreatitis later also experienced higher episodes of necrotizing pancreatitis (11.1% vs. 0), thromboembolic complications (55.6 vs. 12.5%), and higher mortality (37.5 vs. 12.5%).

Conclusion: Acute pancreatitis is not common among patients with COVID-19. Patients with COVID-19 who had acute pancreatitis on admission had more benign course and overall better outcome as compared to the patients who developed acute pancreatitis during hospitalization.
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http://dx.doi.org/10.1097/MEG.0000000000002160DOI Listing
May 2021

Physiological pacing to improve cardiac resynchronization therapy non-responder and a tryst with calcified septum-a case report.

Egypt Heart J 2021 Mar 18;73(1):27. Epub 2021 Mar 18.

SGL Multispeciality Hospital, Jalandhar, Punjab, India.

Background: As per the literature, patients with intraventricular conduction delay (IVCD) do not respond well to cardiac resynchronization therapy (CRT) alone. They need advanced technological approach and out of the box thinking for a good response.

Case: Ours is a case of ischemic cardiomyopathy with wide QRS-IVCD, a non-responder to CRT. While planning for replacement of the device for early replacement indicator (ERI), we decided to do His-optimized CRT/left bundle optimized CRT (HOT-CRT/LOT-CRT) for the patient.

Conclusion: The challenges we faced with the present available hardware paved a way for insisting on the limitation of the available lumenless lead to penetrate calcified the septum and importance of the pre-procedure evaluation of intraventricular septum (IVS) for calcification by more than just echocardiography.
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http://dx.doi.org/10.1186/s43044-021-00145-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973335PMC
March 2021

Action detection using a neural network elucidates the genetics of mouse grooming behavior.

Elife 2021 Mar 17;10. Epub 2021 Mar 17.

The Jackson Laboratory, Bar Harbor, United States.

Automated detection of complex animal behaviors remains a challenging problem in neuroscience, particularly for behaviors that consist of disparate sequential motions. Grooming is a prototypical stereotyped behavior that is often used as an endophenotype in psychiatric genetics. Here, we used mouse grooming behavior as an example and developed a general purpose neural network architecture capable of dynamic action detection at human observer-level performance and operating across dozens of mouse strains with high visual diversity. We provide insights into the amount of human annotated training data that are needed to achieve such performance. We surveyed grooming behavior in the open field in 2457 mice across 62 strains, determined its heritable components, conducted GWAS to outline its genetic architecture, and performed PheWAS to link human psychiatric traits through shared underlying genetics. Our general machine learning solution that automatically classifies complex behaviors in large datasets will facilitate systematic studies of behavioral mechanisms.
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http://dx.doi.org/10.7554/eLife.63207DOI Listing
March 2021

[The impact of unilateral diaphragmatic paralysis on sleep-disordered breathing: a scoping review].

Can J Anaesth 2021 Mar 16. Epub 2021 Mar 16.

Department of Anesthesiology and Pain Management, Women's College Hospital, Toronto, ON, Canada.

Background: Unilateral diaphragm paralysis (UDP) may potentially worsen sleep-disordered breathing (SDB). Unilateral diaphragm paralysis has been associated with proximal brachial plexus blockade, such as interscalene and supraclavicular block. The impact of UDP in patients with SDB is not known in this context. The objectives of this scoping review were to explore the associations between UDP and worsening SDB severity, oxygenation, and pulmonary function.

Methods: A systematic search was developed, peer-reviewed, and applied to Embase, Medline, CINAHL, and Cochrane databases to include studies involving adult patients (≥ 18 yr) with SDB, where the effects of UDP on SDB severity, oxygenation, and pulmonary function were examined.

Results: Six studies (n = 100 patients) with UDP and SDB were included. The sample population was derived exclusively from respirology-sleep clinics, and none were surgical patients. Compared with control (no UDP), UDP was associated with an increased respiratory disturbance index, most pronounced during rapid eye movement (REM) sleep and supine sleep. Supine and REM sleep were associated with obstructive and mixed (both obstructive and central) events, respectively. Compared with control, UDP was associated with a lower mean and minimum oxygen saturation and arterial oxygen tension during all sleep stages and in all body positions. The majority of UDP patients were found to have clinically significant reductions in mean forced expiratory volume in one second and forced vital capacity values, consistent with restrictive ventilatory pattern.

Conclusion: We observed an association between UDP and increasing SDB severity, particularly during REM sleep and while sleeping in the supine position. Although we identified weaknesses in study design and lack of perioperative data, anesthesiologists should be aware of this association when considering proximal brachial plexus blockade in patients with SDB.
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http://dx.doi.org/10.1007/s12630-021-01970-yDOI Listing
March 2021

Role of nuclear localization signals in the DNA delivery function of Chikungunya virus capsid protein.

Arch Biochem Biophys 2021 May 15;702:108822. Epub 2021 Mar 15.

Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, New Delhi, 110016, India. Electronic address:

Capsids of several RNA viruses are reported to have unconventional roles attributed to their subcellular trafficking property. The capsid of CHIKV is also found to localize in the nucleus, but the rationale is not yet clear. To understand the role of the nuclear-localized capsid, we examined the nucleic acid binding and cargo delivery activity of the CHIKV capsid. We used bacterially purified capsid protein to probe the binding affinity with CHIKV genome-specific and non-specific nucleic acids. We found that the capsid was able to bind non-specifically to different forms of nucleic acids. The successful transfection of GFP-tagged plasmid DNA by CHIKV capsid protein shows the DNA delivery ability of the protein. Further, we selected and investigated the DNA binding and cargo delivery activity of commercially synthesized Nuclear Localization Signal sequences (NLS 1 and NLS2) of capsid protein. Both peptides showed comparable DNA binding affinity, however, only the NLS1 peptide was capable of delivering plasmid DNA inside the cell. Furthermore, the cellular uptake study using the FITC-labelled NLS1 peptide was performed to highlight the membrane penetrating ability. Structural analysis was performed using circular dichroism and NMR spectroscopy to elucidate the transfection ability of the NLS1 peptides. Our findings suggest that the capsid of CHIKV might influence cellular trafficking in the infected cell via non-specific interactions. Our study also indicates the significance of NLS sequences in the multifunctionality of CHIKV capsid protein.
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http://dx.doi.org/10.1016/j.abb.2021.108822DOI Listing
May 2021

Angiogenic hydrogels for dental pulp revascularization.

Acta Biomater 2021 Mar 6. Epub 2021 Mar 6.

Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ, USA; Department of Oral Biology, Department of Endodontics, Rutgers School of Dental Medicine, Newark, NJ, USA; Department of Chemical and Materials Engineering, New Jersey Institute of Technology, Newark, NJ, USA; Department of Restorative Dentistry, Rutgers School of Dental Medicine, Newark, NJ, USA. Electronic address:

Angiogenesis is critical for tissue healing and regeneration. Promoting angiogenesis in materials implanted within dental pulp after pulpectomy is a major clinical challenge in endodontics. We demonstrate the ability of acellular self-assembling peptide hydrogels to create extracellular matrix mimetic architectures that guide in vivo development of neovasculature and tissue deposition. The hydrogels possess facile injectability, as well as sequence-level functionalizability. We explore the therapeutic utility of an angiogenic hydrogel to regenerate vascularized pulp-like soft tissue in a large animal (canine) orthotopic model. The regenerated soft tissue recapitulates key features of native pulp, such as blood vessels, neural filaments, and an odontoblast-like layer next to dentinal tubules. Our study establishes angiogenic peptide hydrogels as potent scaffolds for promoting soft tissue regeneration in vivo. STATEMENT OF SIGNIFICANCE: A major challenge to endodontic tissue engineering is the lack of in situ angiogenesis within intracanal implants, especially after complete removal of the dental pulp. The lack of a robust vasculature in implants limit integration of matrices with the host tissue and regeneration of soft tissue. We demonstrate the development of an acellular material that promotes tissue revascularization in vivo without added growth factors, in a preclinical canine model of pulp-like soft-tissue regeneration. Such acellular biomaterials would facilitate pulp revascularization approaches in large animal models, and translation into human clinical trials.
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http://dx.doi.org/10.1016/j.actbio.2021.03.001DOI Listing
March 2021

Synthesis and preliminary evaluation of At-labeled inhibitors of prostate-specific membrane antigen for targeted alpha particle therapy of prostate cancer.

Nucl Med Biol 2021 Mar-Apr;94-95:67-80. Epub 2021 Jan 23.

Department of Radiology, Duke University Medical Center, Durham, NC, USA. Electronic address:

Introduction: The high potency and short tissue range of α-particles are attractive features for targeted radionuclide therapy, particularly for cancers with micro-metastases. In the current study, we describe the synthesis of a series of At-labeled prostate-specific membrane antigen (PSMA) inhibitors and their preliminary evaluation as potential agents for metastatic prostate cancer treatment.

Methods: Four novel Glu-urea based PSMA ligands containing a trialkyl stannyl group were synthesized and labeled with At, and for comparative purposes, I, via halodestannylation reactions with N-chlorosuccinimide as the oxidant. A PSMA inhibitory assay was performed to evaluate PSMA binding of the unlabeled, iodinated compounds. A series of paired-label biodistribution experiments were performed to compare each At-labeled PSMA ligand to its I-labeled counterpart in mice bearing subcutaneous PC3 PSMA+ PIP xenografts.

Results: Radiochemical yields ranged from 32% to 65% for the At-labeled PSMA inhibitors and were consistently lower than those obtained with the corresponding I-labeled analogue. Good localization in PC3 PSMA+ PIP but not control xenografts was observed for all labeled molecules studied, which exhibited a variable degree of in vivo dehalogenation as reflected by thyroid and stomach activity levels. Normal tissue uptake and in vivo stability for several of the compounds was markedly improved compared with the previously evaluated compounds, [At]DCABzL and [*I]DCIBzL.

Conclusions And Implications For Patient Care: Compared with the first generation compound [At]DCABzL, several of the novel At-labeled PSMA ligands exhibited markedly improved stability in vivo and higher tumor-to-normal tissue ratios. [At]GV-620 has the most promising characteristics and warrants further evaluation as a targeted radiotherapeutic for prostate cancer.
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http://dx.doi.org/10.1016/j.nucmedbio.2021.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987787PMC
January 2021

Rituximab in primary membranous nephropathy: a comparative study of three dosing regimens.

Nephrol Dial Transplant 2021 Feb 12. Epub 2021 Feb 12.

Department of Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

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http://dx.doi.org/10.1093/ndt/gfab037DOI Listing
February 2021

Immune checkpoint inhibitors in advanced upper and lower tract urothelial carcinoma: a comparison of outcomes.

BJU Int 2021 Feb 8. Epub 2021 Feb 8.

Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA, USA.

Objectives: To compare clinical outcomes between patients with locally advanced (unresectable) or metastatic urothelial carcinoma (aUC) in the upper and lower urinary tract receiving immune checkpoint inhibitors (ICIs).

Patients And Methods: We performed a retrospective cohort study collecting clinicopathological, treatment, and outcome data for patients with aUC receiving ICIs from 2013 to 2020 across 24 institutions. We compared the objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) between patients with upper and lower tract UC (UTUC, LTUC). Uni- and multivariable logistic and Cox regression were used to assess the effect of UTUC on ORR, OS, and PFS. Subgroup analyses were performed stratified based on histology (pure, mixed) and line of treatment (first line, subsequent line).

Results: Out of a total of 746 eligible patients, 707, 717, and 738 were included in the ORR, OS, and PFS analyses, respectively. Our results did not contradict the hypothesis that patients with UTUC and LTUC had similar ORRs (24% vs 28%; adjusted odds ratio [aOR] 0.73, 95% confidence interval [CI] 0.43-1.24), OS (median 9.8 vs 9.6 months; adjusted hazard ratio [aHR] 0.93, 95% CI 0.73-1.19), and PFS (median 4.3 vs 4.1 months; aHR 1.01, 95% CI 0.81-1.27). Patients with mixed-histology UTUC had a significantly lower ORR and shorter PFS vs mixed-histology LTUC (aOR 0.20, 95% CI 0.05-0.91 and aHR 1.66, 95% CI 1.06-2.59), respectively).

Conclusion: Overall, patients with UTUC and LTUC receiving ICIs have comparable treatment response and outcomes. Subgroup analyses based on histology showed that those with mixed-histology UTUC had a lower ORR and shorter PFS compared to mixed-histology LTUC. Further studies and evaluation of molecular biomarkers can help refine patient selection for immunotherapy.
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http://dx.doi.org/10.1111/bju.15324DOI Listing
February 2021

A 3D Bioprinted Material That Recapitulates the Perivascular Bone Marrow Structure for Sustained Hematopoietic and Cancer Models.

Polymers (Basel) 2021 Feb 3;13(4). Epub 2021 Feb 3.

Department of Medicine, Rutgers New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, USA.

Translational medicine requires facile experimental systems to replicate the dynamic biological systems of diseases. Drug approval continues to lag, partly due to incongruencies in the research pipeline that traditionally involve 2D models, which could be improved with 3D models. The bone marrow (BM) poses challenges to harvest as an intact organ, making it difficult to study disease processes such as breast cancer (BC) survival in BM, and to effective evaluation of drug response in BM. Furthermore, it is a challenge to develop 3D BM structures due to its weak physical properties, and complex hierarchical structure and cellular landscape. To address this, we leveraged 3D bioprinting to create a BM structure with varied methylcellulose (M): alginate (A) ratios. We selected hydrogels containing 4% (/) M and 2% (/) A, which recapitulates rheological and ultrastructural features of the BM while maintaining stability in culture. This hydrogel sustained the culture of two key primary BM microenvironmental cells found at the perivascular region, mesenchymal stem cells and endothelial cells. More importantly, the scaffold showed evidence of cell autonomous dedifferentiation of BC cells to cancer stem cell properties. This scaffold could be the platform to create BM models for various diseases and also for drug screening.
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http://dx.doi.org/10.3390/polym13040480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913313PMC
February 2021

Catalytic asymmetric transformations of oxa- and azabicyclic alkenes.

Chem Soc Rev 2021 Mar 5;50(5):3013-3093. Epub 2021 Feb 5.

Synthesis and Solid State Pharmaceutical Centre, Centre for Synthesis and Chemical Biology, School of Chemistry, University College Dublin, Dublin 4, Ireland.

Oxa- and azabicyclic alkenes can be readily activated by transition-metal complexes with facial selectivity, because of the intrinsic reactivity of strained bicyclic structures. Synthetically, these compounds are important synthons that offer an important platform for the construction of biologically/medicinally significant compounds with two or more stereocenters. This Review comprehensively compiles the diverse catalytic processes involving the enantioselective transformations of oxa- and azabicyclic alkenes. It has been organized according to reaction type, including asymmetric ring opening (ARO) reactions, hydrofunctionalizations, cycloadditions and C-H activation reactions. The ARO section has been subdivided based on the type of nucleophiles employed, and further subdivided based on the metal used, with a separate topic dedicated to asymmetric ring-opening metathesis. Lastly, the presentation of each method/group of reactions is accompanied by concise discussions on their advantages and limitations.
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http://dx.doi.org/10.1039/d0cs00702aDOI Listing
March 2021

Interplay effect modeling in stereotactic body radiotherapy treatment of liver cancer using volumetric modulated arc therapy.

Phys Eng Sci Med 2021 Mar 4;44(1):123-134. Epub 2021 Feb 4.

Radiation Oncology Department, Institute of Liver and Biliary Sciences, New Delhi, India.

To model the interplay effect and minimize it by a selection of optimum parameters value using a predictive model for SBRT of liver cancers. Ten cases of liver tumors treated with the VMAT technique were selected retrospectively. The dosimetric error due to the interplay effect was measured with a micro ionization chamber (0.015cm) in a Quasar phantom simulating the moving tumor. The interplay effect dependent parameter's viz. patient breaths per minute, the amplitude of respiration, fractional dose (FD), plan complexity due to different energies (Relative degree of modulation), degree of modulation due to a different level of dose optimization constraints, and dose rate (DR) were measured. For the predictive model, mathematical equations were modeled in python from 300 combinations of proposed parameters using multivariate regression analysis. It was observed that the dose variation reduced from -8.44% to -5.16% for change in the BPM values from 7 to 31 and similarly for amplitude, the dose variation reduced from -9.44% to -4.93% for change in amplitude value from 16 mm to 2 mm. The DR and FD have a prominent effect with R values of 0.990 and 0.880 respectively. The calculated mean square errors of equations excluding amplitude for the predictive model were 0.90 and 0.82 whereas those for equations excluding BPM were 1.31 and 1.41 for 6 MV and 10 MV beams respectively. The values of the parameters can be prospectively optimized by the use of the predictive model according to clinical situations, so dose variation can be minimized.
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http://dx.doi.org/10.1007/s13246-020-00961-5DOI Listing
March 2021

Impact of dose heterogeneity in target on TCP and NTCP for various radiobiological models in liver SBRT: different isodose prescription strategy.

Biomed Phys Eng Express 2021 Jan 30;7(1):015020. Epub 2021 Jan 30.

Centre for Medical Physics, Panjab University, Chandigarh, India. Department of Radiation Oncology, Institute of Liver and Biliary Sciences, New Delhi, India.

Introduction: The impact of dose heterogeneity within the tumor on TCP and NTCP was studied using various radiobiological models. The effect of the degree of heterogeneity index (HI) on TCP was also analyzed.

Materials And Methods: Thirty-seven pre-treated liver SBRT cases were included in this study. Two different kinds of treatment techniques were employed. In both arms, the prescribed dose was received by 95% of the PTV. Initially, the inhomogeneous treatment plans (IHTP) were made in which the spatial change of dose within the PTV was high and the maximum dose within the PTV can go up to 160%. Subsequently, in another arm, homogeneous treatment plans (HTP) were generated in which PTV was covered with the same prescription isodose and the maximum dose can go up to 120%. As per RTOG 1112, all organs at risk (OAR's) were considered while optimization of the treatment plans. TCP was calculated using the Niemierko and Poisson model. NTCP was calculated using the Niemierko and LKB fractionated model.

Results: For the IHTP, TCP was decreasing as 'a' value decreased in the Niemierko model whereas, for HTP, TCP was found to be the same. NTCP of the normal liver was less in IHTP as compared to HTP, and the Niemierko model overestimates the NTCP as compared to LKB fractionated model. NTCP for all other OAR's was <1% in both kinds of treatment plans.

Conclusion: IHTP is found to be clinically better than HTP because NTCP of the normal liver was significantly less and TCP was more for certain 'a' values of the Niemierko model and the Poisson model. There is not any effect of HI on TCP was observed. Advances in knowledge: IHTP could be used clinically because of the dose-escalation and subsequently, leads to an increase in the TCP.
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http://dx.doi.org/10.1088/2057-1976/abd3f0DOI Listing
January 2021

Alternate method for endocardial pacemaker lead implantation: A hybrid mini-thoracotomy approach.

Indian Pacing Electrophysiol J 2021 Jan 22. Epub 2021 Jan 22.

Department of Cardiology, Max Superspeciality Hospital, New Delhi, India. Electronic address:

Although the conventional methods for endo-cardial pacemaker lead implantation via subclavian or cephalic or axillary vein routes is common, but sometimes due to anatomical variations it is not feasible to access these veins Emergence of newer techniques are useful for lead implantation. This case report focuses on a hybrid approach of combined mini-thoracotomy for endocardial pacemaker lead implantation. This fluoroscopy guided minimal thoracotomy approach with endocardial MRI compatible lead placement had the benefits of simple procedural, minimal hospital stay, low early complication rates and economically viable to the patient.
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http://dx.doi.org/10.1016/j.ipej.2021.01.007DOI Listing
January 2021

Trends in Early Mortality From Multiple Myeloma: A Population-Based Analysis.

Clin Lymphoma Myeloma Leuk 2020 Dec 24. Epub 2020 Dec 24.

Division of Hematology-Oncology, Mayo Clinic, Jacksonville, FL; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL. Electronic address:

Introduction: Despite significant improvements in multiple myeloma (MM) treatment modalities, patient mortality early in the course of disease has been identified as a persistent phenomenon with variable reported rates and causes. Trends in early mortality over time have not been clearly defined.

Patients And Methods: The Surveillance Epidemiology and End Results (SEER) database was used to identify adult patients with MM between 1975 and 2015. Association of available sociodemographic factors with all-cause and MM-specific early mortality (death within 6 months after the diagnosis of MM) was conducted by multivariate analysis. Trends in early mortality were studied by joinpoint regression analysis.

Results: Of the 90,975 MM cases included in this analysis, early mortality was noted in 21%. Median age was 68 years overall, and 75 years for the early mortality cohort (P < .01). The most common causes of death for early mortality were MM itself, followed by cardiovascular, infections, and renal failure. Male gender, "other" race/ethnicity group, advancing age, and West, Midwest or South regions (reference Northeast) were associated with increased risk of both all-cause and MM-specific early mortality. Joinpoint regression analysis of trends data resulted in 1 joinpoint for all-cause 6-month mortality (2006-2015), while 2 joinpoints were noticed for myeloma-specific 6-month mortality (1975-1987 and 2003-2015).

Conclusion: Early mortality remains a significant unmet need for MM patient care, despite improving trends in recent years. Understanding the factors associated with early mortality can help develop individualized plans of patient care and mitigate circumstances that may contribute to early mortality among MM patients.
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http://dx.doi.org/10.1016/j.clml.2020.12.023DOI Listing
December 2020

A Qualitative Exploration to Understand Hospitalists' Attitude Toward the Patient Experience Scoring System.

J Patient Exp 2020 Dec 20;7(6):1036-1043. Epub 2020 Jul 20.

Division of Hospital Medicine, University of Kentucky College of Medicine, Lexington, KY, USA.

Patient's perception of their inpatient experience is measured by the Center for Medical Services' (CMS) administered Hospital Consumer Assessment of Healthcare Providers & Systems (HCAHPS) survey. There is scant existing literature on physicians' perceptions toward the HCAHPS scoring system. Understanding hospitalist knowledge and attitude toward the HCAHPS survey can help guide efforts to impact HCAHPS survey scores by improving the patient's perception of their hospital experience. The goal of this study is to explore hospitalists' knowledge and perspective of the physician communication domain of the HCAHPS survey at an academic medical center. Seven hospitalists at an academic medical center were interviewed for this report using a semistructured interview. Thematic analysis approach was used to analyze data. Open, line-by-line coding was performed on all 7 transcripts. Categories were derived in an inductive fashion. Categories were refined using the techniques of constant comparison and axial coding. We generated themes reflecting hospitalists' knowledge of the HCAHPS scoring system, their perception of the HCAHPS scoring system and the impact of the HCAHPS scoring system on their practice. While hospitalists acknowledged physician-patient communication is a challenging area to study, they are unlikely to embrace the feedback provided by HCAHPS surveys. There is a need to deploy tactics that provide timely and actionable feedback to providers on their bedside communication skills.
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http://dx.doi.org/10.1177/2374373520942418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786727PMC
December 2020

A New Prognostic Model in Patients with Advanced Urothelial Carcinoma Treated with First-line Immune Checkpoint Inhibitors.

Eur Urol Oncol 2021 Jan 7. Epub 2021 Jan 7.

Division of Medical Oncology, Department of Medicine, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, University of Washington, Seattle, WA, USA. Electronic address:

Background: While immune checkpoint inhibitors (ICIs) are approved in the first-line (1L) setting for cisplatin-unfit patients with programmed death-ligand 1 (PD-L1)-high tumors or for platinum (cisplatin/carboplatin)-unfit patients, response rates remain modest and outcomes vary with no clinically useful biomarkers (except for PD-L1).

Objective: We aimed to develop a prognostic model for overall survival (OS) in patients receiving 1L ICIs for advanced urothelial cancer (aUC) in a multicenter cohort study.

Design, Setting, And Participants: Patients treated with 1L ICIs for aUC across 24 institutions and five countries (in the USA and Europe) outside clinical trials were included in this study.

Outcome Measurements And Statistical Analysis: We used a stepwise, hypothesis-driven approach using clinician-selected covariates to develop a new risk score for patients receiving ICIs in the 1L setting. Demographics, clinicopathologic data, treatment patterns, and OS were collected uniformly. Univariate Cox regression was performed on 18 covariates hypothesized to be associated with OS based on published data. Variables were retained for multivariate analysis (MVA) if they correlated with OS (p < 0.2) and were included in the final model if p < 0.05 on MVA. Retained covariates were assigned points based on the beta coefficient to create a risk score. Stratified median OS and C-statistic were calculated.

Results And Limitations: Among 984 patients, 357 with a mean age of 71 yr were included in the analysis, 27% were female, 68% had pure UC, and 13% had upper tract UC. Eastern Cooperative Oncology Group performance status ≥2, albumin <3.5 g/dl, neutrophil:lymphocyte ratio >5, and liver metastases were significant prognostic factors on MVA and were included in the risk score. C index for new 1L risk score was 0.68 (95% confidence interval 0.65-0.71). Limitations include retrospective nature and lack of external validation.

Conclusions: We developed a new 1L ICI risk score for OS based on data from patients with aUC treated with ICIs in the USA and Europe outside of clinical trials. The score components highlight readily available factors related to tumor biology and treatment response. External validation is being pursued.

Patient Summary: With multiple new treatments under development and approved for advanced urothelial carcinoma, it can be difficult to identify the best treatment sequence for each patient. The risk score may help inform treatment discussions and estimate outcomes in patients treated with first-line immune checkpoint inhibitors, while it can also impact clinical trial design and endpoints. TAKE  HOME MESSAGE: A new risk score was developed for advanced urothelial carcinoma treated with first-line immune checkpoint inhibitors. The score assigned Eastern Cooperative Oncology Group performance status ≥2, albumin <3.5 g/dl, neutrophil:lymphocyte ratio >5, and liver metastases each one point, with a higher score being associated with worse overall survival.
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http://dx.doi.org/10.1016/j.euo.2020.12.006DOI Listing
January 2021

Differential Dynamic Behavior of Prefusion Spike Proteins of SARS Coronaviruses 1 and 2.

bioRxiv 2020 Dec 26. Epub 2020 Dec 26.

Within the last two decades, severe acute respiratory syndrome (SARS) coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2) have caused two major outbreaks. For reasons yet to be fully understood the COVID-19 outbreak caused by SARS-CoV-2 has been significantly more widespread than the 2003 SARS epidemic caused by SARS-CoV-1, despite striking similarities between the two viruses. One of the most variable genes differentiating SARS-CoV-1 and SARS-CoV-2 is the S gene that encodes the spike glycoprotein. This protein mediates a crucial step in the infection, i.e., host cell recognition and viral entry, which starts with binding to the host cell angiotensin converting enzyme 2 (ACE2) protein for both viruses. Recent structural and functional studies have shed light on the differential binding behavior of the SARS-CoV-1 and SARS-CoV-2 spike proteins. In particular, cryogenic electron microscopy (cryo-EM) studies show that ACE2 binding is preceded by a large-scale conformational change in the spike protein to expose the receptor binding domain (RBD) to its binding partner. Unfortunately, these studies do not provide detailed information on the dynamics of this activation process. Here, we have used an extensive set of unbiased and biased microsecond-timescale all-atom molecular dynamics (MD) simulations of SARS-CoV-1 and SARS-CoV-2 spike protein ectodomains in explicit solvent to determine the differential behavior of spike protein activation in the two viruses. Our results based on nearly 50 microseconds of equilibrium and nonequilibrium MD simulations indicate that the active form of the SARS-CoV-2 spike protein is considerably more stable than the active SARS-CoV-1 spike protein. Unlike the active SARS-CoV-2 spike, the active SARS-CoV-1 spike spontaneously undergoes a large-scale conformational transition to a pseudo-inactive state, which occurs in part due to interactions between the N-terminal domain (NTD) and RBD that are absent in the SARS-CoV-2 spike protein. Steered MD (SMD) simulations indicate that the energy barriers between active and inactive states are comparatively lower for the SARS-CoV-1 spike protein. Based on these results, we hypothesize that the greater propensity of the SARS-CoV-2 spike protein to remain in the active conformation contributes to the higher transmissibility of SARS-CoV-2 in comparison to SARS-CoV-1. These results strongly suggest that the differential binding behavior of the active SARS-CoV-1 and 2 spike proteins is not merely due to differences in their RBDs as other domains of the spike protein such as the NTD could play a crucial role in the effective binding process, which involves the prebinding activation. Therefore, our hypothesis predicts that mutations in regions such as the NTD, which is not directly involved in binding, may lead to a change in the effective binding behavior of the coronavirus.
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http://dx.doi.org/10.1101/2020.12.25.424008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781306PMC
December 2020

Optimization and evaluation of fluorescence in situ hybridization chain reaction in cleared fresh-frozen brain tissues.

Brain Struct Funct 2021 Mar 2;226(2):481-499. Epub 2021 Jan 2.

Michigan Neuroscience Institute, University of Michigan, 205 Zina Pitcher pl, Ann Arbor, MI, 48109, USA.

Transcript labeling in intact tissues using in situ hybridization chain reaction has potential to provide vital spatiotemporal information for molecular characterization of heterogeneous neuronal populations. However, large tissue labeling in non-perfused or fresh-frozen rodent and postmortem human samples, which provide more flexible utilization than perfused tissues, is largely unexplored. In the present study, we optimized the combination of in situ hybridization chain reaction in fresh-frozen rodent brains and then evaluated the uniformity of neuronal labeling between two clearing methods, CLARITY and iDISCO. We found that CLARITY yielded higher signal-to-noise ratios but more limited imaging depth and required longer clearing times, whereas, iDISCO resulted in better tissue clearing, greater imaging depth and a more uniform labeling of larger samples. Based on these results, we used iDISCO-cleared fresh-frozen rodent brains to further validate this combination and map the expression of a few genes of interest pertaining to mood disorders. We then examined the potential of in situ hybridization chain reaction to label transcripts in cleared postmortem human brain tissues. The combination failed to produce adequate mRNA labeling in postmortem human cortical slices but produced visually adequate labeling in the cerebellum tissues. We next, investigated the multiplexing ability of in situ hybridization chain reaction in cleared tissues which revealed inconsistent fluorescence output depending upon the fluorophore conjugated to the hairpins. Finally, we applied our optimized protocol to assess the effect of glucocorticoid receptor overexpression on basal somatostatin expression in the mouse cortex. The constitutive glucocorticoid receptor overexpression resulted in lower number density of somatostatin-expressing neurons compared to wild type. Overall, the combination of in situ hybridization chain reaction with clearing methods, especially iDISCO, may find broad application in the transcript analysis in rodent studies, but its limited use in postmortem human tissues can be improved by further optimizations.
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http://dx.doi.org/10.1007/s00429-020-02194-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962668PMC
March 2021

Perioperative Management of Metastatic Paraganglioma-Pheochromocytoma of the Humerus with the Aid of Regional Anesthesia.

Case Rep Anesthesiol 2020 11;2020:2482793. Epub 2020 Dec 11.

Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA.

A 38-year-old female with a past history of pheochromocytoma and subsequent malignant paraganglioma presented with right arm pain after a fall. Imaging demonstrated a malunited humeral shaft associated with a large cortical destructive lesion and extraosseous extension. Here, we report the use of a multidisciplinary team approach including an endocrinologist, anesthesiologist, and orthopedic surgeon in the perioperative management of a patient with metastatic paraganglioma undergoing a surgical resection of the humerus, internal fixation, reconstruction, and placement of endoprosthesis. The challenges of perioperative anesthetic management and the use of regional anesthesia, especially peripheral nerve block for perioperative pain management, are highlighted.
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http://dx.doi.org/10.1155/2020/2482793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748908PMC
December 2020

Control of Traumatic Superior Mesenteric Vein Pseudoaneurysm With a Covered Endovascular Stent Using Transhepatic Approach.

Am Surg 2020 Dec 19:3134820972089. Epub 2020 Dec 19.

Division of Trauma Surgery and Critical Care, Department of Surgical Disciplines, JPNATC, 28730AIIMS, New Delhi, India.

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http://dx.doi.org/10.1177/0003134820972089DOI Listing
December 2020

Community-Acquired AKI in Asia: An Update.

Semin Nephrol 2020 Sep;40(5):456-467

George Institute for Global Health, University of New South Wales, New Delhi, India; School of Public Health, Imperial College, London, UK; Manipal Academy of Higher Education, Manipal, India. Electronic address:

Community-acquired acute kidney injury (CA-AKI) is the dominant form of AKI encountered in developing countries in Asia. Economic disparities, variations in access to health care services, geographic conditions, environmental risk factors, and sociocultural circumstances shape the causes and outcomes of CA-AKI. Infections, drugs, plant and chemical toxins, envenomations, and obstetric complications are common causes of CA-AKI. Previously healthy young individuals who often work outdoors in fields or farms are exposed to a wide variety of work-related or environmental risk factors for CA-AKI. Improving disease definitions, better data, and evolving host-pathogen interactions have changed disease descriptions and presentations over the past 20 years. Among infections, although the incidence of malaria has decreased, the number of cases with dengue and scrub typhus have increased sharply. The recognition of AKI in relation to Plasmodium knowlesi, Plasmodium vivax, scrub typhus, and leptospirosis in areas not traditionally considered at risk, association of infections with the future development of chronic kidney disease, and the role of complement dysregulation in infection-associated AKI are important new findings. Snake-bite-related toxic envenomation continues to be an important cause of AKI in some counties and is a neglected public health problem. On the other hand, significant decreases in the incidence of AKI related to acute diarrheal illness or obstetric causes are signs of hope. Coordinated efforts between administrative stakeholders, society, and health care delivery services at all levels have the potential to propel research and improve outcomes in CA-AKI.
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http://dx.doi.org/10.1016/j.semnephrol.2020.08.002DOI Listing
September 2020

Effectiveness of a Breathing Training Program on Quality of Life in Patients with Predialysis Chronic Kidney Disease: A Randomized Controlled Trial.

Indian J Palliat Care 2020 Jul-Sep;26(3):271-275. Epub 2020 Aug 29.

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

Context: Chronic kidney disease (CKD) patients have suboptimal quality of life (QOL). Various studies/researches have revealed that breathing exercises have a positive and favorable impact on different systems of the body.

Aims: This study aims to assess the effect of a breathing training program on QOL in patients with predialysis CKD.

Settings: The study was a single-center study conducted at PGIMER, Chandigarh.

Design: Randomized controlled trial.

Methods: Sixty individuals were enrolled and randomized using lottery method. QOL was assessed or evaluated by Kidney Disease and QOL questionnaire (KDQOL™-36). Breathing exercises were taught to the intervention group. Patients included in control group continued with the routine care. Assessment of QOL was done after 4 weeks in both the groups.

Results: Change in KDQOL™-36 scores showed significant difference between control and the intervention group. The mean scores of control group in the subscale effects of kidney disease, SF-12 Physical functioning (Physical Health Composite) and SF-12 Mental functioning (Mental Health Composite) were 84.79, 39.16 and 37.40, respectively, whereas in intervention group, the respective mean scores were 91.88, 43.92, and 44.16. The difference was statistically significant ( = 0.04, = 0.01, and = 0.003, respectively).

Conclusions: Breathing training program improves QOL in patients with predialysis CKD.
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http://dx.doi.org/10.4103/IJPC.IJPC_118_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725169PMC
August 2020

Chimeric status of biological samples after HSCT for personal identification: Y-STR based DNA analysis in sex mismatch cases.

Forensic Sci Int 2021 Jan 1;318:110639. Epub 2020 Dec 1.

JPNATC, All India Institute of Medical Sciences, New Delhi, India. Electronic address:

Identification of an individual is the prime object in forensic case works both in civil or criminal situations like paternity/maternity disputes, sexual assaults, murder, mass disaster victims etc. STR analysis has already proved its potential to give accurate results. In addition to autosomal chromosomes, sex determination at many times is crucial in forensic situations, especially in situations like rape cases or in cases of missing persons. The chances of wrong interpretations may arise due to false detection (or non-detection) of STR fragments overall or only at amelogenin-specific fragments, in situation like mutations, intersex conditions, trans-sexualism etc., due to natural or artificial chimersim. The forensic relevance of the possible misinterpretation of STR's or amelogenin should never be underestimated. The present study was carried out to identify an individual using Y-STR in sex mismatch patients who received hematopoietic stem cell transplantation. Hematopoietic stem cell transplantation is a method to replace patient's stem cell with the stem cell donated by the donor preferably biological related in order to cure malignant and non malignant diseases. This study enrolled ten female patients of HSCT. Samples were collected as pre and post transplant after 15 days, 30 days, 60 days, and 90 days of time interval from sex mismatch patient (female) and from donor (male) and chimeric status of the patient was analyzed using Y-STR markers (23 loci). Results demonstrated that donor genotype existed in blood and buccal swab of the recipient but no genetic profile existed for Y-STR in hair follicle of the recipient. This study suggests that only hair follicle out of three biological samples tested serves as reliable source of recipient's origin after HSCT for accurate personal identification especially in forensic situations.
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http://dx.doi.org/10.1016/j.forsciint.2020.110639DOI Listing
January 2021

Evolution and competition between chiral spin textures in nanostripes with symmetry.

Sci Adv 2020 Dec 4;6(49). Epub 2020 Dec 4.

Max Planck Institute of Microstructure Physics, Weinberg 2, 06120 Halle, Germany.

Chiral spin textures are of considerable interest for applications in spintronics. It has recently been shown that magnetic materials with symmetry can sustain several distinct spin textures. Here, we show, using Lorentz transmission electron microscopy, that single and double chains of antiskyrmions can be generated at room temperature in nanostripes less than 0.5 μm in width formed from the Heusler compound MnPtPdSn. Typically, truncated helical spin textures are formed in low magnetic fields, whose edges are terminated by half antiskyrmions. These evolve into chains of antiskyrmions with increasing magnetic field. Single chains of these objects are located in the middle of the nanostripes even when the stripes are much wider than the antiskyrmions. Moreover, the chains can even include elliptical Bloch skyrmions depending on details of the applied magnetic field history. These findings make materials special and highly interesting for applications such as magnetic racetrack memory storage devices.
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http://dx.doi.org/10.1126/sciadv.abc0723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821896PMC
December 2020

Preclinical evaluation of Bi-/Ac-labeled low-molecular-weight compounds for radiopharmaceutical therapy of prostate cancer.

J Nucl Med 2020 Nov 27. Epub 2020 Nov 27.

Johns Hopkins Medical Institutions.

Prostate-specific membrane antigen (PSMA) targeted radiopharmaceutical therapy is a new treatment option for patients with advanced prostate cancer refractory to other treatments. Previously we synthesized a β-particle-emitting low-molecular-weight compound, Lu-L1, which demonstrated reduced off-target effects in a xenograft model of prostate cancer. Here we leveraged that scaffold to synthesize α-particle-emitting analogs of L1, Bi-L1, and Ac-L1 to evaluate their safety and cell kill effect in PSMA+ xenograft models. Radiochemical synthesis, cell uptake, cell kill effect, and biodistribution of Bi-L1 and Ac-L1 were evaluated. The efficacy of Ac-L1 was determined in human PSMA+ subcutaneous and micrometastatic models. Subacute toxicity at 8 weeks and chronic toxicity at one year after administration were evaluated for Ac-L1. Radiation absorbed dose of Ac-L1 was determined using the biodistribution data and α-camera imaging. Bi-/Ac-L1 demonstrated specific cell uptake and cell kill in PSMA+ cells. Biodistribution of Bi-L1 and Ac-L1 revealed specific uptake of radioactivity within PSMA+ lesions. Treatment studies of Ac-L1 demonstrated activity-dependent, specific inhibition of tumor growth in the PSMA+ flank tumor model. Ac-L1 also showed an increased survival benefit in the micrometastatic model compared to Lu-L1. Activity-escalated acute and chronic toxicity studies of Ac-L1 revealed off-target radiotoxicity, mainly in kidneys and liver. The estimated maximum tolerated activity was ~1 MBq/kg. α-camera imaging of Ac-L1 revealed high renal cortical accumulation at 2 h followed by fast clearance at 24 h. Ac-L1 demonstrated activity-dependent efficacy with minimal treatment-related organ radiotoxicity issues. Ac-L1 is a promising therapeutic for further clinical evaluation.
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http://dx.doi.org/10.2967/jnumed.120.256388DOI Listing
November 2020