Accura balloon dilatation catheter for percutaneous balloon pulmonary valvuloplasty among adult patients-its protean use.

BACKGROUND: Percutaneous balloon pulmonary valvuloplasty (PBPV) is the treatment of choice for hemodynamically significant pulmonary stenosis (PS). Currently, the Tyshak balloon is preferred but requires multiple dilatations because of its instability across the valve leading to a watermelon seeding effect. Accura balloon (Vascular Concept, UK) offers an advantage in its self-positioning configuration, variable diameter, and rapid inflation-deflation sequence which shortens the procedural time and valve injury. METHOD: 43 patients with severe pulmonary valve stenosis underwent PBPV using an Accura balloon at LPS Institute of Cardiology, GSVM Medical College, Kanpur, UP, India from March 2018 to February 2022. The procedure was carried out using the standard technique but the metallic straightener was removed when the catheter reached the right atrium to facilitate its delivery across the pulmonary valve. Patients were followed up by 2D echo at 24 hours and 6 months. RESULT: Successful BPV was done in all 43 patients [with mean age 21.9 (range 18-41); 31 males and 12 females] among which 5 patients had dysplastic valves. The mean diameter of the annulus was 18.5 (range 15-21) mm. Immediate hemodynamic improvement was observed in 38 patients (88%) as peak systolic gradient reduced from 84±13 to 22±12 mmHg (P<0.005) while 5 patients (12%) had <50% reduction of resting gradient, though it came down significantly at 6 months. Fluoroscopy and procedural time were 5.2±1.9 min and 22.6±3.4 min respectively. Major complications (death, cardiac perforation, tamponade, tricuspid regurgitation, requirement of blood transfusion) were none. Minor complications (transient hypotension, ventricular premature contraction, transient bradycardia) were reported in all patients. Accura balloon being bulky were delivered over left atrial and super stiff Amplatz wire in 36 and 7 patients respectively. CONCLUSION: PBPV using Accura balloon is safe and effective for both stenosed and dysplastic valves. In a few patients, maximal effect will be observed over a period of 6 months.

Efficient Deep Learning Based Hybrid Model to Detect Obstructive Sleep Apnea.

An increasing number of patients and a lack of awareness about obstructive sleep apnea is a point of concern for the healthcare industry. Polysomnography is recommended by health experts to detect obstructive sleep apnea. The patient is paired up with devices that track patterns and activities during their sleep. Polysomnography, being a complex and expensive process, cannot be adopted by the majority of patients. Therefore, an alternative is required. The researchers devised various machine learning algorithms using single lead signals such as electrocardiogram, oxygen saturation, etc., for the detection of obstructive sleep apnea. These methods have low accuracy, less reliability, and high computation time. Thus, the authors introduced two different paradigms for the detection of obstructive sleep apnea. The first is MobileNet V1, and the other is the convergence of MobileNet V1 with two separate recurrent neural networks, Long-Short Term Memory and Gated Recurrent Unit. They evaluate the efficacy of their proposed method using authentic medical cases from the PhysioNet Apnea-Electrocardiogram database. The model MobileNet V1 achieves an accuracy of 89.5%, a convergence of MobileNet V1 with LSTM achieves an accuracy of 90%, and a convergence of MobileNet V1 with GRU achieves an accuracy of 90.29%. The obtained results prove the supremacy of the proposed approach in comparison to the state-of-the-art methods. To showcase the implementation of devised methods in a real-life scenario, the authors design a wearable device that monitors ECG signals and classifies them into apnea and normal. The device employs a security mechanism to transmit the ECG signals securely over the cloud with the consent of patients.

Network pharmacology of apigeniflavan: a novel bioactive compound of Trema orientalis Linn. in the treatment of pancreatic cancer through bioinformatics approaches.

Pancreatic cancer is the seventh most prevalent cause of mortality globally. Since time immemorial, plant-derived products have been in use as therapeutic agents due to the existence of biologically active molecules called secondary metabolites. Flavonoids obtained from plants participate in cell cycle arrest, induce autophagy and apoptosis, and decrease oxidative stress in pancreatic cancer. The present study involves network pharmacology-based study of the methanolic leaf extract of Trema orientalis (MLETO) Linn. From the high-resolution mass spectrometry (HRMS) analysis, 21 nucleated flavonoids were screened out, of which only apigeniflavan was selected for further studies because it followed Lipinski's rule and showed no toxicity. The pharmacokinetics and physiochemical characteristics of apigeniflavan were performed using the online web servers pkCSM, Swiss ADME, and ProTox-II. This is the first in silico study to report the efficiency of apigeniflavan in pancreatic cancer treatment. The targets of apigeniflavan were fetched from SwissTargetPrediction database. The targets of pancreatic cancer were retrieved from DisGeNET and GeneCards. The protein-protein interaction of the common genes using Cytoscape yielded the top five hub genes: KDR, VEGFA, AKT1, SRC, and ESR1. Upon molecular docking, the lowest binding energies corresponded to best docking score which indicated the highest protein-ligand affinity. Kyoto Encyclopaedia of Genes and Genomes (KEGG) database was employed to see the involvement of hub genes in pathways related to pancreatic cancer. The following, pancreatic cancer pathway, MAPK, VEGF, PI3K-Akt, and ErbB signaling pathways, were found to be significant. Our results indicate the involvement of the hub genes in tumor growth, invasion and proliferation in the above-mentioned pathways, and therefore necessitating their downregulation. Moreover, apigeniflavan can flourish as a promising drug for the treatment of pancreatic cancer in future.

Network pharmacology-based anti-pancreatic cancer potential of kaempferol and catechin of Trema orientalis L. through computational approach.

In pancreatic cancer, healthy cells in the pancreas begin to malfunction and proliferate out of control. According to our conventional knowledge, many plants contain several novel bioactive compounds, having pharmaceutical applications for the treatment of disease like pancreatic cancer. The methanolic fraction of fruit extract of Trema orientalis L. (MFETO) was analysed through HRMS. In this in silico study, pharmacokinetic and physicochemical properties of the identified flavonoids from MFETO were screened out by ADMET analysis. Kaempferol and catechin followed Lipinski rules and showed no toxicity in Protox II. Targets of these compounds were taken from SwissTarget prediction and TCMSP whilst targets for pancreatic cancer were taken from GeneCards and DisGeNET databases. The protein-protein interaction (PPI) network of common genes was generated through STRING and then exported to the Cytoscape to get top 5 hub genes (AKT1, SRC, EGFR, TNF, and CASP3). The interaction between compounds and hub genes was analysed using molecular docking, and high binding affinity between them can be visualised by Biovia discovery studio visualizer. Our study shows that, five hub genes related to pancreatic cancer play an important role in tumour growth induction, invasion and migration. Kaempferol effectively check cell migration by inhibiting ERK1/2, EGFR-related SRC, and AKT pathways by scavenging ROS whilst catechin inhibited TNFα-induced activation and cell cycle arrest at G1 and G2/M phases by induction of apoptosis of malignant cells. Kaempferol and catechin containing MFETO can be used for formulation of potent drugs for pancreatic cancer treatment in future.

Twelve-month clinical outcomes of "nano-crush technique" for the treatment of bifurcation lesions using ultra-thin (60 µm) sirolimus-eluting coronary stents.

BACKGROUND: Provisional stenting is preferred for bifurcation lesion; however, certain anatomical substrate does require two stents as a part of dedicated stent technique. Here, the present study evaluated outcomes of ultra-thin (60 µm) Supra family sirolimus-eluting stent (SES) (Sahajanand Medical Technologies Limited, Surat, India) for dedicated bifurcation lesions using nano-crush technique at 12 months angiographic follow-up. METHODS: This was prospective, single-center observational study which enrolled patients with de novo bifurcation lesion and underwent angioplasty with Supra family SES using nano-crush technique at a tertiary care center in India, between March-2017 and February-2019. Primary endpoint at 12 months was target lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction (TV-MI), and clinically driven target lesion revascularization (CD-TLR). Secondary endpoints included patient-oriented composite endpoint (POCE), all-cause death, any revascularization, clinically driven target vessel revascularization, stent thrombosis, periprocedural and spontaneous MI, and device failure. RESULTS: The study enrolled total 63 patients with a mean age of 62.5±4.9 years and had male dominance (89%). Left main (LM) bifurcation and non-LM bifurcation were observed in 21 (33%) and 42 (67%) patients, respectively. Total 50 (80%) patients had Medina class- 1,1,1. At 12 months, TLF occurred in 4 (6%) patients which included one cardiac death (1.5%), two (3.0%) TV-MI, and one CD-TLR (1.5%). POCE was observed in 6 (9.6%) patients. Stent failure was seen in 2 (3.1%) patient and one patient (1.5%) developed late stent thrombosis. Twelve months angiographic follow-up indicated intact stent patency in all other patients. On multivariate analysis, LM bifurcation, renal dysfunction, LM bifurcation with renal dysfunction, ejection fraction (<35%) and calcified lesion were found as predictors of TLF. CONCLUSIONS: Dedicated stenting with ultra-thin Supra family SES for complex bifurcation lesion using nano-crush technique reported acceptable clinical outcomes among real-world patients and can be performed safely with ease without any procedural complications.

Transcatheter closure of secundum atrial septal defect using Cocoon septal occluder: immediate and long-term results.

BACKGROUND: Atrial septal defect (ASD) is one of the common congenital heart defects. Its management has transformed dramatically in the last 4 decades with the transition from surgical to percutaneous transcatheter closure for most secundum-type ASDs. Various devices are available for transcatheter closure of ASD with Amplatzer atrial septal occluder being most commonly used worldwide. Cocoon septal occlude has a nanocoating of platinum using nano-fusion technology over nitinol framework that imparts better radiopacity and excellent biocompatibility and prevents leaching of nickel into circulation, and by smoothening nitinol wire makes this device very soft and smooth. The aim of this study was to evaluate feasibility, effectiveness, safety, and long-term outcome of transcatheter closure of ASD using Cocoon septal occluder (Vascular Innovation, Thailand). RESULTS: All patients undergoing transcatheter closure of hemodynamically significant ASD between September 2012 and July 2019 in our institute were included into this single-center, prospective study. Exclusion criteria were defect > 40 mm, unsuitable anatomy, Eisenmenger syndrome, and anomalous pulmonary venous return. Three hundred and twenty patients underwent device closure, of which 238 (74%) were female. The mean age was 14.6 years (range 6-29), and the median weight was 30.2 kg (range 10-53 kg). Procedure was performed under fluoroscopy using transthoracic and transesophageal echocardiography in 298 (93.1%) and 22(6.9%) patients, respectively. Balloon-assisted technique was used, when septal defect was ≥ 34 mm, in 9 (2.8%) patients. The mean diameter of defect and device was 21.4 mm (range 12-36 mm) and 26.9 mm (range 14-40 mm), respectively. Aortic rim was absent in 11 (3.4%) patients. Primary success was achieved in 312 (97.5%) patients. Early embolization to right ventricle was noted in 2 (0.6%) patients. In both cases, 40-mm device was attempted for defect of 36 mm with inadequate aortic rim using balloon-assisted technique. One (0.3%) patient developed perforation of right atrium. All were surgically repaired. Three (0.9%) patients developed complete heart block following device deployment requiring device retrieval. Two patients had had moderate residual shunt at 6 months of follow-up. After mean follow-up of 50.92 months (range 12.5-89 months), no erosion, allergic reactions to nickel, or other major complications were reported. CONCLUSIONS: Percutaneous transcatheter closure of ASD by Cocoon septal occluder (up to 36 mm) is safe and feasible with high success rate and without any significant device-related major complications over long-term follow-up. With unique device design and excellent long-term safety, it could be preferred dual-disk occluder for transcatheter closure of atrial septal defect. In most of the patients, ASD device can be safely deployed under transthoracic echocardiographic guidance.

Assessment of the Left Atrial Reservoir Function and Left Atrial Volume After Percutaneous Balloon Mitral Valvuloplasty Using Peak Atrial Longitudinal Strain.

Objective To evaluate the impact of successful percutaneous balloon mitral valvuloplasty (BMV) on left atrial (LA) reservoir function and LA volume in patients with severe mitral stenosis (MS) using peak atrial longitudinal strain (PALS). Method This was a prospective, non-randomized observational study conducted at the Laxmipat Singhania (LPS) Institute of Cardiology, Kanpur from August 2018 to February 2020 among patients with severe rheumatic MS undergoing BMV to assess LA reservoir function and its volume after BMV using PALS. Inclusion criteria were symptomatic severe rheumatic MS (NYHA ≥II), normal ventricular systolic function, and suitable valve morphology. Exclusion criteria were the coexistence of aortic valve involvement, left atrial appendage clot, mitral leak more than mild, pregnancy, hypertension, diabetes, and coronary artery disease. To assess LA reservoir function and its volume after BMV, PALS was used. LA was divided into six regions of interest and longitudinal strain curves of individual segments together with global strain were recorded. PALS was calculated at baseline 24 hours following the intervention, and at three months of follow-up. Result Successful BMV was performed in 260 patients (109 or 41.9% males and 151 or 58.1% females), resulting in significant improvement in mitral valve area (MVA) (0.89±0.11 cm2 vs. 1.83±0.3 cm2; p<0.001). The mean age of patients was 26.7±4.7 years; 214 (82.3%) patients were in normal sinus rhythm (NSR) while 46 (17.7%) had atrial fibrillation (AF). Significant improvement in PALS was noted immediately following the procedure (6.5±11.6% vs. 7.7±10.5%; p< 0.001) and it continued to improve at three months of follow-up (6.5±11.6% vs. 11.3±12.5%; p<0.001), which was 24% and 74% improvement from baseline respectively. Significant reduction in indexed left atrial (LA) volume was observed immediately following the procedure (56.8±14.3 ml/m2 vs 48.4±12.5 ml/m2; p=0.003), and at three months of follow-up (56.8±14.3 ml/m2 vs. 45.4±13.3 ml/m2; p=0.002). Those with AF had lesser improvement in PALS in comparison to those with NSR (60% vs. 84%; p=0.044) at three months of follow-up. At three months, the increase in PALS was also lower in patients with a history of stroke as compared to those without it (55% vs 80%; p=0.039). Both LA volume and indexed LA volume reduced significantly immediately at 24 hours and during follow-up. Conclusion LA reservoir function, as assessed by PALS, is reduced in patients with severe MS. It improved significantly within 24 hours following BMV and continued to improve at three months of follow-up. It is an underutilized modality among patients of MS for decision-making prior to intervention and to assess the effect of the intervention.

Maternal metabolizable protein restriction during gestation affects the vascular function of maternal and fetal placental arteries in sheep.

We hypothesized isocaloric diets low in protein would decrease the sensitivity of caruncular (CAR) and cotyledonary (COT) arteries compared to placental arteries from ewes receiving adequate metabolizable protein (MP) requirements. Pregnant ewes were fed one of three isocaloric dietary treatments that provided 60% (MP60), 80% (MP80), or 100% (MP100) of the MP requirements. Diets were fed from day 100-130 of gestation. In vitro dose response curves to bradykinin (BK), sodium nitroprusside (SNP), potassium chloride (KCl), and phenylephrine (PE) in CAR and COT arteries were performed. As MP decreased, the sensitivity to a low dose of KCl increased (P = 0.05) in the COT arteries. There was an overall treatment effect in the CAR and COT arteries for the BK dose response curve, where CAR arteries of MP80 ewes were more sensitive (P = 0.05) to BK compared with MP60 and MP100 ewes, and COT arteries of MP60 and MP80 ewes were more sensitive (P = 0.01) to BK compared with MP100 ewes. There were no treatment effects (P ≥ 0.09) on the SNP or PE dose response curves in CAR or COT arteries. The mechanism of the BK induced vasodilation needs to be elucidated. Moreover, MP restriction appears to alter placental vascular function, which could help explain the differences in nutrient flux previously reported.

Perforated balloon technique mediated intracoronary delivery of nicorandil to treat coronary no-reflow phenomenon: a novel pharmacological solution to precarious situation.

BACKGROUND: Coronary no-reflow (NRF) following percutaneous coronary intervention (PCI) is infrequent but one of the most dreaded complication which results from impaired flow of microvascular bed. It is associated with adverse outcome if flow is not restored. Objective of this study was to find safety, effectiveness and outcome of intracoronary nikorandil (IC) administered using perforated balloon technique (PBT) to reverse NRF. METHOD: 2-4 mg of nicorandil was diluted with 5 ml of normal saline and administered using PBT over 5-minute. Its effectiveness was evaluated after 10 minute qualitatively using TIMI flow and quantitatively corrected TIMI frame count (cTFC) method. RESULT: Study comprised of 84 patients (out of 1789 patients undergoing PCI between January 2019 and February 2020). Their mean age was 57.8±17.9 years. Following PBT, TIMI III flow was successfully normalized in 71 subjects (84.5%), ten (12%) patients had TIMI II flow and it was not successful in three (3.5%) patients. TIMI flow grade got bettered from 1.03 to 2.58 and cTIMI frame count regressed from 52.9±11 to 16.5±5 (P < 0.001). PBT was well tolerated except short lived drop in blood pressure (n=10; 11.9%). CONCLUSION: This study, for the first time to the best our knowledge, demonstrated that PBT mediated intracoronary administration of nikorandil distally was rapid, safe, and efficacious method to deal with NRF.

An echocardiographic evaluation to determine the immediate and short-term changes in biventricular systolic and diastolic functions after PDA device closure-an observational analytical prospective study (echo- PDA study).

OBJECTIVES: -This prospective study with a sizable cohort was undertaken to assess changes in left and right ventricle systolic and diastolic functions after percutaneous patent ductus arteriosus device closure with appropriate follow up evaluation. METHODS: - It is an observational analytical prospective study. Ninety-eight patients were recruited out of which sixty-eight patients underwent percutaneous PDA device closure and were taken for final analysis. The primary objective was to study the left and right ventricular systolic and diastolic functions pre- and post-procedure at 48 h with follow up analysis at six months. RESULTS: - The mean age of the patients was 7.88 ± 5.05 years with the female to male ratio was 3.85:1. Thirty-three (48.52%) of the patients had immediate post PDA device closure LV systolic dysfunction. It was more common in those having pre-procedure mean low LVEF and those having a significant reduction in mitral A velocity. It became normal at six months follow up. The study reported immediate decrease in mea/n LVEF from 63.55 ± 8.11% to 48.19 ± 7.9%. The changes in LVEDD, LVEF, LVFS and LVEDV were statistically significant (p < 0.0001). In diastolic functions, there were significant reductions in peak early and late diastolic velocities. There was no statistically significant difference in right chamber functional assessment. CONCLUSION: Asymptomatic LV systolic and diastolic dysfunction in immediate post PDA closure period is a common complication and reported in around 48.5% cases. It was more common in those having pre-procedure mean low LVEF and those having a significant reduction in mitral A velocity.

To determine the correlation between echocardiographic diastolic parameters and invasively measured left ventricular end diastolic pressure in patients with heart failure with preserved ejection fraction- an observational, descriptive study. (CEAL-HFpEF study).

OBJECTIVES: Though invasive monitoring is the most accurate to estimate diastolic dysfunction but it has its own risk. The purpose of this study was to find out any standardized correlation between invasive and non -invasive parameters. METHODS: It is an observational, descriptive study comprising of a total of 500 patients. The primary objective of the study was to determine the correlation between echocardiographic diastolic parameters and invasively measured left ventricular end diastolic pressure (LVEDP). RESULTS: On studying correlation of different invasive and non-invasive data it was reported that there was a weak correlation between peak E velocity (r = 0.14, p = 0.631), Peak A velocity (r = 0.67, p = 0.59), IVRT (r = -0.35, p = 0.178), Mitral deceleration time (DT) (r = -0.06, p = 0.842), pulmonary venous peak systolic (r = -0.02, p = 0.966) and diastolic flows (r = 0.47, p = 0.201) to LVEDP. There was a good positive correlation between elevated LVEDP and difference in duration of pulmonary venous and mitral flow at atrial contraction (A-Ard) and E/Ea at all four longitudinal segments of the left ventricle. The sensitivity and specificity for detecting an elevated LVEDP of more than 12 mm Hg, using a cut off value of E/Ea< 8, were 89% and 90%.Lateral E/Ea ≥ 12, LAVI ≥34 mL/m2, and Ard-Ad > 30 msec have the greatest diagnostic value for diagnosing diastolic dysfunction in HFpEF patients. CONCLUSION: Lateral E/Ea ≥ 12, LAVI ≥34 mL/m2, and Ard-Ad > 30 msec have the greatest diagnostic value for diagnosing diastolic dysfunction in HFpEF patients and have good correlation with invasively measured LVEDP.

Balloon Deflection Technique to Facilitate Stent Delivery in Impassable Situations During Percutaneous Coronary Intervention.

BACKGROUND: Long and multiple lesions especially in the background of tortuous coronary artery often require multiple stents. The entry and passage of another stent through an already deployed stent becomes challenging because of poorly expanded stent struts, calcified tissue, underlying tortuosity, highly angulated takeoff of the vessel, and lack of coaxiality. It can be facilitated by balloon deflection technique (BDT) where balloon at proximal edge of main vessel stent over a buddy wire helps to deflect second stent either distally or into side branch by blocking potential dead. METHODS: The present retrospective, single-center study included 16,189 consecutive patients who underwent percutaneous coronary intervention (PCI) either through transfemoral or transradial route from January 2014 to August December 2019 at LPS Institute of Cardiology, GSVM Medical College, Kanpur, UP, India where BDT was used in situation of impassable stent among 37 patients. RESULTS: The mean age of patients was 75.4 ± 6.5 years. The commonest clinical presentation was chronic coronary syndrome (n = 19; 51.3%) followed by non-ST-segment elevation myocardial infarction (NSTEMI) (n = 9; 24.4%), ST-segment elevation myocardial infarction (STEMI) (n = 5; 13.5%), and unstable angina (UA) (n = 10; 10.8%). Type B2 lesion was commonest (45.9%) followed by type C (35.2%) and B1 (18.9%). The commonest indication for BDT was angulation (n = 10; 27.1%) followed by tortuosity (n = 9; 24.3%), chronic total occlusion (n = 8; 17.9%), calcification (n = 7; 18.9%), and distally located lesion (n = 3; 8.1%). The left circumflex artery (LCX) was the most commonly intervened artery (n = 16; 43.2%) followed by left anterior descending (n = 11; 29.7%) and right coronary artery (n = 10; 27.1%). Mean diameter and mean length of stents were 3.3 ± 0.9 mm and 18 ± 6 mm respectively. The mean diameter and mean length of deflection balloon were 3 ± 0.5 mm and 20 ± 5 mm respectively. Lesions were modified using aggressive pre-dilatation in all cases while 19.4% of lesion required cutting balloon for additional modification. Additional wire as buddy wire was used in 54% of cases while wire in main vessel acted as buddy wire in dedicated bifurcation stenting. Stent implantation was successful in 36 cases with success rate of 97.3%; while in one case, stent could not be delivered using BDT. Stent was finally delivered using GuideZilla mother-in-child catheter. Overall failure rate was 2.7% which was contributed by extreme tortuosity, angulation, and severe calcification. CONCLUSIONS: In selected cases of impassable lesions; the deflection balloon technique may provide a simple, convenient, and inexpensive solution without further need of additional hardwares except a buddy wire and a balloon.

The Relationship Between Busulfan Exposure and Achievement of Sustained Donor Myeloid Chimerism in Patients with Non-Malignant Disorders.

The overall objective of allogeneic hematopoietic cell transplantation (HCT) in patients with non-malignant conditions involves replacing a dysfunctional or absent cell or gene product for disease correction. It is unclear whether lower busulfan exposure may be sufficient in this population to facilitate durable myeloid engraftment and limit toxicity. Given that neither the ideal level of mixed myeloid chimerism for specific non-malignant diseases nor how to condition a patient to achieve stable mixed myeloid chimerism is fully known, we sought to analyze the relationships among busulfan exposure, myeloid chimerism, and outcomes in patients with non-malignant conditions receiving busulfan as a part of combination pretransplant conditioning at our institution. This was a single-center, retrospective study including pediatric patients with a variety of non-malignant disorders who underwent allogeneic HCT at the University of California San Francisco Benioff Children's Hospital from March 2007 to June 2018. The busulfan cumulative area under the curve (cAUC) was estimated using a validated population pharmacokinetic model and nonlinear mixed effects modeling. Median busulfan cAUC for all patients was 70 mg·h/L (range, 53 to 108). All of the 29 patients with a busulfan cAUC of ≥70 mg·h/L achieved long-term disease correction with full or stable mixed (>20%) myeloid chimerism, compared to 78.5% (22/28) of patients with a cAUC of <70 mg·h/L (P = .01). Overall ksurvival was evaluated up to 3 years and was identical in patients with busulfan cAUC < 70 mg·h/L and patients with busulfan cAUC ≥70 mg·h/L (96% versus 93%; P = .92). Only three patients died, at days 65, 164 and 980 days post-HCT. Severe busulfan-related toxicities and graft-versus-host-disease (GVHD) were rare, with veno-occlusive disease occurring in four patients (7%), acute respiratory distress syndrome in three patients (5%), and GVHD in five patients (9%). These results demonstrate excellent outcomes and extremely low rates of toxicity across our entire cohort. Based on the results of this study, we recommend a busulfan exposure target of 75 mg·h/L (range, 70 to 80) in all non-malignant patients receiving allogeneic HCT to ensure optimal exposure for achievement of high-level stable myeloid chimerism.

Telecardiology and its outcome among patients with implantable cardiac devices during COVID-19 pandemic.

BACKGROUND: During ongoing coronavirus disease 2019 (COVID-19) pandemic, social isolation and lockdown measures were implemented to prevent spread of virus which created enormous challenges to patient healthcare. In order to overcome these challenges, teleconsultation (telecardiology) was initiated. Objective of this study was to assess outcome of telecardiology using audio/visual/audio-visual consultation among patients with implantable cardiac devices. METHODS: Telecardiology was performed (either physician-initiated or patient-initiated) among 1200 patients over a five-month period (July 13 to December 13, 2020) to review health status of patients to decide further course of treatment and to access their satisfaction level with telecardiology. RESULTS: Teleconsultation was cardiologist- and patient-initiated in 1042 (86.8%) and 158 (13.2%) cases, respectively. 1117 (93.2%) patients were stable, while scheduled admission, urgent hospitalization, and death were noted in 20 (1.8%), 45 (3.9%), and 18 (1.5%) patients, respectively. Next visit was rescheduled in 986 (82.2%), while 127 (10.6%) were called earlier because of battery depletion. Majority (n = 1077, 89.8%) were satisfied. CONCLUSION: Telecardiolgy is an effective option during COVID-19 to minimize interpersonal contact, spread of disease, psychological stress, and burden on already stretched healthcare.

Study of Safety and Efficacy of Novel Sirolimus-Eluting Stent Incorporating Properties of Drug Coating Balloon Among Real World Patients Focusing Younger Population (<35 years).

OBJECTIVE: Aim of study was to evaluate safety and efficacy of abluminal Mitigator DES + Sirolimus Eluting Stent (Envision Scientific, Surat, India) incorporating novel technology of fusion coating of bioresorbable polymer on both abluminal surface of stent and exposed parts of balloon among real world patients specially focusing younger patients (<35 years). METHOD: 1293 patients received Mitigator DES + at LPS Institute of Cardiology, Kanpur, India. Primary outcome was target lesion failure (TLF)- composite of cardiovascular death, target vessel myocardial infarction (TVMI), and target lesion revascularization (TLR) and secondary end points including peri-procedural device failure (failure of stent delivery, change of stent, stent fracture), target vessel failure (TVF), and patient oriented composite end point (POCE)-composite of all deaths, MI, and revascularization and stent thrombosis (ST) at 1-year follow-up. RESULT: Younger population comprised of 374 (29%) patients. Various indications of interventions were STEMI (n = 614; 47.4%), NSTEMI (n = 416; 32.2%), UA (n = 161; 12.5%), and CCS (n = 102; 7.9%). TLF at 1 year in young and overall population were 3.4% and 3.5% respectively which was driven by TVMI and TLR in 1.3% and 1.1% patients respectively. POCE was observed in 9.5% in each group mainly contributed by any revascularization (3.9%). Device failure was significantly lower in young group than overall population (1.3% vs. 2.2%; p = 0.04) which was mainly driven by stent delivery (1.1%) and edge dissection (0.5%). Definite and probable ST was 1.3% and 1.7% respectively which was not significant. Young patients showed insignificantly lower TLF, TVF, ST and POCE and significantly lower device failure (1.3% vs. 2.6%; p = 0.04) when compared to patients >35 years. On multivariate regression analysis, complex lesion, in-stent restenosis, failure of stent delivery and edge dissection were independent predictors of events or device success rate. CONCLUSION: Mitigator DES+™ is safe among real world patients, including young population.

Lower Exposure to Busulfan Allows for Stable Engraftment of Donor Hematopoietic Stem Cells in Children with Mucopolysaccharidosis Type I: A Case Report of Four Patients.

Busulfan is an alkylating agent routinely used in conditioning regimens prior to allogeneic hematopoietic cell transplantation (HCT) for various nonmalignant disorders, including inborn errors of metabolism. The combination of model-based dosing and therapeutic drug monitoring (TDM) of busulfan pharmacokinetics (PK) to a lower exposure target has the potential to reduce the regimen-related toxicity while opening marrow niches sufficient for engraftment in diseases such as mucopolysaccharidosis type I (MPS I). We present four cases of the severe form of MPS I or Hurler syndrome, demonstrating successful and stable CD14/15 donor chimerism following the prospective application of model-based dosing and TDM aimed to achieve lower busulfan exposure. All patients received a busulfan-based conditioning regimen with a median cumulative area-under-the-curve (cAUC) target of 63.7 mg h/L (range, 62.4 to 65.0) in protocol-specific combination of chemotherapeutic regimen. The donor source was unrelated umbilical cord blood for three patients and matched sibling donor bone marrow for one patient. The observed median busulfan cAUC was 66.1 mg h/L (range, 65.2 to 70.6) and was within 10% of the intended target. Stable, full donor myeloid chimerism was achieved for three patients, while one patient achieved a stable mixed chimerism (76% donor CD14/15 at 53 months) without a recurring need for enzyme replacement. The normalization of α-L-iduronidase enzyme levels followed the attainment of successful donor myeloid chimerism in all patients. Regimen-related toxicity remained low with no evidence of acute graft-versus-host disease (GVHD) grades II to IV and chronic GVHD.

Assessment of a Model-Informed Precision Dosing Platform Use in Routine Clinical Care for Personalized Busulfan Therapy in the Pediatric Hematopoietic Cell Transplantation (HCT) Population.

INTRODUCTION: Population pharmacokinetic (PK) studies demonstrate model-based dosing for busulfan that incorporates body size and age improve clinical target attainment as compared to weight-based regimens. Recently, for clinical dosing of busulfan and TDM, our institution transitioned to a cloud-based clinical decision support tool (www.insight-rx.com). The goal of this study was to assess the dose decision tool for the achievement of target exposure of busulfan in children undergoing hematopoietic cell transplantation (HCT). PATIENTS AND METHODS: Patients (N = 188) were grouped into cohorts A, B, or C based on the method for initial dose calculation and estimation of AUC: Cohort A: Initial doses were based on the conventional dosing algorithm (as outlined in the manufacturers' package insert) and non-compartmental analysis (NCA) estimation using the trapezoidal rule for estimation of AUC following TDM. Cohort B: Initial doses for busulfan were estimated by a first-generation PK model and NCA estimation of AUC following TDM. Cohort C: Initial doses were calculated by an updated, second-generation PK model available in the dose decision tool with an estimation of AUC following TDM. RESULTS: The percent of individuals achieving the exposure target at the time of first PK collection was higher in subjects receiving initial doses provided by the model-informed precision dosing platform (cohort C, 75%) versus subjects receiving initial doses based on either of the two other approaches (conventional guidelines/cohort A, 25%; previous population PK model and NCA parameter estimation, cohort B, 50%). Similarly, the percent of subjects achieving the targeted cumulative busulfan exposure (cAUC) in cohort C was 100% vs. 66% and 88% for cohort A and B, respectively. For cAUC, the variability in the spread of target attainment (%CV) was low at 4.1% for cohort C as compared to cohort A (14.8%) and cohort B (17.1%). CONCLUSION: Achievement of goal exposure early on in treatment was improved with the updated model for busulfan and the Bayesian platform. Model-informed dosing and TDM utilizing a Bayesian-based platform provides a significant advantage over conventional guidelines for the achievement of goal cAUC exposure.

Exosomes From Induced Pluripotent Stem Cell-Derived Cardiomyocytes Promote Autophagy for Myocardial Repair.

Background Induced pluripotent stem cells and their differentiated cardiomyocytes (iCMs) have tremendous potential as patient-specific therapy for ischemic cardiomyopathy following myocardial infarctions, but difficulties in viable transplantation limit clinical translation. Exosomes secreted from iCMs (iCM-Ex) can be robustly collected in vitro and injected in lieu of live iCMs as a cell-free therapy for myocardial infarction. Methods and Results iCM-Ex were precipitated from iCM supernatant and characterized by protein marker expression, nanoparticle tracking analysis, and functionalized nanogold transmission electron microscopy. iCM-Ex were then used in in vitro and in vivo models of ischemic injuries. Cardiac function in vivo was evaluated by left ventricular ejection fraction and myocardial viability measurements by magnetic resonance imaging. Cardioprotective mechanisms were studied by JC-1 (tetraethylbenzimidazolylcarbocyanine iodide) assay, immunohistochemistry, quantitative real-time polymerase chain reaction, transmission electron microscopy, and immunoblotting. iCM-Ex measured ≈140 nm and expressed CD63 and CD9. iCM and iCM-Ex microRNA profiles had significant overlap, indicating that exosomal content was reflective of the parent cell. Mice treated with iCM-Ex demonstrated significant cardiac improvement post-myocardial infarction, with significantly reduced apoptosis and fibrosis. In vitro iCM apoptosis was significantly reduced by hypoxia and exosome biogenesis inhibition and restored by treatment with iCM-Ex or rapamycin. Autophagosome production and autophagy flux was upregulated in iCM-Ex groups in vivo and in vitro. Conclusions iCM-Ex improve post-myocardial infarction cardiac function by regulating autophagy in hypoxic cardiomyoytes, enabling a cell-free, patient-specific therapy for ischemic cardiomyopathy.

Exploration of some new secretory proteins to be employed for companion diagnosis of Mycobacterium tuberculosis.

Tuberculosis (TB) is a highly infectious disease and its early and precise diagnosis is essential to reduce morbidity and mortality of patients. Since the routine diagnostic tests (like Monteux, AFB smear microscopy, chest X-Ray) do not give infallible results, additional tests are always recommended. Therefore to address the concerns about non-specificity of the present battery of diagnostic tests, we have attempted to analyze some unique secretory antigens which could be able to identify the stage specific infection of MTB. In this study, we have used recombinant proteins CFP-10, ESAT-6, Ag85 A, Ag85B, Ag85C, PE3, PE4 and Mycp1 to eliminate heterogeneity and cross reactivity in clinical diagnosis. Amplified genes were cloned and over-expressed in Escherichia coli BL21 (DE3). The recombinantly purified proteins were used as antigens against 158 sera samples of TB patients. Secretory proteins showed better response than the PPD control. Among all the used antigens PE3 and PE4 proteins showed better reactivity levels among all the groups of TB patients. The secretions of CFP-10 and ESAT-6 were also higher as compared to other secretory proteins like Ag85 A, Ag85B, Ag85C and MycP1.The clinical use of these newly identified secretory antigens could be of significant value for the confirmatory, rapid, simple and low-cost diagnosis of TB patients.

Leishmania donovani molecules recognized by sera of filaria infected host facilitate filarial infection.

We earlier found that F6 fraction of human filaria Brugia malayi cross-reacted with sera of Leishmania donovani infected hamsters and immunization with F6 inhibited both filarial and leishmanial infections. In the present study, we identified a 52.9-93.6 kDa fraction (Ld1) of L. donovani that cross-reacted with sera of B. malayi infected animals and investigated effect of Ld1 on filarial infection. Immunization of BALB/c mice with Ld1 facilitated B. malayi infection with remarkable increase in parasite burden. Facilitation of filarial infection was associated with downregulated cell proliferation, IL-5, IL-13, IFN-γ, TNF-α, and IL-2 levels and upregulated IL-4 and TGF-ß. Ld1 exposure also suppressed MHC class-I, MHC class-II, and FcεR1 expression, and phagocytosis in naive mouse macrophages, and CD4+, CD8+, and CD19+ cell population in mouse spleen. Two-dimensional electrophoresis and matrix-assisted laser desorption ionization-time of flight-mass spectrometry revealed eight proteins in Ld1: putative heat shock protein (HSP) 70-related protein 1, HSP70 mitochondrial precursor, alanine aminotransferase, 2,3-bisphosphoglycerate-independent phosphoglycerate mutase, protein disulfide isomerase, putative ATPase beta subunit, trypanothione reductase, and a hypothetical protein. HSP70 protein mitochondrial precursor and trypanothione reductase showed homology with Trypanosoma cruzi and L. donovani, respectively, and the rest 6 proteins including hypothetical protein bear homology with L. infantum. In conclusion, the present study for the first time shows that immunization with filarial cross-reactive Ld1 fraction of L. donovani facilitates filarial infection by modulating Th1 and Th2 responses. Ld1 molecules may therefore facilitate filarial infection in filaria-leishmania co-infection.