Conduction system pacing versus biventricular pacing: Reduced repolarization heterogeneity in addition to improved depolarization.

INTRODUCTION: His-bundle pacing (HBP) and left-bundle-area pacing (LBAP) are conduction system pacing (CSP) modalities increasingly used as alternatives to conventional biventricular pacing (BiVP). While effects of CSP on ventricular depolarization have been reported, effects on ventricular repolarization have not. METHODS: QRS duration (QRSd) and validated ECG parameters of ventricular repolarization associated with arrhythmic risk (T-peak-to-T-endTransmural , T-peak-to-T-endTotal , T-peak dispersion, QTc, QTc dispersion) were analyzed post-implant in 107 patients: 60 with CSP (HBP: n = 35, LBAP: n = 25) and 47 with BiVP. T-wave memory resolution and QTc shortening were analyzed on ECGs obtained ≥25 days post-implant. Twenty blinded measurements were obtained by both authors to assess Interobserver variability. RESULTS: Although QRSd was shorter with HBP versus LBAP (119 ± 7 ms vs. 132 ± 9 ms, p = .02), there were no significant differences in any repolarization parameters between these methods of CSP. However, when comparing CSP (HBP + LBAP) to BiVP, both QRSd (125 ± 5 ms vs. 147 ± 7 ms, p < .0001) and repolarization parameters (T-peak-to-T-endTransmural : 83 ± 5 ms vs. 107 ± 8 ms; T-peak-to-T-endTotal : 110 ± 7 ms vs. 137 ± 10 ms; QTc: 470 ± 12 ms vs. 506 ± 12 ms; all p ≤ .0001) were significantly shorter with CSP. Improved T-peak-to-T-end values were unrelated to pre-implant QRSd or LV function. Interobserver variability was 4.6 ± 1.9 ms. Frontal QRS-T angle narrowing (132° to 104°, p = .001) and QTc shortening (483 ± 13 ms to 464 ± 12 ms, p = .008) were seen only with CSP. CONCLUSIONS: In addition to improved depolarization, CSP reduced repolarization heterogeneity and provided greater T-wave memory resolution as compared to BiVP. Both modalities of CSP (HBP + LBAP) resulted in comparably reduced repolarization heterogeneity regardless of baseline QRSd and LV function. These observations may confer lower arrhythmogenic risk and warrant further study.

Clinical profile and outcome of COVID-19 in haematological malignancies: experience from tertiary care centre in India.

There is limited evidence on various clinical aspects of SARS-CoV-2 infection in patients with haematological cancers. The risk factors, prognosis, and outcome of patients with haematological cancers with coexistent COVID-19 need to be explored in different subsets of population. A single-institutional prospective observational study was conducted at a tertiary level medical institute in North India. The clinical details of the recruited patients having haematological malignancies and diagnosed with COVID-19 between 15 March 2020 and 31 May 2021 were prospectively collected through the electronic patient database system. The outcomes with respect to 28-day and 56-day mortality and the associated risk factors for prognostication were analysed. Of the 5750 hospital admissions (inpatient and day-care) during the study period, two hundred and forty-two patients (4.2%) were diagnosed with COVID-19. Acute leukaemia was the most common haematological malignancy, seen in 117 (48.3%) patients. Eighty-nine (36.8%) patients had moderate-to-severe COVID-19 while 153 (63.2%) patients presented with mild infection. The 28-day and 56-day mortality rates in our cohort were 13.3% and 19.8% respectively. Amongst the risk factors associated with poor outcome, the severity of COVID-19 (HR = 1.8, 95% CI 1.16-10.35; p = 0.04), presence of secondary infection (HR = 2.1, 95% CI 2.45-21.3; p = 0.023), and need for invasive mechanical ventilation (HR = 2.3, 95% CI 1.8-18.43; p = 0.01) were prognostically significant on multivariate log rank analysis. The risk of SARS-CoV-2 infection does not increase with haematological malignancies; however, the outcome remains poor in patients with severe COVID-19, requirement of invasive mechanical ventilation, and pre-existing bacterial/fungal infection at presentation.

Real-world challenges in the management of acute myeloid leukemia: a single-center experience from North India.

BACKGROUND: The outcome of acute myeloid leukemia (AML) in low-middle-income countries (LMIC) is dismal due to delayed clinical presentation and infection-related complications. We aimed to analyze the outcome of patients with AML and the factors associated with its prognosis. METHODS: A retrospective observational study was conducted at a tertiary care university hospital in North India from January 2015 to December 2019. RESULTS: A total of 137 AML patients (median age 32 year (3-66 years) received intensive chemotherapy during study period. The median delay from diagnosis to treatment was 45 days (6-177 days). Among the 352 febrile neutropenia (FN) episodes analyzed, 175 (49.7%) were culture positive; Gram-negative multi-drug resistant organism (MDRO) sepsis during induction being 57.4% with 34.5% infections due to carbapenem-resistant Enterobacteriaceae (CRE) leading to a mortality rate of 14.6%. The median EFS and OS were 12.0 ± 1.57 (95% CI 8.91-15.08) and 15.0 ± 2.44 (95% CI 10.21-19.78) months respectively. Multivariable analysis revealed significant difference in median OS between favorable vs high risk AML groups (20.0 (95% CI: 12.50-27.49) vs 9.0 (95% CI: 2.99-15.01) months; p = 0.002); time from diagnosis to treatment (< 30 days vs ≥ 30 days; not reached vs 9.0 (95% CI: 6.81-11.18) months; p = 0.001), performance status (1 vs 2 vs 3; not reached vs 12.0 (95% CI: 10.32-13.67) vs 4.0 (95% CI:2.77-5.22); p = 0.001), and attainment of complete remission vs induction failure (not reached vs 6.0 (95% CI: 3.78-8.21); p = 0.002). CONCLUSION: Patient-related factors like delayed treatment initiation and high incidence of MDRO-associated sepsis are critical determinants of AML outcome in LMIC.

New insights into development and mortality of COVID-19-associated pulmonary aspergillosis in a homogenous cohort of 1161 intensive care patients.

BACKGROUND: COVID-19-associated pulmonary aspergillosis (CAPA) has been widely reported but homogenous large cohort studies are needed to gain real-world insights about the disease. METHODS: We collected clinical and laboratory data of 1161 patients hospitalised at our Institute from March 2020 to August 2021, defined their CAPA pathology, and analysed the data of CAPA/non-CAPA and deceased/survived CAPA patients using univariable and multivariable models. RESULTS: The overall prevalence and mortality of CAPA in our homogenous cohort of 1161 patients were 6.4% and 47.3%, respectively. The mortality of CAPA was higher than that of non-CAPA patients (hazard ratio: 1.8 [95% confidence interval: 1.1-2.8]). Diabetes (odds ratio [OR] 1.92 [1.15-3.21]); persistent fever (2.54 [1.17-5.53]); hemoptysis (7.91 [4.45-14.06]); and lung lesions of cavitation (8.78 [2.27-34.03]), consolidation (9.06 [2.03-40.39]), and nodules (8.26 [2.39-28.58]) were associated with development of CAPA by multivariable analysis. Acute respiratory distress syndrome (ARDS) (2.68 [1.09-6.55]), a high computed tomography score index (OR 1.18 [1.08-1.29]; p < .001), and pulse glucocorticoid treatment (HR 4.0 [1.3-9.2]) were associated with mortality of the disease. Whereas neutrophilic leukocytosis (development: 1.09 [1.03-1.15] and mortality: 1.17 [1.08-1.28]) and lymphopenia (development: 0.68 [0.51-0.91] and mortality: 0.40 [0.20-0.83]) were associated with the development as well as mortality of CAPA. CONCLUSION: We observed a low but likely underestimated prevalence of CAPA in our study. CAPA is a disease with high mortality and diabetes is a significant factor for its development while ARDS and pulse glucocorticoid treatment are significant factors for its mortality. Cellular immune dysregulation may have a central role in CAPA from its development to mortality.

Diagnostic yield and safety of percutaneous CT-guided biopsy of retroperitoneal lesions and analysis of imaging features.

BACKGROUND: Computed tomography (CT)-guided biopsy is emerging as a preferred method for obtaining tissue samples from retroperitoneal lesions due to clear visualization of needle and vessels. PURPOSE: To assess diagnostic yield and safety of CT-guided biopsy of retroperitoneal lesions and compare CT findings in different disease categories. MATERIAL AND METHODS: This retrospective analytical study included 86 patients with retroperitoneal lesions who underwent CT-guided biopsy from December 2010 to March 2020. All procedures were performed with co-axial technique and multiple cores were obtained and subjected to histopathology. Additional tests like immunohistochemistry or microbiological analysis were done depending on clinical suspicion. Diagnostic yield calculation and comparison of imaging findings was done by one-way ANOVA, chi-square, and Fisher's exact tests. RESULTS: CT-guided biopsy was technically successful in all cases with a diagnostic yield of 91.9%. Minor complications in the form of small hematomas were seen in two patients. Major disease categories on final diagnosis were lymphoma, tuberculosis, and metastases. A variety of malignant and benign soft-tissue neoplasms were also noted less commonly. With help of immunohistochemistry, lymphoma subtype was established in 88.8% of cases. Addition of microbiological tests like the GeneXpert assay helped in the diagnosis of tuberculosis in some cases. A mass-like appearance and vascular encasement was common in metastatic group and lymphoma. CONCLUSION: Percutaneous CT-guided biopsy is a safe method for the sampling of retroperitoneal lesions with high diagnostic yield. Imaging findings are mostly overlapping; however, some features are more common in a particular disease condition.

Extra-nasal NK/T-cell lymphoma: A rare case with a rarer presentation.

Extra-nodal (NK/T) cell lymphoma (NKTCL) of nasal type (ENKL) presents with extranodal involvement and is associated with EBV. They are localized primarily to nasal and upper airway region but can rarely involve skin, testis, intestine, muscle, or present as a disseminated disease. We present a case of a 65-year-old male presented with bilateral orbital swelling, right parotid swelling, fever, mediastinal nodes, pleural effusion and hepatomegaly. Cytology of pleural fluid showed monomorphic lymphoid cells with folded nuclei, vesicular chromatin, inconspicuous nucleoli and granular cytoplasm. Few histiocytes showing hemophagocytosis were also noted in a background of inflammatory cells. Flow cytometric immunophenotyping of pleural fluid showed abnormal lymphoid cells which were positive for CD45, CD2 and CD56. Histopathological examination of the right eye swelling showed many atypical lymphoid cells which were positive for CD56 and negative for B and T cell markers. Based on morphological and immunophenotypic features a diagnosis of NKTCL, extra-nasal type was suggested. Patient succumbed to the disease despite aggressive therapy.

Transient left ventricular dysfunction after therapeutic pericardiocentesis - Takotsubo cardiomyopathy or pericardial decompression syndrome.

We present a case of reversible left ventricular (LV) dysfunction with characteristic stress or "Takotsubo" cardiomyopathy (SCM) after therapeutic pericardiocentesis in a patient with tubercular pericardial effusion. SCM following pericardiocentesis is uncommon, as opposed to the well-defined entity, pericardial decompression syndrome (PDS). PDS is defined as a paradoxical deterioration of hemodynamics and development of severe biventricular dysfunction, cardiogenic shock, and pulmonary edema after uneventful, often large volume pericardiocentesis in patients of pericardial effusion.

An Analysis of M-protein in Plasma cell Dyscrasia Patients Identifies that IgG Lambda Subtype is More Commonly Associated with Normal Serum Free Light Chain (SFLC) Ratio.

The determination of monoclonal protein (M-protein) by SPE, IFE and SFLC assay is fundamental in the diagnosis of Plasma cell proliferative disorder (PCPD). In the present study, we seek to assess the diagnostic performance and concordance of these three techniques in un-treated PCPD patients. All new patients with dysproteinemia and/or suspected PCPD were included in this retrospective observational study. The baseline parameters were retrieved from electronic medical records. SPE was performed on gel electrophoresis system; monoclonal component was identified by IFE. SFLC assays were performed by nephelometry using a latex-enhanced immunoassay. Total 402 patients of PCPD were included (10.9% of MGUS/SMM and 89.1% of multiple myeloma). The combination of SPE + rSFLC (ratio of kappa/lambda light chain) and SPE + IFE + rSFLC was able to detect M-protein across all subgroups of patients. In 61 patients, rSFLC values were within normal range (54.5% of MGUS/SMM and 10.3% of MM) and was more commonly seen with IgG lambda M-protein (57.4% vs. all-others). The median dFLC value, among these patients, was higher for MM than MGUS/SMM patients (23.8 vs. 14.4 mg/L, respectively). The combination of SPE and rSFLC can be reliably used to detect M-protein in PCPD patients. In a small subgroup of MM patients, despite the presence of an intact immunoglobulin (M-protein), the rSFLC is not abnormal. Historically, these patients should respond better to treatment. However, a further follow-up analysis with more number of such patients would be advantageous for better understanding.

Clinical profile, outcome and challenges in the management of pediatric Burkitt lymphoma: a single center experience.

This study was conducted with the aim to assess the clinico-pathological profile, treatment outcomes and the challenges faced in Low Middle Income Countries (LMIC) during management of pediatric Burkitt lymphoma cases on intensive chemotherapy protocol. This was a single center retrospective analysis of pediatric Burkitt lymphoma cases (age <18 years) managed uniformly with Lymphomes Malins B (LMB) 96 chemotherapy protocol between January 2015 and September 2019. 40 cases were analyzed with a median age 11.5 years (range 4-18 years) and male: female ratio =4.7:1. Patients belonging to different LMB risk groups were: A-3 (7.5%), B-31 (77.5%), and C-06 (15%). 25 (62.5%) patients had abdominal disease at presentation. The survival analysis of different treatment risk groups showed statistically significant difference in mean Overall Survival (OS) between group A-100%, group B- 87%±6.1% and group C-44.4%±16.2%; (p value = .016). On multivariate analysis of prognostic factors affecting survival, CNS involvement (p value = .03) and median time from diagnosis to treatment initiation more than 30 days (p value = .04) were significantly associated with poor outcome. Incidence of culture positive febrile neutropenia episodes was 28.2% of which 69.2% infections were caused due to carbapenem resistant gram-negative organisms. In our study, although the outcomes in risk group A and B patients were comparable to LMB 96 treatment results, the outcome in risk group C was considerably poor primarily due to advanced disease at presentation and delayed diagnosis. The critical challenges that we faced in our cohort were delayed diagnosis, treatment cost affordability, poor nutritional status, and high infection related mortality.

Organic Anion Transporting Polypeptide-Mediated Hepatic Uptake of Glucuronide Metabolites of Androgens.

We previously established that androgen glucuronides are effluxed by multidrug resistance-associated proteins 2 and 3. However, no data exist on the mechanism of hepatic uptake of these metabolites. The first goal of this study was to explore the role of hepatic uptake transporters and characterize transport kinetics of glucuronides of testosterone (TG), dihydrotestosterone (DHTG), androsterone (AG), and etiocholanolone (EtioG) using cell lines overexpressing organic anion transporting polypeptides (OATP1B1, OATP1B3, and OATP2B1). Using a quantitative proteomics-guided approach, we then estimated the fractional contribution of individual OATPs in hepatic uptake of these glucuronides. The transport screening assays revealed that the glucuronides were primarily taken up by OATP1B1 and OATP1B3. The K m values for OATP1B1-mediated uptake were low for EtioG (6.2 µM) as compared with AG, TG, and DHTG (46.2, 56.7, and 71.3 µM, respectively), whereas the K m value for OATP1B3-mediated uptake for EtioG, AG, DHTG, and TG were 19.8, 29.3, 69.6, and 110.4 µM, respectively. Both OATP1B1 and OATP1B3 exhibited the highest transport rate toward AG as compared with other glucuronides. When adjusted for the transporter abundance in human livers, EtioG and DHTG were predicted to be transported by both OATP1B1 and OATP1B3, whereas TG and AG were preferentially (>68%) transported by OATP1B3. Collectively, this report elucidates the mechanisms of hepatic uptake of androgen glucuronides. Perturbation of these processes by genetic polymorphisms, disease conditions, or drug interactions can lead to changes in enterohepatic recycling of androgens. TG and AG can be further investigated as potential biomarkers of OATP1B3 inhibition. SIGNIFICANCE STATEMENT: This is the first study to elucidate the mechanism of hepatic uptake of androgen glucuronides and estimate the fractional contribution of individual OATPs using quantitative proteomics. Our results show that both OATP1B1 and OATP1B3 are responsible for the hepatic uptake of major circulating testosterone glucuronides. The apparent higher selectivity of OATP1B3 toward testosterone glucuronide and androsterone glucuronide can be leveraged for establishing these metabolites as clinical biomarkers of OATP1B3 activity.

Comparison of In Vitro to In Vivo Extrapolation Approaches for Predicting Transporter-Mediated Hepatic Uptake Clearance Using Suspended Rat Hepatocytes.

Clearance (CL) prediction remains a significant challenge in drug discovery, especially when complex processes such as drug transporters are involved. The present work explores various in vitro to in vivo extrapolation (IVIVE) approaches to predict hepatic CL driven by uptake transporters in rat. Broadly, two different IVIVE methods using suspended rat hepatocytes were compared: initial uptake CL (PSu,inf) and intrinsic metabolic CL (CLint,met) corrected by unbound hepatocytes to medium partition coefficient (Kpuu). Kpuu was determined by temperature method (Temp Kpuu,ss), homogenization method (Hom Kpuu,ss), and initial rate method (Kpuu,V0). In addition, the impact of bovine serum albumin (BSA) on each of these methods was investigated. Twelve compounds, which are known substrates of organic anion-transporting polypeptides representing diverse chemical matter, were selected for these studies. As expected, CLint,met alone significantly underestimated hepatic CL for all the test compounds. Overall, predicted hepatic CL using PSu,inf with BSA, Hom Kpuu,ss with BSA, and Temp Kpuu,ss showed the most robust correlation with in vivo rat hepatic CL. Adding BSA improved hepatic CL prediction for selected compounds when using the PSu,inf and Hom Kpuu,ss methods, with minimal impact on the Temp Kpuu,ss and Kpuu,V0 methods. None of the IVIVE approaches required an empirical scaling factor. These results suggest that supplementing rat hepatocyte suspension with BSA may be essential in drug discovery research for novel chemical matters to improve CL prediction. SIGNIFICANCE STATEMENT: The current investigation demonstrates that hepatocyte uptake assay supplemented with 4% bovine serum albumin is a valuable tool for estimating unbound hepatic uptake clearance (CL) and Kpuu. Based upon the extended clearance concept, direct extrapolation from these in vitro parameters significantly improved the overall hepatic CL prediction for organic anion-transporting polypeptide substrates in rat. This study provides a practical in vitro to in vivo extrapolation strategy for predicting transporter-mediated hepatic CL in early drug discovery.

How I do it? Endoscopic discectomy using a new trocar "Endospine Plus" for lumbar prolapsed intervertebral disc.

BACKGROUND: Endoscopic spine surgery is a promising minimally invasive technique and use of trocars like Metrx (Neurosurgery 51(5):S129-36, 2002), Destandau (Neurol Res 21:39-42, 1999), and Easy go (Acta Neurochir (Wien) 151:1027­33, 2009) has revolutionized this field. However, the steep learning curve makes this procedure elusive to many parts of the world. METHODS: The authors describe the technique of pure endoscopic discectomy using a specialized trocar devised by the senior author "Endospine Plus" which makes the technique easy to learn along with the advantages and complications of the procedure. CONCLUSIONS: Endoscopic lumbar discectomy is a safe and effective technique for the treatment of prolapsed intervertebral disc.

Molecular Mechanisms for Species Differences in Organic Anion Transporter 1, OAT1: Implications for Renal Drug Toxicity.

Species differences in renal drug transporters continue to plague drug development with animal models failing to adequately predict renal drug toxicity. For example, adefovir, a renally excreted antiviral drug, failed clinical studies for human immunodeficiency virus due to pronounced nephrotoxicity in humans. In this study, we demonstrated that there are large species differences in the kinetics of interactions of a key class of antiviral drugs, acyclic nucleoside phosphonates (ANPs), with organic anion transporter 1 [(OAT1) SLC22A6] and identified a key amino acid residue responsible for these differences. In OAT1 stably transfected human embryonic kidney 293 cells, the Km value of tenofovir for human OAT1 (hOAT1) was significantly lower than for OAT1 orthologs from common preclinical animals, including cynomolgus monkey, mouse, rat, and dog. Chimeric and site-directed mutagenesis studies along with comparative structure modeling identified serine at position 203 (S203) in hOAT1 as a determinant of its lower Km value. Furthermore, S203 is conserved in apes, and in contrast alanine at the equivalent position is conserved in preclinical animals and Old World monkeys, the most related primates to apes. Intriguingly, transport efficiencies are significantly higher for OAT1 orthologs from apes with high serum uric acid (SUA) levels than for the orthologs from species with low serum uric acid levels. In conclusion, our data provide a molecular mechanism underlying species differences in renal accumulation of nephrotoxic ANPs and a novel insight into OAT1 transport function in primate evolution.

A unique case of concomitant intra and extracranial Hansen's disease.

Leprosy is a debilitating disease that usually involves the peripheral branches of the cranial nerves leading to anesthetic/hypoesthetic skin lesions and thickened peripheral nerves. However, the involvement of the central nervous system (CNS) is extremely rare. To the best of the author's knowledge, the involvement of the cranial nerve nuclei by leprosy has not been reported in the literature and the present case is the first report of involvement of the facial nerve nuclei by leprosy.

Fusidic Acid Inhibits Hepatic Transporters and Metabolic Enzymes: Potential Cause of Clinical Drug-Drug Interaction Observed with Statin Coadministration.

Fusidic acid (FA), which was approved in the 1960s in many European and Asian countries, has gained renewed interest due to its continued effectiveness against methicillin-resistant Staphylococcus aureus As rhabdomyolysis has been reported upon coadministration of FA with statins, we aimed to elucidate the underlying molecular mechanisms that contribute to FA-statin drug-drug interactions. Because of the association between rhabdomyolysis and increased exposure to statins, we investigated if cytochrome P450 (CYP) enzymes and transporters involved in the disposition of various statins are inhibited by FA. FA was found to inhibit BCRP and OATP1B1 but not P-gp. In overexpressing cell systems, FA inhibited BCRP-mediated efflux (50% inhibitory concentration [IC50], ∼50 to 110 µM) and OATP1B1-mediated uptake (IC50, ∼4 to 35 µM) of statins at clinically relevant concentrations achievable in the intestine and liver (based on a 550-mg oral dose of FA, the expected maximum theoretical gastrointestinal concentration is ∼4 mM, and the maximum total or unbound concentration in the inlet to the liver was reported to be up to 223 µM or 11 µM, respectively, upon multiple dosing). Similarly, FA inhibited metabolism of statins in human liver microsomes (IC50, ∼17 to 195 µM). These data suggest that FA inhibits at least 3 major dispositional pathways (BCRP, OATP1B1, and CYP3A) and thus affects the clearance of several statins. We confirmed that FA is eliminated via phase 1 metabolism (primarily via CYP3A); however, there is also some phase 2 metabolism (mediated primarily by UGT1A1). Taken together, these data provide evidence for molecular mechanisms that may explain the occurrence of rhabdomyolysis when FA is administered with statins.

Quantitative transporter proteomics by liquid chromatography with tandem mass spectrometry: addressing methodologic issues of plasma membrane isolation and expression-activity relationship.

To predict transporter-mediated drug disposition using physiologically based pharmacokinetic models, one approach is to measure transport activity and relate it to protein expression levels in cell lines (overexpressing the transporter) and then scale these to via in vitro to in vivo extrapolation (IVIVE). This approach makes two major assumptions. First, that the expression of the transporter is predominantly in the plasma membrane. Second, that there is a linear correlation between expression level and activity of the transporter protein. The present study was conducted to test these two assumptions. We evaluated two commercially available kits that claimed to separate plasma membrane from other cell membranes. The Qiagen Qproteome kit yielded very little protein in the fraction purported to be the plasma membrane. The Abcam Phase Separation kit enriched the plasma membrane but did not separate it from other intracellular membranes. For the Abcam method, the expression level of organic anion-transporting polypeptides (OATP) 1B1/2B1 and breast cancer resistance protein (BCRP) proteins in all subcellular fractions isolated from cells or human liver tissue tracked that of Na⁺-K⁺ ATPase. Assuming that Na⁺-K⁺ ATPase is predominantly located in the plasma membrane, these data suggest that the transporters measured are also primarily located in the plasma membrane. Using short hairpin RNA, we created clones of cell lines with varying degrees of OATP1B1 or BCRP expression level. In these clones, transport activity of OATP1B1 or BCRP was highly correlated with protein expression level (r² > 0.9). These data support the use of transporter expression level data and activity data from transporter overexpressing cell lines for IVIVE of transporter-mediated disposition of drugs.