Salvage Using Polatuzumab Vedotin Based Therapy in Relapsed Refractory Large B-Cell Lymphomas: Early Experience from a Real-World Middle-Income Setting Using Named-Patient Compassionate Access Program.

Polatuzumab vedotin is a novel immunotherapy antibody-drug conjugate targeting CD79b. It has been used in relapsed/refractory (R/R) large B-cell lymphomas since its FDA approval in 2019. Presently, this drug is unaffordable or unavailable for patients in Lower-Middle Income Countries (LMIC) like India. This is a retrospective study of adult (> 18 years) patients with R/R large B-cell lymphoma failing two prior lines of therapy, who received Polatuzumab based salvage therapy on a compassionate or named-patient access program. Between May 2019 and April 2022, 10 patients received Polatuzumab vedotin, and 9 were evaluable. The most common regimen used was Polatuzumab-Bendamustine-Rituximab. Out of 43 infusions administered, the adverse event profile was manageable [One grade-2 infusion reaction, 4 patients developed grade 3-4 hematological toxicity and none had grade 3-4 non-hematological toxicities]. Ten infusions were administered in the day care service. After a median of 4.5 cycles (range 1-8), 4 patients achieved CR, 2 had partial response (PR), and 3 had progressive disease (PD). With a median follow up of 491 days (range 8-1048 days), four patients are alive (three in CR and one in PR), three patients have died and three patients were lost to follow up. Early real-world experience from a LMIC setting demonstrates feasibility and a favourable safety profile of Polatuzumab vedotin based approach, along with encouraging response rates in a subset of patients.

Riverine landscape dynamics of the Upper Ganga River (Haridwar-Narora), India.

Earth observation data provides an exceptional opportunity to study the temporal dynamics of large rivers. The availability of spatially continuous, synoptic and temporally repetitive satellite data allows the reconstruction of historical dynamics of large rivers along with the identification of the causal factors. An absolute paucity of information on the effect of hydrogeomorphic processes on the dynamics of the Upper Ganga River (UGR), especially upon its entry in the plains, motivated this research. This study aims to analyse morphological changes in the river channel, map temporal changes in the land use/land cover (LULC) within the riverscape and thereby understand the landscape dynamics in the UGR (Haridwar to Narora) during 1993-2017 by means of earth observation data. The analysis showed that the river remains straight with a sinuosity index of < 1; however, the braiding increased considerably (from 3.79 to 4.53). Erosion being more prominent on the left bank in comparison to the right bank with 85.89 km2 eroded on the left bank in comparison to 59.21 km2 eroded along the right bank. Riverine landscape has been observed to have a higher rate of accretion in comparison to erosion (8.09 km2 yr-1 and 6.04 km2 yr-1, respectively). Morphological change has brought a transition in the land use patterns with marked variation in vegetation and agriculture along with built-up. Significant changes in the composition of the LULC are largely due to the manifold increase in the agriculture extent (≈ 12 times), built-up (5 times) and the decrease in vegetation cover from 43.9% in 1993 to just 10.94% in 2017.

Spatial and temporal variations of air pollution over 41 cities of India during the COVID-19 lockdown period.

In this study, we characterize the impacts of COVID-19 on air pollution using NO2 and Aerosol Optical Depth (AOD) from TROPOMI and MODIS satellite datasets for 41 cities in India. Specifically, our results suggested a 13% NO2 reduction during the lockdown (March 25-May 3rd, 2020) compared to the pre-lockdown (January 1st-March 24th, 2020) period. Also, a 19% reduction in NO2 was observed during the 2020-lockdown as compared to the same period during 2019. The top cities where NO2 reduction occurred were New Delhi (61.74%), Delhi (60.37%), Bangalore (48.25%), Ahmedabad (46.20%), Nagpur (46.13%), Gandhinagar (45.64) and Mumbai (43.08%) with less reduction in coastal cities. The temporal analysis revealed a progressive decrease in NO2 for all seven cities during the 2020 lockdown period. Results also suggested spatial differences, i.e., as the distance from the city center increased, the NO2 levels decreased exponentially. In contrast, to the decreased NO2 observed for most of the cities, we observed an increase in NO2 for cities in Northeast India during the 2020 lockdown period and attribute it to vegetation fires. The NO2 temporal patterns matched the AOD signal; however, the correlations were poor. Overall, our results highlight COVID-19 impacts on NO2, and the results can inform pollution mitigation efforts across different cities of India.

Heavy metal pollution in surface water of the Upper Ganga River, India: human health risk assessment.

To assess the risk on human health, heavy metal contamination was analysed from surface water in the Upper Ganga river, India. Spatial and seasonal distribution of Fe, Mn, Zn, Cr and Pb was evaluated at eight sites during pre-monsoon and post-monsoon season of 2017. Average concentration of heavy metals was high, often exceeding the limits prescribed for surface water by Bureau of Indian Standard (BIS) and the World Health Organization (WHO). Based on heavy metal pollution index (HPI), 87% of the river stretch was classified as medium to highly polluted. Simultaneous assessment of the health risk employing chronic daily intake (CDI) and hazard quotient (HQ) indicates that exposure through ingestion and dermal pathways currently poses no serious threat to human health (CDI < 1, HQ < 1). For the two population groups analysed, HQIngestion values for Cr (adults 0.51, child 0.55) and Pb (adult 0.31, child 0.34) were significantly higher as compared with other heavy metals. HIIngestion varied from 0.85 to 1.64 for adult and 0.92 to 1.77 for child group, indicating health risk to both groups with child group being more risk prone from either of the exposure pathways. In addition, HI values revealed an increased risk to health for both groups during the post-monsoon season. Higher hazard index (HI) values (> 1) in the Upper Ganga river indicate an ever-increasing non-carcinogenic risk to the exposed population within the riverine landscape. The study highlights the impact of heavy metals in degrading the water quality of the Upper Ganga river and also advocates immediate attention towards reducing human health risk.

Impact of heavy metals on inhibitory concentration of Escherichia coli-a case study of river Yamuna system, Delhi, India.

The occurrence of resistant bacteria to specific heavy metals can be associated with increasing load of the metals in the environment. River Yamuna is polluted by various toxic heavy metals discharged by several industrial and agricultural sources. Therefore, the use of heavy metal-resistant bacteria as an indicator of metal pollution was tested in the present study. For the purpose of the study, the heavy metal resistance status of 42 Escherichia coli strains isolated from River Yamuna water from 7 sampling sites within a span of 2 years was determined using growth curves and plate dilution method in terms of minimum inhibitory concentration (MIC) values by comparing with MIC value of control strain. Seasonally, the lowest mean MIC value was observed for bacterial strains isolated in post-monsoon (December) 2013 and highest mean MIC value was observed for bacterial strains isolated in monsoon (August) 2015. Site-wise analysis of the maximum mean MIC values for all the isolated strains showed the highest mean Ni MIC value for the bacterial strains isolated from site S4 (ITO), highest mean Cu MIC, Cr MIC, and Fe MIC values for the bacterial strains isolated from site S2 (Najafgarh drain intermixing zone) and highest mean Cd MIC, Pb MIC, and Zn MIC values for the bacterial strains isolated from site S7 (Shahdara drain intermixing zone). Correlation analysis between mean MIC site-wise results with mean heavy metal site-wise concentrations showed significant positive correlation indicating that the higher the mean concentration of a given heavy metal at a given site, the higher the mean MIC value for the strains isolated from the same site indicating higher level of resistance. Overall, the present study has shown that the presence of heavy metals in River Yamuna caused due to indiscriminate discharge of various effluents from different kind of sources as well as due to insufficient treatment capacity of sewage treatment plants as well as common effluent treatment plants, has serious impacts on its bacterial microflora as it leads to the development of resistant strains.

Trophic state assessment of Bhindawas Lake, Haryana, India.

Trophic state allows for identification of problems and pressures that an ecosystem faces as well as demarcation of remedial measures. This study focuses on spatial and temporal variations in the trophic state and detection of possible causes of its divergence in Bhindawas Lake, India. The trophic state of the lake undulated between eutrophic and hyper-eutrophic state throughout the study period. Higher phosphorus concentration within the lake ecosystem is the dominant causal factor for its eutrophic state. The influence of other water quality parameters has also been analyzed using Spearman's coefficient of correlation. Deviations between trophic state index (TSI)-chlorophyll-a (Chl-a), TSI-total phosphorus (TP), and TSI-Secchi depth (SD) pointed out that the lake is principally phosphorus limited, and its trophic status is influenced by non-algal turbidity to a large extent. Spatial analysis of trophic levels in geographic information system (GIS) helped in identification of pollution sources and chemical attributes affecting the trophic state of the lake. This study provides a rationale for further investigation of nutrient and sediment loading into the lake system and development of sustainable management and conservation strategy identifying suitable measures ascertaining the ecosystem integrity.

Peficitinib, a JAK Inhibitor, in the Treatment of Moderate-to-Severe Rheumatoid Arthritis in Patients With an Inadequate Response to Methotrexate.

OBJECTIVE: To evaluate the efficacy and safety of orally administered once-daily peficitinib in combination with methotrexate (MTX) in patients with moderate-to-severe rheumatoid arthritis (RA) who had an inadequate response to MTX. METHODS: In this multinational, phase IIb, randomized, double-blind, placebo-controlled, dose-ranging trial, patients with RA (n = 378) were treated with peficitinib 25 mg, 50 mg, 100 mg, or 150 mg plus MTX, or matching placebo plus MTX once daily for 12 weeks. The primary end point was the percentage of patients who met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at week 12. RESULTS: ACR20 response rates at week 12 were 43.9%, 61.5% (P < 0.05 versus placebo), 46.4%, 57.7%, and 44.4% in the peficitinib 25 mg, 50 mg, 100 mg, 150 mg, and placebo groups, respectively. Significant decreases from baseline in the Disease Activity Score in 28 joints using the C-reactive protein level were seen in the peficitinib 50 mg (P < 0.05) and 150 mg (P < 0.01) groups compared with placebo at week 12. Overall, the incidence of adverse events (AEs) was similar between peficitinib and placebo. The most common AEs were urinary tract infection (n = 22 [6%]), upper respiratory tract infection (n = 16 [4%]), and diarrhea (n = 16 [4%]). There were 3 cases of herpes zoster infection (2 in the peficitinib 100 mg group and 1 in the 150 mg group) and 2 cases of serious infection (viral infection in the peficitinib 100 mg group and erysipelas in the 150 mg group). CONCLUSION: The ACR20 response rate in the group receiving peficitinib 50 mg plus MTX was significantly different compared with the rate in patients receiving placebo, but there were no apparent dose-dependent responses, and the placebo response rate was high. Peficitinib plus MTX in patients with moderate-to-severe RA was well tolerated, with limited safety signals emerging.

Gender and age differences in cardiovascular complications in anorexia nervosa patients.

BACKGROUND: Anorexia nervosa (AN) is characterized by severe malnutrition and electrolyte imbalances. Differences in cardiovascular complications between males and females with AN have not been studied. Additionally, coronary artery disease (CAD) prevalence and cardiovascular complications in patients with AN >65years have not been reported. METHODS: AN patients>18years were identified in the Nationwide Inpatient Sample 2009-2010 database using the Ninth Revision of International Classification of Disease code 307.1. Demographics, risk factors, and cardiovascular event rates were compared to general population data. RESULTS: CAD incidence was lower in all AN patients compared to the general population (4.4% vs 18.4%, p<0.001). Despite AN males having higher prevalences of hypertension and diabetes than AN females, there was no difference in CAD. AN males had higher rates of cardiac arrests, arrhythmias, and heart failure. Interestingly, 4.3% of patients with AN were >65years old. When compared to the general population>65years, older AN patients had lower rates of CAD (35% vs 16%; p<0.001). Older AN patients still had higher CAD rates compared to the general population under 65 (8.6%) and AN patients under 65 (4%; p<0.001). Older AN patients had a lower incidence of heart failure (24% vs 16%; p=0.04), and a trend towards less arrhythmias (30% vs 21%; p=0.08). CONCLUSIONS: Our data suggests that male AN patients experienced more cardiac arrests, arrhythmias, and heart failure than female AN patients. Additionally, older AN patients have a decreased incidence of CAD and heart failure compared to the general population>65years old.

Primary hyperparathyroidism predicts hypertension: Results from the National Inpatient Sample.

INTRODUCTION: Primary hyperparathyroidism (pHPT), most commonly caused by solitary parathyroid adenomas, leads to mobilization of calcium and is known to result in nephrolithiasis and osteoporosis. To date, studies of pHPT and cardiovascular risk factors and events have produced discrepant findings, likely due to small sample sizes and enrolling populations with varying disease severity. HYPOTHESIS: We utilized a national registry, hypothesizing an association between pHPT and cardiovascular risk factors and events. METHODS: Patients >18years with a diagnosis of pHPT were identified in the Nationwide Inpatient Sample 2009-2010 database using the Ninth Revision of International Classification of Diseases code 252.01. Demographics, risk factors, and cardiovascular event rates were collected and compared to general population data. RESULTS: pHPT was present in 0.1% (n=37,922) of hospital admissions. There was a significant increase in the prevalence of most cardiac risk factors including hypertension (HTN), diabetes mellitus, hyperlipidemia, obesity, and chronic kidney disease. The rates of heart failure (HF) and coronary artery disease (CAD) were higher in the pHPT population. However, after performing multivariate regression for age and cardiac risk factors, pHPT did not independently predict HF or CAD. The risk of HTN, however, was independently predicted by pHPT (OR 1.3; p<0.001). CONCLUSIONS: Primary hyperparathyroidism independently predicted the risk of hypertension in a patient population from a large national database. Despite significant differences in univariate analysis of cardiac risk factors and events, pHPT did not independently predict risk of HF or CAD after multivariate regression analysis. Future studies should explore potential mechanisms relating hypertension to pHPT.

Wetland assessment, monitoring and management in India using geospatial techniques.

Satellite remote sensing and GIS have emerged as the most powerful tools for inventorying, monitoring and management of natural resources and environment. In the special context of wetland ecosystems, remotely sensed data from orbital platforms have been extensively used in India for the inventory, monitoring and preparation of action plans for conservation and management. First scientific inventory of wetlands in India was carried out in 1998 by Space Applications Centre (ISRO), Ahmedabad using indigenous IRS (Indian Remote Sensing Satellite) data of 1992-93 timeframe, which stimulated extensive use of geospatial techniques for wetland conservation and management. Subsequently, with advances in GIS, studies were carried out for development of Wetland Information System for a state (West Bengal) and for Loktak lake wetland (a Ramsar site) as a prelude to National Wetland Information System. Research has also been carried out for preparation of action plans especially for Ramsar sites in the country. In a novel research, use of the geospatial technology has also been demonstrated for biodiversity conservation using landscape ecological metrics. A country-wide estimate of emission of methane, a Green House Gas, from wetlands has also been made using MODIS data. Present article critically reviews the work carried out in India for wetland conservation and management using geospatial techniques.

Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND:Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina.RESULTS:During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P=0.98). There were no significant between-group differences in rates of acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32).

Intrinsic to extrinsic phonon lifetime transition in a GaAs-AlAs superlattice.

We have measured the lifetimes of two zone-center longitudinal acoustic phonon modes, at 320 and 640 GHz, in a 14 nm GaAs/2 nm AlAs superlattice structure. By comparing measurements at 296 and 79 K we separate the intrinsic contribution to phonon lifetime determined by phonon-phonon scattering from the extrinsic contribution due to defects and interface roughness. At 296 K, the 320 GHz phonon lifetime has approximately equal contributions from intrinsic and extrinsic scattering, whilst at 640 GHz it is dominated by extrinsic effects. These measurements are compared with intrinsic and extrinsic scattering rates in the superlattice obtained from first-principles lattice dynamics calculations. The calculated room-temperature intrinsic lifetime of longitudinal phonons at 320 GHz is in agreement with the experimentally measured value of 0.9 ns. The model correctly predicts the transition from predominantly intrinsic to predominantly extrinsic scattering; however the predicted transition occurs at higher frequencies. Our analysis indicates that the 'interfacial atomic disorder' model is not entirely adequate and that the observed frequency dependence of the extrinsic scattering rate is likely to be determined by a finite correlation length of interface roughness.

Post LASIK progressive astigmatism in a child with partially accommodative esotropia.

INTRODUCTION: Refractive surgery is considered a safe and effective method for correction of refractive errors in adults. OBJECTIVE: To report an unusual case of a young child with partially accommodative esotropia presenting with deterioration of vision and worsening of esotropia following refractive surgery. CASE REPORT: Unanticipated and progressive irregular corneal astigmatism along with deterioration of visual acuity and loss of stereopsis developed post- LASIK in a seven-year-old Indian child with partially accommodative esotropia. CONCLUSION: Keratorefractive surgery in young children has to be undertaken with caution, especially in such cases where there is no medical indication for refractive surgery and waiting beyond teenage years is a viable option.

A phase I/II randomized open-label multicenter trial of efalizumab, a humanized anti-CD11a, anti-LFA-1 in renal transplantation.

Leukocyte function associated antigen-1 (LFA-1) has a multifaceted role in the immune response, including adhesion and trafficking of leukocytes, stabilizing the immune synapse of the MHC-TCR complex and providing costimulation signals. Monoclonal antibodies to the CD11a chain of LFA-1 have been seen to result in effective immunosuppression in experimental models. Efalizumab, a humanized IgG1 anti-CD11a, is approved for use in psoriasis and may provide effective immunosuppression in organ transplantation. Thirty-eight patients undergoing their first living donor or deceased renal transplant were randomized to receive efalizumab 0.5 or 2 mg/kg weekly subcutaneously for 12 weeks. Patients were maintained on full dose cyclosporine, mycophenolate mofetil and steroids or half dose cyclosporine, sirolimus and prednisone. At 6 months following transplant patient survival was 97% and graft survival was 95%. Clinical biopsy-proven acute rejection in the first 6 months after transplantation was confirmed in 4 of 38 patients (11%). Three patients (8%) developed post transplant lymphoproliferative disease, all treated with the higher dose efalizumab and full dose cyclosporine. The two doses of efalizumab resulted in comparable saturation and modulation of CD11a. This phase II trial suggests that efalizumab may warrant further investigation in transplantation.

Phylogenetic characterization of novel transport protein families revealed by genome analyses.

As a result of recent genome sequencing projects as well as detailed biochemical, molecular genetic and physiological experimentation on representative transport proteins, we have come to realize that all organisms possess an extensive but limited array of transport protein types that allow the uptake of nutrients and excretion of toxic substances. These proteins fall into phylogenetic families that presumably reflect their evolutionary histories. Some of these families are restricted to a single phylogenetic group of organisms and may have arisen recently in evolutionary time while others are found ubiquitously and may be ancient. In this study we conduct systematic phylogenetic analyses of 26 families of transport systems that either had not been characterized previously or were in need of updating. Among the families analyzed are some that are bacterial-specific, others that are eukaryotic-specific, and others that are ubiquitous. They can function by either a channel-type or a carrier-type mechanism, and in the latter case, they are frequently energized by coupling solute transport to the flux of an ion down its electrochemical gradient. We tabulate the currently sequenced members of the 26 families analyzed, describe the properties of these families, and present partial multiple alignments, signature sequences and phylogenetic trees for them all.

The LysE superfamily: topology of the lysine exporter LysE of Corynebacterium glutamicum, a paradyme for a novel superfamily of transmembrane solute translocators.

In Corynebacterium glutamicum the LysE carrier protein exhibits the unique function of exporting L-lysine. We here analyze the membrane topology of LysE, a protein of 236 amino acyl residues, using PhoA- and LacZ-fusions. The amino-terminal end of LysE is located in the cytoplasm whereas the carboxy-terminal end is found in the periplasm. Although 6 hydrophobic domains were identified based on hydropathy analyses, only five transmembrane spanning helices appear to be present. The additional hydrophobic segment may dip into the membrane or be surface localized. We show that LysE is a member of a family of proteins found, for example, in Escherichia coil, Bacillus subtilis, Mycobacterium tuberculosis and Helicobacter pylori. This family, which we have designated the LysE family, is distantly related to two additional protein families which we have designated the YahN and CadD families. These three families, the members of which exhibit similar sizes, hydropathy profiles, and sequence motifs comprise the LysE superfamily. Functionally characterized members of the LysE superfamily export L-lysine, cadmium and possibly quarternary amines. We suggest that LysE superfamily members will prove to catalyze export of a variety of biologically important solutes.

Epidermal calmodulin levels in psoriasis before & after therapy.

Epidermal calmodulin (CaM) levels were measured in the involved and uninvolved skin in 26 psoriasis patients before and after treatment either with dithranol topically or methotrexate orally. The mean epidermal calmodulin levels (+/- SD) in the involved and uninvolved psoriatic skin before treatment were 21.99 +/- 10.22 and 11.97 +/- 3.50 in the patients to be treated with short contact dithranol therapy (SCDT) while it was 19.46 +/- 8.13 and 11.27 +/- 7.23 in the patients to be treated with systemic methotrexate. Clearance of psoriatic lesions was associated with a significant fall (P less than 0.05) in epidermal calmodulin, activity irrespective of the treatment modality used. Also, there was a significant reduction (P less than 0.05) in the calmodulin levels in the epidermis of uninvolved skin following successful treatment.