Computational investigation of binding of chloroquinone and hydroxychloroquinone against PLPro of SARS-CoV-2.

Novel coronavirus SARS-CoV-2 has infected 18 million people with 700,000+ mortalities worldwide and this deadly numeric figure is rapidly rising. With very few success stories, the therapeutic targeting of this epidemic has been mainly attributed to main protease (Mpro), whilst Papain-like proteases (PLpro) also plays a vital role in the processing of replicase polyprotein. Multifunctional roles of PLpro such as viral polypeptide cleavage, de-ISGlyation and immune suppression have made it a promising drug target for therapeutic interventions. Whilst there have been a number of studies and others are on-going on repurposing and new-small molecule screening, albeit previously FDA approved drugs viz. Chloroquine (CQ) and Hydroxychloroquine (HCQ) have only been found effective against this pandemic. Inspired by this fact, we have carried out molecular docking and dynamics simulation studies of FDA approved CQ and HCQ against SARS-CoV-2 PLpro. The end aim is to characterise the binding mode of CQ and HCQ and identify the key amino acid residues involved in the mechanism of action. Further, molecular dynamics simulations (MDS) were carried out with the docked complex to search for the conformational space and for understanding the integrity of binding mode. We showed that the CQ and HCQ can bind with better binding affinity with PLpro as compared to reference known PLpro inhibitor. Based on the presented findings, it can be anticipated that the SARS-CoV-2 PLpro may act as molecular target of CQ and HCQ, and can be projected for further exploration to design potent inhibitors of SARS-CoV-2 PLpro in the near future.

Trends in maternal mortality in India over two decades in nationally representative surveys.

OBJECTIVE: To assess national and regional trends and causes-specific distribution of maternal mortality in India. DESIGN: Nationally representative cross-sectional surveys. SETTING: All of India from 1997 to 2020. SAMPLE: About 10 000 maternal deaths among 4.3 million live births over two decades. METHODS: We analysed trends in the maternal mortality ratio (MMR) from 1997 through 2020, estimated absolute maternal deaths and examined the causes of maternal death using nationally representative data sources. We partitioned female deaths (aged 15-49 years) and live birth totals, based on the 2001-2014 Million Death Study to United Nations (UN) demographic totals for the country. MAIN OUTCOME MEASURES: Maternal mortality burden and distribution of causes. RESULTS: The MMR declined in India by about 70% from 398/100 000 live births (95% CI 378-417) in 1997-98 to 99/100 000 (90-108) in 2020. About 1.30 million (95% CI 1.26-1.35 million) maternal deaths occurred between 1997 and 2020, with about 23 800 (95% CI 21 700-26 000) in 2020, with most occurring in poorer states (63%) and among women aged 20-29 years (58%). The MMRs for Assam (215), Uttar Pradesh/Uttarakhand (192) and Madhya Pradesh/Chhattisgarh (170) were highest, surpassing India's 2016-2018 estimate of 113 (95% CI 103-123). After adjustment for education and other variables, the risks of maternal death were highest in rural and tribal areas of north-eastern and northern states. The leading causes of maternal death were obstetric haemorrhage (47%; higher in poorer states), pregnancy-related infection (12%) and hypertensive disorders of pregnancy (7%). CONCLUSIONS: India could achieve the UN 2030 MMR goals if the average rate of reduction is maintained. However, without further intervention, the poorer states will not. TWEETABLE ABSTRACT: We estimated that 1.3 million Indian women died from maternal causes over the last two decades. Although maternal mortality rates have fallen by 70% overall, the poorer states lag behind.

HLA Desensitization Based on Results of the Luminex Technique in Kidney Transplant - A Single-center Experience.

BACKGROUND: There is little experience of human leucocyte antigen (HLA) desensitization in India based on the Luminex single-antigen bead (SAB) testing. We retrospectively analyzed our patients, who underwent HLA desensitization based on Luminex SAB results. METHOD: Between 2014 and 2018, patients with complement-dependent cytotoxicity cross-match (CDC-XM) negativity but flow cytometry crossmatch (FC-XM) positivity were further analyzed with Luminex SAB for donor-specific antibodies (DSAs). A total of 12 patients who had DSA mean fluorescent intensity (MFI) of >1000 and <10,000 were included in the study. Our protocol for desensitization consisted of plasmapheresis (PP) followed by low dose intravenous immunoglobulin (IV IG) 100 mg/kg and induction with antithymocyte globulin (ATG). Patients were taken for transplant when either MFI was <1000 and/or FC-XM was negative. RESULTS: All 12 patients were first transplant and 10 had a history of some sensitizing event; pregnancy in 4, blood transfusions in 4, and both in 2 patients. FC-XM was positive for T-cell in 4, B-cell in 6, and both in 2 patients. On evaluation by Luminex SAB, 6 patients had MFI from 1000 to 2000, and 6 had MFI of >2000. All underwent desensitization successfully. Two patients had an increase in posttransplant DSA titers requiring posttransplant PP. The mean follow-up was 26.6 ± 13.9 months. On follow-up, only one patient developed acute T cell-mediated rejection 1 year after transplant, which responded to pulse steroids. There was no graft or patient loss until the last follow-up. CONCLUSION: This study shows that HLA desensitization is feasible and successful in the Indian setting if patients are properly selected.

Projecting potential impact of COVID-19 on major cereal crops in Senegal and Burkina Faso using crop simulation models.

CONTEXT: The rapid emergence of COVID-19 could have direct and indirect impacts on food production systems and livelihoods of farmers. From the farming perspective, disruption of critical input availability, supply chains and labor, influence crop management. Disruptions to food systems can affect (a) planting area; and (b) crop yields. OBJECTIVES: To quantify the impacts of COVID-19 on major cereal crop's production and their cascading impact on national economy and related policies. METHODS: We used the calibrated crop simulation model (DSSAT suite) to project the impact of potential changes in planting area and grain yield of four major cereal crops (i.e., rice, maize, sorghum, and millet) in Senegal and Burkina Faso in terms of yield, total production, crop value and contribution to agricultural gross domestic product (GDP). Appropriate data (i.e., weather, soil, crop, and management practices) for the specific agroecological zones were used as an input in the model. RESULTS AND CONCLUSIONS: The simulated yields for 2020 were then used to estimate crop production at country scale for the matrix of different scenarios of planting area and yield change (-15, -10, -5, 0, +5, +10%). Depending on the scenario, changes in total production of four cereals combined at country levels varied from 1.47 M tons to 2.47 M tons in Senegal and 4.51 M tons to 7.52 M tons in Burkina Faso. The economic value of all four cereals under different scenarios ranged from $771 Million (M) to $1292 M in Senegal and from $1251 M to $2098 M in Burkina Faso. These estimated total crop values under different scenarios were compared with total agricultural GDP of the country (in 2019 terms which was $3995 M in Senegal and $3957 M in Burkina Faso) to assess the economic impact of the pandemic on major cereal grain production. Based on the scenarios, the impact on total agricultural GDP can change -7% to +6% in Senegal and - 8% to +9% in Burkina Faso. SIGNIFICANCE: Results obtained from this modeling exercise will be valuable to policymakers and end-to-end value chain practitioners to prepare and develop appropriate policies to cope or manage the impact of COVID-19 on food systems.

Environmental management partner selection for reverse supply chain collaboration: A sustainable approach.

The Indian electronics industry is facing immense pressure to include sustainability practices in order to meet customer expectations, comply with legislation and create an edge over competitors. This growing need for inclusion of sustainability is driving original equipment manufacturers (OEMs) to collaborate with third-party reverse logistics providers (3PRLPs) to sustainably manage returns. Collaboration with 3PRLP will put OEMs in a stronger position regarding compliance with government legislation, improving upon their corporate image and customer satisfaction. It is a win-win situation for the OEM. On the other hand, from the 3PRLP's point of view, it is important to know the capabilities of the OEMs before entering into a collaborative endeavour. Hence, it is firstly necessary to identify the most appropriate attributes of the manufacturer which are essential for a sustainable collaboration. In this context, the study proposes a novel framework for investigating the performance attributes of the OEMs from the economic, environmental and social aspects of sustainability. Since the evaluation of each attribute for each dimension of sustainability differs in terms of the nature of the information needed and the time and resources required, it is necessary to conduct a pre-evaluation of the attributes using the Complex Proportional Assessment (COPRAS) method. Furthermore, the shortlisted attributes for each sustainability dimension are evaluated and prioritized using the best worst method (BWM). The novelty of the attribute selection process lies in simultaneously considering the degree of importance of the attribute as well as the degree of difficulty of the collection of data required for the assessment of the OEM. The result of this study helps decision-makers and practitioners to comprehend the most influential attributes of OEMs which are crucial for collaboration, thus enhancing the overall sustainability impact of the supply chain. The managerial implications drawn from the resulting analysis provide the 3PRLP with a sustainable evaluation framework which can be ideally used for the selection of collaborative partners. The above model is validated using the case of an Indian 3PRLP company that handles electronic products.

Synthesis and investigations into the anticancer and antibacterial activity studies of ß-carboline chalcones and their bromide salts.

A series of sixteen ß-carbolines, bearing chalcone moiety at C-1 position, were prepared from easily accessible 1-acetyl-ß-carboline and various aldehydes under basic conditions followed by N2-alkylation using different alkyl bromides. The prepared compounds were evaluated for in vitro cytotoxicity against a panel of human tumor cell lines. N2-Alkylated-ß-carboline chalcones 13a-i represented the interesting anticancer activities compared to N2-unsubstituted ß-carboline chalcones 12a-g. Off the prepared ß-carbolines, 13g exhibited broad spectrum of activity with IC50 values lower than 22.5 µM against all the tested cancer cell lines. Further, the N2-alkylated-ß-carboline chalcone 13g markedly induced cell death in MDA-MB-231 cells by AO/EB staining assay. The most cytotoxic compound 13g possessed a relatively high drug score of 0.48. Additionally, the prepared ß-carboline chalcones displayed moderate antibacterial activities against tested bacterial strains.

Renal Artery Thrombosis with Renal Infarction: A Rare Cause of Acute Abdomen.

Renal artery thrombosis with renal infarction is a rare entity. Due to the nonspecific clinical presentation, the diagnosis is usually delayed. We describe such a case in a middle-aged man with membranous nephropathy who was in remission and presented with severe abdominal pain. He was managed with selective intra-arterial thrombolysis with a good outcome.

Targeting renin-angiotensin system in malignant hypertension in atypical hemolytic uremic syndrome.

Hypertension is common in hemolytic uremic syndrome (HUS) and often difficult to control. Local renin-angiotensin activation is believed to be an important part of thrombotic microangiopathy, leading to a vicious cycle of progressive renal injury and intractable hypertension. This has been demonstrated in vitro via enhanced tissue factor expression on glomerular endothelial cells which is enhanced by angiotensin II. We report two pediatric cases of atypical HUS with severe refractory malignant hypertension, in which we targeted the renin-angiotensin system by using intravenous (IV) enalaprilat, oral aliskiren, and oral enalapril with quick and dramatic response of blood pressure. Both drugs, aliskiren and IV enalaprilat, were effective in controlling hypertension refractory to multiple antihypertensive medications. These appear to be promising alternatives in the treatment of severe atypical HUS-induced hypertension and hypertensive emergency.

Remission of post-transplant focal segmental glomerulosclerosis with angiotensin receptor blockers.

Recurrence of focal segmental glomerulosclerosis (FSGS) is common after kidney transplantation. Plasmapheresis (PP) is considered to be the most effective treatment; however, results are variable and relapse is common after stopping plasmapheresis. Here, we report an unusual case of recurrent FSGS, who achieved complete remission with angiotensin receptor blocker therapy.

Eculizumab for atypical hemolytic-uremic syndrome in India: First report from India and the challenges faced.

Much progress has been made in understanding the pathophysiology and treatment of atypical hemolytic uremic syndrome (aHUS). Plasma therapy is the mainstay of treatment for aHUS. The availability of the first effective anti-complement therapeutic agent, eculizumab, has dramatically changed the outlook of this disease. However, its use in clinical practice raises important questions, such as who should receive the drug, when to start such therapy, and is it safe to stop treatment once the disease is controlled. We describe here for the 1st time in India, use of eculizumab in a 12-year-old boy with aHUS. We also describe in this report challenges faced in procuring the drug, and an ideal, evidence-based method of treating aHUS in children.

ABO-incompatible renal transplantation in developing world - crossing the immunological (and mental) barrier.

ABO incompatibility has been considered as an important immunological barrier for renal transplantation. With the advent of effective preconditioning protocols, it is now possible to do renal transplants across ABO barrier. We hereby present a single center retrospective analysis of all consecutive ABOi renal transplants performed from November 2011 to August 2014. Preconditioning protocol consisted of rituximab, plasmapheresis and intravenous immunoglobulin (IVIG) and maintenance immunosuppression consisted of tacrolimus, mycophenolate sodium, and prednisolone. The outcome of these ABOi transplants was compared with all other consecutive ABO-compatible (ABOc) renal transplants performed during same time. Twenty ABOi renal transplants were performed during the study period. Anti-blood group antibody titer varied from 1:2 to 1:512. Patient and graft survival was comparable between ABOi and ABOc groups. Biopsy proven acute rejection rate was 15% in ABOi group, which was similar to ABOc group (16.29%). There were no antibody-mediated rejections in ABOi group. The infection rate was also comparable. We conclude that the short-term outcome of ABOi and ABOc transplants is comparable. ABOi transplants should be promoted in developing countries to expand the donor pool.

Synthesis and docking studies of pyrazine-thiazolidinone hybrid scaffold targeting dormant tuberculosis.

The persistence of Mycobacterium tuberculosis (MTB) in dormant stage assists the pathogen to develop resistance against current antimycobactrial drugs. To address this issue, we report herein the synthesis of N-(4-oxo-2 substituted thiazolidin-3 yl) pyrazine-2-carbohydrazide derivatives designed by following the molecular hybridization approach using pyrazine and thiazolidenone scaffolds. The compounds were evaluated against MTB H37Ra and Mycobacterium bovis BCG in dormancy model. Most of the compounds had IC50 values in 0.3-1 µg/ml range. The active compounds were further tested for anti-proliferative activity against THP-1, Panc-1, A549, and MCF-7 cell lines using MTT assay and exhibited no significant cytotoxicity. We also report molecular docking studies using active analogs and MTB - Decaprenylphosphoryl-ß-d-ribose-2'-epimerase (DprE1) to rationalize the biological activity and to provide an insight into the probable mechanism of action and binding mode of hybridized structures. The results obtained validate the use of molecular hybridization approach and also suggest that reported compounds can provide a novel pharmacophore to synthesize lead compounds against dormat MTB.

Efficiently functionalized oxacalix[4]arenes: Synthesis, characterization and exploration of their biological profile as novel HDAC inhibitors.

A series of novel substituted oxacalix[4]arene has been synthesized and explored for their biological profile by evaluating anticancer, antifungal and antibacterial properties. The derivatives have been characterized by various spectroscopic techniques such as IR, (1)H NMR, (13)C NMR and Mass spectrometry. Many compounds showed strong inhibition (MIC) in the range of ∼0-50 µM with interesting cytotoxic activities against Hela cells in particular. The compounds were theoretically evaluated by docking studies as potential histone deacetylase inhibitors (HDACi). The study indicates that compounds bound adequately with HDAC, and hence complemented the experimental findings.

The impact of cigarette smoking on life expectancy between 1980 and 2010: a global perspective.

INTRODUCTION: Tobacco smoking is among the leading causes of preventable mortality worldwide. We assessed the impact of smoking on life expectancy worldwide between 1980 and 2010. METHODS: We retrieved cause-specific mortality data from the WHO Mortality Database by sex, year and age for 63 countries with high or moderate quality data (1980-2010). Using the time of the peak of the smoking epidemic by country, relative risks from the three waves of the Cancer Prevention Study were applied to calculate the smoking impact ratio and population attributable fraction. Finally, we estimated the potential gain in life expectancy at age 40 if smoking-related deaths in middle age (40-79 years) were eliminated. RESULTS: Currently, tobacco smoking is related to approximately 20% of total adult mortality in the countries in this study (24% in men and 12% in women). If smoking-related deaths were eliminated, adult life expectancy would increase on average by 2.4 years in men (0.1 in Uzbekistan to 4.8 years in Hungary) and 1 year in women (0.1 in Kyrgyzstan to 2.9 years in the USA). The proportion of smoking-related mortality among men has declined in most countries, but has increased in the most populous country in the world, that is, China from 4.6% to 7.3%. Increases in the impact of tobacco on life expectancy were observed among women in high-income countries. CONCLUSIONS: Recent trends indicate a substantial rise in the population-level impact of tobacco smoking on life expectancy in women and in middle-income countries. High-quality local data are needed in most low-income countries.

Paired kidney exchange transplantation: Maximizing the donor pool.

In the last decade, paired kidney exchange (PKE) transplantation has gained popularity worldwide as a viable alternative for end stage renal disease (ESRD) patients who have incompatible or sensitized donors. This study presents our experience with PKE transplantation and compares outcome between PKE and non-PKE renal transplant recipients. Between February 2010 and November 2013, 742 transplants were performed, of which 26 (3.5%) were PKE transplantations. All were two-way exchanges. PKE recipients were significantly older than non-PKE (46.73 ± 9.71 vs. 40.08 ± 13.36 years; P = 0.012) while donor ages were comparable. PKE patients had significantly higher number of HLA mismatches (5.03 ± 1.14 vs. 3.49 ± 1.57; P < 0.0001). After a median follow-up of 20 months (range: 3-47 months), there was no significant difference in patient survival (PKE 96.16% vs. non-PKE 96.65%; P = 0.596) and death censored graft survival (PKE 96.16% vs. non-PKE 96.37%; P = 1). Mean serum creatinine at 1 month and at last follow-up was lower in PKE versus non-PKE group (0.98 ± 0.33 vs. 1.3 ± 0.61 mg/dl; P = 0.008 and 0.96 ± 0.30 vs. 1.27 ± 0.57 mg/dl, P = 0.006, respectively). Biopsy proven acute rejection rate was 11.5% in PKE group and 16.89% in non-PKE patients (P = 0.6). To conclude, paired kidney donation is an excellent way of increasing the donor pool and needs to be promoted to overcome the shortage of suitable kidney in our country.

Invasive gastric mucormycosis and cytomegalovirus infection in an ABO incompatible renal transplant recipient.

Opportunistic infections are common in immunocompromised patients, such as solid organ transplant recipients. Both fungal and viral infections in posttransplant period increase morbidity and mortality. Cytomegalovirus (CMV) remains one of the most important pathogens. CMV disease may manifest as a nonspecific febrile syndrome or tissue-invasive infections. Zygomycosis is a rare infection, usually presents in rhino-cerebral, pulmonary and disseminated forms; gastrointestinal (GI) tract being a rare site of involvement. Newer techniques for early diagnosis and efficient therapies are essential for a better outcome of the disease; however, mortality rate remains high despite aggressive therapy. We report a renal transplant recipient, who developed gastric mucormycosis along with tissue invasive CMV disease, within 4 weeks of renal transplant and was diagnosed on the basis of upper GI endoscopy and gastric biopsy. The patient succumbed to the infection in spite of gastrectomy, antifungal and antiviral therapy.

Pyoderma gangrenosum in a renal transplant recipient: A case report and review of literature.

Pyoderma gangrenosum (PG) is a rare disorder of unknown etiology characterized by multiple cutaneous ulcers with mucopurulent or hemorrhagic exudate. This sterile neutrophilic dermatosis is known to occur in association with malignancy, infection, autoimmune disorders and drugs. Occurrence of PG in a renal transplant recipient, who is already on immunosuppressants, is rare. We hereby report a renal transplant recipient who developed PG 1-month after transplant and responded well to treatment with escalated dose of oral steroid.