Skin pharmacokinetics of miltefosine in the treatment of post-kala-azar dermal leishmaniasis in South Asia.

INTRODUCTION: Post-kala-azar dermal leishmaniasis (PKDL) arises as a dermal complication following a visceral leishmaniasis (VL) infection. Current treatment options for PKDL are unsatisfactory, and there is a knowledge gap regarding the distribution of antileishmanial compounds within human skin. The present study investigated the skin distribution of miltefosine in PKDL patients, with the aim to improve the understanding of the pharmacokinetics at the skin target site in PKDL. METHODS: Fifty-two PKDL patients underwent treatment with liposomal amphotericin B (20 mg/kg) plus miltefosine (allometric dosing) for 21 days. Plasma concentrations of miltefosine were measured on study days 8, 15, 22 and 30, while a punch skin biopsy was taken on day 22. A physiologically based pharmacokinetic (PBPK) model was developed to evaluate the distribution of miltefosine into the skin. RESULTS: Following the allometric weight-based dosing regimen, median miltefosine concentrations on day 22 were 43.73 µg/g (IQR: 21.94-60.65 µg/g) in skin and 33.29 µg/mL (IQR: 25.9-42.58 µg/mL) in plasma. The median individual concentration ratio of skin to plasma was 1.19 (IQR: 0.79-1.9). In 87% (45/52) of patients, skin exposure was above the suggested EC90 PK target of 10.6 mg/L associated with in vitro susceptibility. Simulations indicated that the residence time of miltefosine in the skin would be more than 2-fold longer than in plasma, estimated by a mean residence time of 604 versus 266 hours, respectively. CONCLUSION: This study provides the first accurate measurements of miltefosine penetration into the skin, demonstrating substantial exposure and prolonged retention of miltefosine within the skin. These findings support the use of miltefosine in cutaneous manifestations of leishmaniasis. In combination with parasitological and clinical data, these results are critical for the future optimization of combination therapies with miltefosine in the treatment of PKDL.

Environmental plastics in the context of UV radiation, climate change, and the Montreal Protocol.

There are close links between solar UV radiation, climate change, and plastic pollution. UV-driven weathering is a key process leading to the degradation of plastics in the environment but also the formation of potentially harmful plastic fragments such as micro- and nanoplastic particles. Estimates of the environmental persistence of plastic pollution, and the formation of fragments, will need to take in account plastic dispersal around the globe, as well as projected UV radiation levels and climate change factors.

Assembly and Disassembly of Supramolecular Hypervalent Iodine Macrocycles via Anion Coordination.

This study explores the dynamic self-assembly and disassembly of hypervalent iodine-based macrocycles (HIMs) guided by secondary bonding interactions. The reversible disassembly and reassembly of HIMs are facilitated through anion binding via the addition of tetrabutylammonium (TBA) salts or removal of the anion by the addition of silver nitrate. The association constants for HIM monomers with TBA(Cl) and TBA(Br) are calculated and show a correlation with the strength of the iodine-anion bond. A unique tetracoordinate hypervalent iodine-based compound was identified as the disassembled monomer. Last, the study reveals the dynamic bonding nature of these macrocycles in solution, allowing for rearrangement and participation in dynamic bonding chemistry.

Plastics in the environment in the context of UV radiation, climate change and the Montreal Protocol: UNEP Environmental Effects Assessment Panel, Update 2023.

This Assessment Update by the Environmental Effects Assessment Panel (EEAP) of the United Nations Environment Programme (UNEP) considers the interactive effects of solar UV radiation, global warming, and other weathering factors on plastics. The Assessment illustrates the significance of solar UV radiation in decreasing the durability of plastic materials, degradation of plastic debris, formation of micro- and nanoplastic particles and accompanying leaching of potential toxic compounds. Micro- and nanoplastics have been found in all ecosystems, the atmosphere, and in humans. While the potential biological risks are not yet well-established, the widespread and increasing occurrence of plastic pollution is reason for continuing research and monitoring. Plastic debris persists after its intended life in soils, water bodies and the atmosphere as well as in living organisms. To counteract accumulation of plastics in the environment, the lifetime of novel plastics or plastic alternatives should better match the functional life of products, with eventual breakdown releasing harmless substances to the environment.

Transcriptome Analysis of Dermal Fibroblasts Derived From Visceral Leishmaniasis and Post-Kala-Azar Dermal Leishmaniasis Patients Reveal Disease-Specific Gene Expression and Pathological Regulation.

BACKGROUND: Post-kala-azar dermal leishmaniasis (PKDL), a dermal form of the disease, occurs in some visceral leishmaniasis (VL) patients following treatment. The PKDL disease mechanism is not yet clearly understood. Here we have studied the role of dermal fibroblasts in VL and PKDL disease mechanism. METHODS: Dermal fibroblasts were grown from skin biopsy explants collected from individual VL and PKDL patients and healthy controls. Fibroblasts from the third passage were subjected to RNA sequencing to analyze differentially expressed genes (DEGs). Significantly important genes were further validated by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). RESULTS: Transcriptome analysis of PKDL versus VL identified 516 DEGs (263 were overrepresented and 253 were underrepresented in PKDL). Among the top hub genes, MMP2, IL1B, CXCL8, IFIH1, NFKB1A, IL6, ISG15, and EGFR were underexpressed and ACTB, HSP90AA1, RAB7A, and RPS27A were overexpressed in PKDL compared to VL. CONCLUSIONS: Our data indicate that PKDL fibroblasts may present antigens through the MHC I pathway activating CD8+ T-cell mediated response, while VL fibroblasts express nuclear factor-κB (NFκB)-mediated chemokines, IL1B, IL6, and IL8, resulting in the recruitment of natural killer (NK)-cells and monocytes to the site of infection, leading to the clearance of parasite from the skin and visceralization of the disease.

Controlling the Energetic Properties of N-Methylene-C-Linked 4-Hydroxy-3,5-dinitropyrazole- and Tetrazole-Based Compounds via a Selective Mono- and Dicationic Salt Formation Strategy.

In the quest to synthesize high-performing insensitive high-energy density materials (HEDMs), the main challenge is establishing an equilibrium between energy and stability. For this purpose, we explored 4-hydroxy-3,5-dinitropyrazole- and tetrazole-based energetic scaffolds connected via a N-methylene-C bridge. The hydroxy functionality between nitro groups on the pyrazole ring promotes physical stability via inter- and intramolecular hydrogen bonding and contributes to oxygen balance, supporting better energetic performance. Due to two acidic sites (OH and NH) with different reactivities, a series of monocationic and dicationic salts were synthesized, and their overall performance was compared. All compounds synthesized in this study have high physical stability with impact sensitivity >40 J and friction sensitivity >360 N. Monocationic salts were generally found to have better thermal stability with respect to their corresponding dicationic energetic salts, which showed better energetic performance. The salt formation strategy effectively improved the thermal stability of 2 (Td = 168 °C), where most energetic salts have decomposition temperatures higher than 220 °C. All of the compounds were characterized through IR, multinuclear NMR spectroscopy, high-resolution mass spectrometry (HRMS), and elemental analysis. The structure-property relationship was studied using Hirshfeld surface analysis, noncovalent interaction (NCI) analysis, and electrostatic potential studies.

Polynitro-functionalized 4-phenyl-1H-pyrazoles as heat-resistant explosives.

A new class of heat-resistant explosives was synthesized by coupling N-methyl-3,5-dinitropyrazole with polynitrobenzene moieties through carbon-carbon bonds. Simple Pd(0)-based Suzuki cross-coupling reactions between N-methyl-4-bromo-3,5-dinitropyrazole and 4-chloro/3-hydroxy-phenylboronic acid followed by nitration, amination and oxidation lead to the formation of C-C connected penta-nitro energetic derivatives 6 and 10. Various other energetic derivatives, such as amino (5), azido (7), nitramino (8) and energetic salts (11-14), were also explored to fine-tune their properties. All the compounds were thoroughly characterized using IR, NMR [1H, 13C{1H}], differential scanning calorimetry (DSC), elemental analysis, and HRMS studies. Compounds 5, 10 and 13 were further characterized through 15N NMR, and the crystal structures of 6 and 14 were confirmed through single-crystal X-ray diffraction studies. The physicochemical and energetic properties of all the energetic compounds were explored. Most of the synthesized compounds demonstrated high thermal stability (decomposition temperature Tdec > 250 °C), among which compounds 5 and 6 showed excellent thermal stability, having decomposition temperatures above 300 °C. The excellent thermal stability, acceptable sensitivity and good energetic properties of compounds 5, 6, 10 and 13 make them promising heat-resistant explosives. Furthermore, these compounds were found to be more thermally stable than the known N-methyl-3,5-dinitropyrazole-based and C-N coupled 3,4,5-trinitrobenzene-azole-based energetic compounds.

Thermal Hysteresis and Ordering Behavior of Magnetic Skyrmion Lattices.

The physics of phase transitions in two-dimensional (2D) systems underpins research in diverse fields including statistical mechanics, nanomagnetism, and soft condensed matter. However, many aspects of 2D phase transitions are still not well understood, including the effects of interparticle potential, polydispersity, and particle shape. Magnetic skyrmions are chiral spin-structure quasi-particles that form two-dimensional lattices. Here, we show, by real-space imaging using in situ cryo-Lorentz transmission electron microscopy coupled with machine learning image analysis, the ordering behavior of Néel skyrmion lattices in van der Waals Fe3GeTe2. We demonstrate a distinct change in the skyrmion size distribution during field-cooling, which leads to a loss of lattice order and an evolution of the skyrmion liquid phase. Remarkably, the lattice order is restored during field heating and demonstrates a thermal hysteresis. This behavior is explained by the skyrmion energy landscape and demonstrates the potential to control the lattice order in 2D phase transitions.

Double transplantation as a climate resilient and sustainable resource management strategy for rice production in eastern Uttar Pradesh, north India.

-Enhancing the productivity of rainfed crops, especially rice, while coping with climate adversities and saving critical natural resources is essential for ensuring the food and nutrition security of a growing population. With this context, the present study was undertaken to validate promising farm innovation and adaptation practices used by small-medium landholding farmers for rice cultivation in eastern Uttar Pradesh (UP), north India, as well as to examine the sustainability of innovative practices for large-scale adoption. For this, a 3-year study comprising extensive field surveys and experiments was undertaken to compare single transplantation (ST) and double transplantation (DT) in rice along with organic addition (farm-yard manure, FYM) on crop growth, yield, climate resilience, soil quality, and overall sustainability i.e., social (women involvements and labour productivity), environmental (water productivity and nutrient use efficiency), and economic (benefit:cost ratio) dimensions of sustainability. Field experiments were conducted in triplicate using two local rice varieties (MotiNP-360 and Sampurna Kaveri) in two agroclimatic zones, namely the middle Gangetic plains and the Vindhyan zone, in the Mirzapur district of eastern Uttar Pradesh. The DT practices of rice with and without farm yard manure (FYM) (replacing at a dose of 25% NPK) were evaluated over conventional methods of rice cultivation (i.e., ST, as control) and analysis was done periodically. The DT practice improved growth (p < 0.05), percent fertile tiller and grain (p < 0.05), and rice yield (15-20% higher than ST), while also improving soil quality, yield indices, water and labour productivity, and the benefit-cost ratio. The DT practice also resulted in early maturity (10-15 days earlier than ST), created more labour days for women, decreased lodging and pest/disease incidence, as well as a subsequent reduction in the use of synthetic chemical pesticides and associated environmental costs. Importantly, the residual effects of FYM application significantly improved (p < 0.05) the grain yield in subsequent years of cropping. Optimizing DT cultivation practices, preferably with FYM input for various agro-climatic regions, is essential for large-scale sustainable rice production under changing climatic conditions.

Barriers to the effective management and prevention of post kala-azar dermal leishmaniasis (PKDL) in the Indian subcontinent.

Post kala-azar dermal leishmaniasis (PKDL) is a skin disease that usually occurs among individuals with a past history of visceral leishmaniasis (VL). PKDL cases act as a reservoir of parasites and may play a significant role in disease transmission. Hence, prompt detection and complete treatment of PKDL cases are crucial for the control and elimination of VL. The purpose of this review was to highlight the barriers to effective control and prevention of VL/PKDL as well as potential solutions in India. Main obstacles are lack of knowledge about the disease and its vector, poor treatment-seeking behaviours, ineffective vector control measures, lack of confirmatory diagnostics in endemic areas, limited drug choices, treatment noncompliance among patients, drug resistance, and a lack of an adequate number of trained personnel in the health system. Therefore, in order to control and successfully eliminate VL in the Indian subcontinent, early detection of PKDL cases, improved diagnosis and treatment, raising awareness, and effective vector control mechanisms are necessary.

AmBisome Monotherapy and Combination AmBisome-Miltefosine Therapy for the Treatment of Visceral Leishmaniasis in Patients Coinfected With Human Immunodeficiency Virus in India: A Randomized Open-Label, Parallel-Arm, Phase 3 Trial.

BACKGROUND: Visceral leishmaniasis (VL) in patients with human immunodeficiency virus (HIV) presents an increasingly important patient cohort in areas where both infections are endemic. Evidence for treatment is sparce, with no high-quality studies from the Indian subcontinent. METHODS: This is a randomized, open-label, parallel-arm, phase 3 trial conducted within a single hospital in Patna, India. One hundred and fifty patients aged ≥18 years with serologically confirmed HIV and parasitologically confirmed VL were randomly allocated to 1 of 2 treatment arms, either a total 40 mg/kg intravenous liposomal amphotericin B (AmBisome; Gilead Pharmaceuticals) administered in 8 equal doses over 24 days or a total 30 mg/kg intravenous AmBisome administered in 6 equal doses given concomitantly with a total 1.4 g oral miltefosine administered through 2 daily doses of 50 mg over 14 days. The primary outcome was intention-to-treat relapse-free survival at day 210, defined as absence of signs and symptoms of VL or, if symptomatic, negative parasitological investigations. RESULTS: Among 243 patients assessed for eligibility, 150 were recruited between 2 January 2017 and 5 April 2018, with no loss to follow-up. Relapse-free survival at day 210 was 85% (64/75; 95% CI, 77-100%) in the monotherapy arm, and 96%, (72/75; 90-100%) in the combination arm. Nineteen percent (28/150) were infected with concurrent tuberculosis, divided equally between arms. Excluding those with concurrent tuberculosis, relapse-free survival at day 210 was 90% (55/61; 82-100%) in the monotherapy and 97% (59/61; 91-100%) in the combination therapy arm. Serious adverse events were uncommon and similar in each arm. CONCLUSIONS: Combination therapy appears to be safe, well tolerated, and effective, and halves treatment duration of current recommendations. CLINICAL TRIALS REGISTRATION: Clinical Trial Registry India (CTRI/2015/05/005807; the protocol is available online at https://osf.io/avz7r).

A Novel Antigen, Otubain Cysteine Peptidase of Leishmania donovani, for the Serodiagnosis of Visceral Leishmaniasis and for Monitoring Treatment Response.

Tests for visceral leishmaniasis (VL) are not uniformly effective for all endemic regions. In a serological assay, a novel antigen, otubain cysteine peptidase, compared with rK39, showed comparable sensitivity with Indian VL serum samples and prominently increased sensitivity with Brazilian samples, as well as improved monitoring of the treatment response.

Oxidant activated soluble adenylate cyclase of Leishmania donovani regulates the cAMP-PKA signaling axis for its intra-macrophage survival during infection.

Adenosine 3',5'-cyclic monophosphate (cAMP) is a stress sensor molecule that transduces the cellular signal when Leishmania donovani moves from insect vector to mammalian host. At this stage, the parasite membrane-bound receptor adenylate cyclase predominantly produces cAMP to cope with the oxidative assault imposed by host macrophages. However, the role of soluble adenylate cyclase of L. donovani (LdHemAC) has not been investigated fully. In the present investigation, we monitored an alternative pool of cAMP, maintained by LdHemAC. The elevated cAMP effectively transmits signals by binding to Protein Kinase A (PKA) present in the cytosol and regulates antioxidant gene expression and phosphorylates several unknown PKA substrate proteins. Menadione-catalyzed production of reactive oxygen species (ROS) mimics host oxidative condition in vitro in parasites where cAMP production and PKA activity were found increased by ~1.54 ± 0.35, and ~1.78 ± 0.47-fold, respectively while expression of LdHemAC gene elevated by ~2.18 ± 0.17-fold. The LdHemAC sense these oxidants and became activated to cyclize ATP to enhance the cAMP basal level that regulates antioxidant gene expression to rescue parasites from oxidative stress. In knockdown parasites (LdHemAC-KD), the downregulated antioxidant genes expression, namely, Sod (2.30 ± 0.46), Pxn (2.73 ± 0.15), Tdr (2.7 ± 0.12), and Gss (1.57 ± 0.15) results in decreased parasite viability while in overexpressed parasites (LdHemAC-OE), the expression was upregulated by ~5.7 ± 0.35, ~2.57 ± 0.56, ~4.7 ± 0.36, and ~2.4 ± 0.83, respectively, which possibly overcomes ROS accumulation and enhances viability. Furthermore, LdHemAC-OE higher PKA activity regulates phosphorylation of substrate proteins (~56 kDs in membrane fraction and ~25 kDs in the soluble fraction). It reduced significantly when treated with inhibitors like DDA, Rp-cAMP, and H-89 and increased by ~2.1 ± 0.28-fold, respectively under oxidative conditions. The LdHemAC-KD was found less infective to RAW 264.7 macrophages and more prone to oxidative damage as compared to LdHemAC-OE and control parasites. Together, this study demonstrates mechanistic links among LdHemAC, cAMP, and PKA in parasite survival and invasion under host oxidative condition.

The success of the Montreal Protocol in mitigating interactive effects of stratospheric ozone depletion and climate change on the environment.

The Montreal Protocol and its Amendments have been highly effective in protecting the stratospheric ozone layer, preventing global increases in solar ultraviolet-B radiation (UV-B; 280-315 nm) at Earth's surface, and reducing global warming. While ongoing and projected changes in UV-B radiation and climate still pose a threat to human health, food security, air and water quality, terrestrial and aquatic ecosystems, and construction materials and fabrics, the Montreal Protocol continues to play a critical role in protecting Earth's inhabitants and ecosystems by addressing many of the United Nations Sustainable Development Goals.

Centrosymmetric or Noncentrosymmetric? Transition Metals Talking in K2TGe3S8(T = Co, Fe).

Two new quaternary sulfides K2TGe3S8(T = Co, Fe) have been synthesized by a high-temperature solid-state routine and flux growth method. The crystal growth process of K2TGe3S8(T = Co, Fe) was elucidated by in situ powder X-ray diffraction and DSC thermal analysis. The millimeter-sized crystals of K2TGe3S8(T = Co, Fe) were grown. K2CoGe3S8 crystallizes in a new structure type in centrosymmetric space group P1 (no. 2) with unit cell parameters of a = 7.016(1) Å, b= 7.770(1) Å, c = 14.342(1) Å, α = 93.80(1)°, ß = 92.65(1)°, γ = 114.04(1)°. K2FeGe3S8 crystallizes in the K2FeGe3Se8 structure type and the noncentrosymmetric space group P21 (no. 4) with unit cell parameters of a = 7.1089(5)Å, b = 11.8823(8) Å, c = 16.7588(11) Å, ß = 96.604(2)°. There is a high structural similarity between K2CoGe3S8 and K2FeGe3S8. The larger volume coupled with higher degrees of distortion of the [FeS4] tetrahedra compared to the [CoS4] tetrahedra accounts for the structure's shift from centrosymmetric to noncentrosymmetric. The theory simulation confirms that [TS4]T= Co or Fe tetrahedra play a crucial role in controlling the structure and properties of K2TGe3S8(T = Co, Fe). The measured optical bandgaps of K2CoGe3S8 and K2FeGe3S8 are 2.1(1) eV and 2.6(1) eV, respectively. K2FeGe3S8 shows antiferromagnetic ordering at 24 K while no magnetic ordering was detected in K2CoGe3S8. The magnetic measurements also demonstrate the divalent nature of transition metals in K2TGe3S8(T = Co, Fe).

Evaluation of Cysteine Protease C of Leishmania donovani in Comparison with Glycoprotein 63 and Elongation Factor 1α for Diagnosis of Human Visceral Leishmaniasis and for Posttreatment Follow-Up Response.

Visceral leishmaniasis (VL) is a threat in many developing countries. Much effort has been put to eliminating this disease, for which serodiagnosis remains the mainstay for VL control programs. New and improved antigens as diagnostic candidates are required, though, as the available antigens fail to demonstrate equal optimum performance in all areas of endemicity. Moreover, these diagnoses are dependent on invasive serum sampling. In the current study, we cloned and expressed Leishmania donovani cysteine protease C (CPC) and evaluated its diagnostic and test-of-cure possibilities by detecting the antibody levels in human serum and urine through ELISA and immunoblot assays. Two immunodominant antigens, recombinant glycoprotein 63 (GP63) and elongation factor 1α (EF1α), identified earlier by our group, were also assessed by employing human serum and urine samples. Of these three antigens in ELISAs, CPC demonstrated the highest sensitivities of 98.15% and 96% positive testing in serum and urine of VL patients, respectively. Moreover, CPC yielded 100% specificity with serum and urine of nonendemic healthy controls compared to GP63 and EF1α. Urine samples were found to be more specific than serum for distinguishing endemic healthy controls and other diseases by means of all three antigens. In all cases, CPC gave the most promising results. Unlike serum, urine tests demonstrated a significant decrease in antibody levels for CPC, GP63, and EF1α after 6 months of treatment. The diagnostic and test-of-cure performances of CPC in the immunoblot assay were found to be better than those of GP63 and EF1α. In conclusion, CPC, followed by GP63 and EF1α, may be utilized as candidates for diagnosis of VL and to assess treatment response.

Evaluating the immunomodulatory responses of LdODC-derived MHC Class-II restricted peptides against VL.

In a bid to develop a novel immunoprophylactic measure against visceral leishmaniasis (VL), MHC class-II-restricted epitopes of LdODC were identified by reverse vaccinology approach. Five consensus HLA-DRB1*0101-restricted epitopes were screened. The analysis revealed that the set of epitopes was presented by at least 54 diverse MHC class-II alleles. Based on in silico screening, followed by molecular dynamics simulation, population coverage analysis, and HLA cross-presentation ability, five best epitopes were evaluated. PBMCs isolated from treated VL subjects, when stimulated with synthetic peptide alone or as a cocktail of peptides, triggered a secretory IFN-γ, but not the IL-10 level. Support in this notion came from intracellular cytokine level with a considerable up-regulated IFN-γ produced by CD4+ T cells. Also, the enhanced IFN-γ seemed to be augmented with the activation of macrophages with prominent IL-12 production. Therefore, it can be concluded that the screened MHC class-II-restricted epitope hotspots derived from Leishmania ODC can trigger CD4+ T cells, which can skew macrophage functions towards protection. However, a detailed analysis can explore its potentiality as a vaccine candidate.

Non-invasive biomonitoring of mercury in birds near thermal power plants: lessons from Maharashtra, India.

Thermal power plants (TPPs) have emerged as a major source of air, water, and soil pollution because of the presence of many toxic metals. The presence of mercury (Hg) in fly ash has proven to be toxic in nature because of its tendency to get bioaccumulated and biomagnified in the food chain. The aim of the present study was to understand the presence of toxic Hg in the feathers of wetland birds undertaking the study around a TPP located in Nagpur, India. Local wetland birds especially cattle egrets, heron, and Moorhen were commonly observed dwelling close to fly ash ponds for various purposes (roosting, breeding, feeding, etc.). Samples of fly ash, soil, water, plants, and bird feather were collected, cleaned, and processed for Hg analysis. A mercury analyzer was used to assess the concentration of toxic levels of Hg in samples. Our results reflect leaching of Hg in soil and uptake by plant samples, whereas in water, ash, and bird feather samples concentrations of Hg were fairly below the prescribed limits (World Health Organization). A non-invasive method for understanding the mercury concentration in wetland birds has been established as a potential important monitoring tool to track the fate of toxic metal Hg in the food chain. In summary, our results indicate fairly low Hg levels in feather samples projecting non-invasive biomonitoring as a promising strategy. The study also suggests that a comprehensive monitoring action plan in place for Hg and other toxic metals in the food chain that comes from TPP will be efficient to avoid any pitfalls. Graphical abstract.

Molecular docking studies of chloroquine and its derivatives against P23pro-zbd domain of chikungunya virus: Implication in designing of novel therapeutic strategies.

The arthropod-transmitted chikungunya virus has emerged as an epidemic menace that causes debilitating polyarthritis. With this life-threatening impact on humans, the possible treatment requires to cure the viral infectivity. But, devoid of any vaccine against the chikungunya virus (CHIKV), there is a need to develop a novel chemotherapeutic strategy to treat this noxious infection. CHIKV carries highly compact P23pro-zbd structure that possesses potential RNA-binding surface domains which extremely influences the use of RNA template during genome replication at the time of infection and pathogenesis. Therefore, computational approaches were used to explore the novel small molecule inhibitors targeting P23pro-zbd domain. The tertiary structure was modeled and optimized using in silico approaches. The results obtained from PROCHECK (93.1% residues in favored regions), ERRAT (87.480 overall model quality) and ProSA (Z-score: -11.72) revealed the reliability of the proposed model. Interestingly, a previously reported inhibitor, chloroquine possesses good binding affinities with the target domain. In-depth analysis revealed that chloroquine derivatives such as didesethyl chloroquine hydroxyacetamide, cletoquine, hydroxychloroquine exhibited a better binding affinity. Notably, MD simulation analysis exhibited that Thr1312, Ala1355, Ala1356, Asn1357, Asp1364, Val1366, Cys1367, Ala1401, Gly1403, Ser1443, Tyr1444, Gly1445, Asn1459, and Thr1463 residues are the key amino acid responsible for stable ligand-protein interaction. The results obtained from this study provide new insights and advances the understanding to develop a new approach to consider effective and novel drug against chikungunya. However, a detailed in vivo study is required to explore its drug likeliness against this life-threatening disease.

Assessment of quality of life using WHOQOL-BREF in patients with visceral leishmaniasis.

BACKGROUND: This study was aimed to assess the impact of quality of life using WHOQOL-BREF in patients with Visceral leishmaniasis (VL). METHODS: A total of 95 VL cases and 95 healthy participants filled out the questionnaires. Data on socio-demographic aspects along with disease duration were collected. Data were compared using a t-test, analysis of variance and chi-square test. RESULTS: VL patients experienced very high impact on their quality of life. Study cohort had male preponderance (72.63%). Majority (64.21%) were aged < 40 years. Longer disease duration was found to have significantly poor quality of life (p < 0.05). The physical domain was found to be most affected domains of quality of life (QOL). QOL was affected most in illiterate, married, housewife, rural population and patients with longer disease duration (p < 0.05). The psychological and environmental domains were significantly affected in > 40 years of age group married patients (p < 0.05). CONCLUSIONS: VL significantly impaired the patients' (QOL) in all four domains (physical, psychological, social relationship and environmental). Physical domain was significantly the most affected domain.