A series of pyrazolo(dihydro)pyridines was synthesized and evaluated for antileishmanial efficacy against experimental visceral leishmaniasis (VL). Among all compounds, 6d and 6j exhibited better activity than miltefosine against intracellular amastigotes. Compound 6j (50 mg/kg/day) was further studied against Leishmania donovani/BALB/c mice via the intraperitoneal route for 5 days and displayed >91 and >93% clearance of splenic and liver parasitic burden, respectively. Combination treatment of 6j with a subcurative dose of miltefosine (5 mg/kg) in BALB/c mice almost completely ameliorated the disease (>97% inhibition) by augmenting nitric oxide generation and shifting the immune response toward Th1. Furthermore, investigating the effect of 6j on Leishmania promastigotes revealed that it induced molecular events, such as a loss in mitochondrial membrane potential, externalization of phosphatidylserine, and DNA fragmentation, that ultimately resulted in the programmed cell death of the parasite. These results along with pharmacokinetic studies suggest that 6j could be a promising lead for treating VL as an adjunct therapy with miltefosine.

Immuno-modulators in combination with antileishmanial drug miltefosine is a better therapeutic approach for treatment of Visceral Leishmaniasis (VL) as it not only reduces the dose of miltefosine but also shortens the treatment regimen. However, immunological mechanisms behind the perceived benefits of this combination therapy have not been investigated in detail. In the present study, we hypothesized that potential use of drugs that target the host in addition to the parasite might represent an alternative strategy for combination therapy. We investigated immune responses generated in Leishmania donovani infected animals (hamsters and mice) treated with combination of CpG-ODN-2006 and miltefosine at short dose regimen. Infected animals were administered CpG-ODN-2006 (0.4 mg/kg, single dose), as free and liposomal form, either alone or in combination with miltefosine for 5 consecutive days and parasite clearance was evaluated at day 4 and 7 post treatment. Animals that received liposomal CpG-ODN-2006 (lipo-CpG-ODN-2006) and sub-curative miltefosine (5 mg/kg) showed the best inhibition of parasite multiplication (∼97%) which was associated with a biased Th1 immune response in. Moreover, compared to all the other treated groups, we observed increased mRNA expression levels of pro-inflammatory cytokines (IFN-γ, TNF-α and IL-12) and significantly suppressed levels of Th2 cytokines (IL-10 and TGF-β) on day 4 post treatment in animals that underwent combination therapy with lipo-CpG-ODN-2006 and sub-curative miltefosine. Additionally, same therapy also induced heightened iNOS mRNA levels and NO generation, increased IgG2 antibody level and strong T-cell response in these hamsters compared with all the other treated groups. Collectively, our results suggest that combination of lipo-CpG-ODN-2006 and sub-curative miltefosine generates protective T-cell response in an animal model of visceral leishmaniasis which is characterized by strong Th1 biased immune response thereby underlining our hypothesis that combination therapy, at short dose regimen can be used as a novel way of treating visceral leishmaniasis.

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Background Depression among the elderly is well-documented and associated with socio-economic factors, physical and mental health conditions. Few studies have focused on older adults’ physical limitations and depressive symptoms. However, very little is known about marital status’ role in such associations, especially in India. The present study examines the association between physical limitations and self-reported depressive symptoms and moderating role of marital status in such association separately for men and women. Methods The present study used data from the Longitudinal Ageing Study in India (LASI) wave 1, 2017–2018, a nationally and state representative longitudinal large-scale survey of ageing and health. For the present research, a total sample of 20,806 older adults aged 60+ years was selected after excluding missing values. Along with descriptive statistics, binary logistic regression analysis and interaction effect of marital status were applied to examine the association between physical limitations (functional limitations and mobility difficulty) with the depressive symptoms separately for men and women. Results About 58, 50, and 45% elderly reported having depressive symptoms and had difficulty in 2+ ADLs, 2+ IADLs, and 2+ mobility difficulties, respectively. By the marital status, the prevalence of depressive symptoms was higher among currently unmarried than currently married, irrespective of type and number of physical limitations. The unadjusted, marital and multivariate-adjusted association suggested that elderly with more than two ADLs, IADLs, and mobility difficulty had higher odds of depressive symptoms. The gender stratified interaction effect of marital status and physical limitations on depressive symptoms indicated that currently unmarried elderly, particularly unmarried older women with 2+ ADLs (OR = 2.85; CI 95% = 1.88–3.09), 2+ IADLs (OR = 2.01; CI 95% = 1.74–2.31) and 2+ mobility difficulty (OR = 2.20; CI 95% = 1.86–2.60) had higher odds of depressive symptoms. However, such association was only valid for unmarried men having mobility difficulty. Conclusion The study highlights that the elderly with physical limitations such as ADLs, IADLs, and mobility difficulty require attention and care. Although married elderly are less likely to have depressive symptoms even with all the mentioned physical limitations, unmarried women are more vulnerable to have depressive symptoms with physical limitations.

1. The robust estimate of Basic Reproduction Rate (R0) of COVID-19 based on a meta-analysis performed on the pieces of evidence available across countries is 3.11 (2.49-3.71) persons for a generalised population in the absence of any control measures 2. The robust estimate of Case Fatality Rate (CFR) based on a meta-analysis performed on the pieces of evidence available across countries equals to 2.56 (2.06-3.05) per cent for a generalised population in approximately one-and-a-half months from the onset of the disease COVID-19. A significant regional variation is evident for the Basic Reproduction Rate (R0)but not for the Case Fatality Rate (CFR) 4. The peer-reviewed articles with a small sample size do not suffer from publication bias in a meta-analysis of COVID-19. Added Value of this StudyOut study combine available evidence of the parameter values, such as reproduction rate and case fatality rate, of the generalised epidemiological models for coronavirus disease of 2019 . In this way, we have reduced the dependency on data from a particular region or time or a homogeneous population. By applying meta-analysis, we estimated the robust estimate of reproduction rate and case fatality rate, which is applicable across heterogeneous populations. We proclaim that the reproduction rate of COVID-19 varies across subgroups of populations and regions and periods, but the case fatality rate remained the same. These estimates of reproduction rate and case fatality rate are worthwhile for developing countries like India and at a lower level of geography, in ambivalence. AbstractBackground: The outbreak of novel coronavirus disease of 2019 (COVID-19) has a wider geographical spread than other previous viruses such as Ebola and H1N1. The onset of disease and its transmission and severity has become a global concern. The policymakers have a serious concern for containing the spread and minimising the risk of death.Aim: This study aims to provide the estimates of basic reproduction rate (R0) and case fatality rate (CFR) which applies to a generalised population.Methods: A systematic review was carried out to retrieve the published estimates of reproduction rate and case fatality rate in peer-reviewed articles from PubMed MEDLINE database with defined inclusion and exclusion criteria in the period 15 December 2019 to 3 May 2020. The systematic review led to the selection of 24 articles for R0 and 17 articles for CFR. These studies used data from China and its provinces, other Asian countries such as Japan, Korea, the Philippines, and countries from other parts of the world such as Nigeria, Iran, Italy, Europe as a whole, France, Latin America, Turkey, the United Kingdom (UK), and the United States of America (USA). These selected articles gave an output of 30 counts of R0 and 29 counts of CFR which were used in a meta-analysis. A meta-analysis, with the inverse variance method, fixed-and random-effects model and the Forest plot, was performed to estimate the mean effect size or mean value of basic reproduction rate and case fat...

Leishmania is an obligatory intracellular protozoan parasite responsible for the development of a spectrum of disease manifestation ranging from cutaneous to the more destructive visceral form 1 . Visceral leishmaniasis (VL) is a neglected tropical disease, mainly caused by the species L. donovani, which is prevalent in the Indian subcontinent with 40,000 cases registered each year and 147 million people under the risk 2 . Macrophages are the primary host for the parasite to survive and multiply in the mammalian system. Development of antileishmanial immunity depends on the Th1 type immune response generated by IL-12 secretion by antigen presenting cells (APCs) which in turn induce IFNγ secretion by T cells. This secreted IFNγ further induce macrophages for generation of nitric oxide (NO) and reactive oxygen species (ROS), which are the major antileishmanial defense molecules 3 . Uncoupling protein (UCP) is a mitochondrial membrane transporter which takes part in the regulation of mitochondrial ROS generation in macrophages 4 . Leishmania developed several strategies to dodge the host immune response to the establishment of successful infection in the hostile environment. This parasite induces the expression of negative regulatory protein UCP2 in macrophages as well as utilizes their own cascade of antioxidant enzymes like ascorbate peroxidase (APX), glutathione synthetase, tryparedoxin peroxidase for the suppression of ROS generation thereby neutralizing oxidative stress in host for their survival [5][6][7][8] . Due to unavailability of effective vaccines, treatment solely relies on chemotherapy. Although pentavalent antimonials were the mainstream therapy for past 70 years, a large percentage of patients are resistant to this drug. Currently, amphotericin B (conventional deoxycholate or liposomal formulations) has emerged as the first line of treatment. Miltefosine is the only oral drug. However, emerging resistance to miltefosine is particularly worrying. Alongside, most of these synthetic antileishmanial drugs are highly expensive and suffer from various side effects, long treatment regimen and acute toxicity, thus pose a real challenge for the management and elimination