Cost Effectiveness of Implementing Integrated Management of Neonatal and Childhood Illnesses Program in District Faridabad,India

Introduction

Despite the evidence for preventing childhood morbidity and mortality, financial resources are cited as a constraint for Governments to scale up the key health interventions in some countries. We evaluate the cost effectiveness of implementing IMNCI program in India from a health system and societal perspective.

Methods

We parameterized a decision analytic model to assess incremental cost effectiveness of IMNCI program as against routine child health services for infant population at district level in India. Using a 15-years time horizon from 2007 to 2022, we populated the model using data on costs and effects as found from a cluster-randomized trial to assess effectiveness of IMNCI program in Haryana state. Effectiveness was estimated as reduction in infant illness episodes, deaths and disability adjusted life years (DALY). Incremental cost per DALY averted was used to estimate cost effectiveness of IMNCI. Future costs and effects were discounted at a rate of 3%. Probabilistic sensitivity analysis was undertaken to estimate the probability of IMNCI to be cost effective at varying willingness to pay thresholds.

Results

Implementation of IMNCI results in a cumulative reduction of 57384 illness episodes, 2369 deaths and 76158 DALYs among infants at district level from 2007 to 2022. Overall, from a health system perspective, IMNCI program incurs an incremental cost of USD 34.5 (INR 1554) per DALY averted, USD 34.5 (INR 1554) per life year gained, USD 1110 (INR 49963) per infant death averted. There is 90% probability for ICER to be cost effective at INR 2300 willingness to pay, which is 5.5% of India’s GDP per capita. From a societal perspective, IMNCI program incurs an additional cost of USD 24.1 (INR 1082) per DALY averted, USD 773 (INR 34799) per infant death averted and USD 26.3 (INR 1183) per illness averted in during infancy.

Conclusion

IMNCI program in Indian context is very cost effective and should be scaled-up as a major child survival strategy.     

Speed adaptation in a powered transtibial prosthesis controlled with a neuromuscular model

Control schemes for powered ankle-foot prostheses would benefit greatly from a means to make them inherently adaptive to different walking speeds. Towards this goal, one may attempt to emulate the intact human ankle, as it is capable of seamless adaptation. Human locomotion is governed by the interplay among legged dynamics, morphology and neural control including spinal reflexes. It has been suggested that reflexes contribute to the changes in ankle joint dynamics that correspond to walking at different speeds. Here, we use a data-driven muscle-tendon model that produces estimates of the activation, force, length and velocity of the major muscles spanning the ankle to derive local feedback loops that may be critical in the control of those muscles during walking. This purely reflexive approach ignores sources of non-reflexive neural drive and does not necessarily reflect the biological control scheme, yet can still closely reproduce the muscle dynamics estimated from biological data. The resulting neuromuscular model was applied to control a powered ankle-foot prosthesis and tested by an amputee walking at three speeds. The controller produced speed-adaptive behaviour; net ankle work increased with walking speed, highlighting the benefits of applying neuromuscular principles in the control of adaptive prosthetic limbs.     

Unconjugated bilirubin inhibits VCAM-1-mediated transendothelial leukocyte migration

During lymphocyte migration, engagement of VCAM-1 stimulates the generation of endothelial cell-derived reactive oxygen species (ROS) and activation of matrix metalloproteinases, facilitating endothelial retraction. Because bilirubin is a potent antioxidant, we examined the hypothesis that this bile pigment inhibits VCAM-1-dependent cellular events. The migration of isolated murine splenic lymphocytes across monolayers of murine endothelial cell lines (which constitutively express VCAM-1) is significantly inhibited by physiological concentrations of bilirubin, in the absence of an effect on lymphocyte adhesion. Bilirubin administration also suppresses VCAM-1-stimulated ROS generation and reduces endothelial cell matrix metalloproteinase activity. In a murine asthma model characterized by VCAM-1-dependent airway inflammation, treatment of C57BL6/J mice with i.p. bilirubin decreases the total leukocyte count in the lung parenchyma and lavage fluid, through specific inhibition of eosinophil and lymphocyte infiltration. Blood eosinophil counts were increased in bilirubin-treated animals, while VCAM-1 expression in the capillary endothelium and cytokine levels in both lung lavage and supernatants from cultured lymph node lymphocytes were unchanged, suggesting that bilirubin inhibits leukocyte migration. Conclusion: bilirubin blocks VCAM-1-dependent lymphocyte migration in vitro and ameliorates VCAM-1-mediated airway inflammation in vivo, apparently through the suppression of cellular ROS production. These findings support a potential role for bilirubin as an endogenous immunomodulatory agent.     

On the logic of Fisherian sexual selection*

In Fisher's model of sexual selection, a female preference for a male trait spreads together with the trait because their genetic bases become correlated. This can be interpreted as a “greenbeard” system: a preference gene, by inducing a female to mate with a trait-bearing male, favors itself because the male is disproportionately likely also to carry the preference gene. Here, we use this logic to argue that Fisherian sexual selection in diploids proceeds via two channels: (i) trait-bearing males are disproportionately the product of matings between preference-bearing mothers and trait-bearing fathers, and thus trait and preference genes are correlated “in trans”; (ii) trait and preference genes come into gametic phase disequilibrium, and thus are correlated “in cis.” Gametic phase disequilibrium is generated by three distinct mechanisms that we identify. The trans channel does not operate when sexual selection is restricted to the haploid phase, and therefore represents a fundamental difference between haploid and diploid models of sexual selection. We show that the cis and trans channels contribute equally to the spread of the preference when recombination between the preference and trait loci is free, but that the trans channel is substantially more important when linkage is tight.     

Radiation resistance in thermophiles: mechanisms and applications

The study of prokaryotic life in high temperature environments viz., geothermal areas, hot, acidic geysers and undersea hydrothermal vents has revealed the existence of thermophiles (or hyperthermophiles). These microorganisms possess various stress adaptation mechanisms which enable them to bypass multiple physical and chemical barriers for survival. The discovery of radiation resistant thermophile Deinococcus geothermalis has given new insights into the field of radiation microbiology. The ability of radiation resistant thermophiles to deal with the lethal effects of ionizing radiations like DNA damage, oxidative bursts and protein damage has made them a model system for exobiology and interplanetary transmission of life. They might be an antiquity of historical transport process that brought microbial life on Earth. These radiation resistant thermophiles are resistant to desiccation as well and maintain their homeostasis by advance DNA repair mechanisms, reactive oxygen species (ROS) detoxification system and accumulation of compatible solutes. Moreover, engineered radioresistant thermophilic strains are the best candidate for bioremediation of radionuclide waste while the extremolytes produced by these organisms may have predicted therapeutic uses. So, the present article delineate a picture of radiation resistance thermophiles, their adaptive mechanisms to evade stress viz., radiation and desiccation, their present applications along with new horizons in near future.     

Synthetic studies of neoclerodane diterpenes from Salvia divinorum: selective modification of the furan ring

A synthetic sequence has been developed to selectively functionalize the furan ring of the natural product salvinorin A (2a). The synthetic routes described convert the furan ring in 2a into an N-sulfonylpyrrole, oxazole or an oxadiazole. In addition, a procedure has been found to remove the furan skeleton completely. Biological results indicate that replacement of the furan ring with an N-sulfonylpyrrole leads to reduced affinity and efficacy at kappa opioid receptors.     

AAV-Mediated Delivery of Zinc Finger Nucleases Targeting Hepatitis B Virus Inhibits Active Replication

Despite an existing effective vaccine, hepatitis B virus (HBV) remains a major public health concern. There are effective suppressive therapies for HBV, but they remain expensive and inaccessible to many, and not all patients respond well. Furthermore, HBV can persist as genomic covalently closed circular DNA (cccDNA) that remains in hepatocytes even during otherwise effective therapy and facilitates rebound in patients after treatment has stopped. Therefore, the need for an effective treatment that targets active and persistent HBV infections remains. As a novel approach to treat HBV, we have targeted the HBV genome for disruption to prevent viral reactivation and replication. We generated 3 zinc finger nucleases (ZFNs) that target sequences within the HBV polymerase, core and X genes. Upon the formation of ZFN-induced DNA double strand breaks (DSB), imprecise repair by non-homologous end joining leads to mutations that inactivate HBV genes. We delivered HBV-specific ZFNs using self-complementary adeno-associated virus (scAAV) vectors and tested their anti-HBV activity in HepAD38 cells. HBV-ZFNs efficiently disrupted HBV target sites by inducing site-specific mutations. Cytotoxicity was seen with one of the ZFNs. scAAV-mediated delivery of a ZFN targeting HBV polymerase resulted in complete inhibition of HBV DNA replication and production of infectious HBV virions in HepAD38 cells. This effect was sustained for at least 2 weeks following only a single treatment. Furthermore, high specificity was observed for all ZFNs, as negligible off-target cleavage was seen via high-throughput sequencing of 7 closely matched potential off-target sites. These results show that HBV-targeted ZFNs can efficiently inhibit active HBV replication and suppress the cellular template for HBV persistence, making them promising candidates for eradication therapy.     

Characterization of microbial communities in anaerobic bioreactors using molecular probes

The microbial community structure of twenty-one single-phase and one two-phase full-scale anaerobic sewage sludge digesters was evaluated using oligonucleotide probes complementary to conserved tracts of the 16S rRNAs of phylogenetically defined groups of methanogens and sulfate-reducing bacteria. These probe results were interpreted in combination with results from traditional chemical analyses and metabolic activity assays. It was determined that methanogens in healthy mesophilic, single-phase sewage sludge digesters accounted for approximately 8–12% of the total community and thatMethanosarcinales andMethanomicrobiales constituted the majority of the total methanogen population.Methanobacteriales andMethanococcales played a relatively minor role in the digesters. Phylogenetic groups of mesophilic, Gram-negative sulfate-reducing bacteria were consistently present at significant levels:Desulfovibrio andDesulfobulbus spp. were the dominant sulfate-reducing populations,Desulfobacter andDesulfobacterium spp. were present at lower levels, andDesulfosarcina, Desulfococcus, andDesulfobotulus spp. were absent. Sulfate reduction by one or more of these populations played a significant role in all digesters evaluated in this study. In addition, sulfate-reducing bacteria played a role in favoring methanogenesis by providing their substrates. The analysis of the two-phase digester indicated that true phase separation was not accomplished: significant levels of active methanogens were present in the first phase. It was determined that the dominant populations in the second phase were different from those in the single-phase digesters.     

Studies on the Neuromodulatory Effects of Ginkgo biloba on Alterations in Lipid Composition and Membrane Integrity of Rat Brain Following Aluminium Neurotoxicity

Neurochemical Research - Brain contains the highest lipid content involved in various structural and physiological activities such as structural development, neurogenesis, synaptogenesis, signal...     

The Ca2+ Sensor Protein Swiprosin-1/EFhd2 Is Present in Neurites and Involved in Kinesin-Mediated Transport in Neurons

Swiprosin-1/EFhd2 (EFhd2) is a cytoskeletal Ca²⁺ sensor protein strongly expressed in the brain. It has been shown to interact with mutant tau, which can promote neurodegeneration, but nothing is known about the physiological function of EFhd2 in the nervous system. To elucidate this question, we analyzed EFhd2^−/−/lacZ reporter mice and showed that lacZ was strongly expressed in the cortex, the dentate gyrus, the CA1 and CA2 regions of the hippocampus, the thalamus, and the olfactory bulb. Immunohistochemistry and western blotting confirmed this pattern and revealed expression of EFhd2 during neuronal maturation. In cortical neurons, EFhd2 was detected in neurites marked by MAP2 and co-localized with pre- and post-synaptic markers. Approximately one third of EFhd2 associated with a biochemically isolated synaptosome preparation. There, EFhd2 was mostly confined to the cytosolic and plasma membrane fractions. Both synaptic endocytosis and exocytosis in primary hippocampal EFhd2^−/− neurons were unaltered but transport of synaptophysin-GFP containing vesicles was enhanced in EFhd2^−/− primary hippocampal neurons, and notably, EFhd2 inhibited kinesin mediated microtubule gliding. Therefore, we found that EFhd2 is a neuronal protein that interferes with kinesin-mediated transport.