Understanding and predicting pregnancy termination in Bangladesh: A comprehensive analysis using a hybrid machine learning approach.

Reproductive health issues, including unsafe pregnancy termination, remain a significant concern for women in developing nations. This study focused on investigating and predicting pregnancy termination in Bangladesh by employing a hybrid machine learning approach. The analysis used data from the Bangladesh Demographic and Health Surveys conducted in 2011, 2014, and 2017 to 2018. Ten independent variables, encompassing factors such as age, residence, division, wealth index, working status, BMI, total number of children ever born, recent births, and number of living children, were examined for their potential associations with pregnancy termination. The dataset undergoes preprocessing, addressing missing values and balancing class distributions. To predict pregnancy termination, 8 classical machine learning models and hybrid models were used in this study. The models' performance was evaluated based on the area under the curve, precision, recall, and F1 score. The results highlighted the effectiveness of the hybrid models, particularly the Voting hybrid model (area under the curve: 91.97; precision: 84.14; recall: 83.87; F1 score: 83.84), in accurately predicting pregnancy termination. Notable predictors include age, division, and wealth index. These findings hold significance for policy interventions aiming to reduce pregnancy termination rates, emphasizing the necessity for tailored approaches that consider regional disparities and socioeconomic factors. Overall, the study demonstrates the efficacy of hybrid machine learning models in comprehending and forecasting pregnancy termination, offering valuable insights for reproductive health initiatives in Bangladesh and similar contexts.

Assessing the critical success factors for implementing industry 4.0 in the pharmaceutical industry: Implications for supply chain sustainability in emerging economies.

The emerging technologies of Industry 4.0 (I4.0) are crucial to incorporating agility, sustainability, smartness, and competitiveness in the business model, enabling long-term sustainability practices in the pharmaceutical supply chain (PSC). By leveraging the latest technologies of I4.0, pharmaceutical companies can gain real-time visibility into their supply chain (SC) operations, allowing them to make data-driven decisions that improve SC performance, efficiency, resilience, and sustainability. However, to date, no research has examined the critical success factors (CSFs) that enable the pharmaceutical industry to adopt I4.0 successfully to enhance overall SC sustainability. This study, therefore, analyzed the potential CSFs for adopting I4.0 to increase all facets of sustainability in the PSC, especially from the perspective of an emerging economy like Bangladesh. Initially, sixteen CSFs were identified through a comprehensive literature review and expert validation. Later, the finalized CSFs were clustered into three relevant groups and analyzed using a Bayesian best-worst method (BWM)-based multi-criteria decision-making (MCDM) framework. The study findings revealed that "sufficient investment for technological advancement", "digitalized product monitoring and traceability", and "dedicated and robust research and development (R&D) team" are the top three CSFs to adopt I4.0 in the PSC. The study's findings can aid industrial practitioners, managers, and policymakers in creating effective action plans for efficiently adopting I4.0 in PSC to avail of its competitive benefits and ensure a sustainable future for the pharmaceutical industry.

Investigation on Mechanical, Biocorrosion, and Biocompatibility Behavior of HAp-Assisted Sr-Based Mg Composites.

Numerous biodegradable Mg-based biomaterials have been developed in recent years because of their outstanding biocompatibility, biodegradation, and mechanical properties. The Mg-based composite is an appropriate candidate for orthopedic implants, such as supporting the fractured bone due to its superb biocompatibility and biodegradation properties. In the present work, a Mg-based biomaterial is developed by incorporating low wt % of alloying elements such as Zn, Ca, Mn, and Sr and ceramic powders such as HAp to improve the biocompatibility and biodegradebility and strengthen the mechanical properties. In this study, the Mg-4Zn-3Ca-1HAp-0.5Mn and Mg-4Zn-2.9Ca-1HAp-0.5Mn-0.1Sr composites are prepared, and the mechanical, microstructure, and in vitro degradation behavior of these composites are studied. The Mg-4Zn-2.9Ca-1HAp-0.5Mn-0.1Sr composite has good mechanical properties and a low uniform in vitro degradation rate (0.587 mm/year). From the dynamic mechanical analysis, it is found that the composites have better damping characteristics than the pure Mg. The composites are chosen for further evaluation. All the composites show no cytotoxicity to MG63 cells. The composite having Sr with PVA/ZrO2 coating showed the highest cell viability. On the basis of the above observation, the viability of the Mg-4Zn-3Ca-1HAp-0.5Mn and Mg-4Zn-2.9Ca-1HAp-0.5Mn-0.1Sr composites is discussed systematically for the use as an orthopedic implant. This investigation delivers a new idea for the evolution of a high-performance Sr-based Mg composite having excellent mechanical and corrosion properties while successfully reducing the cytotoxicity effect.

Pharmacological Characterization of a Potent Inhibitor of Autotaxin in Animal Models of Inflammatory Bowel Disease and Multiple Sclerosis.

Autotaxin is a secreted enzyme that catalyzes the conversion of lysophosphatidyl choline into the bioactive lipid mediator lysophosphatidic acid (LPA). It is the primary enzyme responsible for LPA production in plasma. It is upregulated in inflammatory conditions and inhibition of autotaxin may have anti-inflammatory activity in a variety of inflammatory diseases. To determine the role of autotaxin and LPA in the pathophysiology of inflammatory disease states, we used a potent and orally bioavailable inhibitor of autotaxin that we have recently identified, and characterized it in mouse models of inflammation, inflammatory bowel disease (IBD), multiple sclerosis (MS), and visceral pain. Compound-1, a potent inhibitor of autotaxin with an IC50 of ∼2 nM, has good oral pharmacokinetic properties in mice and results in a substantial inhibition of plasma LPA that correlates with drug exposure levels. Treatment with the inhibitor resulted in significant anti-inflammatory and analgesic effects in the carrageenan-induced paw inflammation and acetic acid-induced visceral pain tests, respectively. Compound-1 also significantly inhibited disease activity score in the dextran sodium sulfate-induced model of IBD, and in the experimental autoimmune encephalomyelitis model of MS. In conclusion, the present study demonstrates the anti-inflammatory and analgesic properties of a novel inhibitor of autotaxin that may serve as a therapeutic option for IBD, MS, and pain associated with inflammatory states.

Circulating αKlotho influences phosphate handling by controlling FGF23 production.

The FGF23 coreceptor αKlotho (αKL) is expressed as a membrane-bound protein (mKL) that forms heteromeric complexes with FGF receptors (FGFRs) to initiate intracellular signaling. It also circulates as an endoproteolytic cleavage product of mKL (cKL). Previously, a patient with increased plasma cKL as the result of a translocation [t(9;13)] in the αKLOTHO (KL) gene presented with rickets and a complex endocrine profile, including paradoxically elevated plasma FGF23, despite hypophosphatemia. The goal of this study was to test whether cKL regulates phosphate handling through control of FGF23 expression. To increase cKL levels, mice were treated with an adeno-associated virus producing cKL. The treated groups exhibited dose-dependent hypophosphatemia and hypocalcemia, with markedly elevated FGF23 (38 to 456 fold). The animals also manifested fractures, reduced bone mineral content, expanded growth plates, and severe osteomalacia, with highly increased bone Fgf23 mRNA (>150 fold). cKL activity in vitro was specific for interactions with FGF23 and was FGFR dependent. These results demonstrate that cKL potently stimulates FGF23 production in vivo, which phenocopies the KL translocation patient and metabolic bone syndromes associated with elevated FGF23. These findings have important implications for the regulation of αKL and FGF23 in disorders of phosphate handling and biomineralization.

Proteomic analysis of demyelinated and remyelinating brain tissue following dietary cuprizone administration.

Cuprizone intoxication is a commonly used model of demyelination that allows the temporal separation of demyelination and remyelination. The underlying biochemical alterations leading to demyelination, using this model, remain unclear and may be multifold. Analysis of proteomic changes within the brains of cuprizone-exposed animals may help elucidate key cellular processes. In the current study, we report the results of the liquid chromatography tandem mass spectrometry analysis of total protein from the brain hemispheres of control and toxin-exposed mice at 6 weeks of exposure and after 3 and 6 weeks of recovery to identify protein changes during the remyelination phase. We found that at 6 weeks of cuprizone exposure, myelin proteins were reduced compared to controls and increased throughout the course of recovery, as expected. In contrast, other protein groups, such as proteins related to mitochondrial function, were increased at 6 weeks of treatment compared to untreated controls and returned toward control levels following withdrawal of toxin. These results suggest that a global proteomic analysis of the brain tissue of cuprizone-treated mice can identify changes related to the demyelination/remyelination process.

IRAK4 kinase activity is required for Th17 differentiation and Th17-mediated disease.

Both IL-23- and IL-1-mediated signaling pathways play important roles in Th17 cell differentiation, cytokine production, and autoimmune diseases. The IL-1R-associated kinase 4 (IRAK4) is critical for IL-1/TLR signaling. We show here that inactivation of IRAK4 kinase in mice (IRAK4 KI) results in significant resistance to experimental autoimmune encephalomyelitis due to a reduction in infiltrating inflammatory cells into the CNS and reduced Ag-specific CD4(+) T cell-mediated IL-17 production. Adoptive transfer of myelin oligodendrocyte glycoprotein 35-55-specific IRAK4 KI Th17 cells failed to induce experimental autoimmune encephalomyelitis in either wild-type or IRAK4 KI recipient mice, indicating the lack of autoantigen-specific Th17 cell activities in the absence of IRAK4 kinase activity. Furthermore, the absence of IRAK4 kinase activity blocked induction of IL-23R expression, STAT3 activation by IL-23, and Th17 cytokine expression in differentiated Th17 cells. Importantly, blockade of IL-1 signaling by IL-1RA inhibited Th17 differentiation and IL-23-induced cytokine expression in differentiated Th17 cells. The results of these studies demonstrate that IL-1-mediated IRAK4 kinase activity in T cells is essential for induction of IL-23R expression, Th17 differentiation, and autoimmune disease.

Study of plasma protein C and inflammatory pathways: biomarkers for dimethylnitrosamine-induced liver fibrosis in rats.

The present investigation was designed to identify potential biomarker(s) and assess the involvement of inflammatory pathway in dimethylnitrosamine (DMN)-induced liver fibrosis in rats. Following DMN-treatment (10 mg/ml/kg, i.p., given three consecutive days each week for 4 weeks) body and liver weights were significantly decreased concurrent with increasing severity of liver damage assessed by bridging fibrosis, a histopathologic assessment and characteristic of human liver disease. Protein C along with albumin, C-reactive-protein (CRP), haptoglobin and total protein were significantly reduced and correlated with changes in liver histopathology. Biochemical markers of liver functions were significantly increased and correlated with changes in liver histopathology and plasma levels of protein C. Soluble intracellular-adhesion-molecule-1 (sICAM-1) levels were increased significantly but were poorly correlated with histopathology and protein C levels. Inflammatory chemokines and other analytes, monocyte-chemoattractant-protein-1 and 3 (MCP-1 and MCP-3), macrophage-colony-stimulating-factor (M-CSF) were significantly increased during the disease progression, whereas macrophage-derived-chemokine (MDC) and CRP were significantly suppressed. Circulating neutrophils and monocytes were also increased along with disease progression. The differential changes in sICAM-1, hyaluronic acid, gamma-glutamyltranspeptidase (GGT), neutrophil and other inflammatory chemokines suggest the involvement of inflammatory pathways in DMN-induced liver fibrosis. In conclusion, the progressive changes in protein C along with other noninvasive biochemical parameters whose levels were significantly correlated with disease progression may serve as biomarkers for pharmacological assessment of targeted therapy for liver fibrosis.

A model of controlled acute hyperglycemia in rats: Effects of insulin and glucagon-like peptide-1 analog.

A rodent model of controlled acute hyperglycemia that is sensitive to glucose-lowering agents insulin and glucagon-like peptide-1 (GLP-1) analog has been developed. The studies show that anesthesia could be induced in fasted rats with ketamine (100 mg/kg) plus a low dose of xylazine (5 mg/kg) without inducing the acute hyperglycemia typically associated with these agents. Under these conditions, continuous infusion of glucose (10 and 20%) via the jugular vein for 30 to 150 min induced hyperglycemia in a time-dependent fashion. Administration of "loading" boluses of glucose (0.2-0.6 ml of a 20% solution) prior to continuous infusion of 10% glucose produced more immediate and sustained hyperglycemia. Plasma levels of a variety of glucoregulatory and stress hormones such as insulin, growth hormone, glucagon, and corticosterone were determined. Only glucagon levels changed significantly during induction and maintenance of hyperglycemia. The infusion of insulin (0.1 U/kg/h) or GLP-1 analog (10 microg/kg/h) effectively lowered blood glucose from its elevated levels. Insulin produced a significant increase in glucagon levels, and GLP-1 analog produced a significant increase in insulin levels without any change in other glucoregulatory and stress hormone levels. In conclusion, the present studies identified a novel approach for the induction of anesthesia and surgical manipulations without inducing hyperglycemia and further defined an approach for producing acute hyperglycemia in a controlled fashion in rodents. This model will be beneficial to study the influence of hyperglycemia in acute models of critical illness where hyperglycemia develops following the precipitating event. This model was responsive to insulin and GLP-1 analog, both of which were effective in ameliorating hyperglycemia.

Acute hyperglycemia induced by ketamine/xylazine anesthesia in rats: mechanisms and implications for preclinical models.

The effects of anesthetic agents, commonly used in animal models, on blood glucose levels in fed and fasted rats were investigated. In fed Sprague-Dawley rats, ketamine (100 mg/kg)/xylazine (10 mg/kg) (KX) produced acute hyperglycemia (blood glucose 178.4 +/- 8.0 mg/dl) within 20 min. The baseline blood glucose levels (104.8 +/- 5.7 mg/dl) reached maximum levels (291.7 +/- 23.8 mg/dl) at 120 min. Ketamine alone did not elevate glucose levels in fed rats. Isoflurane also produced acute hyperglycemia similar to KX. Administration of pentobarbital sodium did not produce hyperglycemia in fed rats. In contrast, none of these anesthetic agents produced hyperglycemia in fasted rats. The acute hyperglycemic effect of KX in fed rats was associated with decreased plasma levels of insulin, adrenocorticotropic hormone (ACTH), and corticosterone and increased levels of glucagon and growth hormone (GH). The acute hyperglycemic response to KX was dose-dependently inhibited by the specific alpha2-adrenergic receptor antagonist yohimbine (1-4 mg/kg). KX-induced changes of glucoregulatory hormone levels such as insulin, GH, ACTH, and corticosterone were significantly altered by yohimbine, whereas the glucagon levels remained unaffected. In conclusion, the present study indicates that both KX and isoflurane produce acute hyperglycemia in fed rats. The effect of KX is mediated by modulation of the glucoregulatory hormones through stimulation of alpha2-adrenergic receptors. Pentobarbital sodium did not produce hyperglycemia in either fed or fasted rats. Based on these findings, it is suggested that caution needs to be taken when selecting anesthetic agents, and fed or fasted state of animals in studies of diabetic disease or other models where glucose and/or glucoregulatory hormone levels may influence outcome and thus interpretation. However, fed animals are of value when exploring the hyperglycemic response to anesthetic agents.