Therapeutic efficacy of an alpha-particle emitter labeled anti-GD2 humanized antibody against osteosarcoma-a proof of concept study.

PURPOSE: Current treatments for osteosarcoma (OS) have a poor prognosis, particularly for patients with metastasis and recurrence, underscoring an urgent need for new targeted therapies to improve survival. Targeted alpha-particle therapy selectively delivers cytotoxic payloads to tumors with radiolabeled molecules that recognize tumor-associated antigens. We have recently demonstrated the potential of an FDA approved, humanized anti-GD2 antibody, hu3F8, as a targeted delivery vector for radiopharmaceutical imaging of OS. The current study aims to advance this system for alpha-particle therapy of OS. METHODS: The hu3F8 antibody was radiolabeled with actinium-225, and the safety and therapeutic efficacy of the [225Ac]Ac-DOTA-hu3F8 were evaluated in both orthotopic murine xenografts of OS and spontaneously occurring OS in canines. RESULTS: Significant antitumor activity was proven in both cases, leading to improved overall survival. In the murine xenograft's case, tumor growth was delayed by 16-18 days compared to the untreated cohort as demonstrated by bioluminescence imaging. The results were further validated with magnetic resonance imaging at 33 days after treatment, and microcomputed tomography and planar microradiography post-mortem. Histological evaluations revealed radiation-induced renal toxicity, manifested as epithelial cell karyomegaly and suggestive polyploidy in the kidneys, suggesting rapid recovery of renal function after radiation damage. Treatment of the two canine patients delayed the progression of metastatic spread, with an overall survival time of 211 and 437 days and survival beyond documented metastasis of 111 and 84 days, respectively. CONCLUSION: This study highlights the potential of hu3F8-based alpha-particle therapy as a promising treatment strategy for OS.

Longevity Spinach (Gynura procumbens) Ameliorated Oxidative Stress and Inflammatory Mediators in Cisplatin-Induced Organ Dysfunction in Rats: Comprehensive in†vivo and in silico Studies.

This study focused to assess the efficacy of Gynura procumbens (GP) leaf extract against cisplatin (CP)-induced hepatorenal complications in Wister albino rats. Additionally, it aims to detect polyphenolic compounds using high-performance liquid chromatography with diode-array detection (HPLC-DAD). The rats were treated intraperitoneally with CP (7.5 mg/kg) to mediate hepatorenal damage. They were then treated with GP extract (75 and 150 mg/kg, P.O.) for 7 consecutive days. Although GP extract significantly ameliorated CP-mediated hepatorenal biomarkers like alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, and blood urea nitrogen (BUN) levels in a dose-dependent manner, GP extract at 150 mg/kg dose normalized hepatorenal biomarkers ALP (45.11 U/L), ALT (34 U/L), AST (29 U/L), creatinine (10.3 mg/dl) and BUN (11.19 mg/dl) while comparing to control and disease group. Similarly, though it significantly reduced CP-induced oxidative stress inducers, including nitric oxide (NO) and advanced oxidative protein products (AOPP), higher dose (150 mg/kg) exhibited better activity in reducing NO (281.54 mmol/gm tissue in liver and 52.73 mmol/gm tissue in the kidney) and AOPP (770.95 mmol/mg protein in liver and 651.90 mmol/mg protein in the kidney). Besides, it showed better enhancement in the antioxidant enzymes superoxide dismutase, and glutathione levels at a higher dose (150 mg/kg). Histopathological studies showed that CP caused collagen accumulation in the liver and kidney tissues. GP extract drained the collagen mass and acted against hepatorenal damage. Ellagic acid, gallic acid, quercetin hydrate, kaempferol, and rutin hydrate were revealed in GP extract. In-silico modelling showed good docking scores of the polyphenolic compounds with molecular targets including CYP4502E1, NF-κB, caspase-3, and TNF-α. GP could be an effective therapeutic option for management of anticancer drugs' complications like CP-induced organ damage, although clinical studies are required to establish herbal formulation.

Prevalence and determinants of contraceptive method use among Bangladeshi women of reproductive age: a multilevel multinomial analysis.

BACKGROUND: Much scholarly debate has centered on Bangladesh's family planning program (FPP) in lowering the country's fertility rate. This study aimed to investigate the prevalence of using modern and traditional contraceptive methods and to determine the factors that explain the contraceptive methods use. METHODS: The study used data from the 2017-18 Bangladesh Demographic and Health Survey (BDHS), which included 11,452 (weighted) women aged 15-49 years in the analysis. Multilevel multinomial logistic regression was used to identify the factors associated with the contraceptive method use. RESULTS: The prevalence of using modern contraceptive methods was 72.16%, while 14.58% of women used traditional methods in Bangladesh. In comparison to women in the 15-24 years age group, older women (35-49 years) were more unwilling to use modern contraceptive methods (RRR: 0.28, 95% CI: 0.21-0.37). Women who had at least a living child were more likely to use both traditional and modern contraceptive methods (RRR: 4.37, 95% CI: 3.12-6.11). Similarly, given birth in the previous 5 years influenced women 2.41 times more to use modern method compared to those who had not given birth (RRR: 2.41, 95% CI: 1.65-3.52). Husbands'/partners' decision for using/not using contraception were positively associated with the use of both traditional (RRR: 4.49, 95% CI: 3.04-6.63) and modern methods (RRR: 3.01, 95% CI: 2.15-4.17) rather than using no method. This study suggests rural participants were 21% less likely to utilize modern methods than urban participants (RRR: 0.79, 95% CI: 0.67-0.94). CONCLUSION: Bangladesh remains a focus for contraceptive use, as it is one of the most populous countries in South Asia. To lower the fertility rate, policymakers may design interventions to improve awareness especially targeting uneducated, and rural reproductive women in Bangladesh. The study also highlights the importance of male partners' decision-making regarding women's contraceptive use.

QbD Approach towards Robust Design Space for Flutamide/PiperineSelf-Emulsifying Drug Delivery System with Reduced Liver Injury.

Flutamide which is used to treat prostate cancer and other diseases induces liver damage during and after the therapy. The aim of this study was to develop a flutamide/piperineco-loaded self-emulsifying drug delivery system (FPSEDDS) to inhibit flutamide-induced liver injury by utilizing piperine as a metabolic inhibitor. The development of SEDDS was carried out following a quality by design (QbD) approach. The risk assessment study was performed to identify critical quality attributes (CQAs) and critical material attributes (CMAs)/critical process parameters (CPPs). I-optimal mixture design was executed with three CMAs as the independent variables and CQAs as the dependable variables. The effectiveness of optimized SEDDS to circumvent flutamide-induced hepatotoxicity was assessed in mice. The numerical optimization suggested an optimal formulation with a desirability value of 0.621, using CQAs targets as optimization goals with 95% prediction intervals (α = 0.05). The optimal formulation exhibited the grade A SEDDS characteristics with the guarantee of high payloads in self-formed oily droplets. The design space was also obtained from the same optimization goals. All CQA responses of verification points were found within the 95% prediction intervals of the polynomial models, indicating a good agreement between actual versus predicted responses within the design space. These obtained responses also passed CQAs acceptance criteria. Finally, hematoxylin-eosin staining revealed the minimal flutamide-induced hepatotoxicity from the optimal SEDDS formulation as compared to the control and flutamide/piperine normal suspension. We demonstrate that the piperine containing optimized SEDDS formulation developed by QbD significantly reduces the flutamide-induced liver injury in mice.

DeepACTION: A deep learning-based method for predicting novel drug-target interactions.

Drug-target interactions (DTIs) play a key role in drug development and discovery processes. Wet lab prediction of DTIs is time-consuming, expensive, and tedious. Fortunately, computational approaches can identify new interactions (drug-target pairs) and accelerate the process of drug repurposing. However, a vast number of interactions remain undiscovered; therefore, we proposed a deep learning-based method (deepACTION) for predicting potential or unknown DTIs. Here, each drug chemical structure and protein sequence are transformed according to structural and sequence information using different descriptors to represent their features correctly. There have been some challenges, such as the high dimensionality and class imbalance of data during the prediction process. To address these problems, we developed the MMIB technique to balance the majority and minority instances in the dataset and utilized a LASSO model to handle the high dimensionality of the data. In addition, we trained the convolutional neural network algorithm with balanced and reduced features for accurate prediction of DTIs. In this study, the AUC is considered a primary evaluation metric for comparing the performance of the deep ACTION model with that of existing methods by a 5-fold cross-validation test. Our experiential dataset obtained from the DrugBank database and our deepACTION model achieved an AUC of 0.9836 for this dataset. The experimental results ensured that the model can predict significant numbers of new DTIs and provide complete information to motivate scientists to develop drugs.

Pharmacological, Mechanistic, and Pharmacokinetic Assessment of Novel Melatonin-Tamoxifen Drug Conjugates as Breast Cancer Drugs.

Tamoxifen is used to prevent and treat estrogen receptor-positive (ER+) breast cancer (BC); however, its chronic use can increase uterine cancer risk and induce tamoxifen resistance. Novel melatonin-tamoxifen drug conjugates may be promising to treat BC and may help offset the adverse effects of tamoxifen usage alone due to the presence of melatonin. We synthesized and screened five drug conjugates (C2, C4, C5, C9, and C15 linked) for their effects on BC cell (MCF-7, tamoxifen-resistant MCF-7, mouse mammary carcinoma, MDA-MB-231, and BT-549) viability, migration, and binding affinity to melatonin receptor 1 (MT1R) and estrogen receptor 1 (ESR1). C4 and C5 demonstrated the most favorable pharmacological characteristics with respect to binding profiles (affinity for ESR1 and MT1R) and their potency/efficacy to inhibit BC cell viability and migration in four phenotypically diverse invasive ductal BC cell lines. C4 and C5 were further assessed for their actions against tamoxifen-resistant MCF-7 cells and a patient-derived xenograft triple-negative BC cell line (TU-BcX-4IC) and for their mechanisms of action using selective mitogen-activated protein kinase kinase MEK1/2, MEK5, and phosphoinositide 3-kinase (PI3K) inhibitors. C4 and C5 inhibited tamoxifen-resistant MCF-7 cells with equal potency (IC50 = 4-8 µM) and efficacy (∼90% inhibition of viability and migration) but demonstrated increased potency (IC50 = 80-211 µM) and efficacy (∼140% inhibition) to inhibit migration versus cell viability (IC50 = 181-304 mM; efficacy ∼80% inhibition) in TU-BcX-4IC cells. Unique pharmacokinetic profiles were observed, with C4 having greater bioavailability than C5. Further assessment of C4 and C5 demonstrates that they create novel pharmacophores within each BC cell that is context specific and involves MEK1/2/pERK1/2, MEK5/pERK5, PI3K, and nuclear factor κB. These melatonin-tamoxifen drug conjugates show promise as novel anticancer drugs and further preclinical and clinical evaluation is warranted.

Long-Term Gastrointestinal Consequences are Frequent Following Sporadic Acute Infectious Diarrhea in a Tropical Country: A Prospective Cohort Study.

BACKGROUND: Postinfection irritable bowel syndrome (PI-IBS) and functional dyspepsia (PI-FD), though reported from the temperate countries, have not been studied in the tropics; PI-malabsorption syndrome (MAS), which mimics PI-IBS, is reported from the tropics. No report till date on PI-IBS excluded PI-MAS. We studied: (i) the frequency of continuing bowel dysfunction after acute gastroenteritis (AG), (ii) its predictors, and (iii) PI-MAS among patients with PI-IBS. METHODS: 345 consecutive subjects each, with AG and age- and gender-matched healthy controls were followed up 3-monthly for 12 months using a translated-validated questionnaire and functional gastrointestinal disorders (FGIDs) were diagnosed by Rome III criteria. Symptom duration >3 months but <6 months was diagnosed as chronic bowel dysfunction (CBD) and dyspeptic symptoms, respectively. MAS was diagnosed if 2/3 tests (D-xylose H2 breath test, Sudan III-stained stool microscopy, and duodenal histology) were abnormal. Fecal microbiological studies were performed in 245/345 (71%) patients. RESULTS: AG patients more often developed PI-IBS and PI-FD than controls (16.5 vs. 2.6% and 7.4 vs. 0.6%, respectively; p<0.001). Presence of FD was a risk factor for PI-IBS and IBS for PI-FD. On multivariate analysis, dyspeptic symptoms, CBD, and weight loss were the risk factors for PI-FGIDs. The frequency of PI-IBS following Vibrio cholera and other bacterial infection was comparable. Malabsorption was present among 2/23 (9%) patients with PI-IBS. CONCLUSION: FGIDs are common after AG; dyspeptic symptoms, CBD, and weight loss were risk factors for PI-FGIDs. Vibrio cholerae infection caused PI-FGID, which was never reported. About 9 % patients fulfilling the criteria for PI-IBS had PI-MAS.

A systematic review on the neuroprotective perspectives of beta-caryophyllene.

Beta (ß)-caryophyllene (BCAR) is a major sesquiterpene of various plant essential oils reported for several important pharmacological activities, including antioxidant, anti-inflammatory, anticancer, cardioprotective, hepatoprotective, gastroprotective, nephroprotective, antimicrobial, and immune-modulatory activity. Recent studies suggest that it also possesses neuroprotective effect. This study reviews published reports pertaining to the neuropharmacological activities of BCAR. Databases such as PubMed, Scopus, MedLine Plus, and Google Scholar with keywords "beta (ß)-caryophyllene" and other neurological keywords were searched. Data were extracted by referring to articles with information about the dose or concentration/route of administration, test system, results and discussion, and proposed mechanism of action. A total of 545 research articles were recorded, and 41 experimental studies were included in this review, after application of exclusion criterion. Search results suggest that BCAR exhibits a protective role in a number of nervous system-related disorders including pain, anxiety, spasm, convulsion, depression, alcoholism, and Alzheimer's disease. Additionally, BCAR has local anesthetic-like activity, which could protect the nervous system from oxidative stress and inflammation and can act as an immunomodulatory agent. Most neurological activities of this natural product have been linked with the cannabinoid receptors (CBRs), especially the CB2R. This review suggests a possible application of BCAR as a neuroprotective agent.

Oxyprenylated Phenylpropanoids Bind to MT1 Melatonin Receptors and Inhibit Breast Cancer Cell Proliferation and Migration.

Oxyprenylated compounds (i.e., ferulic acid and coumarin derivatives) demonstrate neuroprotection and anticancer properties as reported in previous studies. We have tested the affinity of oxyprenylated ferulic acid (1-4) and umbelliferone derivatives (5-11) to melatonin receptors as well as their antiproliferation and antimigratory properties against breast cancer (BC) cell lines. All the compounds except for ferulic acid, boropinic acid, and umbelliferone had binding affinities to melatonin receptors in the nM to µM range, and both auraptene and umbellinprenin reduced BC cell proliferation and migration in phenotypically diverse BC including triple negative.

Cardamom powder supplementation prevents obesity, improves glucose intolerance, inflammation and oxidative stress in liver of high carbohydrate high fat diet induced obese rats.

BACKGROUND: Cardamom is a well-known spice in Indian subcontinent, used in culinary and traditional medicine practices since ancient times. The current investigation was untaken to evaluate the potential benefit of cardamom powder supplementation in high carbohydrate high fat (HCHF) diet induced obese rats. METHOD: Male Wistar rats (28 rats) were divided into four different groups such as Control, Control + cardamom, HCHF, HCHF + cardamom. High carbohydrate and high fat (HCHF) diet was prepared in our laboratory. Oral glucose tolerance test, organs wet weight measurements and oxidative stress parameters analysis as well as liver marker enzymes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) activities were assayed on the tissues collected from the rats. Plasma lipids profiles were also measured in all groups of animals. Moreover, histological staining was also performed to evaluate inflammatory cells infiltration and fibrosis in liver. RESULTS: The current investigation showed that, HCHF diet feeding in rats developed glucose intolerance and increased peritoneal fat deposition compared to control rats. Cardamom powder supplementation improved the glucose intolerance significantly (p > 0.05) and prevented the abdominal fat deposition in HCHF diet fed rats. HCHF diet feeding in rats also developed dyslipidemia, increased fat deposition and inflammation in liver compared to control rats. Cardamom powder supplementation significantly prevented the rise of lipid parameters (p > 0.05) in HCHF diet fed rats. Histological assessments confirmed that HCHF diet increased the fat deposition and inflammatory cells infiltration in liver which was normalized by cardamom powder supplementation in HCHF diet fed rats. Furthermore, HCHF diet increased lipid peroxidation, decreased antioxidant enzymes activities and increased advanced protein oxidation product level significantly (p > 0.05) both in plasma and liver tissue which were modulated by cardamom powder supplementation in HCHF diet fed rats. HCHF diet feeding in rats also increased the ALT, AST and ALP enzyme activities in plasma which were also normalized by cardamom powder supplementation in HCHF diet fed rats. Moreover, cardamom powder supplementation ameliorated the fibrosis in liver of HCHF diet fed rats. CONCLUSION: This study suggests that, cardamom powder supplementation can prevent dyslipidemia, oxidative stress and hepatic damage in HCHF diet fed rats.

Supplementation of Syzygium cumini seed powder prevented obesity, glucose intolerance, hyperlipidemia and oxidative stress in high carbohydrate high fat diet induced obese rats.

BACKGROUND: Obesity and related complications have now became epidemic both in developed and developing countries. Cafeteria type diet mainly composed of high fat high carbohydrate components which plays a significant role in the development of obesity and metabolic syndrome. This study investigated the effect of Syzygium cumini seed powder on fat accumulation and dyslipidemia in high carbohydrate high fat diet (HCHF) induced obese rats. METHOD: Male Wistar rats were fed with HCHF diet ad libitum, and the rats on HCHF diet were supplemented with Syzygium cumini seed powder for 56 days (2.5% w/w of diet). Oral glucose tolerance test, lipid parameters, liver marker enzymes (AST, ALT and ALP) and lipid peroxidation products were analyzed at the end of 56 days. Moreover, antioxidant enzyme activities were also measured in all groups of rats. RESULTS: Supplementation with Syzygium cumini seed powder significantly reduced body weight gain, white adipose tissue (WAT) weights, blood glucose, serum insulin, and plasma lipids such as total cholesterol, triglyceride, LDL and HDL concentration. Syzygium cumini seed powder supplementation in HCHF rats improved serum aspartate amino transferase (AST), alanine amino transferase (ALT), and alkaline phosphatase (ALP) activities. Syzygium cumini seed powder supplementation also reduced the hepatic thiobarbituric acid reactive substances (TBARS) and elevated the antioxidant enzyme superoxide dismutase (SOD) and catalase (CAT) activities as well as increased glutathione (GSH) concentration. In addition, histological assessment showed that Syzygium cumini seed powder supplementation prevented inflammatory cell infiltration; fatty droplet deposition and fibrosis in liver of HCHFD fed rats. CONCLUSION: Our investigation suggests that Syzygium cumini seed powder supplementation prevents oxidative stress and showed anti-inflammatory and antifibrotic activity in liver of HCHF diet fed rats. In addition, Syzygium cumini seed powder may be beneficial in ameliorating insulin resistance and dyslipidemia probably by increasing lipid metabolism in liver of HCHF diet fed rats.

CHARACTERIZATION OF BINDING SITES OF CLOPIDOGREL AND INTERFERENCE OF LINOLEIC ACID AT THE BINDING SITE ON BOVINE SERUM ALBUMIN.

Binding of clopidogrel to serum albumin has been characterized in the presence and absence of linoleic acid by equilibrium dialysis method where ranitidine and diazepam were used as specific probes. Our findings suggested two binding sites for clopidogrel: a high affinity site (k1 = 11.5 x 105 M⁻¹) with low capaci- ty (n1 = 1.2) and low affinity site (k2 = 2.1 x 105 M⁻¹) with high capacity (n. = 9.3). Interaction of linoleic acid with clopidogrel in the presence of ranitidine shows an increment of clopidogrel from 71 to 85.5% at concen- tration of (1 x 105 M) to (6 x 105 M). However, interaction of linoleic acid with clopidogrel in the presence of diazepam exhibits significant rise in free fraction of clopidogrel from 93 to 116% at concentration of (0 x 10' M) to (4 x 105 M). At higher concentrations, linoleic acid displaced clopidogrel from its binding sites on serum albumin. This may cause escalation of free drug in the blood, which alters pharmacokinetic properties of clopi- dogrel taken with high fat diet.

Astaxanthin ameliorates prenatal LPS-exposed behavioral deficits and oxidative stress in adult offspring.

BACKGROUND: Prenatal maternal lipopolysaccharide (LPS) exposure leads to behavioral deficits such as depression, anxiety, and schizophrenia in the adult lives. LPS-exposure resulted in the production of cytokines and oxidative damage. On the contrary, astaxanthin is a carotenoid compound, showed neuroprotective properties via its antioxidant capacity. This study examines the effect of astaxanthin on the prenatal maternal LPS-induced postnatal behavioral deficit in mice. RESULTS: We found that prenatal LPS-exposed mice showed extensive immobile phase in the tail suspension test, higher frequent head dipping in the hole-board test and greater hypolocomotion in the open field test. All these values were statistically significant (p < 0.05). In addition, a marked elevation of the level of lipid peroxidation, advanced protein oxidation product, nitric oxide, while a pronounced depletion of antioxidant enzymes (superoxide dismutase, catalase and glutathione) were observed in the adult offspring mice that were prenatally exposed to LPS. To the contrary, 6-weeks long treatment with astaxanthin significantly improved all behavioral deficits (p < 0.05) and diminished prenatal LPS-induced oxidative stress markers in the brain and liver. CONCLUSIONS: Taken together, these results suggest that prenatal maternal LPS-exposure leads to behavioral deficits in the adults, while astaxanthin ameliorates the behavioral deficits presumably via its antioxidant property.

Angiotensin-converting enzyme inhibitor prevents oxidative stress, inflammation, and fibrosis in carbon tetrachloride-treated rat liver.

Hepatic fibrosis is a common feature of chronic liver injury, and the involvement of angiotensin II in such process has been studied earlier. We hypothesized that anti-angiotensin II agents may be effective in preventing hepatic fibrosis. In this study, Long Evans female rats were used and divided into four groups such as Group-I, Control; Group-II, Control + ramipril; Group-III, CCl4; and Group-IV, CCl4 + ramipril. Group II and IV are treated with ramipril for 14 d. At the end of treatment, the livers were removed, and the level of hepatic marker enzymes (aspartate aminotransferase, Alanine aminotransferase, and alkaline phosphatase), nitric oxide, advanced protein oxidation product , catalase activity, and lipid peroxidation were determined. The degree of fibrosis was evaluated through histopathological staining with Sirius red and trichrome milligan staining. Carbon-tetrachloride (CCl4) administration in rats developed hepatic dysfunction and raised the hepatic marker enzymes activities significantly. CCl4 administration in rats also produced oxidative stress, inflammation, and fibrosis in liver. Furthermore, angiotensinogen-inhibitor ramipril normalized the hepatic enzymes activities and improved the antioxidant enzyme catalase activity. Moreover, ramipril treatment ameliorated lipid peroxidation and hepatic inflammation in CCl4-treated rats. Ramipril treatment also significantly reduced hepatic fibrosis in CCl4-administered rats. In conclusion, our investigation suggests that the antifibrotic effect of ramipril may be attributed to inhibition of angiotensin-II mediated oxidative stress and inflammation in liver CCl4-administered rats.

A systematic review of effectiveness and safety of different regimens of levonorgestrel oral tablets for emergency contraception.

BACKGROUND: Unintended pregnancy is a complex phenomenon which raise to take an emergency decision. Low contraceptive prevalence and high user failure rates are the leading causes of this unexpected situation. High user failure rates suggest the vital role of emergency contraception to prevent unplanned pregnancy. Levonorgestrel - a commonly used progestin for emergency contraception. However, little is known about its pharmacokinetics and optimal dose for use. Hence, there is a need to conduct a systematic review of the available evidences. METHODS: Randomized, double-blind trials were sought, evaluating healthy women with regular menstrual cycles, who requested emergency contraception within 72 h of unprotected coitus, to one of three regimens: 1.5 mg single dose levonorgestrel, two doses of 0.75 mg levonorgestrel given 12 h apart or two doses of 0.75 mg levonorgestrel given 24 h apart. The primary outcome was unintended pregnancy; other outcomes were side-effects and timing of next menstruation. RESULTS: Every trial under consideration successfully established the contraceptive effectiveness of levonorgestrel for preventing unintended pregnancy. Moreover, a single dose of levonorgestrel 1.5 mg for emergency contraception supports its safety and efficacy profile. If two doses of levonorgestrel 0.75 mg are intended for administration, the second dose can positively be taken 12-24 h after the first dose without compromising its contraceptive efficacy. The main side effect was frequent menstrual irregularities. No serious adverse events were reported. CONCLUSIONS: The review shows that, emergency contraceptive regimen of single-dose levonorgestrel is not inferior in efficacy to the two-dose regimen. All the regimens studied were very efficacious for emergency contraception and prevented a high proportion of pregnancies if taken within 72 h of unprotected coitus. Single levonorgestrel dose (1.5 mg) can substitute two 0.75 mg doses 12 or 24 h apart. With either regimen, the earlier the treatment is given, the more effective it seems to be.

Socio-economic status and pregnancy complications and their impact on antenatal care services provided at home and Upazila health complex.

The stage of pregnancy is crucial for women of reproductive age and their families. However, in low- and middle-income countries like Bangladesh, antenatal and postnatal care are not widely practiced due to various socio-economic factors, such as low education levels, income, age, pregnancy knowledge, and limited healthcare facilities. The objective of this study was to examine the factors associated with antenatal care in two locations in Bangladesh based on the data collected from the Bangladesh Demographic and Health Survey (BDHS) 2017-2018. We explored different variables as explanatory variables related to ANC service. The results showed that most of the respondents were from rural areas, with 77.02% receiving antenatal care at home. Women with secondary education were more likely to receive care at home than those without education. The Chi-square test indicated a positive correlation between antenatal care at home with several variables, whereas, in the case of Upazila health complexes, only three variables showed a positive association. Logistic regression analysis further showed some specific variables such as geographical division, religion, iron intake during pregnancy, and reporting pregnancy complications had a significant impact on ANC at home. In contrast, covariates such as residence, division, and wealth index were significant for antenatal care at Upazila health complexes. The division was a significant covariate in both cases. Interestingly, we observed that mothers who had been informed about the signs of pregnancy complications were 92% more likely to receive antenatal care at home than those who had not experienced pregnancy complications. Conversely, the results revealed that mothers who were unaware of pregnancy complications were 32% more likely to receive antenatal care at home than those who had been informed about complications. This suggests that when women are educated about pregnancy complications, they are more likely to receive more antenatal care. However, Bangladesh's situation is quite different due to a lack of proper education and knowledge of antenatal care services.

Computational analysis and molecular dynamics simulation of high-risk single nucleotide polymorphisms of the ADAM10 gene.

Polymorphisms of the disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) are linked to pathophysiological changes in lung inflammation, cancer, Alzheimer's disease (AD), encephalopathy, liver fibrosis, and cardiovascular diseases. In this study, we predicted the pathogenicity of ADAM10 non-synonymous single nucleotide polymorphisms (nsSNPs) in a wide array of mutation analyzing bioinformatics tools. We retrieved 423 nsSNPs from dbSNP-NCBI for the analysis, and 13 were predicted deleterious by each of the ten tools: SIFT, PROVEAN, CONDEL, PANTHER-PSEP, SNAP2, SuSPect, PolyPhen-2, Meta-SNP, Mutation Assessor and Predict-SNP. Further assessment of amino acid sequences, homology models, conservation profiles, and inter-atomic interactions identified C222G, G361E and C639Y as the most pathogenic mutations. We validated this prediction through structural stability analysis using DUET, I-Mutant Suite, SNPeffect and Dynamut. Molecular dynamics simulations and principal component analysis also indicated considerable instability of the C222G, G361E and C639Y variants. Therefore, these ADAM10 nsSNPs could be candidates for diagnostic genetic screening and therapeutic molecular targeting.Communicated by Ramaswamy H. Sarma.

Virtual screening of flavonoids as potential RIPK1 inhibitors for neurodegeneration therapy.

Background: Global prevalence of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease is increasing gradually, whereas approvals of successful therapeutics for central nervous system disorders are inadequate. Accumulating evidence suggests pivotal roles of the receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in modulating neuroinflammation and necroptosis. Discoveries of potent small molecule inhibitors for RIPK1 with favorable pharmacokinetic properties could thus address the unmet medical needs in treating neurodegeneration. Methods: In a structure-based virtual screening, we performed site-specific molecular docking of 4,858 flavonoids against the kinase domain of RIPK1 using AutoDock Vina. We predicted physicochemical descriptors of the top ligands using the SwissADME webserver. Binding interactions of the best ligands and the reference ligand L8D were validated using replicated 500-ns Gromacs molecular dynamics simulations and free energy calculations. Results: From Vina docking, we shortlisted the top 20 flavonoids with the highest binding affinities, ranging from -11.7 to -10.6 kcal/mol. Pharmacokinetic profiling narrowed down the list to three orally bioavailable and blood-brain-barrier penetrant flavonoids: Nitiducarpin, Pinocembrin 7-O-benzoate, and Paratocarpin J. Next, trajectories of molecular dynamics simulations of the top protein-ligand complexes were analyzed for binding interactions. The root-mean-square deviation (RMSD) was 1.191 Å (±0.498 Å), 1.725 Å (±0.828 Å), 1.923 Å (±0.942 Å), 0.972 Å (±0.155 Å) for Nitiducarpin, Pinocembrin 7-O-benzoate, Paratocarpin J, and L8D, respectively. The radius of gyration (Rg) was 2.034 nm (±0.015 nm), 2.0.39 nm (± 0.025 nm), 2.053 nm (±0.021 nm), 2.037 nm (±0.016 nm) for Nitiducarpin, Pinocembrin 7-O-benzoate, Paratocarpin J, and L8D, respectively. The solvent accessible surface area (SASA) was 159.477 nm2 (±3.021 nm2), 159.661 nm2 (± 3.707 nm2), 160.755 nm2 (±4.252 nm2), 156.630 nm2 (±3.521 nm2), for Nitiducarpin, Pinocembrin 7-O-benzoate, Paratocarpin J, and L8D complexes, respectively. Therefore, lower RMSD, Rg, and SASA values demonstrated that Nitiducarpin formed the most stable complex with the target protein among the best three ligands. Finally, 2D protein-ligand interaction analysis revealed persistent hydrophobic interactions of Nitiducarpin with the critical residues of RIPK1, including the catalytic triads and the activation loop residues, implicated in the kinase activity and ligand binding. Conclusion: Our target-based virtual screening identified three flavonoids as strong RIPK1 inhibitors, with Nitiducarpin exhibiting the most potent inhibitory potential. Future in vitro and in vivo studies with these ligands could offer new hope for developing effective therapeutics and improving the quality of life for individuals affected by neurodegeneration.

On simulations of 3D fractional WBBM model through mathematical and graphical analysis with the assists of fractionality and unrestricted parameters.

This study retrieves some novel exact solutions to the family of 3D space-time fractional Wazwaz-Benjamin-Bona-Mahony (WBBM) equations in the context of diverse nonlinear physical phenomena resulting from water wave mechanics. The family of WBBM equations is transformed for this purpose using a space and time fractional transformation into an ordinary differential equation (ODE). The ODE then uses a strong method, namely the Unified Method. Consequently, lump solutions, dark-bright soliton, singular and multiple soliton solutions, and periodic solutions are investigated. The disparities between the current study's conclusions and previously acquired solutions via other approaches are examined. All wave solutions produced are determined to be novel in terms of fractionality, unrestricted parameters, and implemented technique sense. The impact of unrestricted parameters and fractionality on the obtained solutions are visually presented, along with physical explanations. It is observed that the wave portents are varied with the increase of unrestricted parameters as well as fractionality. We dynamically showed that the appropriate transformation and the applied Unified approach more proficient in the study of water wave dynamics and might be used in future researches to clarify the many physical phenomena. The novelty of this work validate that the proposed method seem simple and useful tools for obtaining the solutions in PDEs and it is expected to use in mathematical physics and optical engineering.