Racial and Ethnic Disparities in Stillbirth among Pregnant Women with Obesity.

OBJECTIVE: The aim of this study was to examine the relationship between obesity and risk of stillbirth among pregnant women with obesity in the United States, with a focus on racial and ethnic disparities. STUDY DESIGN: We conducted a retrospective cross-sectional analysis of birth and fetal data from the 2014 to 2019 National Vital Statistics System (N = 14,938,384 total births) to examine associations between maternal body mass index (BMI) and risk of stillbirth. Cox's proportional hazards regression model was used to compute adjusted hazard ratios (HR) as a measure of risk of stillbirth in relation to maternal BMI. RESULTS: The stillbirth rate was 6.70 per 1,000 births among women with prepregnancy obesity, while the stillbirth rate among women with a normal (nonobese) prepregnancy BMI was 3.85 per 1,000 births. The risk of stillbirth was greater among women with obesity compared with women without obesity (HR: 1.39; 95% confidence interval [CI]: 1.37-1.41). Compared with non-Hispanic (NH) Whites, women identifying as NH-other (HR: 1.66; 95% CI: 1.61-1.72) and NH-Black (HR: 1.31; 95% CI: 1.26-1.35) were at higher risk of stillbirth, while Hispanic women had a decreased likelihood of stillbirth (HR: 0.38; 95% CI: 0.37-0.40). CONCLUSION: Obesity is a modifiable risk factor for stillbirth. Public health awareness campaigns and strategies targeting weight management in women of reproductive age and racial/ethnic populations at highest risk for stillbirth, are needed. KEY POINTS: · Stillbirth rates differ by race and ethnicity.. · Risk of stillbirth was greatest among women with obesity.. · Stillbirth rates rise with ascending prepregnancy BMI..

Racial Disparities in Preterm Birth among Pregnant Women with Obesity.

OBJECTIVES: We assessed the impact of obesity and racial disparities on preterm birth (PTB) in the United States and sought to determine whether obesity widens the racial-ethnic disparity gap in preterm birth with a focus on non-Hispanic Black and White women. METHODS: Using birth data for the years 2014-2019 made publicly available by the Centers for Disease Control and Prevention and obtained from the National Vital Statistics System, we conducted a cross-sectional cohort study analyzing a total of 14,864,844 births from 2014 to 2019. RESULTS: We observed dose-dependent changes in obesity and PTB by defining obesity in subgroups and PTB in a stratified method. PTB occurred more among non-Hispanic Black women than their non-Hispanic White and Hispanic counterparts. We observed a consistent trend of increased PTB among women with high body mass index. Racial disparity existed in PTB among pregnant obese women, with non-Hispanic Black women exhibiting the greatest risk for PTB. CONCLUSIONS: Our work further contributes to the growing knowledge of the existence of health disparity among the Black population.

Anti-Tuberculosis Potential of OJT008 against Active and Multi-Drug-Resistant Mycobacterium Tuberculosis: In Silico and In Vitro Inhibition of Methionine Aminopeptidase.

Despite the recent progress in the diagnosis of tuberculosis (TB), the chemotherapeutic management of TB continues to be challenging. Mycobacterium tuberculosis (Mtb), the etiological agent of TB, is classified as the 13th leading cause of death globally. In addition, 450,000 people were reported to develop multi-drug-resistant TB globally. The current project focuses on targeting methionine aminopeptidase (MetAP), an essential protein for the viability of Mtb. MetAP is a metalloprotease that catalyzes the excision of the N-terminal methionine (NME) during protein synthesis, allowing the enzyme to be an auspicious target for the development of novel therapeutic agents for the treatment of TB. Mtb possesses two MetAP1 isoforms, MtMetAP1a and MtMetAP1c, which are vital for Mtb viability and, hence, a promising chemotherapeutic target for Mtb therapy. In this study, we cloned and overexpressed recombinant MtMetAP1c. We investigated the in vitro inhibitory effect of the novel MetAP inhibitor, OJT008, on the cobalt ion- and nickel ion-activated MtMetAP1c, and the mechanism of action was elucidated through an in silico approach. The compound's potency against replicating and multi-drug-resistant (MDR) Mtb strains was also investigated. The induction of the overexpressed recombinant MtMetAP1c was optimized at 8 h with a final concentration of 1 mM Isopropyl ß-D-1-thiogalactopyranoside. The average yield from 1 L of Escherichia coli culture for MtMetAP1c was 4.65 mg. A preliminary MtMetAP1c metal dependency screen showed optimum activation with nickel and cobalt ions occurred at 100 µM. The half-maximal inhibitory concentration (IC50) values of OJT008 against MtMetAP1c activated with CoCl2 and NiCl2 were 11 µM and 40 µM, respectively. The in silico study showed OJT008 strongly binds to both metal-activated MtMetAP1c, as evidenced by strong molecular interactions and a higher binding score, thereby corroborating our result. This in silico study validated the pharmacophore's metal specificity. The potency of OJT008 against both active and MDR Mtb was <0.063 µg/mL. Our study reports OJT008 as an inhibitor of MtMetAP1c, which is potent at low micromolar concentrations against both active susceptible and MDR Mtb. These results suggest OJT008 is a potential lead compound for the development of novel small molecules for the therapeutic management of TB.

Impact of prophylactic antimalarials in pregnant women living with Human Immunodeficiency Virus on birth outcomes in Botswana.

OBJECTIVES: Until late 2015, Botswana recommended preventive treatment for pregnant women in malarial regions with chloroquine and proguanil (CP). The guideline change provided an opportunity to evaluate CP and adverse birth outcomes. METHODS: The Tsepamo Study performed birth outcomes surveillance at large delivery centres throughout Botswana. We evaluated adverse birth outcomes from 2015 to 2017 at three hospitals where 93% of CP use was recorded. Outcomes included neonatal death (NND), small for gestational age (SGA), very SGA, stillbirth (SB), preterm delivery (PTD) and very PTD. Logistic regression analysis (unadjusted and adjusted) was conducted for each adverse birth outcome. RESULTS: During the study period, 5883 (26%) of 23,033 deliveries were exposed to CP, with the majority (65%) in the most malaria-endemic region. At this site, there was a trend or an association between CP use and reduction of three adverse birth outcomes: PTD (aOR 0.85, 95% CI 0.76-0.96), vPTD (aOR 0.83, 95% CI 0.68-1.01) and NND (aOR 0.65, 95% CI 0.42-1.00). However, at the least malaria-endemic site, the association was in the opposite direction for SB (aOR 1.54, 95% CI 1.08-2.22), SGA (aOR 1.24, 95% CI 1.06-1.44) and vSGA (aOR 1.42, 95% CI 1.14-1.77). The association between CP and reduced PTD was present among women without HIV (aOR 0.77, 95% CI 0.67-0.89) but not among women with HIV (aOR 1.09, 95% CI 0.78-1.35). CONCLUSIONS: Antimalarial prophylaxis was associated with improved birth outcomes in the most malaria-endemic region of Botswana, but not elsewhere. This finding supports current WHO guidance to use prophylaxis strategies among pregnant women in highly malaria-endemic regions. Further studies of the risks and benefits of specific antimalarial regimens in pregnancy are warranted, particularly in areas with lower incidence of malaria.

Diabetes in pregnancy and risk of near-miss, maternal mortality and foetal outcomes in the USA: a retrospective cross-sectional analysis.

BACKGROUND: The prevalence of diabetes in pregnant women has increased in the USA over recent decades. The primary aim of this study was to assess the association between diabetes in pregnancy and maternal near-miss incident, maternal mortality and selected adverse foetal outcomes. METHODS: We conducted a retrospective, cross-sectional analysis among pregnancy-related hospitalizations in USA between 2002 and 2014. We examined the association between DM and GDM as exposures and maternal in-hospital mortality, maternal cardiac arrest, early onset of delivery, poor foetal growth and stillbirth as the outcome variables. RESULTS: Among the 57.3 million pregnant women in the study population, the prevalence of GDM and DM was 5.4 and 1.3%, respectively. We found that pregnant women with DM were three times more likely to experience cardiac arrest (OR = 3.21; 95% CI = 2.57-4.01) and in-hospital maternal death (OR = 3.05; 95% CI = 2.45-3.79), as compared to those without DM. Among pregnant women with GDM and DM, the risk for early onset of delivery was higher, compared to women without GDM or DM. CONCLUSION: A diagnosis of diabetes prior to pregnancy contributes significantly to the risk of maternal cardiac arrest, maternal mortality and adverse foetal outcomes.

MCH Pipeline Training Program: Connecting with Academia to Build Capacity Through Mentoring.

INTRODUCTION: Efforts to recruit and retain diverse Maternal and Child Health (MCH) professionals are of paramount public health significance. Culturally congruent mentorship strategies are key to supporting a successful transition from undergraduate to graduate studies. METHODS: This mixed-method study evaluated a culturally congruent mentorship training used by one of the MCH Pipeline Training programs and described mentorship practices and lessons learned from the six MCH Pipeline programs. A retrospective pre-test post-test survey assessed mentorship competency skills following a mentoring workshop. All MCH Pipeline program leaders completed a questionnaire to elicit responses about mentoring training practices, mentor evaluation strategies, and lessons learned. RESULTS: Maternal and Child Health Pipeline Training Programs supported 1890 undergraduate scholars at universities and institutions nationally. Scholars at six MCH Pipeline Programs participated in MCH education and mentored experiential leadership opportunities in clinical practice, research, and public health education. Qualitative program-level mentor survey themes indicated the importance of creating a reflective space and building mentorship teams. Mean mentor self-assessed improvement in mentor competencies was 14.4 points, 95% CI [10.5, 18.3], p < .001 following completion of a mentoring training workshop implemented by one of the MCH Pipeline programs. DISCUSSION: The Health Resources and Services Administration's Maternal and Child Health Bureau recognized the need to support the development of the next generation of diverse MCH leaders. Pipeline programs that included mentoring workshops and building culturally congruent mentorship teams are two strategies to increase and retain diverse scholars in graduate school and leaders in the public health workforce.

HRSA-Funded MCH Pipeline Training Program: Advancing the MCH Pipeline and Workforce Through Research Collaborations.

PURPOSE: Presently, there are six undergraduate HRSA-funded MCH pipeline training programs (MCHPTP) in the nation and they have gained significant momentum since inception by recruiting, training and mentoring undergraduate students in a comprehensive MCH-focused approach. This article describes the outcomes from the 6 training programs; and primarily Baylor College of Medicine-Texas Southern University (BCM-TSU's) collaborative strategy focusing on the MCH research training and outcomes, which align with HRSA's MCH bureau's missions. DESCRIPTION: Each MCHPTP offers trainees interdisciplinary MCH research experiences through intra/inter-institutional collaborations and partnerships, but BCM-TSU's MCHPTP was the only one with the primary focus to be research. As a case study, the BCM-TSU Program developed an innovative research curriculum integrated with MCH Foundations Course that comprised 2 hour weekly meetings. Students were split into collaborative research groups of 4-5 students, with multidisciplinary peer-mentors, clinical fellows and MCH research faculty from institutions at the world-renowned Texas Medical Center. ASSESSMENT: Since the inception of the MCH mentorship programs, all six MCHPTPs have enrolled up to 1890 trainees and/or interns. BCM-TSU Program trainees are defined as undergraduate students in their 1st or 2nd year of college while research interns are upper classmen in their 3rd or 4th year of college. The case study showed that BCM-TSU Program trainees demonstrated outstanding accomplishments in the area of research through primary and co-authorships of 13 peer-reviewed journal publications by 78 trainees, over a period of 3 years, in addition to dozens of presentations at local, regional and national conferences. CONCLUSIONS: The research productivity of students in the six MCHPTPs is strongly indicative of the success of integrating MCH research mentoring into MCH didactic training. The development of a diverse and robust MCH mentorship program promotes and strengthens research activities in areas of high priority such as addressing health disparities in MCH morbidity and mortality in the U.S.

Success of Maternal and Child Health Pipeline Training Programs: Alumni Survey Results.

INTRODUCTION: The Maternal and Child Health (MCH) Pipeline Training Program, promotes development of a diverse health workforce by training undergraduate students from underrepresented minorities. We aimed to evaluate the success of this program based on three domains: (1) demographic characteristics, (2) academic and career development, and (3) attitudes towards the field of MCH and the training programs among graduates. METHODS: Three domains of success were determined through a collaborative effort between current program directors and the funding agency project officers. The survey with questions related to the three domains was distributed via an online platform to graduates from seven sites (one former site and six current sites). Data were analyzed and presented utilizing descriptive statistics. RESULTS: The survey was distributed to 550 graduates, 162 responded (37% response rate). Demographically, 78% were female, 54% were Black/African American, 22% were Latinx and 83% did not report any disability. Eighty percent of respondents applied to graduate/professional schools, 67% received admission. Graduates often continued to work in MCH fields (70%). Majority felt confident and knowledgeable in the field (89%) and agreed the faculty were supportive at their training sites (90%). CONCLUSION: The study highlights successes in recruiting from underrepresented minorities, particularly Black/African Americans and first-time college goers in the family into the MCH Pipeline Training Programs. Programs were successful in furthering academic and career development for most trainees. Attitudes towards MCH and the training programs were overwhelmingly positive. Continued support of these programs is critical in addressing health disparities and achieving health equity.

Success of Maternal and Child Health Pipeline Training Programs: Alumni Survey Results.

INTRODUCTION: The Maternal and Child Health (MCH) Pipeline Training Program, promotes development of a diverse health workforce by training undergraduate students from underrepresented minorities. We aimed to evaluate the success of this program based on three domains: (1) demographic characteristics, (2) academic and career development, and (3) attitudes towards the field of MCH and the training programs among graduates. METHODS: Three domains of success were determined through a collaborative effort between current program directors and the funding agency project officers. The survey with questions related to the three domains was distributed via an online platform to graduates from seven sites (one former site and six current sites). Data were analyzed and presented utilizing descriptive statistics. RESULTS: The survey was distributed to 550 graduates, 162 responded (37% response rate). Demographically, 78% were female, 54% were Black/African American, 22% were Latinx and 83% did not report any disability. Eighty percent of respondents applied to graduate/professional schools, 67% received admission. Graduates often continued to work in MCH fields (70%). Majority felt confident and knowledgeable in the field (89%) and agreed the faculty were supportive at their training sites (90%). CONCLUSION: The study highlights successes in recruiting from underrepresented minorities, particularly Black/African Americans and first-time college goers in the family into the MCH Pipeline Training Programs. Programs were successful in furthering academic and career development for most trainees. Attitudes towards MCH and the training programs were overwhelmingly positive. Continued support of these programs is critical in addressing health disparities and achieving health equity.

Metabolite Identification of a Novel Anti-Leishmanial Agent OJT007 in Rat Liver Microsomes Using LC-MS/MS.

The purpose of this study was to identify potential metabolic pathways and metabolites of OJT007, a methionine aminopeptidase 1 (MetAP1) inhibitor. OJT007 is a novel drug with potent antiproliferative effects against Leishmania Major. We conducted in vitro Phase I oxidation and Phase II glucuronidation assays on OJT007 using rat liver microsomes. Four unknown metabolites were initially identified using a UPLC-UV system from microsomal incubated samples. LC-MS/MS analysis was then used to identify the structural characteristics of these metabolites via precursor ion scan, neutral loss scan, and product ion scan. A glucuronide metabolite was further confirmed by ß-glucuronidase hydrolysis. The kinetic parameters of OJT007 glucuronidation demonstrated that OJT007 undergoes rapid metabolism. These results demonstrate the liver's microsomal ability to mediate three mono-oxidated metabolites and one mono-glucuronide metabolite. This suggests hepatic glucuronidation metabolism of OJT007 may be the cause of its poor oral bioavailability.

In Vitro and In Vivo Characterization of Potent Antileishmanial Methionine Aminopeptidase 1 Inhibitors.

Leishmania major is the causative agent of cutaneous leishmaniasis (CL). No human vaccine is available for CL, and current drug regimens present several drawbacks, such as emerging resistance, severe toxicity, medium effectiveness, and/or high cost. Thus, the need for better treatment options against CL is a priority. In the present study, we validate the enzyme methionine aminopeptidase 1 of L. major (MetAP1Lm), a metalloprotease that catalyzes the removal of N-terminal methionine from peptides and proteins, as a chemotherapeutic target against CL infection. The in vitro antileishmanial activities of eight novel MetAP1 inhibitors (OJT001 to OJT008) were investigated. Three compounds, OJT006, OJT007, and OJT008, demonstrated potent antiproliferative effects in macrophages infected with L. major amastigotes and promastigotes at submicromolar concentrations, with no cytotoxicity against host cells. Importantly, the leishmanicidal effect in transgenic L. major promastigotes overexpressing MetAP1Lm was diminished by almost 10-fold in comparison to the effect in wild-type promastigotes. Furthermore, the in vivo activities of OJT006, OJT007, and OJT008 were investigated in L. major-infected BALB/c mice. In comparison to the footpad parasite load in the control group, OJT008 decreased the footpad parasite load significantly, by 86%, and exhibited no toxicity in treated mice. We propose MetAP1 inhibitor OJT008 as a potential chemotherapeutic candidate against CL infection caused by L. major infection.

Trends in Appendicitis Among Pregnant Women, the Risk for Cardiac Arrest, and Maternal-Fetal Mortality.

BACKGROUND: Appendicitis is the most common extra-uterine surgical emergency requiring immediate intervention during pregnancy. However, risks for mortality and morbidity among pregnant women with appendicitis remain poorly understood. This study was conducted to determine the temporal trends of appendicitis in pregnant women, and to calculate the risk of maternal-fetal mortality and near-miss marker (i.e., cardiac arrest) among pregnant women in general, and by race/ethnicity. METHODS: We conducted this retrospective study using data from the Nationwide Inpatient Sample (NIS) from January 1, 2002, through December 31, 2015. Joinpoint regression was used to estimate and describe temporal changes in the rates of all and acute appendicitis during the 14-year study period. We also estimated the risk of cardiac arrest, maternal, and fetal mortality among mothers of various racial/ethnic groups with a diagnosis of acute appendicitis. Within each group, patients without acute appendicitis were the referent category. RESULTS AND CONCLUSIONS: Out of the 58 million pregnancy hospitalizations during the study period, 63,145 cases (10.74 per 10,000 hospitalizations) were for acute appendicitis. There was a 5% decline (95% CI: - 5.1, - 5.0) in the rate of appendicitis hospitalizations over the period of the study. After adjusting for covariates, pregnant mothers with acute appendicitis had increased likelihood when compared to those without acute appendicitis to suffer fetal loss (OR: 2.05, 95% CI: 1.85-2.28) and nearly fivefold increase for inpatient maternal death. In conclusion, appendicitis during pregnancy remains an important cause of in-hospital maternal-fetal mortality overall and regardless of race/ethnicity.

Opioid-Related Disorders Among Pregnant Women with Sickle Cell Disease and Adverse Pregnancy Outcomes.

OBJECTIVE: Opioid use during pregnancy has increased in recent years, parallel with the opioid epidemic in the general population. Opioids are commonly used as an analgesic for pain crisis, a hallmark symptom of sickle cell disease (SCD). With the amplified frequency and severity of SCD pain crisis during pregnancy, the use of opioids may increase concurrently. The aim of this study was to examine trends in opioid-related disorders (ORDs) among pregnant women with and without SCD, as well as assess the risk for preterm labor, maternal sepsis, and poor fetal growth among patients with SCD and ORD. METHODS: We conducted a retrospective analysis of inpatient pregnancy- and childbirth-related hospital discharge data from the 2002-2014 National (Nationwide) Inpatient Sample database. The primary outcome was the risk of ORD in pregnant women with SCD and its impact on threatened preterm labor, fetal growth, and maternal sepsis. RESULTS: Among the >57 million pregnancy-related hospitalizations examined, 9.6 per 10,000 had SCD. ORD in mothers with SCD was four times as prevalent as in those without SCD (2% vs 0.5%). A significant rise in ORD occurred throughout the study period and was associated with an increased risk of maternal sepsis, threatened preterm labor, and poor fetal growth. CONCLUSIONS: Pregnant women with SCD have a fourfold increased risk of ORD compared with their non-SCD counterparts. The current opioid epidemic continues to worsen in both groups, warranting a tailored and effective public health response to reduce the resulting adverse pregnancy outcomes.

Opioid Use Among HIV-Positive Pregnant Women and the Risk for Maternal-Fetal Complications.

OBJECTIVE: To assess patient- and hospital-level characteristics associated with opioid use in human immunodeficiency virus (HIV)-positive pregnant women and fetal health outcomes. METHODS: Using the 2002-2014 Nationwide Inpatient Sample database, we analyzed discharge records to describe the rates of opioid use among HIV-positive pregnant women. Logistic regression was used to quantify the magnitude of the association between exposure status and maternal-fetal outcomes. RESULTS: Opioid use was fourfold greater among HIV-positive pregnant women compared with their HIV-negative counterparts (odds ratio 4.0; 95% confidence interval 3.15-5.12). Relatively smaller but significant increases in the early onset of delivery, poor fetal growth, abortive pregnancy, and spontaneous abortion also were observed in association with HIV-positive status and opioid drug use during pregnancy. CONCLUSIONS: An increased risk of negative maternal-fetal complications persists among HIV-positive women who use opioids during pregnancy. Focusing on predisposing factors and monitoring opioid dispensing may mitigate overuse or abuse in this vulnerable population.

Inhibitory mechanism of clioquinol and its derivatives at the exopeptidase site of human angiotensin-converting enzyme-2 and receptor binding domain of SARS-CoV-2 viral spike.

The outbreak of SARS-CoV-2 infections around the world has prompted scientists to explore different approaches to develop therapeutics against COVID-19. This study focused on investigating the mechanism of inhibition of clioquinol (CLQ) and its derivatives (7-bromo-5-chloro-8-hydroxyquinoline (CLBQ), 5, 7-Dichloro-8-hydroxyquinoline (CLCQ)) against the viral glycoprotein, and human angiotensin-converting enzyme-2 (hACE-2) involved in SARS-CoV-2 entry. The drugs were docked at the exopeptidase site of hACE-2 and receptor binding domain (RBD) sites of SARS-CoV-2 Sgp to calculate the binding affinity of the drugs. To understand and establish the inhibitory characteristics of the drugs, molecular dynamic (MD) simulation of the best fit docking complex performed. Evaluation of the binding energies of the drugs to hACE-2 after 100 ns MD simulations revealed CLQ to have the highest binding energy value of -40.4 kcal/mol close to MLN-7640 (-45.4 kcal/mol), and higher than the exhibited values for its derivatives: CLBQ (-34.5 kcal/mol) and CLCQ (-24.8 kcal/mol). This suggests that CLQ and CLBQ bind more strongly at the exopeptidase site than CLCQ. Nevertheless, the evaluation of binding affinity of the drugs to SARS-CoV-2 Sgp showed the drugs are weakly bound at the RBD site, with CLBQ, CLCQ, CLQ exhibiting relatively low energy values of -16.8 kcal/mol, -16.34 kcal/mol, -12.5 kcal/mol, respectively compared to the reference drug, Bisoxatin (BSX), with a value of -25.8 kcal/mol. The structural analysis further suggests decrease in systems stability and explain the mechanism of inhibition of clioquinol against SARS-CoV-2 as reported in previous in vitro study.Communicated by Ramaswamy H. Sarma.

Analogs of N'-hydroxy-N-(4H,5H-naphtho[1,2-d]thiazol-2-yl)methanimidamide inhibit Mycobacterium tuberculosis methionine aminopeptidases.

Our previous target validation studies established that inhibition of methionine aminopeptidases (MtMetAP, type 1a and 1c) from Mycobacterium tuberculosis (Mtb) is an effective approach to suppress Mtb growth in culture. A novel class of MtMetAP1c inhibitors comprising of N'-hydroxy-N-(4H,5H-naphtho[1,2-d]thiazol-2-yl)methanimidamide (4c) was uncovered through a high-throughput screen (HTS). A systematic structure-activity relationship study (SAR) yielded variants of the hit, 4b, 4h, and 4k, bearing modified A- and B-rings as potent inhibitors of both MtMetAPs. Except methanimidamide 4h that showed a moderate Mtb inhibition, a desirable minimum inhibitory concentration (MIC) was not obtained with the current set of MtMetAP inhibitors. However, the SAR data generated thus far may prove valuable for further tuning of this class of inhibitors as effective anti-tuberculosis agents.

A computational evaluation of structural stability of omicron and delta mutations of SARS-CoV-2 spike proteins and human ACE-2 interactions.

Several more infectious SARS-CoV-2 variants have emerged globally since SARS-CoV-2 pandemic and the discovery of the first D614G variant of SARS-CoV-2 spike proteins in 2020. Delta (B.1.617.2) and Omicron (B.1.1.529) variants have proven to be of major concern out of all the reported variants, considering their influence on the virus' transmissibility and severity. This study aimed at evaluating the impact of mutations on these two variants on stability and molecular interactions between the viral Spike protein and human angiotensin converting enzyme-2 (hACE-2). The spike proteins receptor binding domain (RBD) was docked with the hACE-2 using HADDOCK servers. To understand and establish the effects of the mutations on the structural stability and flexibility of the RBD-hACE-2 complex, molecular dynamic (MD) simulation of the docked complex was performed and evaluated. The findings from both molecular docking analysis and binding free energy showed that the Omicron (OM) variant has high receptiveness towards hACE-2 versus Delta variant (DT), thereby, responsible for its increase in transmission. The structural stability and flexibility evaluation of variants' systems showed that mutations on DT and OM variants disturbed the stability of either the spike protein or the RBD-hACE-2 complex, with DT variant having greater instability impact. This study, therefore, assumed this obvious instability observed in DT variant might be associated or responsible for the reported severity in DT variant disease over the OM variant disease. This study provides molecular insight into the effects of OM and DT variants on stability and interactions between SARS-CoV-2 protein and hACE-2.

Inhibitory mechanism of Ambroxol and Bromhexine Hydrochlorides as potent blockers of molecular interaction between SARS-CoV-2 spike protein and human angiotensin-converting Enzyme-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects the host cells through interaction of its spike protein with human angiotensin-converting enzyme 2 (hACE-2). High binding affinity between the viral spike protein and host cells hACE-2 receptor has been reported to enhance the viral infection. Thus, the disruption of this molecular interaction will lead to reduction in viral infectivity. This study, therefore, aimed to analyze the inhibitory potentials of two mucolytic drugs; Ambroxol hydrochlorides (AMB) and Bromhexine hydrochlorides (BHH), to serve as potent blockers of these molecular interactions and alters the binding affinity/efficiency between the proteins employing computational techniques. The study examined the effects of binding of each drug at the receptor binding domain (RBD) of the spike protein and the exopeptidase site of hACE-2 on the binding affinity (ΔGbind) and molecular interactions between the two proteins. Binding affinity revealed that the binding of the two drugs at the RBD-ACE-2 site does not alter the binding affinity and molecular interaction between the proteins. However, the binding of AMB (-56.931 kcal/mol) and BHH (-46.354 kcal/mol) at the exopeptidase site of hACE-2, significantly reduced the binding affinities between the proteins compared to the unbound, ACE-2-RBD complex (-64.856 kcal/mol). The result further showed the two compounds have good affinity at the hACE-2 site, inferring they might be potent inhibitors of hACE-2. Residue interaction networks analysis further revealed the binding of the two drugs at the exopeptidase site of hACE-2 reduced the number of interacting amino residues, subsequently leading to loss of interactions between the two proteins, with BHH showing better reduction in the molecular interaction and binding affinity than AMB. The result of the structural analyses additionally, revealed that the binding of the drugs considerably influences the dynamic of the complexes when compared to the unbound complex. The findings from this study suggest the binding of the two drugs at the exopeptidase site reduces the binding effectiveness of the proteins than their binding at the RBD site, and consequently might inhibit viral attachment and entry.

Discovery of Clioquinol and analogues as novel inhibitors of Severe Acute Respiratory Syndrome Coronavirus 2 infection, ACE2 and ACE2 - Spike protein interaction in vitro.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent for coronavirus disease 2019 (COVID-19), has resulted in an ongoing pandemic. Presently, there are no clinically approved drugs for COVID-19. Hence, there is an urgent need to accelerate the development of effective antivirals. Herein, we discovered Clioquinol (5-chloro-7-iodo-8-quinolinol (CLQ)), a Food and Drug Administration (FDA) approved drug, and two of its analogues (7-bromo-5-chloro-8-hydroxyquinoline (CLBQ14); and 5, 7-Dichloro-8-hydroxyquinoline (CLCQ)) as potent inhibitors of SARS-CoV-2 infection-induced cytopathic effect in vitro. In addition, all three compounds showed potent anti-exopeptidase activity against recombinant human angiotensin-converting enzyme 2 (rhACE2) and inhibited the binding of rhACE2 with SARS-CoV-2 Spike (RBD) protein. CLQ displayed the highest potency in the low micromolar range, with its antiviral activity showing a strong correlation with inhibition of rhACE2 and rhACE2-RBD interaction. Altogether, our findings provide a new mode of action and molecular target for CLQ and validates this pharmacophore as a promising lead series for the clinical development of potential therapeutics for COVID-19.

The Global Alliance for Maternal and Child Health (GLAM): A Pioneer Organization for MCH Students.

Currently, there is an insufficient representation of racial/ethnic minority groups in the maternal and child health (MCH) workforce. A student-run outreach organization, the Global Alliance for Maternal and Child Health (GLAM), seeks to address this disparity by increasing the representation of racial/ethnic minority groups in MCH workforce. Founded by students at Texas Southern University in Houston, Texas, United States, GLAM, seeks to establish productive alliances and create programs that would help improve the well-being of mothers, infants, and children locally, nationally, and internationally by engaging an active cadre of students passionate about MCH. Through community outreach and global engagement using evidence-based strategies, GLAM is committed to the elimination of health disparities plaguing the MCH population.