Gender-Transformative Interventions for Young Adolescents: What Have We Learned and Where Should We Go?

PURPOSE: To identify the key facilitators and barriers to implementing gender-transformative interventions among young adolescents (ages 10-14 years) in low- and middle-income countries and provide recommendations for guiding the next generation of intervention approaches. METHODS: A scoping review of the literature was first conducted to identify articles that contained the following inclusion criteria: (1) included 10- to 14-year-olds as a target population; (2) addressed gender inequality as a pathway to improved health; (3) implemented in a low- and middle-income country context; and (4) published between 2010 and 2023. Two databases, Scopus and PubMed, were searched as well as the gray literature. Additionally, to collect critical reflections on gender-transformative interventions, two expert meetings and four key informant interviews were conducted. RESULTS: Among the 59 articles which were retrieved and reviewed, 30 were evaluations of specific gender-transformative interventions and the remaining 29 included literature reviews or critical reflections of gender-transformative interventions. Three key themes emerged from our analysis: (1) tailoring approaches for both boys and girls; (2) incorporating multilevel approaches; and (3) engaging multiple sectors, such as health, education, and sports. In each theme, we highlight the primary challenges as well as promising practices for implementation. DISCUSSION: Efforts should continue unpacking the characteristics of intervention approaches where positive results are found among boys and girls in both implementation and impact. In terms of both multilevel and multisectoral programming, more evidence is needed to help identify which intervention activities should target which populations at what levels and how much to achieve positive impacts among young adolescents.

Surgical Outcomes and Predictive Factor Analysis for Facial Nerve Preservation in Patients With Cerebellopontine Angle (CPA) Tumors: A Ten-Year Single Institutional Study.

Objective To analyze the surgical outcome and predictive factors for facial nerve preservation in patients with surgically operated cerebellopontine angle (CPA) tumors. Methodology Methodology Data were retrospectively retrieved from inpatient medical records of patients admitted with CPA tumors from January 1, 2011, to December 31, 2020, at our institute. Epidemiological, clinical and radiological findings, histopathological types, surgical outcomes, and facial nerve function of these patients were recorded using a data-gathering tool. Results Out of 230 patients, 188 (81.7%) were diagnosed histopathologically with vestibular schwannoma (VS), 20 (8.7%) with meningioma, 15 (6.5%) with epidermoid, and 7 (3.1%) with other conditions. The most common clinical features were hearing loss in VS and headaches in meningioma and epidermoid. Preoperatively, 103 (44.8%) had grade 2, 68 (29.6%) had grades 3 or 4, and 8 (3.5%) had grade 5 facial nerve palsy, while post-operatively, 93 (40.9%) patients had grade 2, 83 (36.6%) had grades 3 or 4, and 6 (2.6%) had grade 5 facial palsy. Greater facial nerve preservation was observed in patients with tumor sizes <4 cm (p=0.0041) and in those who underwent near-total (NTR) or subtotal resection (STR) (p=0.0442). Excellent facial nerve outcomes (HB grades 1 or 2) were noted in patients who underwent intraoperative facial nerve monitoring (p<0.0001). CSF leak and meningitis were present in 3.5% and 2.2% of patients, respectively. The mortality rate was 6.1%, with a recurrence rate of 4.8%. Conclusion Intraoperative facial nerve monitoring, tumor size less than 4 cm, and extent of resection (NTR/STR) are predictive factors that significantly affect facial nerve outcomes.

Investigation of an Indian Site with Mafic Rock for Carbon Sequestration.

The increasing extent of greenhouse gas emissions has necessitated the development of techniques for atmospheric carbon dioxide removal and storage. Various techniques are being explored for carbon storage including geological sequestration. The geological sequestration has various avenues such as depleted oil and gas reservoirs, coal-bed methane reservoirs, and mafic and ultramafic rocks. Different trapping mechanisms are in play in these subsurface storage systems. In these sequestration sites, the mafic and ultramafic rocks are best suited for long-term and effective sequestration as they comprise minerals, conducive for chemical alteration, forming stable carbonates. However, these sites often suffer from distinct disadvantages of injectivity issues due to their low permeability and porosity. This study investigates the potential of sequestration in the rock samples obtained from one such site located in India. The rock samples are first characterized using various techniques including X-ray fluorescence, X-ray diffraction, Raman spectroscopy, and field emission scanning electron microscopy (FESEM). The mineralogical characterization shows that the rock sample contains approximately 10% of diopside. The samples were put in the reactor chamber comprising CO2, which were then investigated using FESEM analysis. Additionally, a reservoir block simulation using commercial software was conducted with the representative minerals in the sample to evaluate the CO2 sequestration potential. The simulation result suggests the formation of magnesite which corresponds to a major part of CO2 mineral trapping. The reduced injectivity due to low porosity and permeability in this rock can be addressed using hydraulic fracturing. The geomechanical behavior of the rock sample for hydraulic fracturing is studied using the Brazilian disc test. The Monte Carlo-based uncertainty analysis was conducted using the tensile strength data of the sample. Results suggest that the most likely fracturing pressure is 2100 psi for this rock sample.

Energy-efficient synthetic antiferromagnetic skyrmion-based artificial neuronal device.

Magnetic skyrmions offer unique characteristics such as nanoscale size, particle-like behavior, topological stability, and low depinning current density. These properties make them promising candidates for next-generation spintronics-based memory and neuromorphic computing. However, one of their distinctive features is their tendency to deviate from the direction of the applied driving force that may lead to the skyrmion annihilation at the edge of nanotrack during skyrmion motion, known as the skyrmion Hall effect (SkHE). To overcome this problem, synthetic antiferromagnetic (SAF) skyrmions that having bilayer coupling effect allows them to follow a straight path by nullifying SkHE making them alternative for ferromagnetic (FM) counterpart. This study proposes an integrate-and-fire (IF) artificial neuron model based on SAF skyrmions with asymmetric wedge-shaped nanotrack having self-sustainability of skyrmion numbers at the device window. The model leverages inter-skyrmion repulsion to replicate the IF mechanism of biological neuron. The device threshold, determined by the maximum number of pinned skyrmions at the device window, can be adjusted by tuning the current density applied to the nanotrack. Neuronal spikes occur when initial skyrmion reaches the detection unit after surpassing the device window by the accumulation of repulsive force that result in reduction of the device's contriving current results to design of high energy efficient for neuromorphic computing. Furthermore, work implements a binarized neuronal network accelerator using proposed IF neuron and SAF-SOT-MRAM based synaptic devices for national institute of standards and technology database image classification. The presented approach achieves significantly higher energy efficiency compared to existing technologies like SRAM and STT-MRAM, with improvements of 2.31x and 1.36x, respectively. The presented accelerator achieves 1.42x and 1.07x higher throughput efficiency per Watt as compared to conventional SRAM and STT-MRAM based designs.

Legislation for advancing women's leadership in the health sector in India and Kenya: a 'law cube' approach to identify ways to strengthen legal environments for gender equality.

OBJECTIVES: This paper examines the availability of legal provisions, or the lack thereof, that support women to progress equitably into leadership positions within the health workforce in India and Kenya. METHODS: We adapted the World Bank's Women, Business and Law framework of legal domains relevant to gender equality in the workplace and applied a 'law cube' to analyse the comprehensiveness, accountability and equity and human rights considerations of 27 relevant statutes in India and 11 in Kenya that apply to people in formal employment within the health sector. We assessed those laws against 30 research-validated good practice measures across five legal domains: (1) pay; (2) workplace protections; (3) pensions; (4) care, family life and work-life balance; and (5) reproductive rights. In India, the pension domain and related measures were not assessed because the pension laws do not apply to the public and private sector equally. RESULTS: Several legal domains are addressed inadequately or not at all, including pay in India, reproductive rights in Kenya and the care, family life and the work-life balance domain in both countries. Additionally, we found that among the Kenyan laws reviewed, few specify accountability mechanisms, and equity and human rights measures are mainly absent from the laws assessed in both countries. Our findings highlight inadequacies in the legal environments in India and Kenya may contribute to women's under-representation in leadership in the health sector. The absence of specified accountability mechanisms may impact the effective implementation of legislation, undermining their potential to promote equal opportunities. CONCLUSIONS: Government action is needed in both countries to ensure that legislation addresses best practice provisions, equity and human rights considerations, and provides for independent review mechanisms to ensure accountability for implementation of existing and future laws. This would contribute to ensuring that legal environments uphold the equality of opportunity necessary for realising gender justice in the workplace for the health workforce. PRIMARY SOURCE OF FUNDING: Bill & Melinda Gates Foundation (INV-031372).

Pathways to leadership: what accounts for women's (in)equitable career paths in the health sectors in India and Kenya? A scoping review.

OBJECTIVES: We aimed to capture evidence on enablers and barriers to improving equal opportunity and effective organisational interventions that can advance women's leadership in India and Kenya's health sectors. METHODS: We systematically searched JSTOR, PubMed, SCOPUS and Web of Science databases, reference lists of selected articles and Google Scholar using string searches. We included studies that were published in English from 2000 to 2022 in peer-reviewed journals or grey literature, focused on paid, formal health professionals in India or Kenya, described factors relating to women's representation/leadership. RESULTS: We identified 26 studies, 15 from India and 11 from Kenya. From each country, seven studies focused on nursing. Participants included women and men health sector workers. Seven studies used mixed methods, 11 were qualitative, 5 were quantitative and 3 were commentaries. Factors influencing women's career progression at individual/interpersonal levels included family support, personal attributes (knowledge/skills) and material resources. Factors at the organisational level included capacity strengthening, networking, organisational policies, gender quotas, work culture and relationships, flexibility, and work burden. Nursing studies identified verbal/sexual harassment and professional hierarchies as barriers to career progression. Structural barriers included a lack of infrastructure (training institutes and acceptable working environments). Normative themes included occupational segregation by gender (particularly in nursing), unpaid care work burden for women and gender norms. Studies of interventions to improve women's career progression and sex-disaggregated workforce data in India or Kenya were limited, especially on leadership within career pathways. The evidence focuses on enablers and barriers at work, rather than on organisations/systems to support women's leadership or address gender norms. CONCLUSIONS: Women in India and Kenya's health sectors face multiple impediments in their careers, which impact their advancement to leadership. This calls for gender-transformative interventions to tackle discrimination/harassment, provide targeted training/mentorship, better parental leave/benefits, flexible/remote working, family/coworker support and equal-opportunity policies/legislation.

Probe Substrate Dependencies in CYP3A4 Allosteric Inhibition: A Novel Molecular Mechanism Involving F-F' Loop Perturbations.

The biochemical basis for substrate dependences in apparent inhibition constant values (Ki) remains unknown. Our study aims to elucidate plausible structural determinants underpinning these observations. In vitro steady-state inhibition assays conducted using human recombinant CYP3A4 enzyme and testosterone substrate revealed that fibroblast growth factor receptor (FGFR) inhibitors erdafitinib and pemigatinib noncompetitively inhibited CYP3A4 with apparent Ki values of 10.2 ± 1.1 and 3.3 ± 0.9 µM, respectively. However, when rivaroxaban was adopted as the probe substrate, there were 2.0- and 3.2-fold decreases in its apparent Ki values. To glean mechanistic insights into this phenomenon, erdafitinib and pemigatinib were docked to allosteric sites in CYP3A4. Subsequently, molecular dynamics (MD) simulations of apo- and holo-CYP3A4 were conducted to investigate the structural changes induced. Comparative structural analyses of representative MD frames extracted by hierarchical clustering revealed that the allosteric inhibition of CYP3A4 by erdafitinib and pemigatinib did not substantially modulate its active site characteristics. In contrast, we discovered that allosteric binding of the FGFR inhibitors reduces the structural flexibility of the F-F' loop region, an important gating mechanism to regulate access of the substrate to the catalytic heme. We surmised that the increased rigidity of the F-F' loop engenders a more constrained entrance to the CYP3A4 active site, which in turn impedes access to the larger rivaroxaban molecule to a greater extent than testosterone and culminates in more potent inhibition of its CYP3A4-mediated metabolism. Our findings suggest a potential mechanism to rationalize probe substrate dependencies in Ki arising from the allosteric noncompetitive inhibition of CYP3A4.

Probiotic Consortium Confers Synergistic Anti-Inflammatory Effects in Inflammatory Disorders.

The composition and diversity of gut microbiota significantly influence the immune system and are linked to various diseases, including inflammatory and allergy disorders. While considerable research has focused on exploring single bacterial species or consortia, the optimal strategies for microbiota-based therapeutics remain underexplored. Specifically, the comparative effectiveness of bacterial consortia versus individual species warrants further investigation. In our study, we assessed the impact of the bacterial consortium MPRO, comprising Lactiplantibacillus plantarum HY7712, Bifidobacterium animalis ssp. lactis HY8002, and Lacticaseibacillus casei HY2782, in comparison to its individual components. The administration of MPRO demonstrated enhanced therapeutic efficacy in experimental models of atopic dermatitis and inflammatory colitis when compared to single strains. MPRO exhibited the ability to dampen inflammatory responses and alter the gut microbial landscape significantly. Notably, MPRO administration led to an increase in intestinal CD103+CD11b+ dendritic cells, promoting the induction of regulatory T cells and the robust suppression of inflammation in experimental disease settings. Our findings advocate the preference for bacterial consortia over single strains in the treatment of inflammatory disorders, carrying potential clinical relevance.

Facile fabrication and application of highly efficient reduced graphene oxide (rGO)-wrapped 3D foam for the removal of organic and inorganic water pollutants.

The pace of water contamination is increasing daily due to expanding industrialisation. Finding a feasible solution for effectively remediating various organic and inorganic pollutants from large water bodies remains challenging. However, a nano-engineered advanced hybrid material could provide a practical solution for the efficient removal of such pollutants. This work has reported the development of a highly efficient and reusable absorbent comprising a porous polyurethane (PU) and reduced graphene oxide (rGO) nanosheets (rGOPU) for the removal of different organic oils (industrial oil, engine oil and mustard oil), dyes (MB, MO, RB, EY and MV) and heavy metals (Pb(II), Cr(VI), Cd(II), Co(II) and As(V)). The structure, morphology and properties of the rGOPU hybrid absorbents were analysed by using Raman spectroscopy, field emission scanning electron microscopy (FESEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), thermogravimetric analysis (TGA) and Brunner-Emitte-Teller (BET) analysis. The rGOPU possessed both superhydrophobicity and superoleophilicity with water and oil contact angles of about 164° and 0°, respectively. The prepared rGOPU has demonstrated an excellent oil-water separation ability (up to 99%), heavy metals removal efficiency (more than 75%), toxic dye adsorption (more than 55%), excellent recyclability (> 500 times for oils), extraordinary mechanical stability (90% compressible for > 1000 cycles) and high recoverability. This work presents the first demonstration of rGOPU's multifunctional absorbent capacity in large-scale wastewater treatment for effectively removing a wide variety of organic and inorganic contaminants.

Development of silver nanoparticles and aptamer conjugated biosensor for rapid detection of E. coli in a water sample.

A simple, rapid, and sensitive electrochemical biosensor based on a screen-printed carbon electrode (SPCE) was developed for onsite detection of E. coli in real time. This work analyzed the effect of aptamer conjugation and PBS buffer solution on the colloidal stability of the silver nanoparticles (AgNPs). Aggregations of the AgNPs after aptamer conjugation in PBS buffer were observed from the particle size distribution analysis. The AgNP-aptamer conjugation and its affinity towards E. coli (DH5α) were confirmed by UV-visible spectrophotometry, which showed a linear increment in the absorption with increasing E.coli concentration. The screen-printed carbon electrodes were modified by drop-casting of AgNPs, which were used as an effective immobilization platform for E. coli-specific aptamers. The modified electrode's surface modification and redox behavior were characterized using cyclic voltammetry. Finally, E. coli was detected using differential pulse voltammetry with an optimized incubation time of 15 min. The developed biosensors showed a linear decrease in current intensity with an increase in the concentration of E. coli. The biosensor had a relative standard deviation (RSD) of 6.91% (n = 3), which showed good reproducibility. The developed biosensors are highly sensitive and have a limit of detection (LOD) as low as 150 CFU/ml. The biosensor showed good selectivity for E.coli coli when comparing the signal response obtained for bacteria other than E.coli. Also, the biosensor was found stable for four weeks at room temperature and showed high recoveries from 95.27% to 107% during the tap water sensitivity validation.

Modeling for nonlinear acoustic imaging of an isolated crack via standing waves in a 2D solid.

This paper is concerned with numerical modeling for nondestructive imaging of defects in solids via standing waves excited by a periodic sinewave signal. The stationary solution, purely sinusoidal in an intact sample, contains higher harmonics when damage is present. These harmonics are generated by contact acoustic nonlinearity and form their own standing waves whose intensity maximum usually indicates the position of damage, in a way similar to resonant vibrometry experiments. The key point of the developed numerical tool that describes those wave phenomena is a model of planar damage (crack, delamination) considered here as an inner contact with rough surfaces and friction. The corresponding boundary conditions are given by the previously developed contact model based on the Method of Memory Diagrams (MMD) capable of automating the account for hysteretic frictional effects. Combination of the MMD for boundary conditions and a finite element formulation for waves in a volume (MMD-FEM model) provides a complete description which represents a numerical code applied here for nonlinear standing waves simulations. We present a number of examples obtained for idealized 2D geometry and reveal conditions in which both position and extent of damage are clearly seen as well as cases where only partial detection is possible.

A novel, efficient and economical alternative for the removal of toxic organic, inorganic and pathogenic water pollutants using GO-modified PU granular composite.

Multicomponent wastewater treatment utilising simple and cost-effective materials and methods is an important research topic. This study has reported the fabrication and utilisation of graphene oxide (GO) embedded granular Polyurethane (PU) (GOPU) adsorbent for the treatment of lead ion (Lead ion (Pb(II)), Methylene blue (MB), and E. coli. PU granules were wrapped with GO flakes to improve hydrophilicity, interaction with polluted water, cation-exchange reaction, and binding of pollutants on its surface. Synthesised GOPU granules were characterised by X-Ray Diffraction (XRD), Raman, Fourier transform infrared (FTIR) spectroscopy, and Scanning electron microscopy (SEM) analysis to ensure the successful synthesis of GO and fabrication of GOPU granules. Further, batch and continuous adsorption processes were studied in different operating conditions to evaluate the performance of GOPU granules in practical applications. The kinetic and isotherm analyses revealed that the adsorption of Lead (Pb(II)) ion and Methylene Blue (MB) dye followed the Freundlich and Langmuir isotherm models, respectively, and they showed good agreement with the Pseudo-second-order kinetic model. The adsorption capacities of GOPU granules for the elimination of Pb(II) and MB dye were about 842 mg/g and 899 mg/g, respectively. Additionally, investigations into the fixed bed column revealed that the adsorption column performed best at a flow rate of 5 mL/min and a bed height of 6 cm. Pb(II) adsorption had a bed uptake capacity (qbed) of 88 mg/g and percentage removal efficiency (%R) of 76%. Similarly, MB adsorption had a bed uptake capacity of 202 mg/g and a percentage removal efficiency of 71%. A systematic invention on antibacterial activity toward E. coli showed that The GOPU granules have a removal efficiency of about 100% at an exposure of 24 h. These findings indicated the possible use of GOPU granules as promising adsorbents for various water pollutants.

A statistical analysis of tweets on covid-19 vaccine hesitancy utilizing opinion mining: an Indian perspective.

The world witnessed the emergence of a deadly virus in December 2019, later named COVID-19. The virus was found to be highly contagious, and so people across the world were highly prone to be affected by the virus. Being a virus-borne disease, developing a vaccine was one of the most promising remedies. Thus, research organizations across the globe started working on developing the vaccine. However, it was later found by many researchers that a large number of people were hesitant to receive the vaccine. This paper aims to study the acceptance and hesitancy levels of people in India and compares them with the acceptance and hesitancy levels of people from the UK, the USA, and the rest of the world by analyzing their tweets on Twitter. For this study, 2,98,452 tweets were fetched from January 2020 to March 2022 from Twitter, and 1,84,720 tweets from 1,22,960 unique users were selected based on their country of origin. Machine learning based Sentiment analysis is then used to evaluate and analyze the tweets. The paper also proposes an NLP-based algorithm to perform opinion mining on Twitter data. The study found the public sentiment of the Indian population to be 63% positive, 28% neutral, and 9% negative. While the worldwide sentiment distribution is 45% positive, 34% neutral, and 21% negative, the USA has 42% positive, 34% neutral, and 23% negative and the UK has 50% positive, 29% neutral, and 21% negative. Also, sentiment analysis for individual vaccines in Indian context resulted in "Covaxin" with the highest positive sentiment at 43% followed by "Covishield" at 36%. The outcome of this work yields an insight into the public perception of the COVID-19 vaccine and thus can be used to formulate policies for existing and future vaccine campaigns. This study becomes more relevant as it is the consolidated opinion of Indian people, which is versatile in nature.

Environmental application of amine functionalised magnetite nanoparticles grafted graphene oxide chelants.

This study proposed a two-step method involving hydrothermal and electrostatic self-assembly processes for synthesising an amine-functionalised magnetic ligand graphene oxide-based nanocomposite (EDTA@Fe3O4@GO). The amine groups were successfully attached to the surface of iron (II, III) oxide (Fe3O4), which were embedded on the surface of graphene oxide (GO) (Fe3O4@GO). This EDTA@ Fe3O4@GO nanocomposite was used as a chelating agent to bind the toxic heavy metal ions. EDTA@Fe3O4@GO demonstrated the synergistic effect between the large surface area and magnetic behaviour of Fe3O4@GO and the chelating effect of EDTA, and it showed higher efficiency than the individual GO and Fe3O4. The possible structural and compositional characteristics were proposed based on Fourier transform infrared spectra (FTIR), X-ray diffraction (XRD), scanning electron microscope (SEM), Brunauer-Emmett-Teller (BET) and Raman spectroscopy analysis. The outcomes revealed the mechanism behind the excellent As(V) adsorption onto EDTA@Fe3O4@GO. The adsorption process was studied by fitting the experimental data obtained into various kinetic and isotherm models. The pseudo-second-order (PSO) kinetic model and the Freundlich isotherm model (FIM) were found to be the best fit models for the removal of As(V) by EDTA@Fe3O4@GO. EDTA@Fe3O4@GO has the utmost adsorption capacity of 178.4 mg/g. Furthermore, the EDTA@Fe3O4@GO nanocomposite is reusable, and it showed excellent adsorption capacity up to 5 cycles. This study has provided insight into the potential of EDTA@Fe3O4@GO and its applications in large-scale wastewater treatment.

Sex-disaggregated data matters: tracking the impact of COVID-19 on the health of women and men.

Sex and gender matter to health outcomes, but despite repeated commitments to sex-disaggregate data in health policies and programmes, a persistent and substantial absence of such data remains especially in lower-income countries. This represents a missed opportunity for monitoring and identifying gender-responsive, evidence-informed solutions to address a key driver of the pandemic. In this paper we review the availability of national sex-disaggregated surveillance data on COVID-19 and examine trends on the testing-to-outcome pathway. We further analyse the availability of data according to the economic status of the country and investigate the determinants of sex differences, including the national gender inequality status (according to a global index) in each country. Results are drawn from 18 months of global data collection from over 200 countries. We find differences in COVID-19 prevention behaviours and illness outcomes by sex, with lower uptake of vaccination and testing plus an elevated risk of severe disease and death among men. Supporting and maintaining the collection, collation, interpretation and presentation of sex-disaggregated data requires commitment and resources at subnational, national and global levels, but provides an opportunity for identifying and taking gender-responsive action on health inequities. As a first step the global health community should recognise, value and support the importance of sex-disaggregated data for identifying and tackling an inequitable pandemic.

Direct and Sequential Bioactivation of Pemigatinib to Reactive Iminium Ion Intermediates Culminates in Mechanism-Based Inactivation of Cytochrome P450 3A.

We recently established the mechanism-based inactivation (MBI) of cytochrome P450 3A (CYP3A) by the fibroblast growth factor receptor (FGFR) inhibitors erdafitinib and infigratinib. Serendipitously, our preliminary data have also revealed that pemigatinib (PEM), another clinically approved FGFR1-3 inhibitor, similarly elicited time-dependent inhibition of CYP3A. This was rather unexpected, as it was previously purported that PEM did not pose any metabolism-dependent liabilities due to the absence of glutathione-related conjugates in metabolic profiling experiments conducted in human liver microsomes. Here, we confirmed that PEM inhibited both CYP3A isoforms in a time-, concentration-, and cofactor-dependent manner consistent with MBI, with inactivator concentration at half-maximum rate constant, maximum inactivation rate constant, and partition ratio of 8.69 and 11.95 µM, 0.108 and 0.042 min-1, and approximately 44 and approximately 47 for CYP3A4 and CYP3A5, respectively. Although the rate of inactivation was diminished by coincubation with an alternative substrate or direct inhibitor of CYP3A, the inclusion of nucleophilic trapping agents afforded no such protection. Furthermore, the lack of catalytic activity recovery following dialysis and oxidation with potassium ferricyanide coupled with the absence of a spectrally resolvable peak in the Soret region collectively implied that the underlying mechanism of inactivation was not elicited via the formation of pseudo-irreversible metabolite-intermediate complexes. Finally, utilizing cyanide trapping and high-resolution mass spectrometry, we illuminated the direct and sequential oxidative bioactivation of PEM and its major O-desmethylated metabolite at its distal morpholine moiety to reactive iminium ion hard electrophilic species that could covalently inactivate CYP3A via MBI. SIGNIFICANCE STATEMENT: This study reports for the first time the covalent MBI of CYP3A by PEM and deciphered its bioactivation pathway involving the metabolic activation of PEM and its major O-desmethylated metabolite to reactive iminium ion intermediates. Following which, a unique covalent docking methodology was harnessed to unravel the structural and molecular determinants underpinning its inactivation. Findings from this study lay the foundation for future investigation of clinically relevant drug-drug interactions between PEM and concomitant substrates of CYP3A.

Spatial Variation in Contraceptive Practice Across the Districts of India, 1998-2016.

India is currently one of the most demographically diverse regions of the world. Fertility and mortality rates are known to show considerable variation at the level of regions, states and districts. Little is known however, about the spatial variations of the contraceptive usage-a critical variable that is relevant to fertility as well as health policy. This paper uses data from four national population-based household surveys conducted between 1998 and 2016 to explore district-level variations in the contraceptive prevalence rate. We find no clear evidence of convergence. The gap between the best and worst performing districts is more than 70 percent across the four rounds and does not diminish over time. We also find considerable evidence of spatial clustering across districts. Districts with high prevalence concentrate in Southern states and more recently, in the Northeast of the country. Our analysis suggests that female literacy and health care infrastructure are important correlates of spatial clusters. This suggests that investments in women's human capital and health-care infrastructure play a role in expanding women's opportunities to time their births.

Breast Cancer Transcriptional Regulatory Network Reprogramming by using the CRISPR/Cas9 System: An Oncogenetics Perspective.

Breast cancer (BC) is the second most commonly diagnosed cancer in the world. BC develops due to dysregulation of transcriptional profiles, substantial interpatient variations, genetic mutations, and dysregulation of signaling pathways in breast cells. These events are regulated by many genes such as BRCA1/2, PTEN, TP53, mTOR, TERT, AKT, PI3K and others genes. Treatment options for BC remain a hurdle, which warrants a comprehensive understanding that establishes an interlinking connection between these genes in BC tumorigenesis. Consequently, there is an increasing demand for alternative treatment approaches and the design of more effective treatments. In this regard, it is crucial to build the corresponding transcriptional regulatory networks governing BC by using advanced genetic tools and techniques. In the past, several molecular editing technologies have been used to edit genes with several limitations. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR Associated Protein 9 (CRISPR/Cas9) recently received wise attention due to its potential in biomedical and therapeutic applications. Here, we review the role of various molecular signalling pathways dysregulated in BC development such as PTEN/PI3K/AKT/mTOR as well as BRCA1/BRCA2/TP53/TERT and their interplay between the related gene networks in BC initiation, progression and development of resistance against available targeted therapeutic agents. Use of CRISPR/Cas9 gene-editing technology to generate BC gene-specific transgenic cell lines and animal models to decipher their role and interactions with other gene products has been employed successfully. Moreover, the significance of using CRISPR/Cas9 technology to develop early BC diagnostic tools and treatments is discussed here.

Differential Reversible and Irreversible Interactions between Benzbromarone and Human Cytochrome P450s 3A4 and 3A5.

Mounting evidence has revealed that despite the high degree of sequence homology between cytochrome P450 3A isoforms (i.e., CYP3A4 and CYP3A5), they have the propensities to exhibit vastly different irreversible and reversible interactions with a single substrate. We have previously established that benzbromarone (BBR), a potent uricosuric agent used in the management of gout, irreversibly inhibits CYP3A4 via mechanism-based inactivation (MBI). However, it remains unelucidated if CYP3A5-its highly homologous counterpart-is susceptible to inactivation by BBR. Using three structurally distinct probe substrates, we consistently demonstrated that MBI was not elicited in CYP3A5 by BBR. Our in silico covalent docking models and molecular dynamics simulations suggested that disparities in the susceptibilities toward MBI could be attributed to the specific effects of BBR covalent adducts on the F-F' loop. Serendipitously, we also discovered that BBR reversibly activated CYP3A5-mediated rivaroxaban hydroxylation wherein apparent V max increased and K m decreased with increasing BBR concentration. Fitting data to the two-site model yielded interaction factors α and ß of 0.44 and 5.88, respectively, thereby confirming heterotropic activation of CYP3A5 by BBR. Furthermore, heteroactivation was suppressed by the CYP3A inhibitor ketoconazole in a concentration-dependent manner and decreased with increasing preincubation time, implying that activation was incited via binding of parent BBR molecule within the enzymatic active site. Finally, noncovalent docking revealed that CYP3A5 can more favorably accommodate both BBR and rivaroxaban in concert as compared with CYP3A4, which further substantiated our experimental observations. SIGNIFICANCE STATEMENT: Although it has been previously demonstrated that benzbromarone (BBR) inactivates CYP3A4, it remains uninterrogated whether it also elicits mechanism-based inactivation in CYP3A5, which shares ∼85% sequence similarity with CYP3A4. This study reported that BBR exhibited differential irreversible and reversible interactions with both CYP3A isoforms and further unraveled the molecular determinants underpinning their diverging interactions. These data offer important insight into differential kinetic behavior of CYP3A4 and CYP3A5, which potentially contributes to interindividual variabilities in drug disposition.