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Abstract The specialised structure of the centromere is critical for effective chromosome segregation, but its repetitive nature makes it vulnerable to rearrangements. Centromere fragility can drive tumorigenesis, but protective mechanisms preventing fragility are still not fully understood. The PBAF chromatin remodelling complex is frequently misregulated in cancer, but its role in cancer is incompletely characterized. Here, we identify PBAF as a protector of centromere and pericentromere structure with profound consequences for genome stability. A conserved feature of isogenic cell lines lacking PBRM1, a subunit of PBAF, is compromised centromere and pericentromere integrity. PBAF is present at these regions, and binding patterns of PBAF and H3K9 methylation change when PBRM1 is absent. PBRM1 loss creates a dependence on the spindle assembly checkpoint, which represents a therapeutic vulnerability. Importantly, we find that even in the absence of any perturbations, PBRM1 loss leads to centromere fragility, thus identifying a key player in centromere protection.

Abstract Background Conventional therapies in cancer treatment face challenges including drug resistance, lack of specificity, and severe adverse reactions. This study explores the potential of liposomal transdermal delivery systems as an alternative to current therapies with improved BA and PK. The objective of the study was to formulate gefitinib liposomes by thin film hydration technique (TFH) using lipoid S100. A central composite design (CCD) was used to develop and optimize GEF-LIP-TDDs and to analyze the optimum concentrations of the selected variables (phospholipid, cholesterol) in liposomal formation. The model fitting was performed using Design-Expert (Stat-Ease, Ver 13). The GEF liposomes were evaluated for %EE, mean particle size and PDI. The optimized liposomes were fabricated as a transdermal patch by mercury substrate method and evaluated for %drug content, in vitro diffusion, in vivo biodistribution (PK and BA), and skin irritation studies in female Albino Wistar rats. The stability of the optimized transdermal patch was also assessed for 3 months. Results The CCD model was significant with F-value of 37.97, P-value of 0.0500 and R 2 of 0.9644. The average vesicle size, PDI, and ZP of GEF-LIPs (F1–F13) were found to be between 112.8 to 373.7 nm, 0.186 to 0.510 and − 3.69 to − 82.2 mV, respectively. F3-GEF-LIP exhibited a mean vesicle size of 96.07 nm, ZP of − 46.06 mV, and a PDI of 0.423. F3-GEF-LIP demonstrated exceptional %EE (97.79) and sustained release effect (%CDR, 83.32) following a diffusion-controlled mechanism. TEM images confirmed liposomes of multivesicular type (MVV,

Abstract Background Inhibition of kinases is the ever-expanding therapeutic approach to various types of cancer. Typically, assessment of the treatment response is accomplished by standard, volumetric imaging procedures, performed weeks to months after the onset of treatment, given the predominantly cytostatic nature of the kinase inhibitors, at least when used as single agents. Therefore, there is a great clinical need to develop new monitoring approaches to detect the response to kinase inhibition much more promptly. Noninvasive 1H magnetic resonance spectroscopy (MRS) can measure in vitro and in vivo concentration of key metabolites which may potentially serve as biomarkers of response to kinase inhibition. Methods We employed mantle cell lymphoma (MCL) cell lines demonstrating markedly diverse sensitivity of inhibition of Bruton’s tyrosine kinase (BTK) regarding their growth and studied in-depth effects of the inhibition on various aspects of cell metabolism including metabolite synthesis using metabolomics, glucose and oxidative metabolism by Seahorse XF technology, and concentration of index metabolites lactate, alanine, total choline and taurine by 1H MRS. Results Effective BTK inhibition profoundly suppressed key cell metabolic pathways, foremost pyrimidine and purine synthesis, the citrate (TCA) cycle, glycolysis, and pyruvate and glutamine/alanine metabolism. It also inhibited glycolysis and amino acid-related oxidative metabolism. Finally, it profoundly and quickly decreased concentration of lactate (a product of mainly glycolysis) and alanine (an indicator of amino acid metabolism) and, less universally total choline both in vitro and in vivo, in the MCL xenotransplant model. The decrease correlated directly with the degree of inhibition of lymphoma cell expansion and tumor growth. Conclusions Our results indicate that BTK inhibition exerts a broad and profound suppressive effect on cell metabolism and that the affected index metabolites such as lactate, alanine may serve as early, sensitive, and reliable biomarkers of inhibition in lymphoma patients detectable by noninvasive MRS-based imaging method. This kind of imaging-based detection may also be applicable to other kinase inhibitors, as well as diverse lymphoid and non-lymphoid malignancies.

Takayasu’s arteritis (TA), also known as Pulseless disease, Aortic arch syndrome, Occlusive thromboaortopathy, or Aortoarteritis, is an inflammatory pan-endarteritis leading to thrombotic occlusion and aneurysm of major arteries. Major challenges for anesthesia in patients with TA involve severe uncontrolled hypertension, end-organ dysfunction, stenosis of major blood vessels, and difficulties in monitoring arterial blood pressure (BP). The cardiovascular complications attributed to the disease can be seriously enhanced during pregnancy. This case series describes the successful anesthetic management of three cases of TA presenting for lower segment cesarean section (LSCS). Each parturient had a unique presentation, necessitating a specific strategy. A sequential combined spinal epidural is an attractive option; however, each case requires thorough evaluation and appropriate management.

Abstract Neuronal differentiation requires building a complex intracellular architecture, and therefore the coordinated regulation of defined sets of genes. RNA-binding proteins (RBPs) play a key role in this regulation. However, while their action on individual mRNAs has been explored in depth, the mechanisms used to coordinate gene expression programs shaping neuronal morphology are poorly understood. To address this, we studied how the paradigmatic RBP IMP1 (IGF2BP1), an essential developmental factor, selects and regulates its RNA targets during the human neuronal differentiation. We perform a combination of system-wide and molecular analyses, revealing that IMP1 developmentally transitions to and directly regulates the expression of mRNAs encoding essential regulators of the microtubule network, a key component of neuronal morphology. Furthermore, we show that m6A methylation drives the selection of specific IMP1 mRNA targets and their protein expression during the developmental transition from neural precursors to neurons, providing a molecular principle for the onset of target selectivity.

Background/objectives: Caesarean delivery (CD), though considered a life-saving surgical procedure, poses a public health problem and puts mothers and babies at higher risk of post-delivery complications. The present study aims to explore the post-delivery maternal complications among CD and normal vaginal delivery (NVD) mothers in India. Methods: The present study is a PAN-India study conducted across various Indian states, considering a significant increase in CD rates. Data was collected from face-to-face interviews of 1407 recently delivered mothers during January–March 2023. Results: The findings indicate that 22 % of CD mothers reported post-delivery complications compared to 15 % of NVD mothers. Notable complications among CD mothers include body/abdominal pain (12.9 %), infection/pain in the suture area (6.2 %), and high blood pressure (1.1 %). Conversely, higher proportion of NVD mothers reported pelvic pain (3.3 %). Further, a greater proportion of NVD (22 %) and CD (28 %) mothers reported pain in the pelvic area and infection/pain in the suture area, respectively. Socio-economic and demographic factors such as age, education, and residence significantly influenced the incidence of self-reported maternal complications. Mothers aged 25 and above, with at least ten years of education, and those residing in urban areas reported higher complications. Additionally, CD mothers also experienced longer hospital stays, higher costs, and delays in breastfeeding initiation. Conclusion: The study underscores the necessity for targeted healthcare interventions to mitigate the specific risks associated with CDs and improve maternal outcomes through appropriate policy formation to address the rising trend of CDs and their implications on maternal health.

In the presence of a newly created brightener, the zinc metal is coated on steel using the electro deposition process. Experiments using hull cells are used to optimize the settings and components of plating baths. Tafel Polarization and EIS techniques were used to conduct corrosion experiments, which made it possible to investigate the brilliant zinc coating's effective corrosion resistance. SEM and Reflectance spectroscopy both confirm that the bright zinc coating has modified surface morphology. XRD analysis is used to study and validate changes in crystallite orientation and phase structure. Electrochemical methods and theoretical molecular dynamic (MD) simulations were used to examine the interaction between Zn and the metal surface. FTIR spectroscopy has been used in blend investigations which impacts on the physical characteristics of polymer blends. The results of these research showed how novel brighteners can improve zinc deposits' brightness and corrosion resistance when applied to mild steel substrates.

Abstract Multidrug resistance-associated protein 2 (MRP2/ABCC2) is a polyspecific efflux transporter of organic anions expressed in hepatocyte canalicular membranes. MRP2 dysfunction, in Dubin-Johnson syndrome or by off-target inhibition, for example by the uricosuric drug probenecid, elevates circulating bilirubin glucuronide and is a cause of jaundice. Here, we determine the cryo-EM structure of rat Mrp2 (rMrp2) in an autoinhibited state and in complex with probenecid. The autoinhibited state exhibits an unusual conformation for this class of transporter in which the regulatory domain is folded within the transmembrane domain cavity. In vitro phosphorylation, mass spectrometry and transport assays show that phosphorylation of the regulatory domain relieves this autoinhibition and enhances rMrp2 transport activity. The in vitro data is confirmed in human hepatocyte-like cells, in which inhibition of endogenous kinases also reduces human MRP2 transport activity. The drug-bound state reveals two probenecid binding sites that suggest a dynamic interplay with autoinhibition. Mapping of the Dubin-Johnson mutations onto the rodent structure indicates that many may interfere with the transition between conformational states.

The F‐box and WD repeat domain containing 7 (FBXW7) tumour suppressor gene encodes a substrate‐recognition subunit of Skp, cullin, F‐box (SCF)‐containing complexes. The tumour‐suppressive role of FBXW7 is ascribed to its ability to drive ubiquitination and degradation of oncoproteins. Despite this molecular understanding, therapeutic approaches that target defective FBXW7 have not been identified. Using genome‐wide clustered regularly interspaced short palindromic repeats (CRISPR)‐Cas9 screens, focussed RNA‐interference screens and whole and phospho‐proteome mass spectrometry profiling in multiple FBXW7 wild‐type and defective isogenic cell lines, we identified a number of FBXW7 synthetic lethal targets, including proteins involved in the response to replication fork stress and proteins involved in replication origin firing, such as cell division cycle 7‐related protein kinase (CDC7) and its substrate, DNA replication complex GINS protein SLD5 (GINS4). The CDC7 synthetic lethal effect was confirmed using small‐molecule inhibitors. Mechanistically, FBXW7/CDC7 synthetic lethality is dependent upon the replication factor telomere‐associated protein RIF1 (RIF1), with RIF1 silencing reversing the FBXW7‐selective effects of CDC7 inhibition. The delineation of FBXW7 synthetic lethal effects we describe here could serve as the starting point for subsequent drug discovery and/or development in this area.

In this article, the vegetative drought prediction employing Deep Learning (DL) models is designed, incorporating rainfall data and NOAA satellite-data-derived Vegetation Health Index (VHI) values spanning 1981–2022. Correspondingly, two DL-oriented models based on Generative Adversarial Networks (GANs): 1) Pix2Pix GAN (P2P) and 2) Bidirectional Convolutional LSTM (BiConvLSTM)-P2P GAN (BiCP2P) are developed over the targeted Region of Interest (ROIs). The assimilation of generative DL models for the application of drought forecasting constitutes a novel investigation and a state-of-the-art approach targeted in this work. Subsequently, the primary ROI designated is peninsular India, and the models. efficacy is validated by implementing it on two more ROIs: the Karnataka and Rajasthan states of India. The proposed models. outcomes are compared with several preferred methodologies quantitatively through Coefficient of Determination (R2 score), Mean Squared Error (MSE), and Mean Absolute Error (MAE) and qualitatively employing drought maps denoting the VHI-based drought severity levels over the ROI. Remarkably, excellent performance is demonstrated by the proposed models over peninsular India, with earned R2 score, MSE, and MAE values of 0.971, 0.0016, and 0.020 for P2P and 0.963, 0.0021, and 0.0239 for BiCP2P, respectively. Moreover, generated drought maps efficiently portrayed the drought severities across the land cover and could potentially be extended further for rapid drought risk assessments. The proposed models functioned outstandingly for the developed datasets on the ROIs, corroborating their potential for similar forecasting applications in other climatic zones, which can aid in better planning and preparedness to tackle natural predicaments such as drought calamity.

Introduction: The pulps of healthy teeth used as abutments for Fixed Partial Dentures (FPD) undergo mechanical and thermal stresses during tooth preparation. The remaining dentin thickness, the heat produced during tooth preparation, and the permeability of dentinal tubules influence the severity of pulpal injury. Prophylactic Root Canal Therapy (RCT) could be an option to provide better outcomes for FPD treatment. Aim: To assess dentists’ perception regarding the need for prophylactic RCT of abutment teeth in FPD through a questionnaire. Materials and Methods: A Questionnaire based Cross-sectional Surve was conducted among 200 dental professionals in the Indian states of Kerala and Maharashtra over a period of two months. The participants included dental professionals from private clinics, dental Institutions, and postgraduate students in these states. The Chi-square test of proportion was performed to assess significant differences between each response. Results: Total 67 out of 200 practitioners, accounting for 33.5%, recommended prophylactic RCT, while 60 (30%) practitioners disagreed with it. A total of 152 (76%) practitioners suggested clinical assessment of abutment teeth before starting the tooth preparation. Total 70 (35%) practitioners had never experienced pulpal damage in abutment teeth in their clinical practice. In contrast, 127 (63.5%) practitioners experienced pulpal damage in less than half of the total cases, and 3 (1.5%) practitioners experienced failures like pulp necrosis or irreversible pulpitis in more than half of the total cases. Conclusion: Total 33.5% of the surveyed dental practitioners recommended prophylactic endodontic treatment for abutment teeth in FPDs. Implementing precise elective RCT guidelines into dental curricula was suggested as a potential avenue to enhance decision-making and improve patient outcomes by reducing the incidence of pulpal damage beneath FPDs.

The demand for accurate, faster, and inexpensive sequencing of deoxyribonucleic acid (DNA) is increasing and is driving the emergence of next-generation sequencing (NGS) technologies. NGS can provide useful insights to help researchers and clinicians to develop the right treatment options. NGS has wide applications in novel fields in biology and medicine. These technologies are of great aid to decode mysteries of life, to improve the quality of crops to detect the pathogens, and also useful in improving life qualities. Thousands to millions of molecules can be sequenced simultaneously in parallel using various NGS methods. NGS can identify and characterize the microbial species more comprehensively than culture-based methods. Recently, the NGS approach has been used for oral microbial analysis.

Abstract The acquisition of antimicrobial resistance (AR) genes has rendered important pathogens nearly or fully unresponsive to antibiotics. It has been suggested that pathogens acquire AR traits from the gut microbiota, which collectively serve as a global reservoir for AR genes conferring resistance to all classes of antibiotics. However, only a subset of AR genes confers resistance to clinically relevant antibiotics, and, although these AR gene profiles are well-characterized for common pathogens, less is known about their taxonomic associations and transfer potential within diverse members of the gut microbiota. We examined a collection of 14,850 human metagenomes and 1666 environmental metagenomes from 33 countries, in addition to nearly 600,000 isolate genomes, to gain insight into the global prevalence and taxonomic range of clinically relevant AR genes. We find that several of the most concerning AR genes, such as those encoding the cephalosporinase CTX-M and carbapenemases KPC, IMP, NDM, and VIM, remain taxonomically restricted to Proteobacteria. Even cfiA, the most common carbapenemase gene within the human gut microbiome, remains tightly restricted to Bacteroides, despite being found on a mobilizable plasmid. We confirmed these findings in gut microbiome samples from India, Honduras, Pakistan, and Vietnam, using a high-sensitivity single-cell fusion PCR approach. Focusing on a set of genes encoding carbapenemases and cephalosporinases, thus far restricted to Bacteroides species, we find that few mutations are required for efficacy in a different phylum, raising the question of why these genes have not spread more widely. Overall, these data suggest that globally prevalent, clinically relevant AR genes have not yet established themselves across diverse commensal gut microbiota.

Abstract Soft tissue sarcomas (STS) are rare and diverse mesenchymal cancers with limited treatment options. Here we undertake comprehensive proteomic profiling of tumour specimens from 321 STS patients representing 11 histological subtypes. Within leiomyosarcomas, we identify three proteomic subtypes with distinct myogenesis and immune features, anatomical site distribution and survival outcomes. Characterisation of undifferentiated pleomorphic sarcomas and dedifferentiated liposarcomas with low infiltrating CD3 + T-lymphocyte levels nominates the complement cascade as a candidate immunotherapeutic target. Comparative analysis of proteomic and transcriptomic profiles highlights the proteomic-specific features for optimal risk stratification in angiosarcomas. Finally, we define functional signatures termed Sarcoma Proteomic Modules which transcend histological subtype classification and show that a vesicle transport protein signature is an independent prognostic factor for distant metastasis. Our study highlights the utility of proteomics for identifying molecular subgroups with implications for risk stratification and therapy selection and provides a rich resource for future sarcoma research.

Abstract Lysine acetylation in histone tails is a key post-translational modification that controls transcription activation. Histone deacetylase complexes remove histone acetylation, thereby repressing transcription and regulating the transcriptional output of each gene. Although these complexes are drug targets and crucial regulators of organismal physiology, their structure and mechanisms of action are largely unclear. Here, we present the structure of a complete human SIN3B histone deacetylase holo-complex with and without a substrate mimic. Remarkably, SIN3B encircles the deacetylase and contacts its allosteric basic patch thereby stimulating catalysis. A SIN3B loop inserts into the catalytic tunnel, rearranges to accommodate the acetyl-lysine moiety, and stabilises the substrate for specific deacetylation, which is guided by a substrate receptor subunit. Our findings provide a model of specificity for a main transcriptional regulator conserved from yeast to human and a resource of protein-protein interactions for future drug designs.

Binding to HSP90-CDC37 is essential for the activity of many protein kinases, but its function is unclear. Here, the authors show that HSP90-CDC37 provides a structural platform for the phosphatase PP5 to dephosphorylate a bound kinase, ‘factory resetting’ it prior to release.

The MuvB family of protein complexes regulate cell cycle-dependent transcription, and MuvB in complex with the transcription factors B-MYB and FOXM1 activate mitotic genes during G2. Here the authors present cryo-EM data of a MuvB:B-MYB (MMB) complex in the process of remodelling a nucleosome, and define its stoichiometry, assembly, and chromatin binding.

Measurement(s) Proteomic Profiling Technology Type(s) Liquid Chromatography Mass Spectrometry Factor Type(s) Palbociclib dosage Sample Characteristic - Organism Homo sapiens Sample Characteristic - Environment cell culture

Aneuploidy results in decreased cellular fitness in many species and model systems. However, aneuploidy is commonly found in cancer cells and often correlates with aggressive growth, suggesting that the impact of aneuploidy on cellular fitness is context dependent. The BRG1 (SMARCA4) subunit of the SWI/SNF chromatin remodelling complex is frequently lost in cancer. Here, the authors show that BRG1 loss can lead to changes that allow tolerance to aneuploidy. This creates a setting where karyotype changes can be explored without a fitness penalty, allowing adaptation to changing environments. This could play an important role in the progression of BRG1 deficient cancers.

Summary: Background: Isoniazid preventive therapy (IPT) initiation during pregnancy was associated with increased incidence of adverse pregnancy outcomes in the TB APPRISE trial. Effects of in utero IPT exposure on infant growth are unknown. Methods: This post-hoc analysis used data from the TB APPRISE trial, a multicentre, double-blind, placebo-controlled trial, which randomised women to 28-week IPT starting in pregnancy (pregnancy-IPT) or postpartum week 12 (postpartum-IPT) in eight countries with high tuberculosis prevalence. Participants were enrolled between August 2014 and April 2016. Based on modified intent-to-treat analyses, we analysed only live-born babies who had at least one follow-up after birth and compared time to infant growth faltering between arms to 12 weeks and 48 weeks postpartum in overall and sex-stratified multivariable Cox proportional hazards regression. Factors adjusted in the final models include sex of infant, mother's baseline BMI, age in years, ART regimen, viral load, CD4 count, education, and household food insecurity. Results: Among 898 HIV-exposed uninfected (HEU) infants, 447 (49.8%) were females. Infants in pregnancy-IPT had a 1.47-fold higher risk of becoming underweight by 12 weeks (aHR 1.47 [95% CI: 1.06, 2.03]) than infants in the postpartum-IPT; increased risk persisted to 48 weeks postpartum (aHR 1.34 [95% CI: 1.01, 1.78]). Maternal IPT timing was not associated with stunting or wasting. In sex-stratified analyses, male infants in the pregnancy-IPT arm experienced an increased risk of low birth weight (LBW) (aRR 2.04 [95% CI: 1.16, 3.68), preterm birth (aRR 1.81 [95% CI: 1.04, 3.21]) and becoming underweight by 12 weeks (aHR 2.02 [95% CI: 1.29, 3.18]) and 48 weeks (aHR 1.82 [95% CI: 1.23, 2.69]). Maternal IPT timing did not influence growth in female infants. Interpretation: Maternal IPT during pregnancy was associated with an increased risk of LBW, preterm birth, and becoming underweight among HEU infants, particularly male infants. These data add to prior TB APPRISE data, suggesting that IPT during pregnancy impacts infant growth, which could inform management, and warrants further examination of mechanisms. Funding: The TB APPRISE study Supported by the National Institutes of Health (NIH) (award numbers, UM1AI068632 [IMPAACT LOC], UM1AI068616 [IMPAACT SDMC], and UM1AI106716 [IMPAACT LC]) through the National Institute of Allergy and Infectious Diseases, with cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contract number, HHSN275201800001I) and the National Institute of Mental Health.

Context: In the absence of any specific treatment available for COVID-19, people started practicing traditional nonpharmacological preventive home remedies such as salt water gargling and steam inhalation. The available research evidence on some of these measures opines that steam inhalation, saline gargling, and povidone-iodine gargling does have virucidal properties and do provide symptomatic relief. Aims: The aim is to test this hypothesis, and the present trial was undertaken with an objective to assess the effect of steam inhalation, saline gargling, and povidone-iodine gargling among the COVID-19-positive patients with respect to early test negativity and clinical recovery. Methodology: Open-labeled, parallel, randomized controlled trial was conducted among asymptomatic or mild COVID-19-positive patients in Bangalore from September 2020 to February 2021. In each group of steam inhalation, saline gargling, povidone-iodine gargling, and control, twenty participants were allocated. Daily follow-up was done for 21 days to assess early test negativity and clinical recovery. Trial Registry Number: Clinical Trial Registry India/2020/09/027687. Results: Among 80 participants recruited, 65 (81.3%) were symptomatic. Early test negativity was seen in povidone-iodine gargling group of 6 days (KaplanMeier survival curve, BreslowGeneralized Wilcoxon test P = 0.7 as per the intention-to-treat and as per-protocol P = 0.8). Significant clinical recovery was seen in saline gargling group (4 days, P = 0.01). Conclusion: Povidone-iodine gargling was effective in providing early test negativity, whereas saline gargling was effective in early clinical recovery.

Introduction: Women play an essential role in health care delivery, and it is vital that they have equal representation in health leadership for equity, innovation, and the strengthening of health systems globally. Yet women remain vastly underrepresented in global health leadership positions, providing a clear example of the deeply rooted power imbalances that are central to the calls to decolonize global health. We conducted a multi-country study in Haiti, Tanzania, India, and the USA to examine gender-based challenges to career advancement for women in the global health workforce. Quantitative data on the type and prevalence of gender-based challenges has been previously reported. In this study, we analyze qualitative data collected through focus group discussions and in-depth interviews to understand women’s experiences of gender-based obstacles to career advancement, their perceptions of underlying drivers, and perspectives on effective solutions. Guided by an adaptation of the Social Action Theory, we conducted focus group discussions and in-depth interviews with women at 4 major academic centers for clinical care and research in Haiti, India, Tanzania, and the United States. In total, 85 women participated in focus groups and 15 also participated in in-depth interviews. Discussions and interviews were conducted in the local language, by an experienced local facilitator unaffiliated with the participating institution, between 2017 and 2018. Discussions were recorded, transcribed, and translated. Data were analyzed by interpretive phenomenological methods for emergent themes. Three transcendent themes on gender-based challenges were identified: 1) cultural power imbalance, referring to the prevailing norms and engrained assumptions that women are less capable than men and that women’s primary responsibility should be to their families; 2) institutional power imbalance, referring to the systematic gender bias upheld by existing leadership and power structures, and ranging from exclusion from career development opportunities to sexual harassment and assault; and 3) restricted agency, referring to women’s limited ability to change their circumstances because of unequal cultural and institutional structures. Participants also described local, actionable solutions to address these barriers. These included: 1) formal reporting systems for sexual harassment and assault; 2) peer support and mentorship; and 3) accessible leadership training and mandatory gender equity training. Participants proposed feasible strategies to address gender-based challenges that could improve women’s retention in health careers and foster their rise to leadership. Increasing the representation of women in global health leadership positions responds directly to efforts to decolonize global health and is integral to strengthening health systems and improving health outcomes for women and children worldwide.

The World Health Organization recommends all pregnant women receive screening for gestational diabetes (GDM) with a fasting oral glucose tolerance test (OGTT). However, very few women receive recommended screening in resource-limited countries like India. We implemented a community health worker (CHW)-delivered program to evaluate if home-based, CHW-delivered OGTT would increase GDM screening in a low-resource setting. We conducted a mixed methods study in two urban slum communities in Pune, India. CHWs were trained to deliver home-based, point-of-care fasting OGTT to women in their third trimester of pregnancy. The primary outcome was uptake of CHW-delivered OGTT. Secondary outcomes included GDM prevalence and linkage to GDM care. Individual interviews were conducted with purposively sampled pregnant women, CHWs, and local clinicians to assess barriers and facilitators of this approach. From October 2021-June 2022, 248 eligible pregnant women were identified. Of these, 223 (90%) accepted CHW-delivered OGTT and 31 (14%) were diagnosed with GDM. Thirty (97%) women diagnosed with GDM subsequently sought GDM care; only 10 (33%) received lifestyle counseling or pharmacologic therapy. Qualitative interviews indicated that CHW-delivered testing was considered highly acceptable as home-based testing saved time and was more convenient than clinic-based testing. Inconsistent clinical management of GDM was attributed to providers' lack of time to deliver counseling, and perceptions that low-income populations are not at risk for GDM. Convenience and trust in a CHW-delivered GDM screening program resulted in high access to gold-standard OGTT screening and identification of a high GDM prevalence among pregnant women in two urban slum communities. Appropriate linkage to care was limited by clinician time constraints and misperceptions of GDM risk. CHW-delivered GDM screening and counseling may improve health education and access to preventive healthcare, offloading busy public clinics in high-need, low-resource settings.

A general limitation in assessing the accuracy of land cover mapping is the availability of ground truth data. At sites where ground truth is not available, potentially inaccurate proxy datasets are used for sub-field-scale resolution investigations at large spatial scales, i.e., in the Contiguous United States. The USDA/NASS Cropland Data Layer (CDL) is a popular agricultural land cover dataset due to its high accuracy (>80%), resolution (30 m), and inclusions of many land cover and crop types. However, because the CDL is derived from satellite imagery and has resulting uncertainties, comparisons to available in situ data are necessary for verifying classification performance. This study compares the cropland mapping accuracies (crop/non-crop) of an optical approach (CDL) and the radar-based crop area (CA) approach used for the upcoming NASA-ISRO Synthetic Aperture Radar (NISAR) L- and S-band mission but using Sentinel-1 C-band data. CDL and CA performance are compared to ground truth data that includes 54 agricultural production and research fields located at USDA’s Beltsville Agricultural Research Center (BARC) in Maryland, USA. We also evaluate non-crop mapping accuracy using twenty-six built-up and thirteen forest sites at BARC. The results show that the CDL and CA have a good pixel-wise agreement with one another (87%). However, the CA is notably more accurate compared to ground truth data than the CDL. The 2017–2021 mean accuracies for the CDL and CA, respectively, are 77% and 96% for crop, 100% and 94% for built-up, and 100% and 100% for forest, yielding an overall accuracy of 86% for the CDL and 96% for CA. This difference mainly stems from the CDL under-detecting crop cover at BARC, especially in 2017 and 2018. We also note that annual accuracy levels varied less for the CA (91–98%) than for the CDL (79–93%). This study demonstrates that a computationally inexpensive radar-based cropland mapping approach can also give accurate results over complex landscapes with accuracies similar to or better than optical approaches.

Significance: Kyasanur forest disease (KFD), a re-emerging tick-borne viral disease, causes severe hemorrhagic fever in humans and nonhuman primates. KFD virus (KFDV) is a member of the genus Flavivirus. KFD is now increasingly reported outside its endemic zone in India. Rapid and specific detection of the KFDV plays a critical role in containment of the outbreak. The diagnosis of KFD currently relies on real-time RT-PCR, nested RT-PCR, end point RT-PCR, and serodiagnostic assay. These assays are tedious, time-consuming, and cannot be used as a routine screening platform. Objective: The present study was aimed to develop a one-step reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay for molecular diagnosis of KFD. Design: The gene amplification reaction was accomplished by incubation at a constant temperature of 63 °C for 60 min. Results: The limit of detection of RT-LAMP assay was 10 copies. KFD RT-LAMP assay was successfully evaluated with diverse host samples including humans, monkeys, and tick. The assay correctly picked up different KFD isolates indicating its applicability for divergent strains. Comparative evaluation of RT-LAMP assay with quantitative TaqMan real-time RT-PCR revealed 100% concordance. No cross-reaction with related flavi and other hemorrhagic fever viruses was observed, indicating its high specificity. Conclusion and relevance: The RT-LAMP test developed in this study will serve as a rapid, sensitive alternate detection method for KFDV infection and would be useful for high throughput screening of clinical samples in resource limited areas during outbreaks.

Multi-omics approaches including proteomics analyses are becoming an integral component of precision medicine. As clinical proteomics studies gain momentum and their sensitivity increases, research on identifying individuals based on their proteomics data is here examined for risks and ethics-related issues. A great deal of work has already been done on this topic for DNA/RNA sequencing data, but it has yet to be widely studied in other omics fields. The current state-of-the-art for the identification of individuals based solely on proteomics data is explained. Protein sequence variation analysis approaches are covered in more detail, including the available analysis workflows and their limitations. We also outline some previous forensic and omics proteomics studies that are relevant for the identification of individuals. Following that, we discuss the risks of patient reidentification using other proteomics data types such as protein expression abundance and post-translational modification (PTM) profiles. In light of the potential identification of individuals through proteomics data, possible legal and ethical implications are becoming increasingly important in the field.

Abstract In the present work, the electrodeposition of Zn–Ni alloy from Sulfate bath was carried out in presence of a novel brightener (CG), the condensation product of Cysteine Hydrochloride and Glutaraldehyde. The corrosion studies were carried out using Electrochemical Impedance spectroscopy and Potentiostatic techniques. They confirmed an increase in corrosion resistance and protection ability of bright zinc–nickel alloy coatings. Surface morphology was studied using SEM, FTIR, and reflectance spectroscopy that revealed fine‐grained nature of Zn‐Ni alloy crystallites. X‐ray diffraction studies were used for phase identification and preferred orientation of Zn–Ni alloy crystallites. The preferred orientation of the Zn‐Ni alloy crystallites along (630) planes was configured for bright appearance of the coating. CG was successful in giving an even, homogeneous, refined, and bright Zn‐Ni alloy deposit.

Abstract COVID-19 has emerged as global pandemic with largest damage to the public health, economy and human psyche.The genome sequence data obtained during the ongoing pandemic are valuable to understand the virus evolutionary patterns and spread across the globe. Increased availability of genome information of circulating SARS-CoV-2 strains in India will enable the scientific community to understand the emergence of new variants and their impact on human health. The first case of COVID-19 was detected in Chambal region of Madhya Pradesh state in mid of March 2020 followed by multiple introduction events and expansion of cases within next three months. More than 5000 COVID-19 suspected samples referred to Defence Research and Development Establishment, Gwalior, Madhya Pradesh were analyzed during the nation -wide lockdown and unlock period. A total of 136 cases were found positive over a span of three months that included virus introduction to the region and its further spread. Whole genome sequences employing Oxford nanopore technology were generated for 26 SARS-CoV-2 circulating in 10 different districts in Madhya Pradesh state of India. This period witnessed index cases with multiple travel histories responsible for introduction of COVID-19 followed by remarkable expansion of virus. The genome wide substitutions including in important viral proteins were identified. The detailed phylogenetic analysis revealed the circulating SARS-CoV-2 clustered in multiple clades including A2a, A4 and B. The cluster-wise segregation was observed, suggesting multiple introduction links and subsequent evolution of virus in the region. This is the first comprehensive whole genome sequence analysis from central India, which revealed the emergence and evolution of SARS-CoV-2 during thenation-wide lockdown and unlock.

Abstract Crimean-Congo hemorrhagic fever (CCHF) virus, a highly pathogenic viral agent is responsible for severe fatal hemorrhagic infections in many parts of the world. The early diagnosis of CCHF infection is important for successful clinical management and epidemiological control. The nucleoprotein (NP) of CCHFV being highly conserved and immunogenic is used as early diagnostic marker. In this study, we report a rapid and sensitive double antibody based antigen capture ELISA to detect Crimean-Congo hemorrhagic fever virus (CCHFV). Highly specific polyclonal and monoclonal antibody against NP has been generated and used as capture and detector antibody respectively. The assay was able to detect viral nucleoprotein in different matrices including human serum, ticks and culture supernatant. The detection limit of the developed sandwich ELISA assay was 25 ng of purified antigen. Comparison with a real time RT-PCR revealed its detection limit to be 1000 genome equivalents of CCHFV. Further the assay was comparatively evaluated with a commercial kit employing gamma irradiated CCHFV, revealing a sensitivity and specificity of 100%. This newly developed sandwich ELISA (sELISA) with high sensitivity and specificity could be used as an efficient method for the detection of CCHF virus in humans, ticks and culture supernatant. The assay will be useful as alternate tool for diagnosis of acute infection and is amenable for screening of large scale samples in resource limited settings.

The photodissociation dynamics of small molecules in the vacuum ultraviolet range can have key implications for astrochemical modelling, but revealing such dynamical details is a challenging task. Here the authors, combining high resolution experimental techniques, provide a detailed description of the fragmentation dynamics of selected rotational levels of a predissociated Rydberg state of H2S.

Necroptosis is a form of cell death characterized by membrane rupture via MLKL oligomerization, although mechanistic details remain unclear. Here, the authors show that MLKL ubiquitylation of K219 facilitates high-order membrane assembly and subsequent rupture, promoting cytotoxicity.

Louise van der Weyden et al. report a CRISPRa screen in mice to identify membrane protein-encoding genes that, when overexpressed, enhance the metastatic potential of melanoma cells. They find that high expression of LRRN4CL in melanoma cells increases lung metastases in mice and correlates with poorer survival in melanoma patients, suggesting it could be a promising drug target.

Understanding the molecular effects of disease variants in relevant tissues is essential to understanding and treating disease. Here, the authors discover expression and protein quantitative trait loci in cartilage and synovium from 115 osteoarthritis patients to pinpoint genes of action and potential drug treatments.

Abstract Background Temperatures in arctic-boreal regions are increasing rapidly and pose significant challenges to moose (Alces alces), a heat-sensitive large-bodied mammal. Moose act as ecosystem engineers, by regulating forest carbon and structure, below ground nitrogen cycling processes, and predator-prey dynamics. Previous studies showed that during hotter periods, moose displayed stronger selection for wetland habitats, taller and denser forest canopies, and minimized exposure to solar radiation. However, previous studies regarding moose behavioral thermoregulation occurred in Europe or southern moose range in North America. Understanding whether ambient temperature elicits a behavioral response in high-northern latitude moose populations in North America may be increasingly important as these arctic-boreal systems have been warming at a rate two to three times the global mean. Methods We assessed how Alaska moose habitat selection changed as a function of ambient temperature using a step-selection function approach to identify habitat features important for behavioral thermoregulation in summer (June–August). We used Global Positioning System telemetry locations from four populations of Alaska moose (n = 169) from 2008 to 2016. We assessed model fit using the quasi-likelihood under independence criterion and conduction a leave-one-out cross validation. Results Both male and female moose in all populations increasingly, and nonlinearly, selected for denser canopy cover as ambient temperature increased during summer, where initial increases in the conditional probability of selection were initially sharper then leveled out as canopy density increased above ~ 50%. However, the magnitude of selection response varied by population and sex. In two of the three populations containing both sexes, females demonstrated a stronger selection response for denser canopy at higher temperatures than males. We also observed a stronger selection response in the most southerly and northerly populations compared to populations in the west and central Alaska. Conclusions The impacts of climate change in arctic-boreal regions increase landscape heterogeneity through processes such as increased wildfire intensity and annual area burned, which may significantly alter the thermal environment available to an animal. Understanding habitat selection related to behavioral thermoregulation is a first step toward identifying areas capable of providing thermal relief for moose and other species impacted by climate change in arctic-boreal regions.

Armfield X-linked disability (XLID) disorder has previously been linked to a locus in Xq28. Here, the authors report rare missense variants in FAM50A at Xq28, show that FAM50A interacts with the spliceosome, and that mis-splicing is enriched in knockout zebrafish suggesting it is a spliceosomopathy.

Cytokines critically control the differentiation and functions of activated naïve and memory T cells. Here the authors show, using multi-omics and single-cell analyses, that naïve and memory T cells exhibit distinct cytokine responses, in which an ‘effectorness gradient’ is depicted by a transcriptional continuum, which shapes the downstream genetic programs.

For the H4 protons of glutamate (Glu), glutamine (Gln), and the glutamyl moiety of glutathione (GSH), the effect of the internal strong scalar coupling between the two nonequivalent H4 protons is far greater than that of the external couplings between the H3 and H4 protons. In this work, the roles of the internal and external scalar coupling terms in the dependence of Glu, Gln, and glutamyl GSH H4 peak amplitudes on the placement of the refocusing pulses of the point resolved spectroscopy sequence were investigated by full density matrix simulations. These strong coupling effects allowed practical and approximately simultaneous maximization of the sensitivity of the spectrally resolved Glu, Gln, and glutamyl GSH H4 pseudo singlets for spatially localized in vivo detection of Glu, Gln, and GSH in the human brain using magnetic resonance spectroscopy at the magnetic field strength of 7 Tesla.

Crimean-Congo hemorrhagic fever (CCHF) is an important tick borne zoonotic viral disease of humans. CCHF virus causes sporadic cases of severe illness across a huge geographic area across Africa to Europe to Asia including India. CCHF has emerged as a major public health concern in western Indian states including Gujarat and Rajasthan, where regular human cases were reported since the year 2011. Human serve as the dead-end host, and they gain infection via infected tick bite, in close contact with ruminants and from slaughter house. Currently, the detection of this fatal infection is limited to BSL-4 laboratory which is scarce even in developed economies. Thus, a safe, sensitive assay for early immunodiagnosis is crucial for disease management and containing the outbreak. In this study, the conserved recombinant nucleoprotein was exploited as a safe, scalable alternate antigen for development of indirect IgM and IgG ELISA detection platform. The indirect ELISA was evaluated using suspected clinical samples collected from hotspot areas in India. Comparison with reference MAC ELISA and IgG ELISA revealed a correlation of 95% and 100% respectively. The results indicate that the developed IgM and IgG indirect ELISA has high sensitivity and specificity for detecting CCHFV antibodies among human. These assays are easy to perform and can be employed for high throughput screening of human samples for clinical diagnosis as well as serosurveillance. These assays are also amenable for conversion to low-cost point of care testing formats for application in resource limited settings.

ABSTRACT Most studies of infections at mucosal surfaces have focused on the acute phase of the disease. Consequently, little is known about the molecular processes that underpin tissue recovery and the long-term consequences postinfection. Here, we conducted temporal deep quantitative proteomic analysis of colonic intestinal epithelial cells (cIECs) from mice infected with the natural mouse pathogen Citrobacter rodentium over time points corresponding to the late steady-state phase (10 days postinfection [DPI]), the clearance phase (13 to 20 DPI), and 4 weeks after the pathogen has been cleared (48 DPI). C. rodentium, which relies on a type III secretion system to infect, is used to model infections with enteropathogenic and enterohemorrhagic Escherichia coli. We observe a strong upregulation of inflammatory signaling and nutritional immunity responses during the clearance phase of the infection. Despite morphological tissue recovery, chromogranin B (ChgB)-positive endocrine cells remained significantly below baseline levels at 48 DPI. In contrast, we observed an increased abundance of proteins involved in antigen processing and presentation 4 weeks after pathogen clearance. In particular, long-term changes were characterized by a persistent interferon gamma (IFN-γ) response and the expression of major histocompatibility complex class II (MHCII) molecules in 60% of the EpCAM+ cIECs, which were not seen in Ifnγ−/− mice. Nonetheless, both wild-type and Ifnγ−/− mice mounted similar systemic and colonic IgG responses to C. rodentium and were equally protected from rechallenge, suggesting that cIEC MHCII is not necessary for protective immunity against C. rodentium. IMPORTANCE Mucosal surfaces respond to infection by mounting an array of metabolic, inflammatory, and tissue repair responses. While these have been well studied during acute infection, less is known about tissue recovery after pathogen clearance. We employ the mouse pathogen Citrobacter rodentium, which binds colonic intestinal epithelial cells (cIECs), to investigate the long-term effects of bacterial infection on gut physiology. Using global proteomic analysis, we study cIEC temporal responses during and after the clearance phase of infection. While the overall tissue morphology recovered, cIECs showed persistent signs of infection 4 weeks after pathogen clearance. These were characterized by a strong IFN-γ signature, including the upregulation of major histocompatibility complex class II (MHCII) antigen presentation proteins, suggesting that the tissue remains on “high alert” for weeks after the acute insult is resolved. However, we demonstrate that cIEC MHCII expression, which is induced by IFN-γ, is not required for protective IgG-mediated immunity against C. rodentium; instead, it may play a role in mucosal recovery.

We report a case of a 73-year-old male, who presented with acute gangrene of the left thumb which then progressed to symmetrical peripheral gangrene of digits of all four limbs, with no comorbid diseases. On investigation, there was high D-dimer, normal lipid profile, and two-dimensional Echo. Computed tomography and magnetic resonance angiogram of all limbs revealed atherosclerotic changes. The patient underwent disarticulation of digits under the wrist block. Symmetrical peripheral gangrene, seen in a wide variety of medical conditions presents as symmetrical gangrene of two or more extremities without large vessel obstruction or vasculitis. The fingers and toes (rarely nose, ear lobes, or genitalia) are affected. It may manifest unpredictably in conditions associated with sepsis, diabetes mellitus, low-output states, vasospastic conditions, myeloproliferative disorders, or hyperviscosity syndrome. It carries a high mortality rate with a very high frequency of multiple limb amputations in survivors.

Abstract Background POLG, located on nuclear chromosome 15, encodes the DNA polymerase γ(Pol γ). Pol γ is responsible for the replication and repair of mitochondrial DNA (mtDNA). Pol γ is the only DNA polymerase found in mitochondria for most animal cells. Mutations in POLG are the most common single-gene cause of diseases of mitochondria and have been mapped over the coding region of the POLG ORF. Results Using PhyloCSF to survey alternative reading frames, we found a conserved coding signature in an alternative frame in exons 2 and 3 of POLG, herein referred to as ORF-Y that arose de novo in placental mammals. Using the synplot2 program, synonymous site conservation was found among mammals in the region of the POLG ORF that is overlapped by ORF-Y. Ribosome profiling data revealed that ORF-Y is translated and that initiation likely occurs at a CUG codon. Inspection of an alignment of mammalian sequences containing ORF-Y revealed that the CUG codon has a strong initiation context and that a well-conserved predicted RNA stem-loop begins 14 nucleotides downstream. Such features are associated with enhanced initiation at near-cognate non-AUG codons. Reanalysis of the Kim et al. (2014) draft human proteome dataset yielded two unique peptides that map unambiguously to ORF-Y. An additional conserved uORF, herein referred to as ORF-Z, was also found in exon 2 of POLG. Lastly, we surveyed Clinvar variants that are synonymous with respect to the POLG ORF and found that most of these variants cause amino acid changes in ORF-Y or ORF-Z. Conclusions We provide evidence for a novel coding sequence, ORF-Y, that overlaps the POLG ORF. Ribosome profiling and mass spectrometry data show that ORF-Y is expressed. PhyloCSF and synplot2 analysis show that ORF-Y is subject to strong purifying selection. An abundance of disease-correlated mutations that map to exons 2 and 3 of POLG but also affect ORF-Y provides potential clinical significance to this finding.

Background: Stenotrophomonas maltophilia, once regarded as an organism of low virulence, has evolved as a significant opportunistic pathogen causing severe human infections in both hospital and community settings, especially among highly debilitated patients. Objectives: (1) Identification of S. maltophilia in sepsis and (2) assessment of sensitivity pattern/minimum inhibitory concentration (MIC) of S. maltophilia and its multidrug resistance by VITEK 2 Compact system and by Kirby–Bauer (KB) disk diffusion method. Materials and Methods: This is a retrospective laboratory-based study analysis conducted in a tertiary care center, i.e., Bangalore Medical College and Research Institute, from July 2018 to June 2019. Samples from clinically suspected sepsis patients were processed by standard microbiological methods. VITEK 2 compact (Biomerieux) was used for final identification and MIC. Antibiotic susceptibility was tested by KB disk diffusion method for cotrimoxazole (1.25/23.75 μg) and levofloxacin (5 μg) following the Clinical and Laboratory Standards Institute guidelines M100. Results: Among 18,949 samples collected from suspected sepsis patients, during a 1-year period, 50 isolates were identified as S. maltophilia. Nineteen were isolated from blood; 6 from pus and ascitic fluid; 4 from cerebrospinal fluid, endotracheal aspirate, and pleural fluid; 1 from urine and cornea; and 4 from other sites. The organisms showed multidrug resistances and were sensitive to trimethoprim-sulfamethoxazole and levofloxacin. Conclusion: S. maltophilia was found to be the third most common nonfermenters after Acinetobacter spp. and Pseudomonas aeruginosa with multidrug resistance. As its isolation is increasing, it is important to study the epidemiology, antimicrobial susceptibility profile, and clinical outcomes of these isolates.

The midbody is an organelle present at the bridge connecting two cells at the end of cell division. Here, the authors use mass spectrometry to define the midbody interactome and uncover a role for PP1 phosphatases in microtubule dynamics and regulation of cytokinesis.

Purpose – Around three million infants die within the first four weeks of life each year – nearly all (98%) of these deaths occur in developing countries. Approximately one million newborns die each year in India. Therefore, this study aims to determine the patterns of reported neonatal morbidity and care-seeking behavior and identify factors associated with it. Design/methodology/approach – A cross-sectional study was conducted during November 2016. A systematic random sampling technique was used to select the sample. Statistical techniques like Binary Logistic regression and chi-square test were used. Findings – The results of the study showed that around 31% mothers of neonates reported that their neonates suffered from some kind of morbidity. Fever, jaundice, cough and cold, the low birth-weight and difficulty in breathing were the most common dangers signs reported. Birth order and mother’s knowledge of neonatal danger signs were found to be significantly associated with reporting of neonatal morbidity. In all 95% of the mothers sought care for their newborns. Among those who had problems, 59% consulted private hospitals/clinics, 30% visited District Hospital/Taluka Hospital or higher facilities and another 9% to Primary Health Centers/Community Health Centers. Further, findings show that nearly half of the neonates taken to government facilities have got free treatment, whereas an average cost of 7,156 INR were recorded for treatment, 935 INR for outpatient department and 13,774 INR for inpatient department cases. Originality/value – There is an urgent need to implement intervention modalities that focus on increasing the level of parental education and access to treatment, and advocating the message regarding newborn danger signs during pregnancy is pinpointed.

Purpose - Caesarean section (CS) is being used as a life-saving surgical tool when complications arise in the process of childbirth. CS rates have dramatically increased across the world, especially in recent decades. In this background, the purpose of this paper is to explore the CS rates and its determinants in Karnataka, India. Design/methodology/approach - The study uses multiple rounds of the District Level Household Survey (DLHS) data to show the trends, differentials and determinants in CS deliveries. Both bivariate and multivariate analyses have been carried out, and the χ2 test and logistic regression models were applied. Findings - Result shows a sharp increase in CS rates across Karnataka; further, this is high and reaches an alarming level in southern parts of the state. Along with a huge rural–urban difference, significant biological and socio-economic differences were observed. Further, a very dramatic increase in the CS rate was observed in private health facilities, whereas it was stagnant or even decreased in public health facilities during recent years. Mothers age at birth, birth weight, birth order, multiple births, birth institution and place of residence were significantly associated with CS delivery. Unlike these biological factors, the social-economic factors like maternal education, caste, religion and below poverty line household were not found to be significant in determining CS deliveries. Originality/value - A strong policy to address the dramatic increase in CS deliveries is the need of the hour. Further, there should be a proper mechanism at national, state and sub-state level to provide appropriate checks and monitoring for CS deliveries which are unnecessary.

Women are significantly more likely to develop tuberculosis (TB) disease within the first 90 days after pregnancy than any other time in their lives. Whether pregnancy increases risk of progression from TB infection (TBI) to TB disease is unknown and is an active area of investigation. In this review, we discuss the epidemiology of TB and TBI in pregnancy, TBI diagnostics, and prevalence in pregnancy. We also review TBI treatment and highlight research priorities, such as short-course TB prevention regimens, drug-resistant TB prevention, and additional considerations for safety, tolerability, and pharmacokinetics that are unique to pregnant and postpartum people.