Anaplastic Large Cell Lymphoma (ALCL) With a Sarcomatoid Variant Presenting As Distributive Shock in a 41-Year-Old Female: A Case Report.

The sarcomatoid variant is considered a rare subtype of anaplastic large cell lymphoma. We present a 40-year-old diabetic female who was evaluated in the ER for distributive shock, requiring vasopressors and mechanical ventilation. An extensive workup was negative for infection. A serial CT scan of the abdomen and pelvis showed evolving lymphadenopathy, and a biopsy revealed malignant anaplastic lymphoma cells with a sarcomatous variant. The oncology team recommended the initiation of inpatient chemotherapy; however, the family opted to proceed with comfort care measures.

Identifying and validating MMP family members (MMP2, MMP9, MMP12, and MMP16) as therapeutic targets and biomarkers in kidney renal clear cell carcinoma (KIRC).

Kidney Renal Clear Cell Carcinoma (KIRC) is a malignant tumor that carries a substantial risk of morbidity and mortality. The MMP family assumes a crucial role in tumor invasion and metastasis. This study aimed to uncover the mechanistic relevance of the MMP gene family as a therapeutic target and diagnostic biomarker in Kidney Renal Clear Cell Carcinoma (KIRC) through a comprehensive approach encompassing both computational and molecular analyses. STRING, Cytoscape, UALCAN, GEPIA, OncoDB, HPA, cBioPortal, GSEA, TIMER, ENCORI, DrugBank, targeted bisulfite sequencing (bisulfite-seq), conventional PCR, Sanger sequencing, and RT-qPCR based analyses were used in the present study to analyze MMP gene family members to accurately determine a few hub genes that can be utilized as both therapeutic targets and diagnostic biomarkers for KIRC. By performing STRING and Cytohubba analyses of the 24 MMP gene family members, MMP2 (matrix metallopeptidase 2), MMP9 (matrix metallopeptidase 9), MMP12 (matrix metallopeptidase 12), and MMP16 (matrix metallopeptidase 16) genes were denoted as hub genes having highest degree scores. After analyzing MMP2, MMP9, MMP12, and MMP16 via various TCGA databases and RT-qPCR technique across clinical samples and KIRC cell lines, interestingly, all these hub genes were found significantly overexpressed at mRNA and protein levels in KIRC samples relative to controls. The notable effect of the up-regulated MMP2, MMP9, MMP12, and MMP16 was also documented on the overall survival (OS) of the KIRC patients. Moreover, targeted bisulfite-sequencing (bisulfite-seq) analysis revealed that promoter hypomethylation pattern was associated with up-regulation of hub genes (MMP2, MMP9, MMP12, and MMP16). In addition to this, hub genes were involved in various diverse oncogenic pathways. The MMP gene family members (MMP2, MMP9, MMP12, and MMP16) may serve as therapeutic targets and prognostic biomarkers in KIRC.

Understanding effective post-test linkage strategies for HIV prevention and care: a scoping review.

INTRODUCTION: Following HIV testing services (HTS), the World Health Organization recommends prompt linkage to prevention and treatment. Scale-up of effective linkage strategies is essential to achieving the global 95-95-95 goals for maintaining low HIV incidence by 2030 and reducing HIV-related morbidity and mortality. Whereas linkage to care including same-day antiretroviral therapy (ART) initiation for all people with HIV is now routinely implemented in testing programmes, linkage to HIV prevention interventions including behavioural or biomedical strategies, for HIV-negative individuals remains sub-optimal. This review aims to evaluate effective post-HTS linkage strategies for HIV overall, and highlight gaps specifically in linkage to prevention. METHODS: Using the five-step Arksey and O'Malley framework, we conducted a scoping review searching existing published and grey literature. We searched PubMed, Cochrane Library, CINAHL, Web of Science and EMBASE databases for English-language studies published between 1 January 2010 and 30 November 2023. Linkage interventions included as streamlined interventions-involving same-day HIV testing, ART initiation and point-of-care CD4 cell count/viral load, case management-involving linkage coordinators developing personalized HIV care and risk reduction plans, incentives-financial and non-financial, partner services-including contact tracing, virtual-like social media, quality improvement-like use of score cards, and peer-based interventions. Outcomes of interest were linkage to any form of HIV prevention and/or care including ART initiation. RESULTS: Of 2358 articles screened, 66 research studies met the inclusion criteria. Only nine linkage to prevention studies were identified (n = 9/66, 14%)-involving pre-exposure prophylaxis, voluntary medical male circumcision, sexually transmitted infection and cervical cancer screening. Linkage to care studies (n = 57/66, 86%) focused on streamlined interventions in the general population and on case management among key populations. DISCUSSION: Despite a wide range of HIV prevention interventions available, there was a dearth of literature on HIV prevention programmes and on the use of messaging on treatment as prevention strategy. Linkage to care studies were comparatively numerous except those evaluating virtual interventions, incentives and quality improvement. CONCLUSIONS: The findings give insights into linkage strategies but more understanding of how to provide these effectively for maximum prevention impact is needed.

Exogenous ascorbic acid as a potent regulator of antioxidants, osmo-protectants, and lipid peroxidation in pea under salt stress.

Pea (Pisum sativum L.), a globally cultivated leguminous crop valued for its nutritional and economic significance, faces a critical challenge of soil salinity, which significantly hampers crop growth and production worldwide. A pot experiment was carried out in the Botanical Garden, The Islamia University of Bahawalpur to alleviate the negative impacts of sodium chloride (NaCl) on pea through foliar application of ascorbic acid (AsA). Two pea varieties Meteor (V1) and Sarsabz (V2) were tested against salinity, i.e. 0 mM NaCl (Control) and 100 mM NaCl. Three levels of ascorbic acid 0 (Control), 5 and 10 mM were applied through foliar spray. The experimental design was completely randomized (CRD) with three replicates. Salt stress resulted in the suppression of growth, photosynthetic activity, and yield attributes in pea plants. However, the application of AsA treatments effectively alleviated these inhibitory effects. Under stress conditions, the application of AsA treatment led to a substantial increase in chlorophyll a (41.1%), chl. b (56.1%), total chl. contents (44.6%) and carotenoids (58.4%). Under salt stress, there was an increase in Na+ accumulation, lipid peroxidation, and the generation of reactive oxygen species (ROS). However, the application of AsA increased the contents of proline (26.9%), endogenous AsA (23.1%), total soluble sugars (17.1%), total phenolics (29.7%), and enzymatic antioxidants i.e. SOD (22.3%), POD (34.1%) and CAT (39%) in both varieties under stress. Salinity reduced the yield attributes while foliarly applied AsA increased the pod length (38.7%), number of pods per plant (40%) and 100 seed weight (45.2%). To sum up, the application of AsA alleviated salt-induced damage in pea plants by enhancing photosynthetic pigments, both enzymatic and non-enzymatic activities, maintaining ion homeostasis, and reducing excessive ROS accumulation through the limitation of lipid peroxidation. Overall, V2 (Sarsabz) performed better as compared to the V1 (Meteor).

Stimulatory effects of smoke solution and biogas digestate slurry application on photosynthesis, growth, and methylation profiling of solanum tuberosum.

Biostimulants are obtained from various sources like plants, animals, microorganisms, and industrial by-products as well as waste material. Their utilization in agriculture practices is being increased that is giving positive results. The purpose of the current study was to use plant-derived smoke (SMK) solution and biogas digestate (BGD) slurry as biostimulant to elucidate their impact on potato (Solanum tuberosum) performance. The experiment was conducted in lab as well as field conditions, and SMK and BGD solutions were prepared in varying concentrations such as SMK 1:500, SMK 1:250, BGD 50:50, and BGD 75:25. Foliar applications were performed thrice during experiments and data were collected related to photosynthesis, growth, pigments, and genome-wide methylation profiling. Net photosynthesis rate (A) and water use efficiency (WUE) were found higher in SMK- and BGD-treated lab and field grown plants. Among pigments, BGD-treated plants depicted higher levels of Chl a and Chl b while SMK-treated plants showed higher carotenoid levels. Alongside, enhancement in growth-related parameters like leaf number and dry weight was also observed in both lab- and field-treated plants. Furthermore, DNA methylation profile of SMK- and BGD-treated plants depicted variation compared to control. DNA methylation events increased in all the treatments compared to control except for SMK 1:500. These results indicate that smoke and slurry both act as efficient biostimulants which result in better performance of plants. Biostimulants also affected the genome-wide DNA methylation profile that resultantly might have changed the plant gene expression profiling and played its role in plant responsiveness to these biostimulants. However, there is need to elucidate a possible synergistic effect of SMK and BGD on plant growth along with gene expression profiling.

Evaluation of granular formulated strigolactone analogs for Striga suicidal germination.

BACKGROUND: Striga hermonthica, an obligate root parasitic weed, poses significant threat to cereal production in sub-Saharan Africa. Lowering Striga seed bank in infested soils is a promising strategy to mitigate infestation levels. The dependency of Striga seed germination on strigolactones opens up the possibility of a "suicidal germination" approach, where synthetic germination stimulants induce lethal germination in the absence of a host. Implementing this approach requires active germination stimulants with a suitable formulation for field application. Here, we describe the development of slow-releasing granular formulation of two potent germination stimulants 'Methyl Phenlactonoate 3' and 'Nijmegen-1' and the assessment of their activity under Lab, greenhouse, mini-field, and field conditions. RESULTS: Under laboratory conditions, the granular formulation of either of the two germination stimulants (1.25 mg per plate, corresponding to 0.09 mg a.i.) induced Striga seed germination at a rate of up to 43%. With 10 mg granular product (0.75 mg a.i.) per pot, we observed 77-83% reduction in Striga emergence under greenhouse pot conditions. Application of the formulated stimulants under artificially or naturally infested fields resulted in approximately 56%, 60%, and 72% reduction in Striga emergence in maize, sorghum, and millet fields in Kenya and Burkina Faso, respectively. CONCLUSION: Our findings on the newly designed granular formulation of Methyl Phenlactonoate 3 and Nijmegen-1 reveal encouraging prospects for addressing the Striga problem in Africa. These findings underscore several significant advantages of the formulated stimulants, including suitability for the African agricultural context, and, most importantly, their effectiveness in reducing Striga infection. This article is protected by copyright. All rights reserved.

Geochemical and mineralogical characteristics of shales from the early to middle Permian Dohol Formation in Peninsular Malaysia: Implications for organic matter enrichment, provenance, tectonic setting, palaeoweathering and paleoclimate.

The early to middle Permian Dohol Formation is characterized by a significant presence of shale deposits. While these shales exhibit a low potential to generate hydrocarbons, there is a need to ascertain the possible reasons for the low hydrocarbon generation potential. Also, there are several unidentified properties and attributes associated with these shales in terms of their inorganic geochemical characteristics and their mineralogy. This study is focused on using XRF, ICPMS, and SEM with EDX to determine the mineralogical and geochemical characteristics of these shales and use these data to discuss their provenance history and tectonic setting and interpret the paleoclimatic and paleoweathering conditions. The inorganic geochemical analysis shows that the shales from the Dohol Formation are from a felsic igneous source. The shales were also identified to be from a passive margin based on the bivariate plot of SiO2 vs log (K2O/Na2O) and several multidimensional diagram plots. The CIA and CIW data, as well as the A-CN-K plot, all point to a significant degree of chemical weathering, ranging from mild to intense. The Sr/Cu ratio and C-value, combined with various other geochemical proxies, indicate that the shales were formed in warm-humid climatic conditions. The SEM analysis shows that the samples are mainly composed of kaolinite and illite, and this result was supported by the EDX elemental composition. The high terrigenous influx of sediments, the oxic to sub-oxic conditions in which the sediments were deposited, and finally low marine productivity were found to be the reasons for the low TOC in the shales from the Dohol Formation.

Inoculation of heavy metal resistant bacteria alleviated heavy metal-induced oxidative stress biomarkers in spinach (Spinacia oleracea L.).

Most vegetable crops are severely affected by the uptake of heavy metals from the soil. Heavy metals in vegetable bodies generate reactive oxygen species (ROS) that unbalance the antioxidant defense system. This study was initiated to determine the physiological and biochemical characteristics of spinach plants grown on soil contaminated with heavy metals and responding to Bacillus cereus and Bacillus aerius were isolated from soil contaminated with heavy metals. Heavy metal contamination led to a significant reduction in seed germination, seedling biomass, protein, and total nitrogen content of spinach plants grown in contaminated soils compared to control soils. In contrast, a significant increase in the content of metallothioneins and antioxidant enzymes was observed. Plants inoculated with B. cereus and B. aerius significantly reduced the oxidative stress induced by heavy metals by improving seed germination (%), seedling growth, nitrogen, and protein content. The content of metallothioneins and the activities of antioxidant enzymes were reduced in spinach plants grown from seeds inoculated with bacterial strains. In addition, plants inoculated with, B. cereus and B. aerius showed greater stomata opening than plants grown on soil contaminated with heavy metals, whose stomata were almost closed. These results suggested that both bacterial strains enhanced plant growth by reducing oxidative stress caused by metals.

Exploring water-absorbing capacity: a digital image analysis of seeds from 120 wheat varieties.

Wheat is a staple food crop that provides a significant portion of the world's daily caloric intake, serving as a vital source of carbohydrates and dietary fiber for billions of people. Seed shape studies of wheat typically involve the use of digital image analysis software to quantify various seed shape parameters such as length, width, area, aspect ratio, roundness, and symmetry. This study presents a comprehensive investigation into the water-absorbing capacity of seeds from 120 distinct wheat lines, leveraging digital image analysis techniques facilitated by SmartGrain software. Water absorption is a pivotal process in the early stages of seed germination, directly influencing plant growth and crop yield. SmartGrain, a powerful image analysis tool, was employed to extract precise quantitative data from digital images of wheat seeds, enabling the assessment of various seed traits in relation to their water-absorbing capacity. The analysis revealed significant transformations in seed characteristics as they absorbed water, including changes in size, weight, shape, and more. Through statistical analysis and correlation assessments, we identified robust relationships between these seed traits, both before and after water treatment. Principal Component Analysis (PCA) and Agglomerative Hierarchical Clustering (AHC) were employed to categorize genotypes with similar trait patterns, providing insights valuable for crop breeding and genetic research. Multiple linear regression analysis further elucidated the influence of specific seed traits, such as weight, width, and distance, on water-absorbing capacity. Our study contributes to a deeper understanding of seed development, imbibition, and the crucial role of water absorption in wheat. These insights have practical implications in agriculture, offering opportunities to optimize breeding programs for improved water absorption in wheat genotypes. The integration of SmartGrain software with advanced statistical methods enhances the reliability and significance of our findings, paving the way for more efficient and resilient wheat crop production. Significant changes in wheat seed shape parameters were observed after imbibition, with notable increases in area, perimeter, length, width, and weight. The length-to-width ratio (LWR) and circularity displayed opposite trends, with higher values before imbibition and lower values after imbibition.

Exploring the Diagnostic and Prognostic Predictive Values of Ferroptosis- Related Markers in Lung Adenocarcinoma.

BACKGROUND: Lung Adenocarcinoma (LUAD), a common and aggressive form of lung cancer, poses significant treatment challenges due to its low survival rates. AIM: To better understand the role of ferroptosis driver genes in LUAD, this study aimed to explore their diagnostic and prognostic significance, as well as their impact on treatment approaches and tumor immune function in LUAD. METHOD: To accomplish the defined goals, a comprehensive methodology incorporating both in silico and wet lab experiments was employed. A comprehensive analysis was conducted on a total of 233 ferroptosis driver genes obtained from the FerrDB database. Utilizing various TCGA databases and the RT-qPCR technique, the expression profiles of 233 genes were examined. Among them, TP53, KRAS, PTEN, and HRAS were identified as hub genes with significant differential expression. Notably, TP53, KRAS, and HRAS exhibited substantial up-regulation, while PTEN demonstrated significant down-regulation at both the mRNA and protein levels in LUAD samples. The dysregulation of hub genes was further associated with poor overall survival in LUAD patients. Additionally, targeted bisulfite-sequencing (bisulfite-seq) analysis revealed aberrant promoter methylation patterns linked to the dysregulation of hub genes. RESULT & DISCUSSION: Furthermore, hub genes were found to participate in diverse oncogenic pathways, highlighting their involvement in LUAD tumorigenesis. By leveraging the diagnostic and prognostic potential of ferroptosis driver hub genes (TP53, KRAS, PTEN, and HRAS), significant advancements can be made in the understanding and management of LUAD pathogenesis. CONCLUSION: Therapeutic targeting of these genes using specific drugs holds great promise for revolutionizing drug discovery and improving the overall survival of LUAD patients.

Country uptake of WHO recommendations on differentiated HIV testing services approaches: a global policy review.

OBJECTIVES: In 2015 and 2016, WHO issued guidelines on HIV testing services (HTS) highlighting recommendations for a strategic mix of differentiated HTS approaches. The policy review examines the uptake of differentiated HTS approaches recommendations in national policies. METHODS: Data were extracted from national policies published between January 2015 and June 2019. The WHO-recommended HTS approaches included facility-based testing, community-based testing, HIV self-testing and provider-assisted referral (or assisted partner notification). Other supportive recommendations include pre-test information, post-test counselling, lay provider testing and rapid testing. Descriptive analyses were conducted to examine inclusion of recommendations in national policies. RESULTS: Of 194 countries worldwide, 65 published policies were identified; 24 WHO Africa region (AFR) countries (51%, 24/47), 21 WHO European region (EUR) (40%, 21/53), 6 WHO Eastern Mediterranean region (EMR) (29%, 6/21), 5 Pan-American region (AMR) (14%, 5/35), 5 Western Pacific Region (WPR) (19%, 5/27) and 4 WHO South East Asia Region (SEAR) (36%, 4/11). Only five countries included all recommendations. 63 included a minimum of one. 85% (n=55) included facility-based testing for pregnant women, 75% (n=49) facility-based testing for key populations, 74% (n=48) community-based testing for key populations, 69% (n=45) rapid testing, 57% (n=37) post-test counselling, 45% (n=29) lay provider testing, 38% (n=25) HIV self-testing, 29% (n=19) pre-test information and 25% (n=16) provider-assisted referral. The proportion in each region that included at least one recommendation were: 100% AFR (24/47), 100% EMR (6/6), 100% AMR (5/5), 100% WPR (5/5), 100% SEAR (4/4) and 95% EUR (20/21). AFR followed by EMR included the highest number of reccomendations. CONCLUSION: There was substantial variability in the uptake of the WHO-differentiated HTS recommendations. Those in EMR included the most WHO-differentiated HTS recommendation followed by AFR. Countries within AMR included the least number of recommendations. Ongoing advocacy and efforts are needed to support the uptake of the WHO-differentiated HTS recommendations in country policies as well as their implementation.

Bone morphogenetic protein 1: a prognostic indicator and potential biomarker in three cancer types.

BACKGROUND: Bone morphogenetic protein 1 (BMP1) is a metalloprotease that plays a role in activating both transforming growth factor-ß (TGF-ß) and BMP signaling pathways. TGF-ß has been identified as a factor initiating and facilitating cancer development. Consequently, we propose the hypothesis that dysregulation of BMP1 could potentially contribute to the onset and advancement of human cancers. METHODS: In this research, we aimed to analyze BMP1 expression level and the associated clinical outcomes across various cancers using online cancer OMICS databases, advanced Bioinformatics tools, and molecular analyses. RESULTS: The outcomes of our web server-based expression analysis indicated an up-regulation of BMP1 in a majority of the human cancers examined. External validation using clinical samples also showed higher expression of BMP1. Moreover, heightened BMP1 expression exhibited a noteworthy correlation with reduced overall survival (OS) duration in Bladder Cancer (BLCA), Kidney Renal Clear Cell Carcinoma (KIRC), and Lung Adenocarcinoma (LUAD) patients. This suggests a substantial involvement of the BMP1 gene in the development and progression of these three types of cancers. The major signaling pathways related with BMP1 enriched genes were "ECM-receptor interaction, Amoebiasis, Focal adhesion, Protein digestion and absorption, progesterone-mediated, PI3K-Akt signaling pathway, and platelet activation". Moreover, we also explored some interesting correlations among BMP1 expression and its DNA promoter methylation level, CD8+ T immune cells level, and genetic variations. CONCLUSION: In conclusion, our study has provided some solid basis for BMP1 to be used as a reliable common biomarker for BLCA, KIRC, and LUAD patients.

Double edge resolving set and exchange property for nanosheet structure.

The exploration of edge metric dimension and its applications has been an ongoing discussion, particularly in the context of nanosheet graphs formed from the octagonal grid. Edge metric dimension is a concept that involves uniquely identifying the entire edge set of a structure with a selected subset from the vertex set, known as the edge resolving set. Let's consider two distinct edge resolving sets, denoted as Re1 and Re2, where Re1≠Re2. In such instances, it indicates that the graph G possesses a double-edge resolving set. This implies the existence of two different subsets of the vertex set, each capable of uniquely identifying the entire edge set of the graph. In this article, we delve into the edge metric dimension of nanosheet graphs derived from the octagonal grid. Additionally, we initiate a discussion on the exchange property associated with the edge resolving set. The exchange property holds significance in the study of resolving sets, playing a crucial role in comprehending the structure and properties of the underlying graph.

The role of microRNAs in defining LSECs cellular identity and in regulating F8 gene expression.

Introduction: Coagulation Factor VIII (FVIII) plays a pivotal role in the coagulation cascade, and deficiencies in its levels, as seen in Hemophilia A, can lead to significant health implications. Liver sinusoidal endothelial cells (LSECs) are the main producers and contributors of FVIII in blood, a fact we have previously elucidated through mRNA expression profiling when comparing these cells to other endothelial cell types. Methods: Our current investigation focuses on small microRNAs, analyzing their distinct expression patterns across various endothelial cells and hepatocytes. Results: The outcome of this exploration underscores the discernible microRNAs expression differences that set LSECs apart from both hepatocytes (193 microRNAs at p < 0.05) and other endothelial cells (72 microRNAs at p < 0.05). Notably, the 134 and 35 overexpressed microRNAs in LSECs compared to hepatocytes and other endothelial cells, respectively, shed light on the unique functions of LSECs in the liver. Discussion: Our investigation identified a panel of 10 microRNAs (miR-429, miR-200b-3p, miR-200a-3p, miR-216b-5p, miR-1185-5p, miR-19b-3p, miR-192-5p, miR-122-5p, miR-30c-2-3p, and miR-30a-5p) that distinctly define LSEC identity. Furthermore, our scrutiny extended to microRNAs implicated in F8 regulation, revealing a subset (miR-122-5p, miR-214-3p, miR-204-3p, and miR-2682-5p) whose expression intricately correlates with F8 expression within LSECs. This microRNA cohort emerges as a crucial modulator of F8, both directly through suppression and indirect effects on established F8-related transcription factors. The above microRNAs emerged as potential targets for innovative therapies in Hemophilia A patients.

Impact of HIV self-testing for oral pre-exposure prophylaxis scale-up on drug resistance and HIV outcomes in western Kenya: a modelling study.

BACKGROUND: Community-based oral pre-exposure prophylaxis (PrEP) provision has the potential to expand PrEP coverage. HIV self-testing can facilitate PrEP community-based delivery but might have lower sensitivity than facility-based HIV testing, potentially leading to inappropriate PrEP use among people with HIV and subsequent development of drug resistance. We aimed to evaluate the impact of HIV self-testing use for PrEP scale-up. METHODS: We parameterised an agent-based network model, EMOD-HIV, to simulate generic tenofovir disoproxil fumarate and emtricitabine PrEP scale-up in western Kenya using four testing scenarios: provider-administered nucleic acid testing, provider-administered rapid diagnostic tests detecting antibodies, blood-based HIV self-testing, or oral fluid HIV self-testing. Scenarios were compared with a no PrEP counterfactual. Individuals aged 18-49 years with one or more heterosexual partners who screened HIV-negative were eligible for PrEP. We assessed the cost and health impact of rapid PrEP scale-up with high coverage over 20 years, and the budget impact over 5 years, using various HIV testing modalities. FINDINGS: PrEP coverage of 29% was projected to avert approximately 54% of HIV infections and 17% of HIV-related deaths among adults aged 18-49 years over 20 years; health impacts were similar across HIV testing modalities used to deliver PrEP. The percentage of HIV infections with PrEP-associated nucleoside reverse transcriptase inhibitor (NRTI) drug resistance was 0·6% (95% uncertainty intervals 0·4-0·9) in the blood HIV self-testing scenario and 0·8% (0·6-1·0) in the oral HIV self-testing scenario, compared with 0·3% (0·2-0·3) in the antibody rapid diagnostic testing scenario and 0·2% (0·1-0·2) in the nucleic acid testing scenario. Accounting for background NRTI resistance, we found similarly low proportions of drug resistance across scenarios. The budget impact of implementing PrEP using HIV self-testing and provider-administered rapid diagnostic tests were similar, while nucleic acid testing was approximately 50% more costly. INTERPRETATION: Scaling up PrEP using HIV self-testing has similar health impacts, costs, and low risk of drug resistance as provider-administered rapid diagnostic tests. Policy makers should consider leveraging HIV self-testing to expand PrEP access among those at HIV risk. FUNDING: The Bill and Melinda Gates Foundation.

Deciphering DNA repair gene mutational landscape in uterine corpus endometrial carcinoma patients using next generation sequencing.

Uterine Corpus Endometrial Carcinoma (UCEC) is a significant health concern with a complex genetic landscape impacting disease susceptibility and progression. This study aimed to unravel the spectrum of DNA repair gene mutations in Pakistani UCEC patients through Next Generation Sequencing (NGS) and explore their potential functional consequences via downstream analyses. NGS analysis of genomic DNA from 30 UCEC patients was conducted to identify clinically significant pathogenic mutations in DNA repair genes. This analysis revealed mutations in 4 key DNA repair genes: BRCA1, BRCA2, APC, and CDH1. Kaplan-Meier (KM) analysis was employed to assess the prognostic value of these mutations on patient overall survival (OS) in UCEC. To delve into the functional impact of these mutations, we performed RT-qPCR, immunohistochemistry (IHC), and western blot analyses on the mutated UCEC samples compared to their non-mutated counterparts. These results unveiled the up-regulation in the expression of the mutated genes, suggesting a potential association between the identified mutations and enhanced gene activity. Additionally, targeted bisulfite sequencing analysis was utilized to evaluate DNA methylation patterns in the promoters of the mutated genes. Strikingly, hypomethylation in the promoters of BRCA1, BRCA2, APC, and CDH1 was observed in the mutated UCEC samples relative to the non-mutated, indicating the involvement of epigenetic mechanisms in the altered gene expression. In conclusion, this study offers insights into the genetic landscape of DNA repair gene mutations in Pakistani UCEC patients. The presence of pathogenic mutations in BRCA1, BRCA2, APC, and CDH1, coupled with their down-regulation and hypermethylation, suggests a convergence of genetic and epigenetic factors contributing to genomic instability in UCEC cells. These findings enhance our understanding of UCEC susceptibility and provide potential avenues for targeted therapeutic interventions in Pakistani UCEC patients.

Acute-on-Chronic Liver Failure: Causes, Clinical Parameters, and Predictors of Mortality.

Objectives This study aimed to identify the causes, clinical characteristics, and 28-day in-hospital mortality predictors in patients with acute-on-chronic liver failure (ACLF). Methods A cross-sectional study enrolled sixty-four patients aged 18-70 years with acute-on-chronic liver failure. The study was conducted at the Gastroenterology Department, Lahore General Hospital. The study classified ACLF according to the criteria of the European Association for the Study of the Liver - Chronic Liver Failure (EASL-CLIF). Patients were followed for 28 days for mortality outcomes. The outcomes between Survivor and Non-survivor groups were compared using the Chi-Square/Fisher's Exact Test for categorical variables and the Mann-Whitney U test for continuous variables. Results In this study, age and duration of chronic liver disease were not significantly different between survivors and non-survivors. The etiology of liver disease and ACLF causes had no impact on 28-day mortality. Non-survivors had lower mean arterial pressure, and higher mortality was linked with lower Glasgow Coma Scale scores, upper gastrointestinal bleeding, and Grade IV hepatic encephalopathy. Significant differences in bilirubin, serum creatinine, urea, and C-reactive protein levels were observed at 28 days. Survival rates were highest with single organ failure (35.94%) and decreased with multiple organ failures. The overall survival rate was 51.56%. Predictive validity for mortality was assessed using the Area Under the Curve (AUC), with Child-Turcotte-Pugh (CTP) at 0.679, Model for End-Stage Liver Disease (MELD) at 0.819, and Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) at 0.771. Conclusion This study concludes that in acute-on-chronic liver failure, factors like age, gender, and disease etiology do not significantly predict 28-day mortality. Key mortality indicators include clinical parameters such as lower Glasgow Coma Scale scores, hepatic encephalopathy Grade IV, and laboratory findings like elevated bilirubin and serum creatinine. The MELD score is the most compelling prognostic tool.

Comparison of the Efficacy of Two-Week Vonoprazan Versus Lansoprazole-Based Quadruple Sequential Antibiotic Therapy in Eradicating Helicobacter pylori Infection: A Non-randomized Clinical Trial.

AIM: The prevalence of Helicobacter pylori is escalating in developing countries, exacerbated by unjustified antibiotic usage, which leads to increased resistance. This trend has been notably amplified since the COVID-19 pandemic. Consequently, the effectiveness of existing eradication regimens has been compromised. This study aimed to compare the efficacy of two weeks of vonoprazan-based quadruple sequential therapy and lansoprazole-based quadruple sequential therapy in treating H. pylori infection.  Methods: A non-randomized clinical trial was conducted over 18 months at the Department of Gastroenterology, Lahore General Hospital, Lahore, Pakistan. It included patients presenting with dyspepsia, as defined by the Rome IV criteria, and who tested positive on the urea breath test. Patients were divided into two groups, i.e., Group A and Group B. Group A patients received lansoprazole 30 mg + amoxicillin + tinidazole + tab. colloidal bismuth subcitrate for the first seven days, followed by lansoprazole + levofloxacin + azithromycin + colloidal bismuth subcitrate. Group B patients received vonoprazan + amoxicillin + tinidazole + colloidal bismuth subcitrate for the first seven days, followed by vonoprazan + levofloxacin + azithromycin + colloidal bismuth subcitrate. Both regimes continued for 14 days. Four weeks after 14 days of the treatment, an early morning urea breath test was conducted to evaluate the efficacy of the treatment. Patients were scheduled for follow-up visits at seven and 14 days post-treatment initiation to record adverse events and assess compliance with the treatment regimen. Patients who lost the follow-up and remained non-compliant to the medications were excluded from the final data analysis as per standard protocols of the per-protocol analysis.  Results: A total of 252 patients were included. In Group A and Group B, 6/126 (4.76%) and 8/126 (6.35%) of the patients were lost to follow-up, respectively. The non-compliance rate in Group A was 5/126 (3.97%), compared to Group B with 3/126 (2.38%). Finally, the per-protocol analysis of the results included 115 patients in each group. Baseline characteristics, including demographics, lifestyle, and clinical factors, were comparable between groups with p-values of 0.138 for age, 0.356 for gender, 0.126 for BMI, 0.495 for residence, 0.500 for water source, 0.866 for meal habit, 0.863 for smoking, 0.188 for nonsteroidal anti-inflammatory drug (NSAID) use, 0.145 for proton pump inhibitor (PPI) use, 0.213 for antibiotics, and 0.456 for treatment history. Both treatments effectively eradicated H. pylori, as determined by a negative urea breath test at four weeks post-treatment, with Group B showing a higher eradication rate of 96.5% compared to 92.2% in Group A, although the difference was not statistically significant (p = 0.153). There was no difference in adverse effects in both treatment groups (p-value > 0.05).  Conclusion: The study found that while the vonoprazan-based regime exhibited a slightly higher eradication rate of H. pylori compared to lansoprazole, the difference was not statistically significant. It was concluded that both regimens demonstrated comparable efficacy and similar profiles of adverse effects in treating H. pylori infection.

Strigolactone biosynthesis in rice can occur via a 9-cis-3-OH-10'-apo-ß-carotenal intermediate.

Strigolactones (SLs) play a crucial role in regulating plant architecture and mediating rhizosphere interactions. They are synthesized from all-trans-ß-carotene converted into the intermediate carlactone (CL) via the intermediate 9-cis-ß-apo-10'-carotenal. Recent studies indicate that plants can also synthesize 3-OH-CL from all-trans-ß-zeaxanthin via the intermediate 9-cis-3-OH-ß-apo-10'-carotenal. However, the question of whether plants can form bioactive SLs from 9-cis-3-OH-ß-apo-10'-carotenal remains elusive. In this study, we supplied the 13 C-labeled 9-cis-3-OH-ß-apo-10'-carotenal to rice seedlings and monitored the synthesis of SLs using liquid chromatography-mass spectrometry (LC-MS) and Striga bioassay. We further validated the biological activity of 9-cis-3-OH-ß-apo-10'-carotenal-derived SLs using the ccd7/d17 SL-deficient mutant, which demonstrated increased Striga seed-germinating activity and partial rescue of tiller numbers and plant height. Our results establish 9-cis-3-OH-ß-apo-10'-carotenal as a significant SL biosynthetic intermediate with implications for understanding plant hormonal functions and potential applications in agriculture.

Abscisic acid inhibits germination of Striga seeds and is released by them likely as a rhizospheric signal supporting host infestation.

Seeds of the root parasitic plant Striga hermonthica undergo a conditioning process under humid and warm environments before germinating in response to host-released stimulants, particularly strigolactones (SLs). The plant hormone abscisic acid (ABA) regulates different growth and developmental processes, and stress response; however, its role during Striga seed germination and early interactions with host plants is under-investigated. Here, we show that ABA inhibited Striga seed germination and that hindering its biosynthesis induced conditioning and germination in unconditioned seeds, which was significantly enhanced by treatment with the SL analog rac-GR24. However, the inhibitory effect of ABA remarkably decreased during conditioning, confirming the loss of sensitivity towards ABA in later developmental stages. ABA measurement showed a substantial reduction of its content during the early conditioning stage and a significant increase upon rac-GR24-triggered germination. We observed this increase also in released seed exudates, which was further confirmed by using the Arabidopsis ABA-reporter GUS marker line. Seed exudates of germinated seeds, containing elevated levels of ABA, impaired the germination of surrounding Striga seeds in vitro and promoted root growth of a rice host towards germinated Striga seeds. Application of ABA as a positive control caused similar effects, indicating its function in Striga/Striga and Striga/host communications. In summary, we show that ABA is an essential player during seed dormancy and germination processes in Striga and acts as a rhizospheric signal likely to support host infestation.