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Abstract Aerobic vaginitis (AV) is a recently defined vaginal recurring infection, which is treated with antibiotics. However, excessive and prolonged use of antibiotics disrupts healthy vaginal microflora and leads to the emergence of antibiotic resistance among pathogens. This situation has directed researchers to explore alternative antimicrobials. The current study describes in vitro and in vivo antimicrobial efficacy and pharmaceutical interactions between plant essential oils (EOs) and five lactic acid bacteria (LABs), isolated from the healthy vagina, against E. faecalis, one of the major etiological agents of AV. In vitro experiments confirm good antimicrobial activity of both plant EOs and cell free supernatant (CFS) from LABs. Based on high antimicrobial efficacy, Moringa essential oil (MO) was selected to determine its nature of interaction with CFS of five LAB strains. Synergism was recorded between MO and CFS of L. reuteri (MT180537). To validate in vitro findings, prophylactic responses of individual and synergistic application of MO and L. reuteri (MT180537) were evaluated in an E. faecalis (MW051601) induced AV murine model. The prophylactic efficacy was evidenced by a reduction in intensity of clinical symptoms, E. faecalis (MW051601) count per vaginal tissue along with a reduction in AV associated changes in histological markers of infection in animals receiving Moringa essential oil and L. reuteri (MT180537) alone or in combination. However, significant synergism between Moringa essential oil and L. reuteri (MT180537) could not be observed. Our data confirms the importance of in vivo experiments in deducing pharmacological interactions.

Tacrolimus (TAC) is an immunosuppressive drug, optimally used for liver, kidney, and heart transplant to avoid immune rejection. In retrospect, a multitude of studies have reported effects of TAC, such as nephrotoxicity, diabetes, and other complications. However, limited information is available regarding short-term exposure of TAC on the liver. Therefore, the present study was designed to unravel the effects of short-term exposure of TAC on a rat model. The animal model was established by TAC administration for 6, 12, 24, and 48 h time points. Liver histopathological changes were observed with PAS-D, reticulin stain, and immunostaining of PCNA and CK-7 coupled with glycogen quantification in a liver homogenate. TUNEL assay was performed to evaluate the DNA damage in the liver. Concentration of GSH and activities of SOD and CAT in the serum were measured to assess the antioxidant status, whereas liver tissue MDA level was measured as a biomarker of oxidative stress. Hepatic gene expression analysis of IL-10, IL-13, SOCS-2, and SOCS-3 was performed by RT-PCR. Results revealed marked changes in liver architecture of all TAC-treated groups, as evidenced by sinusoid dilation, hepatocyte derangement, glycogen deposition, and collapsed reticulin fibers. Significant increase in PCNA and CK-7 immunostaining along with the presence of TUNEL-positive cells was revealed in treatment groups as compared to the control group. Serum antioxidant enzyme status was markedly decreased, whereas the liver MDA level was increased in TAC treatment groups indicating oxidative stress induction. The gene expression profile of cytokines was significantly upregulated in treatment groups highlighting an inflammatory response. In conclusion, results of the current study propose that even a short-term TAC exposure can induce change in antioxidant status and lipid peroxidation. Therefore, these factors should be considered to avoid and minimize immunosuppression-related issues in a prolonged course of treatment.

Artificial Intelligence (AI) and Machine Learning (ML) are transforming drug discovery by overcoming traditional challenges like high costs, time-consuming, and frequent failures. AI-driven approaches streamline key phases, including target identification, lead optimization, de novo drug design, and drug repurposing. Frameworks such as deep neural networks (DNNs), convolutional neural networks (CNNs), and deep reinforcement learning (DRL) models have shown promise in identifying drug targets, optimizing delivery systems, and accelerating drug repurposing. Generative adversarial networks (GANs) and variational autoencoders (VAEs) aid de novo drug design by creating novel drug-like compounds with desired properties. Case studies, such as DDR1 kinase inhibitors designed using generative models and CDK20 inhibitors developed via structure-based methods, highlight AI's ability to produce highly specific therapeutics. Models like SNF-CVAE and DeepDR further advance drug repurposing by uncovering new therapeutic applications for existing drugs. Advanced ML algorithms enhance precision in predicting drug efficacy, toxicity, and ADME-Tox properties, reducing development costs and improving drug-target interactions. AI also supports polypharmacology by optimizing multi-target drug interactions and enhances combination therapy through predictions of drug synergies and antagonisms. In nanomedicine, AI models like CURATE.AI and the Hartung algorithm optimize personalized treatments by predicting toxicological risks and real-time dosing adjustments with high accuracy. Despite its potential, challenges like data quality, model interpretability, and ethical concerns must be addressed. High-quality datasets, transparent models, and unbiased algorithms are essential for reliable AI applications. As AI continues to evolve, it is poised to revolutionize drug discovery and personalized medicine, advancing therapeutic development and patient care., Competing Interests: Declaration of competing interest Authors declare NIL conflict of Interest., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Coagulation factor XII (FXII) conveys various functions as an active protease that promotes thrombosis and inflammation, and as a zymogen via surface receptors like urokinase-type plasminogen activator receptor (uPAR). While plasma levels of FXII are increased in diabetes mellitus and diabetic kidney disease (DKD), a pathogenic role of FXII in DKD remains unknown. Here we show that FXII is locally expressed in kidney tubular cells and that urinary FXII correlates with kidney dysfunction in DKD patients. F12-deficient mice (F12 -/- ) are protected from hyperglycemia-induced kidney injury. Mechanistically, FXII interacts with uPAR on tubular cells promoting integrin β1-dependent signaling. This signaling axis induces oxidative stress, persistent DNA damage and senescence. Blocking uPAR or integrin β1 ameliorates FXII-induced tubular cell injury. Our findings demonstrate that FXII-uPAR-integrin β1 signaling on tubular cells drives senescence. These findings imply previously undescribed diagnostic and therapeutic approaches to detect or treat DKD and possibly other senescence-associated diseases., (© 2024. The Author(s).)

Achalasia is a chronic and rare disorder of esophageal motility. It is characterized by spastic or absent esophageal contractions and impairment of relaxation of the lower esophageal sphincter. Treatment modalities include smooth muscle-relaxing medications, botulinum toxin injections to lower the esophageal sphincter, pneumatic dilatation, and surgical interventions. Pneumatic dilatation is deemed to be an effective treatment option and is the most widely used non-surgical intervention. We designed this prospective study to look for any possible correlation between balloon pressure used in pneumatic dilatation, manometric findings, and patient characteristics. And to find any possible association between the need for repeat pneumatic dilatations and factors like gender, age, duration of symptoms, Eckardt score, daily retrosternal pain, manometric findings, and balloon pressures. Thirty-one patients with confirmed achalasia were enrolled in the study. All of these patients underwent pneumatic dilatation. Pearson's correlation coefficient was found to be 0.234 (p-value 0.23) between the required balloon pressure and integrated relaxation pressure (IRP). Six of these patients required repeat pneumatic dilatations. No statistically significant association was noted between the need for repeat intervention and gender, age over 40, age under 20, Eckardt score over 10, daily chest pain, duration of symptoms over two years, and IRP over 30 mmHg. In conclusion, it could be said that pneumatic dilatation does not carry a 100% success rate, and repeat sessions are needed in many of the patients with achalasia. So, long-term follow-up is crucial. Managing expectations and making a realistic plan with proper informational care is important at the beginning of treatment., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Research Forum, RMU and allied hospitals, Rawalpindi, Pakistan. issued approval R-59/RMU. The research proposal titled, ''Correlation of Balloon Pressure Used for Pneumatic Dilatation in Achalasia with Manometric Findings'' conforms to the accepted ethical standards established by institutional research forum. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Furrukh et al.)

Purpose: Urdu is the lingua franca and national language of Pakistan, and is the 10th most-spoken language worldwide with over 230 million speakers. The Urdu phonological system has been examined over the past decades. However, the system has been evolving. This paper aimed to review the available studies investigating various aspects of the Urdu phonological system and to reveal the variations noted among these studies., Method: Twenty-one studies examining the phonological system of Urdu were located. The studies were reviewed in terms of consonants, geminates, consonant clusters, vowels, diphthongs, syllable structure, phonotactic constraints, and stress., Result: The findings indicated that 38 consonants, 23 vowels, and 15 diphthongs are used in contemporary Urdu. Most consonants exist as geminates word medially. There are six syllable structures. The consonant clusters are constrained to the coda position only, and short vowels cannot exist in the word-final position. Like other syllable-timed languages, stress is not prominent in Urdu., Conclusion: Based on this review, a contemporary Urdu phonemic and syllable structure inventory has been proposed. This will serve as a reference for use in further acquisition research and clinical practice.

Alzheimer's disease (AD) presents a complex pathology involving amyloidogenic proteolysis, neuroinflammation, mitochondrial dysfunction, and cholinergic deficits. Oxidative stress exacerbates AD progression through pathways like macromolecular peroxidation, mitochondrial dysfunction, and metal ion redox potential alteration linked to amyloid-beta (Aβ). Despite limited approved medications, heterocyclic compounds have emerged as promising candidates in AD drug discovery. This review highlights recent advancements in synthetic heterocyclic compounds targeting oxidative stress, mitochondrial dysfunction, and neuroinflammation in AD. Additionally, it explores the potential of nanomaterial-based drug delivery systems to overcome challenges in AD treatment. Nanoparticles with heterocyclic scaffolds, like polysorbate 80-coated PLGA and Resveratrol-loaded nano-selenium, show improved brain transport and efficacy. Micellar CAPE and Melatonin-loaded nano-capsules exhibit enhanced antioxidant properties, while a tetra hydroacridine derivative (CHDA) combined with nano-radiogold particles demonstrates promising acetylcholinesterase inhibition without toxicity. This comprehensive review underscores the potential of nanotechnology-driven drug delivery for optimizing the therapeutic outcomes of novel synthetic heterocyclic compounds in AD management. Furthermore, the inclusion of various promising heterocyclic compounds with detailed ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) data provides valuable insights for planning the development of novel drug delivery treatments for AD., Competing Interests: Declaration of Competing Interest None, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Early pregnancy nutritional status can be associated with adverse birth outcomes such as small-for-gestational age (SGA) and low birth weight (LBW). BMI (Body Mass Index) and MUAC (Mid-upper arm circumference) are easy to use assessments and are indicative of the pre-pregnancy nutritional status if obtained in the first trimester. This study primarily assesses the association of maternal nutritional status using BMI and MUAC with SGA in a community-based cohort of Pakistani women. It also aims to determine the predictive ability of MUAC and BMI in predicting SGA. Secondarily, we assessed the association between maternal nutrition and large for gestational age (LGA) and LBW., Methods: This study is a secondary analysis of an ongoing pregnancy cohort "Pregnancy Risk Infant Surveillance and Measurement Alliance (PRISMA)"in Ibrahim Hyderi and Rehri Goth, Karachi. PRISMA participants who were enrolled between January 2021 to August 2022 were included given they had a gestational age < 14 weeks confirmed via ultrasound, MUAC and BMI measurements were available and birth weight was captured within 72 hours. Multivariable logistic regression was used to determine an association between maternal nutritional status and SGA. The PRISMA study was approved by the Aga Khan University Ethics Review Committee (2021-5920-15,518)., Results: Of 926 women included in the analysis, 26.6% (n = 247) had a low MUAC (< 23 cm) while 18.4% (n = 171) were underweight (BMI < 18.5 kg/m2). Nearly one third of low MUAC and underweight women delivered SGA infants (34.4 and 35.1% respectively). Underweight women and women with low MUAC had a statistically significant association with SGA (Underweight: OR 1.49, 95% CI 1.1,2.4; Low MUAC-OR 1.64, 95% CI 1.2,2.3) as well as LBW (Underweight: OR-1.63, 95% CI 1.1,2.4; Low MUAC-OR-1.63, 95% CI 1.2,2.3). ROC curves showed that MUAC and BMI had modest predictability for SGA (AUC < 0.7)., Conclusion: Maternal nutritional status as indicated by BMI and MUAC are strongly associated with adverse pregnancy outcomes including SGA, LGA and LBW. Although MUAC and BMI are widely used to determine maternal nutritional status, they have poor predictive ability for newborn size. Further research is needed to identify other tools or a combination of tools to better predict adverse birth outcomes in resource-limited settings and plan interventions., (© 2024. The Author(s).)

Introduction Discharge summaries (DS) allow continued patient care after being discharged from the hospital. Only a few quality improvement projects (QIPs) focused on assessing and improving the quality and completeness of DS at tertiary care hospitals have been undertaken in Pakistan. This QIP aimed to evaluate and enhance the quality and completeness of DS at a tertiary care hospital in Pakistan to facilitate seamless healthcare transitions. Methods A QIP was conducted in the medical unit of a tertiary care hospital in Rawalpindi, Pakistan. The DS were assessed using the e-discharge summary self-assessment checklist devised by the Royal College of Physicians (RCP). This QIP was done by the plan, do, study, act (PDSA) cycle. The PDSA cycle comprised two audit cycles and an intervention in between them. The first audit cycle (AC) was conducted on 150 DS. Its duration was from March 2023 to June 2023. An educational workshop was conducted before the re-audit cycle (RAC) to address deficiencies and reinforce the implementation of the guidelines provided by the RCP. The RAC was conducted from June 2023 to August 2023. 100 DS were studied and analyzed to assess for improvement in the completeness of DS. Frequencies and percentages were calculated in each audit cycle. The Chi-squared test was applied to compare the statistical difference between the results of both audit cycles. Results A total of 150 DS were analyzed in the first AC and 100 DS in the RAC. The results of the first AC show that the details of any allergies were recorded only in 3% of the DS; this percentage significantly improved to 51% after the RAC (p-value <0.05). Relevant past medical history was included in 52% and 88% of the DS during the first AC and RAC, respectively (p-value <0.05). Secondary diagnoses were written in 54% and 71% of the DS during the first AC and RAC, respectively (p-value <0.05). Details of relevant investigations were included in 60% and 88% of the DS during the first AC and RAC, respectively (p-value <0.05). The post-discharge management plan was written in 90% and 98% of the DS during the first AC and RAC, respectively (p-value <0.05). The follow-up plan was written clearly in 65% and 93% of the DS during the first AC and RAC, respectively (p-value <0.05).  Conclusion The DS was found to be incomplete after analyzing the results of the first AC. The details related to allergies, medications, operations, and procedures were found to be missing in the majority of the cases. No mention of the patient's concerns or expectations was made in the DS. The results of the RAC showed improvement in the level of completeness of DS. The majority of the weak points observed after the first AC seemed to have improved after the RAC, which shows that intervention proved to be quite effective in improving the completeness and quality of DS. The RAC showed significant improvement in the completeness of the details relating to investigations, allergies, past medical history, secondary diagnoses, and the post-discharge follow-up plan. QIP must be routinely carried out to assess and improve the completeness and quality of DS at hospitals., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Fazal et al.)

Introduction Bacterial meningitis (BM) is a neurologic emergency mainly affecting children under the age of two. Clinical symptoms are rarely evident in children, thus making a diagnosis is a challenge. Antibiotic therapy should be started timely to ensure the avoidance of significant morbidity and mortality. This study aims to assess the outcomes, mortality, and symptomatology of children presenting with BM in allied hospitals of Rawalpindi Medical University, Pakistan. Methods It is a cross-sectional study employing a sample size of 201, conducted at the Allied Hospitals of Rawalpindi Medical University, Pakistan from a period of January 2023 to August 2023. Non-probability convenience sampling was used. Children aged between newborns and 14 years of age with a confirmed diagnosis of bacterial meningitis were included in this study. The study population was divided into five different age groups. Three different outcomes were studied including complete recovery, development of complications, and death. Data was entered into and analyzed by Statistical Package for the Social Sciences (SPSS) version 25 (IBM Corp., Armonk, NY, USA). Descriptive statistics were applied to the demographic data. The chi-square analytical test was applied to study the association between the categorical variables. Results One hundred nineteen (59.2%) of the study's population were males. One hundred twenty-six (62.7%) of the patients were born through a spontaneous vaginal delivery (SVD). The majority (54%) of the study population were infants. Twenty-three percent were newborns, 13% were toddlers, 6% were preschool children, and 4% were school-age children. The majority (85%) of the study participants belonged to lower socioeconomic backgrounds. Ninety percent of the cases had symptoms of fever, seizures, and poor feeding. Neck stiffness was significantly associated with death as an outcome (p-value=0.01). The overall mortality amongst the study population was 20%. Forty-nine percent of the study population recovered completely, whereas 31% had complications following the diagnosis. Neonates had a higher mortality rate than infants (45% vs 9% respectively). Conclusion The most common presenting symptoms were fever, vomiting, seizures, and neck stiffness. Poor feeding was also seen in most cases. The rate of complications and death is observed to be relatively higher following the diagnosis of bacterial meningitis as compared to rates in the surrounding and developed countries. Out of all signs and symptoms, the presence of neck stiffness was significantly associated with death as an outcome among children with bacterial meningitis., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Zarak Khan et al.)

Objective The study aims to evaluate the effectiveness of a professionalism program by conducting focus group discussions (FGDs). The research focuses on understanding how the program influences the development of professionalism skills among medical students, as well as their perceptions and experiences regarding the program. The study's objectives revolve around identifying the strengths and weaknesses of the program from the perspective of the students. Methods This was a qualitative study done after obtaining approval from the Institutional Review Committee, Islamic International Medical College. Students of 4th year Bachelor of Medicine and Bachelor of Surgery (MBBS; 56 students) were selected for the study. A convenience sampling technique was used to select the participants for FGDs. Seven separate FGDs were conducted, with eight participants in each group. All the FGDs were audiotaped. Data were transcribed and translated. Data were analyzed using the thematic analysis on Atlas. Both obvious and hidden content were analyzed. Codes and themes were identified, which were then finalized with consensus. Codes were then categorized into sub-themes, and finally, themes were generated. Results Participants identified the problems associated with applying professionalism during FGDs. These challenges encompassed hefty workloads and a perceived disparity between theoretical knowledge and practical implementation. The students highlighted the importance of practical teaching methods, the cultivation of role models, the alignment of curriculum with real-world experiences, and the revision of assessment methods. This study analyzes the obstacles and potential advantages associated with professionalism education and presents significant perspectives on improving it for upcoming healthcare practitioners. Conclusion Professionalism is a crucial component, and each graduate of a medical school should be fully qualified as a professional after graduation. As we want our future doctors to be skilled at both professional qualities and diagnosis, it is crucial that medical institutions teach professionalism., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Amin et al.)

Cancer stem cells (CSCs) have become a key player in the growth of tumors, the spread of cancer, and the resistance to therapeutic interventions. Targeting these elusive cell populations has the potential to fundamentally alter cancer treatment plans. CSCs, also known as tumor-initiating cells (TICs), are thought to play a role in both medication resistance and cancer recurrence. This is explained by their capacity to regenerate themselves and change into different kinds of cancer cells. Due to their higher expression of ATP-binding cassette (ABC) membrane transporters, enhanced epithelial to mesenchymal (EMT) characteristics, improved immune evasion, activation of survival signaling pathways, and improved DNA repair mechanisms, CSCs exhibit extraordinary resistance to therapies. This comprehensive analysis delves into advancements in the domain of Targeted Cancer Stem Cell Therapeutics, concentrating on unraveling the distinctive traits of CSCs and the therapeutic methods devised to eliminate them., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives: To determine the association between maternal exposure to intimate partner violence (IPV) and child stunting using the Demographic Health Survey (DHS) data comparing four South Asian countries., Design: A secondary analysis., Setting: Data from the seventh round of the DHS data of four South Asian countries; Pakistan, Nepal, India and Maldives., Participants: Married women of reproductive age (15-49 years) from each household were randomly selected, having at least one child less than 5 years of age for whom all anthropometric measures were available., Outcome Measure: The exposure variable was maternal IPV including, sexual violence, physical violence or both. The outcome variable was moderate or severe stunting, measured based on the height-for-age Z-score of children aged 6-59 months old . Multiple Cox proportional regression analyses were used separately on each country's data to determine the association between maternal IPV and child stunting., Results: The prevalence of IPV among women ranged from 10.17% in the Maldives to 31% in India. The burden of child stunting was the lowest in the Maldives at 14.04% and the highest in Pakistan at 35.86%. The number of severely stunted children was the highest in Pakistan (16.60%), followed by India (14.79%). In India, children whose mothers were exposed to IPV showed a 7% increase in the prevalence of moderate to severe child stunting (OR 1.07; 95% CI 1.01 to 1.14). Additionally, in Nepal, severe stunting was strongly associated with the prevalence of physical IPV (OR 1.66; 95% CI 1.01 to 2.87)., Conclusion: Our study findings suggest that maternal exposure to IPV is associated with child stunting. Further research investigating the relationship between IPV and child outcomes using improved and advanced statistical analyses can provide substantial evidence to enhance public awareness and potentially reduce the burden of child stunting in South Asian countries., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Tissue factor (TF), which is a member of the cytokine receptor family, promotes coagulation and coagulation-dependent inflammation. TF also exerts protective effects through unknown mechanisms. Here, we showed that TF bound to interferon-α receptor 1 (IFNAR1) and antagonized its signaling, preventing spontaneous sterile inflammation and maintaining immune homeostasis. Structural modeling and direct binding studies revealed binding of the TF C-terminal fibronectin III domain to IFNAR1, which restricted the expression of interferon-stimulated genes (ISGs). Podocyte-specific loss of TF in mice (Pod ΔF3 ) resulted in sterile renal inflammation, characterized by JAK/STAT signaling, proinflammatory cytokine expression, disrupted immune homeostasis, and glomerulopathy. Inhibiting IFNAR1 signaling or loss of Ifnar1 expression in podocytes attenuated these effects in Pod ΔF3 mice. As a heteromer, TF and IFNAR1 were both inactive, while dissociation of the TF-IFNAR1 heteromer promoted TF activity and IFNAR1 signaling. These data suggest that the TF-IFNAR1 heteromer is a molecular switch that controls thrombo-inflammation., Competing Interests: Declaration of interests The authors J.M. and B.I. have applied for a patent related to this work., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Increasing global temperatures due to climate change have raised serious concerns regarding its potential impact on health outcomes. Pregnant women and their fetuses are among the most vulnerable groups being affected by these dramatic changes resulting in adverse outcomes for both the mother and the developing fetus. Evidence regarding heat-related pregnancy adversities in high-income countries is conclusive, however, such evidence is rare in low- and middle-income countries (LMICs). This review was conducted to bridge the knowledge gap by providing evidence-based insights into the specific repercussions of high heat exposures during pregnancy and its effect on birth outcomes in LMICs. A systematic review was conducted to assess the impact of high environmental or ambient temperatures on pregnancy outcomes (abortion, stillbirth, preterm birth, and low birthweight (LBW)) in LMICs. Electronic searches were conducted on MEDLINE, Embase, CINAHL, Web of Science, and Scopus. Observational studies published between 2010 and 2023 were included in the review. Screening of studies was done using Covidence software, data was extracted on Excel sheets and quality assessment was done using the National Institutes of Health's National Heart, Lung, and Blood Institute tool. We included 11 studies. Four of six studies that included preterm births showed an association between heat and preterm births. Four of five studies reported an association between heat exposure and LBW. Three of four studies on stillbirths showed a significant association between heat exposure and stillbirths. One of the two studies that reported spontaneous abortion revealed a significant association of heat with abortion. Meta-analysis could not be performed due to the lack of homogeneity in defining heat exposure. Amongst the included studies, seven were categorized as "good" and four were categorized as "fair" on methodological quality. This study concluded that ambient temperature and heat exposure during pregnancy can impact birth outcomes such as preterm births, LBWs, abortions, and stillbirths in LMICs. Urgent action is imperative on both national and global scales to facilitate a comprehensive and definitive assessment of heat exposure in LMICs, enabling a deeper understanding of its repercussions on pregnant women. Longitudinal studies are paramount for confirming these associations and devising targeted interventions and strategies aimed at enhancing maternal and child health within LMIC contexts. Registration: PROSPERO ID: CRD42023449173.

Disputes about the probable availability of safe water and the efficacy of processed wastewater are key issues that necessitate a suitable solution to enhance the quality of clean water. The current research emphasizes the synthesis of ZnSe-reduced graphene oxide nanocomposites (ZnSe:rGO) with different weight ratios of rGO (represented as X = 0.6, 1 and 1.6 g)via one-step hydrothermal method. The photocatalytic performance for the degradation of methyl violet (MV) dye was investigated under visible light irradiation by varying the reaction parameters. The crystal structure, elemental composition, surface functionality and morphology of the synthesized ZnSe-XrGO nanocomposites were estimated by powder X-ray diffraction (XRD), energy dispersive X-ray spectroscopy (EDX), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopic (SEM) techniques. UV-visible spectroscopy was used to investigate the optical properties. The highest efficiency is obtained for ZnSe-XrGO in 1:1 and it showed pseudo 1st order behavior with rate constant of 0.0167min -1 and 94 % photodegradation of MV in just 3 h. Furthermore, hazardous effects of MV were investigated on the germination and growth of Zea mays seeds by giving them aqueous solution of MV (0, 8, 12, 24 and 48 ppm) and the decontaminated water after photodegradation of MV with the synthesized photoactive composite. The results showed profound negative effect on both germination and seedling growth at higher concentration (>12 ppm) of the dye solution. No hazardous effects were observed on both these parameters when it was given the dye degraded water which reflects the practical use of the synthesized catalyst for water remediation. The current study fulfills the goal of designing an efficient visible-light active nano-photocatalyst and its direct applicability on life sciences for water purification., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

Conjugated linoleic acid (CLA) is perceived to protect the body from metabolic diseases. This study was conducted to determine the effect of Lactiplantibacillus plantarum ( Lp. plantarum ) on CLA production and sensory characteristics of cheddar cheese. Lp. plantarum can convert linoleic acid (LA) to CLA. To increase CLA in cheddar cheese and monitor the conversion of LA to CLA by Lp. plantarum , the LA content of cheese milk (3.4% fat) was increased by partially replacing fat with safflower oil (85% LA of oil) at 0, 3, 6, and 9% concentrations (T 1 , T 2 , T 3 , and T 4 ). Furthermore, Lp. plantarum 10 8 colony-forming units (CFU)/mL (8 log CFU mL -1 ) was added in all treatments along with traditional cheddar cheese culture ( Lactococcus lactis ssp. lactis and L. lactis ssp. cremoris ). After 30 days of ripening, Lp. plantarum in T 1 , T 2 , T 3 , and T 4 was 6.75, 6.72, 6.65, and 6.55 log CFU g -1 . After 60 days of ripening, Lp. plantarum in T 1 , T 2 , T 3 , and T 4 was 6.35, 6.27, 6.19, and 6.32 log CFU g -1 . After 60 days of ripening, Lp. plantarum in T 1 , T 2 , T 3 , and T 4 was 6.41, 6.25, 6.69, and 6.65 log CFU g -1 . GC-MS analysis showed that concentrations of CLA in the 90 days' control, T 1 , T 2 , T 3 , and T 4 were 1.18, 2.73, 4.44, 6.24, and 9.57 mg/100 g, respectively. HPLC analysis revealed that treatments containing Lp. plantarum and LA presented higher concentrations of organic acids than the control sample. The addition of safflower oil at all concentrations did not affect cheese composition, free fatty acids (FFA), and the peroxide value (POV) of cheddar cheese. Color flavor and texture scores of experimental cheeses were not different from the control cheese. It was concluded that Lp. plantarum and safflower oil can be used to increase CLA production in cheddar cheese.

A variety of foods fermented with lactic acid bacteria (LAB) serve as dietary staples in many countries. The incorporation of health-promoting probiotics into fermented milk products can have profound effects on human health. Considering the health benefits of Yakult, the current study was undertaken to develop an enriched Yakult-like fermented skimmed milk drink by the addition of two probiotic strains, namely Lacticaseibacillus casei (Lc) and Lacticaseibacillus rhamnosus (Lr). The prepared drinks were compared in terms of various parameters, including their physicochemical properties, proximate chemical composition, mineral estimation, microbial viable count, antioxidant activity, and sensory evaluation. Each strain was employed at five different concentrations, including 1% (T 1 ), 1.5% (T 2 ), 2% (T 3 ), 2.5% (T 4 ), and 3% (T 5 ). The prepared Yakult samples were stored at 4 °C and analyzed on days 0, 7, 14, 21, and 28 to evaluate biochemical changes. The findings revealed that the concentration of the starter culture had a significant ( p ≤ 0.05) impact on the pH value and moisture and protein contents, but had no marked impact on the fat or ash content of the developed product. With the Lc strain, Yakult's moisture content ranged from 84.25 ± 0.09 to 85.65 ± 0.13%, whereas with the Lr strain, it was from 84.24 ± 0.08 to 88.75 ± 0.13%. Protein levels reached their highest values with T 5 (3% concentration). The acidity of all treatments increased significantly due to fermentation and, subsequently, pH showed a downward trend ( p ≤ 0.05). The total soluble solids (TSS) content decreased during storage with Lc as compared to Lr, but the presence of carbohydrates had no appreciable impact. The drink with Lc exhibited a more uniform texture and smaller pore size than Yakult with Lr. Except for the iron values, which showed an increasing trend, the contents of other minerals decreased in increasing order of the added probiotic concentration used: 1% (T 1 ), 1.5% (T 2 ), 2% (T 3 ), 2.5% (T 4 ), and 3% (T 5 ). The highest lactobacilli viable count of 8.69 ± 0.43 colony-forming units (CFU)/mL was observed with the T 1 Lr-containing drink at the end of the storage period. Regarding the storage stability of the drink, the highest value for DPPH (88.75 ± 0.13%) was found with the T 1 Lc drink on day 15, while the highest values for FRAP (4.86 ± 2.80 mmol Fe 2+ /L), TPC (5.97 ± 0.29 mg GAE /mL), and TFC (3.59 ± 0.17 mg GAE /mL) were found with the T 5 Lr drink on day 28 of storage. However, the maximum value for ABTS (3.59 ± 0.17%) was noted with the T 5 Lr drink on the first day of storage. The results of this study prove that Lc and Lr can be used in dairy-based fermented products and stored at refrigerated temperatures.

Alzheimer's disease (AD) has been recognized as the most important cause of dementia, which is estimated to contribute more than 2 trillion USD in medical costs. AD patients encounter progressive neurodegenerative dementia associated with behavioural, linguistic, and visuospatial deficits. Although studies on the discovery of amyloid β (Aβ) and tau (the essential elements of plaques and tangles in AD) have shed light on the molecular pathological processes of AD, the exact cause of the condition is still largely unknown. The involvement of various proteins, such as amyloid-β, prion protein, tau, and α-synuclein has been linked to AD pathogenesis. The current AD treatments are mainly based on symptomatic management and restoration of neurotransmitters' balance. There is a significant need to develop medications that can alter the underlying disease process and prevent its progression. The present manuscript provides a review of various hypotheses that have been proposed for AD pathogenesis. The manuscript has also explored the development of novel anti-AD drugs based on various pathogenic pathways, which are recently under various clinical trial phases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Oils derived from plant sources, mainly fixed oils from seeds and essential oil from other parts of the plant, are gaining interest as they are the rich source of beneficial compounds that possess potential applications in different industries due to their preventive and therapeutic actions. The essential oils are used in food, medicine, cosmetics, and agriculture industries as they possess antimicrobial, anticarcinogenic, anti-inflammatory and immunomodulatory properties. Plant based oils contain polyphenols, phytochemicals, and bioactive compounds which show high antioxidant activity. The extractions of these oils are a crucial step in terms of the yield and quality attributes of plant oils. This review paper outlines the different modern extraction techniques used for the extraction of different seed oils, including microwave-assisted extraction (MAE), pressurized liquid extraction (PLE), cold-pressed extraction (CPE), ultrasound-assisted extraction (UAE), supercritical-fluid extraction (SFE), enzyme-assisted extraction (EAE), and pulsed electric field-assisted extraction (PEF). For the identification and quantification of essential and bioactive compounds present in seed oils, different modern techniques-such as high-performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS), Fourier transform infrared spectroscopy (FTIR), gas chromatography-infrared spectroscopy (GC-IR), atomic fluorescence spectroscopy (AFS), and electron microscopy (EM)-are highlighted in this review along with the beneficial effects of these essential components in different in vivo and in vitro studies and in different applications. The primary goal of this research article is to pique the attention of researchers towards the different sources, potential uses and applications of oils in different industries.

Even with healthy foods, there is still a need to protect the functionality during processing. The stabilization and enrichment of fish oil (FO) extracted from fish fillets using solvent extraction might make this healthy oil more available. FO was stabilized by mixing it with chia seed oil (CSO) at 50:50 at room temperature. The antioxidant properties of the blends were evaluated using the total phenolic content (TPC), free radical scavenging activity (DPPH), ferric reducing antioxidant potential (FRAP), and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) activities with FO and CSO as controls. The blends of FO and CSO increased the oxidative stability, while FO was the most susceptible to degradation. The stability and bioactivity of antioxidants against environmental factors were improved by using encapsulation. Response surface methodology (RSM) was used to optimize spray-drying operating conditions for spray-dried microcapsules (SDMs). The independent variables were the inlet air temperature (IAT), which varied from 125 to 185 °C; wall material (WM) concentration, which varied from 5 to 25%; pump speed (PS), which varied from 3 to 7 mL/min; and needle speed (NS), which varied from 3 to 11 s. The results indicated that the maximum antioxidant activity of SDM was obtained at 140 °C IAT, 10% WM, 4 mL/min PS, and 5 s NS, while the minimum value was obtained at 170 °C IAT, 20% WM, 6 mL/min PS, and 9 s NS. The IAT had a significant effect on the antioxidant activities, and the stability of SDMs was increased. These SDMs can be used in the formulation of food matrices due to their therapeutic and nutritional properties., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

A direct regulation of adaptive immunity by the coagulation protease activated protein C (aPC) has recently been established. Preincubation of T cells with aPC for 1 hour before transplantation increases FOXP3+ regulatory T cells (Tregs) and reduces acute graft-versus-host disease (aGVHD) in mice, but the underlying mechanism remains unknown. Because cellular metabolism modulates epigenetic gene regulation and plasticity in T cells, we hypothesized that aPC promotes FOXP3+ expression by altering T-cell metabolism. To this end, T-cell differentiation was assessed in vitro using mixed lymphocyte reaction or plate-bound α-CD3/CD28 stimulation, and ex vivo using T cells isolated from mice with aGVHD without and with aPC preincubation, or analyses of mice with high plasma aPC levels. In stimulated CD4+CD25- cells, aPC induces FOXP3 expression while reducing expression of T helper type 1 cell markers. Increased FOXP3 expression is associated with altered epigenetic markers (reduced 5-methylcytosine and H3K27me3) and reduced Foxp3 promoter methylation and activity. These changes are linked to metabolic quiescence, decreased glucose and glutamine uptake, decreased mitochondrial metabolism (reduced tricarboxylic acid metabolites and mitochondrial membrane potential), and decreased intracellular glutamine and α-ketoglutarate levels. In mice with high aPC plasma levels, T-cell subpopulations in the thymus are not altered, reflecting normal T-cell development, whereas FOXP3 expression in splenic T cells is reduced. Glutamine and α-ketoglutarate substitution reverse aPC-mediated FOXP3+ induction and abolish aPC-mediated suppression of allogeneic T-cell stimulation. These findings show that aPC modulates cellular metabolism in T cells, reducing glutamine and α-ketoglutarate levels, which results in altered epigenetic markers, Foxp3 promoter demethylation and induction of FOXP3 expression, thus favoring a Treg-like phenotype., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Food is a crucial source for the endurance of individuals, and quality concerns of consumers are being raised with the progression of time. Edible coatings and films (ECFs) are increasingly important in biobased packaging because they have a prime role in enhancing the organoleptic characteristics of the food products and minimizing the spread of microorganisms. These sustainable ingredients are crucial for a safer and healthier environment. These are created from proteins, polysaccharides, lipids, plasticizers, emulsifiers, and active substances. These are eco-friendly since made from innocuous material. Nanocomposite films are also beginning to be developed and support networks of biological polymers. Antioxidant, flavoring, and coloring compounds can be employed to improve the quality, wellbeing, and stability of packaged foods. Gelatin-enhanced fruit and vegetable-based ECFs compositions have the potential to produce biodegradable films. Root plants like cassava, potato, and sweet potato have been employed to create edible films and coatings. Achira flour, amylum, yam, ulluco, and water chestnut have all been considered as novel film-forming ingredients. The physical properties of biopolymers are influenced by the characteristics, biochemical confirmation, compatibility, relative humidity, temperature, water resistance, and application procedures of the components. ECFs must adhere to all regulations governing food safety and be generally recognized as safe (GRAS). This review covers the new advancements in ECFs regarding the commitment of novel components to the improvement of their properties. It is expected that ECFs can be further investigated to provide innovative components and strategies that are helpful for global financial issues and the environment., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Background and objectives: The inappropriate use of antibiotics in hospitals can potentially lead to the development and spread of antibiotic resistance, increased mortality, and high economic burden. The objective of the study was to assess current patterns of antibiotic use in leading hospitals of Pakistan. Moreover, the information collected can support in policy-making and hospital interventions aiming to improve antibiotic prescription and use. Methodology and materials: A point prevalence survey was carried out with data abstracted principally from patient medical records from 14 tertiary care hospitals. Data were collected through the standardized online tool KOBO application for smart phones and laptops. For data analysis, SPSS Software was used. The association of risk factors with antimicrobial use was calculated using inferential statistics. Results: Among the surveyed patients, the prevalence of antibiotic use was 75% on average in the selected hospitals. The most common classes of antibiotics prescribed were third-generation cephalosporin (38.5%). Furthermore, 59% of the patients were prescribed one while 32% of the patients were prescribed two antibiotics. Whereas the most common indication for antibiotic use was surgical prophylaxis (33%). There is no antimicrobial guideline or policy for 61.9% of antimicrobials in the respected hospitals. Conclusions: It was observed in the survey that there is an urgent need to review the excessive use of empiric antimicrobials and surgical prophylaxis. Programs should be initiated to address this issue, which includes developing antibiotic guidelines and formularies especially for empiric use as well as implementing antimicrobial stewardship activities.

Background: Many COVID-19 patients are left with symptoms several months after resolution of the acute illness; this syndrome is known as post-acute sequalae of COVID-19 (PASC). We aimed to determine the prevalence of objective hemodynamic cardiovascular autonomic abnormalities (CAA), explore sex differences, and assess the prevalence of CAA among hospitalized vs nonhospitalized patients with PASC., Methods: Patients with PASC (n = 70; female [F] = 56; 42 years of age; 95% confidence interval [CI], 40-48) completed standard autonomic tests, including an active stand test 399 days (338, 455) after their COVID-19 infection. Clinical autonomic abnormalities were evaluated., Results: Most patients with PASC met the criteria for at least 1 CAA (51; 73%; F = 43). The postural orthostatic tachycardia syndrome hemodynamic (POTS HR ) criterion of a heart rate increase of > 30 beats per minute within 5 to 10 minutes of standing was seen in 21 patients (30%; F = 20; P = 0.037 [by sex]). The initial orthostatic hypotension hemodynamic (IOH 40 ) criterion of a transient systolic blood pressure change of > 40 mm Hg in the first 15 seconds of standing was seen in 43 (61%) patients and equally among female and male patients (63% vs 57%; P = 0.7). Only 9 (13%) patients were hospitalized; hospitalized vs nonhospitalized patients had similar frequencies of abnormalities (67% vs 74%; P = 0.7)., Conclusions: Patients with PASC have evidence of CAA, most commonly IOH 40 , which will be missed unless an active stand test is used. Female patients have increased frequency of POTS HR , but IOH 40 is equally prevalent between sexes. Finally, even nonhospitalized "mild" infections can result in long-term CAAs., (Copyright © 2022 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

The subject of this study is to determine the best solvent and optimum extraction conditions for the extraction of maximum antioxidant phenolic compounds and antioxidant activity from strawberry fruits ( Fragaria x ananassa Duch .). Extractions were carried out using solvents with different polarities (water, methanol, ethanol, acetonitrile, and acetone). Box-Behnken Design was used to optimize extraction conditions, including extraction time (t), temperature (°C), and liquid/solid (L/S) ratio. In the study, extracts obtained with acetone indicated the highest total phenolic content (TPC), total flavonoid content (TFC), and antioxidant activity. The optimal extraction conditions for both responses were determined to be time of 17.5 min, temperature 52.5 °C, and liquid/solid ratio of 30:1. The maximum TPC and TFC values were found as 18.78 ± 0.22 mg of gallic acid equivalent (GAE/g) and 10.52 ± 0.35 mg of catechin equivalents (CE/g) under optimum extraction conditions. The results indicated that optimizing extraction conditions is critical for quantifying antioxidant phenolic compounds. The present model can contribute to finding a cheap way of delivering natural antioxidants in the food, cosmeceutical, and pharmaceutical industries. Furthermore, these results indicate that strawberry fruits ( Fragaria x ananassa Duch .) can be a natural food colorant in dietary applications with potential health benefits., Competing Interests: Competing interestsThe authors declare no competing interests.Conflict of InterestHyrije Koraqi declares no competing interests. Anka Trajkovska Petkoska declares no competing interests. Waseem Khalid declares no competing interests. Aqeela Sehrish declares no competing interests. Saadia Ambreen declares no competing interests. Jose Manuel Lorenzo declares no competing interests., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Objectives: To determine the correlation of serum anti-müllerian hormone with follicular stimulating hormone, luteinizing hormone and testosterone levels in male patients of depression., Methods: The cross-sectional analytical study was conducted at the Islamic International Medical College and the Armed Forces Institute of Mental Health, Military Hospital, Rawalpindi, Pakistan, from March 4, 2017, to March 29, 2018, and comprised male patients aged 18-60 years suffering from depression diagnosed on the basis of Siddiqui Shah Depression Scale. Serum anti-müllerian hormone, follicular stimulating hormone, luteinizing hormone and testosterone levels of all patients were measured using enzyme-linked immunosorbent assay kits. Correlation of anti-müllerian hormone with the rest was explored. Data was analysed using SPSS 21., Results: There were 72 male subjects with mean age 35.19±9.97 years. A significant negative correlation was observed between serum anti-müllerian hormone levels and serum follicular stimulating hormone levels (p=0.001), but the correlation was not significant with serum luteinizing hormone and serum testosterone levels (p>0.05)., Conclusions: Anti-Müllerian Hormone was found to be significantly correlated with follicular stimulating hormone, but not with luteinizing hormone and testosterone.

Objective: To determine the frequency, clinical presentation, and etiological factors of cauda equina syndrome (CES)., Materials and Method: This retrospective study was done on 256 participants, and aimed to analyze the frequency and patterns of clinical presentation in suspected cases of CES. The inclusion criteria included participants aged 18 or older with medical records available for review and having red-flagged symptoms for CES. The study collected information on various factors such as age, gender, confirmation of CES on MRI, neurological deficits, etiological factors, duration of symptoms, and more. The data collected was analyzed using descriptive statistics and logistic regression to identify significant variables between MRI-proven CES and suspected CES., Results: The mean age was 58.05 ± 19.26 years, with 151 females (58.98%) and 105 males (41.02%). The majority (50.78%) had a neurological deficit, while other symptoms included difficulty initiating micturition or impaired sensation of urinary flow (17.58%), loss of sensation of rectal fullness (3.12%), urinary or faecal incontinence (35.16%), bilateral sciatica (21.88%), neurological symptoms in the lower limbs (25.00%), anaesthesia or any leg weakness (24.22%), and bilateral sciatica as the predominant symptom (21.88%). Symptoms were chronic in 47.27% and acute in 21.88%. The odds of MRI-proven CES increase by 3% per year of age. Neurological deficit was strongly associated with MRI-proven CES (OR = 14.97), while loss of sensation of rectal fullness increased the odds by 10-fold (OR = 10.62)., Conclusion: CES can present with various symptoms, including the bilateral neurological deficit, urinary and faecal incontinence, and bilateral sciatica, with age, severe bilateral neurological deficit, and loss of sensation of rectal fullness being associated with MRI-proven CES. Early diagnosis and treatment are crucial for better outcomes., (© The Authors, published by EDP Sciences, 2023.)

Efficient therapies for diabetic kidney disease (DKD), now the leading cause of kidney failure, are lacking. One hallmark of DKD is sterile inflammation (inflammation in absence of microorganisms), but the underlying molecular mechanisms remain poorly understood. The NLRP3 inflammasome (innate immune system receptors and sensors regulating activation of caspase-1) is a mechanism of sterile inflammation known to be activated by metabolic stimuli and reactive metabolites associated with DKD, including inflammasome activation in podocytes. However, whether NLRP3 inflammasome activation in podocytes contributes to sterile inflammation and glomerular damage in DKD remains unknown. Here, we found that kidney damage, as reflected by increased albuminuria, glomerular mesangial expansion and glomerular basement membrane thickness was aggravated in hyperglycemic mice with podocyte-specific expression of an Nlrp3 gain-of-function mutant (Nlrp3A350V). In contrast, hyperglycemic mice with podocyte-specific Nlrp3 or Caspase-1 deficiency showed protection against DKD. Intriguingly, podocyte-specific Nlrp3 deficiency was fully protective, while podocyte-specific caspase-1 deficiency was only partially protective. Podocyte-specific Nlrp3, but not caspase-1 deficiency, maintained glomerular autophagy in hyperglycemic mice, suggesting that podocyte Nlrp3 exerts both canonical and non-canonical effects. Thus, podocyte NLRP3 inflammasome activation is both sufficient and required for DKD and supports the concept that podocytes exert some immune cell-like functions. Hence, as podocyte NLRP3 exerts non-canonical and canonical effects, targeting NLRP3 may be a promising therapeutic approach in DKD., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Diabetic kidney disease (DKD) is an emerging pandemic, paralleling the worldwide increase in obesity and diabetes mellitus. DKD is now the most frequent cause of end-stage renal disease and is associated with an excessive risk of cardiovascular morbidity and mortality. DKD is a consequence of systemic endothelial dysfunction. The endothelial-dependent cytoprotective coagulation protease activated protein C (aPC) ameliorates glomerular damage in DKD, in part by reducing mitochondrial ROS generation in glomerular cells. Whether aPC reduces mitochondrial ROS generation in the tubular compartment remains unknown. Here, we conducted expression profiling of kidneys in diabetic mice (wild-type and mice with increased plasma levels of aPC, APC high mice). The top induced pathways were related to metabolism and in particular to oxidoreductase activity. In tubular cells, aPC maintained the expression of genes related to the electron transport chain, PGC1-α expression, and mitochondrial mass. These effects were associated with reduced mitochondrial ROS generation. Likewise, NLRP3 inflammasome activation and sterile inflammation, which are known to be linked to excess ROS generation in DKD, were reduced in diabetic APC high mice. Thus, aPC reduces mitochondrial ROS generation in tubular cells and dampens the associated renal sterile inflammation. These studies support approaches harnessing the cytoprotective effects of aPC in DKD.

Diabetes mellitus is a metabolic disease largely due to lifestyle and nutritional imbalance, resulting in insulin resistance, hyperglycemia and vascular complications. Diabetic kidney disease (DKD) is a major cause of end-stage renal failure contributing to morbidity and mortality worldwide. Therapeutic options to prevent or reverse DKD progression are limited. Endothelial and glomerular filtration barrier (GFB) dysfunction and sterile inflammation are associated with DKD. Neutrophil extracellular traps (NETs), originally identified as an innate immune mechanism to combat infection, have been implicated in sterile inflammatory responses in non-communicable diseases. However, the contribution of NETs in DKD remains unknown. Here, we show that biomarkers of NETs are increased in diabetic mice and diabetic patients and that these changes correlate with DKD severity. Mechanistically, NETs promote NLRP3 inflammasome activation and glomerular endothelial dysfunction under high glucose stress in vitro and in vivo. Inhibition of NETs (PAD4 inhibitor) ameliorate endothelial dysfunction and renal injury in DKD. Taken together, NET-induced sterile inflammation promotes diabetes-associated endothelial dysfunction, identifying a new pathomechanism contributing to DKD. Inhibition of NETs may be a promising therapeutic strategy in DKD.

Diabetes mellitus is hallmarked by accelerated atherosclerosis, a major cause of mortality among patients with diabetes. Efficient therapies for diabetes-associated atherosclerosis are absent. Accelerated atherosclerosis in diabetic patients is associated with reduced endothelial thrombomodulin (TM) expression and impaired activated protein C (aPC) generation. Here, we directly compared the effects of high glucose and oxidized LDL, revealing that high glucose induced more pronounced responses in regard to maladaptive unfolded protein response (UPR), senescence, and vascular endothelial cell barrier disruption. Ex vivo, diabetic ApoE -/- mice displayed increased levels of senescence and UPR markers within atherosclerotic lesions compared with nondiabetic ApoE -/- mice. Activated protein C pretreatment maintained barrier permeability and prevented glucose-induced expression of senescence and UPR markers in vitro. These data suggest that high glucose-induced maladaptive UPR and associated senescence promote vascular endothelial cell dysfunction, which-however-can be reversed by aPC. Taken together, current data suggest that reversal of glucose-induced vascular endothelial cell dysfunction is feasible.

Diabetes mellitus, which is largely driven by nutritional and behavioral factors, is characterized by accelerated atherosclerosis with impaired plaque stability. Atherosclerosis and associated complications are the major cause of mortality in diabetic patients. Efficient therapeutic concepts for diabetes-associated atherosclerosis are lacking. Atherosclerosis among diabetic patients is associated with reduced endothelial thrombomodulin (TM) expression and impaired activated protein C (aPC) generation. Here, we demonstrate that atherosclerotic plaque stability is reduced in hyperglycemic mice expressing dysfunctional TM (TM Pro/Pro mice), which have a pro-coagulant phenotype due to impaired thrombin inhibition and markedly reduced aPC generation. The vessel lumen and plaque size of atherosclerotic lesions in the truncus brachiocephalic were decreased in diabetic TM Pro/Pro ApoE -/- mice compared to diabetic ApoE -/- mice. While lipid accumulation in lesions of diabetic TM Pro/Pro ApoE -/- mice was lower than that in diabetic ApoE -/- mice, morphometric analyses revealed more prominent signs of instable plaques, such as a larger necrotic core area and decreased fibrous cap thickness in diabetic TM Pro/Pro ApoE -/- mice. Congruently, more macrophages and fewer smooth muscle cells were observed within lesions of diabetic TM Pro/Pro ApoE -/- mice. Thus, impaired TM function reduces plaque stability, a characteristic of hyperglycemia-associated plaques, thus suggesting the crucial role of impaired TM function in mediating diabetes-associated atherosclerosis.

Objective: Atherosclerosis, the main pathology underlying cardiovascular diseases is accelerated in diabetic patients. Genetic mouse models require breeding efforts which are time-consuming and costly. Our aim was to establish a new nongenetic model of inducible metabolic risk factors that mimics hyperlipidemia, hyperglycemia, or both and allows the detection of phenotypic differences dependent on the metabolic stressor(s)., Methods and Results: Wild-type mice were injected with gain-of-function PCSK9 D377Y (proprotein convertase subtilisin/kexin type 9) mutant adeno-associated viral particles (AAV) and streptozotocin and fed either a high-fat diet (HFD) for 12 or 20 weeks or a high-cholesterol/high-fat diet (Paigen diet, PD) for 8 weeks. To evaluate atherosclerosis, two different vascular sites (aortic sinus and the truncus of the brachiocephalic artery) were examined in the mice. Combined hyperlipidemic and hyperglycemic (HGHCi) mice fed a HFD or PD displayed characteristic features of aggravated atherosclerosis when compared to hyperlipidemia (HCi HFD or PD) mice alone. Atherosclerotic plaques of HGHCi HFD animals were larger, showed a less stable phenotype (measured by the increased necrotic core area, reduced fibrous cap thickness, and less α-SMA-positive area) and had more inflammation (increased plasma IL-1β level, aortic pro-inflammatory gene expression, and MOMA-2-positive cells in the BCA) after 20 weeks of HFD. Differences between the HGHCi and HCi HFD models were confirmed using RNA-seq analysis of aortic tissue, revealing that significantly more genes were dysregulated in mice with combined hyperlipidemia and hyperglycemia than in the hyperlipidemia-only group. The HGHCi-associated genes were related to pathways regulating inflammation (increased Cd68, iNos , and Tnfa expression) and extracellular matrix degradation ( Adamts4 and Mmp14 ). When comparing HFD with PD, the PD aggravated atherosclerosis to a greater extent in mice and showed plaque formation after 8 weeks. Hyperlipidemic and hyperglycemic mice fed a PD (HGHCi PD) showed less collagen (Sirius red) and increased inflammation (CD68-positive cells) within aortic plaques than hyperlipidemic mice (HCi PD). HGHCi-PD mice represent a directly inducible hyperglycemic atherosclerosis model compared with HFD-fed mice, in which atherosclerosis is severe by 8 weeks., Conclusion: We established a nongenetically inducible mouse model allowing comparative analyses of atherosclerosis in HCi and HGHCi conditions and its modification by diet, allowing analyses of multiple metabolic hits in mice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gaul, Shahzad, Medert, Gadi, Mäder, Schumacher, Wirth, Ambreen, Fatima, Boeckel, Khawaja, Haas, Brune, Nawroth, Isermann, Laufs and Freichel.)

Objective To determine the incidence of cognitive impairment established on the mini-mental state assessment in type 2 diabetic patients presenting at Holy Family Hospital, Rawalpindi. Materials and methods This cross-sectional descriptive study was carried out from June 2019 to December 2019. Individuals with a diagnosis of type 2 diabetes mellitus were included, and detailed history, physical examination, and biochemical variables were noted. They were assessed through Mini-Mental State Examination (MMSE) (Urdu translation) to look for the primary outcome variable, i.e., cognitive impairment. All patients with type 2 diabetes mellitus diagnosed at least one year back, irrespective of gender, were included in this investigation. Patients with a previous history of head injury, epilepsy, stroke, those on an antidepressant or antipsychotic medications, those with deranged renal function tests, and those already diagnosed with dementia were excluded from the study. Results Three hundred thirty-two patients meeting the inclusion criteria were included in the study. The mean ± standard deviation age of the study population was 65.32 ± 11.33 years, with maximum age being 80 years and the minimum being 50 years. Two hundred patients (60.24%) were below 65 years of age, and 132 patients (39.76%) were 65 years of age or above. Two hundred sixteen (65.06%) were males, and 116 (34.96%) were females. The mean duration of diabetes mellitus (DM) was 10.17 ± 4.81. The mean MMSE score was 22.69 ± 5.26. Out of 332 patients, 81 (24.4%) patients had cognitive impairment. Patients who were 65 or older had a significantly higher proportion of cognitive impairment, compared to those below 65 years of age (p-value = 0.0214). There was no significant difference in the proportion of cognitively impaired patients between males and females (p-value = 0.2497). Similarly, there was no significant difference between those who were diagnosed with type 2 diabetes for 10 years or more and those who were diagnosed less than 10 years ago (p-value = 0.3791). Conclusion Cognitive impairment is common in individuals having type 2 diabetes mellitus. It is also associated with the increasing age of diabetic patients. However, cognitive impairment in type 2 diabetes mellitus is not associated with gender. In addition, there is no significant difference in cognitive impairment between the patients who were diagnosed with diabetes more than 10 years ago and those who had it diagnosed less than 10 years ago., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Malik et al.)

Objectives: To compare the levels of cortisol in patients of vasovagal syncope (VVS) and postural tachycardia syndrome (POTS)., Methods: A cross-sectional analytical study was conducted at Islamic International Medical College, Rawalpindi and Electrophysiology Department at (AFIC). This study included 80 subjects, comprising of 35 patients in each group of vasovagal syncope and postural tachycardia syndrome and 10 healthy subjects. Patients with complaint of syncope was evaluated for vasovagal syncope and postural tachycardia syndrome using Head Up Tilt Test (HUTT. Blood samples of all the participants were taken and serum cortisol was analyzed using ELISA method. Results were analyzed on SPSS Statistics 21 using ANOVA with a p value of ≤0.05 regarded as significant., Results: Hormonal analysis shows that cortisol levels in the vasovagal, postural tachycardia syndrome and in control group was 153±16.7pg/ml, 160.17±pg/ml, and 69.65± 5.8pg/ml respectively. Cortisol levels were significantly higher in both vasovagal and POTS groups as compared to controls with a p-value of 0.04 and 0.023 respectively. However, there was no significant difference between vasovagal and POTS patients with p value 0.570., Conclusion: It is concluded from the study that cortisol responses of VVS and POTS were positive., Competing Interests: Conflict of interest: None., (Copyright: © Pakistan Journal of Medical Sciences.)