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Background: Endoscopic ultrasound guided celiac plexus neurolysis (EUS- CPN) has been reported to be an effective way to help with pain in pancreatic cancer patient. The aim of our updated meta-analysis is to assess the efficacy of pain relief in patients with pancreatic cancer who underwent EUS guided neurolysis. Methods: Pooled proportions were calculated using both Mantel-Haenszel method (fixed effects model) and DerSimonian Laird method (random effects model). The heterogeneity among studies was tested using Cochran’s Q test based upon inverse variance weights. Results: Initial search identified 176 reference articles, of which 34 were selected and reviewed in detail. Sixteen studies that met the inclusion criteria were included in this analysis. The mean age of patients undergoing neurolysis was 56.31 ± 19.72 years. Number of males, N = 563 (57.4%), was higher than the number of females, N = 417 (42.5%). The pooled proportion of patients who showed pain relief with EUS-guided neurolysis was 71% (95% CI = 68–74). Bias calculated using Begg–Mazumdar was not significant (p = 0.8). In a subgroup analysis, when comparing the central and bilateral techniques, the pooled proportion of patients with pain relief was 66% (95% CI = 61–71) and 57% (95% CI = 48–67), respectively. Conclusions: Our results show that EUS guided CPN could provide relief in as much as 70% of patients with central neurolysis technique having some edge over peripheral neurolysis. Further larger scale randomized controlled trials may further help to elaborate the efficacy of central vs peripheral neurolysis.

Abstract The article proposes a novel approach to assess rotor angle stability in microgrids by enhancing the Modified Galerkin Method (MGM), which is based on the Polynomial Approximation, using real-time RFID data acquisition. Due to their reliance on assumptions, traditional rotor angle stability methodologies frequently fail in online transient stability testing. MGM successfully captures the dynamic behavior of microgrids by approximating state variables using a sequence of polynomials and coefficients. Redundant data, like as vibrations or noise signals, can cause delays in defect diagnosis and decrease diagnostic accuracy. This problem is addressed by integrating RFID technology. RFID technology could potentially be used with a hybrid CNN-LSTM model to develop a sophisticated fault diagnostic system. This entails identifying fault characteristics through the use of signal processing techniques and feature extraction methods, such as the Fourier transform and time-domain statistical features. In addition, we use Total Harmonic Distortion (THD) to reduce superfluous data. The suggested techniques significantly increase fault detection efficiency and precision, outperforming existing techniques with a 0.94 classification accuracy. An extensive case study on an IEEE 3-machine 9-bus system is used to illustrate its efficacy, showing observable improvements in fault detection speed and accuracy that make microgrid operations safer and more dependable.

Multiple randomized controlled trials (RCTs) have examined first-line pharmacological agents such as anticholinergics and β3 agonists for the management of overactive bladder symptoms (OAB). Although earlier systematic reviews and (network) meta-analyses aimed to summarize the evidence, a substantial number of trials were not included, so a comprehensive and methodologically rigorous evaluation of the comparative effectiveness of all first-line pharmacological treatments is lacking. We aim to conduct a series of systematic reviews and network meta-analyses (NMAs) for a comprehensive assessment of the effectiveness and safety of first-line pharmacological treatments for OAB. Eligible studies will include RCTs comparing anticholinergics and β3 agonists to one another or to placebo in adults with OAB or detrusor overactivity. Pairs of reviewers with methodological training will independently evaluate candidate studies to determine eligibility and extract relevant data. We will incorporate patient-important outcomes, including urinary urgency episodes, urgency incontinence episodes, any type of incontinence episodes, urinary frequency, nocturia, and adverse events. We will conduct the NMAs using a frequentist framework and a graph theory model for each outcome. Analysis will follow rigorous methodologies, including handling of missing data and assessment of the risk of bias. We will conduct sensitivity and subgroup analyses and will apply the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to rate evidence certainty. Our approach aims to address the knowledge gap in the treatment of OAB by synthesizing evidence from RCTs worldwide. We will employ robust statistical methods, including frequentist NMA, to general clinically relevant and patient-important insights. Sensitivity and subgroup analyses will enhance the robustness and generalizability of our findings. Our reviews strive to inform evidence-based decisions in the management of OAB, to ultimate improve patient outcomes. Our study results may guide health policy decisions, such as reimbursement policies, and future studies in functional urology.The protocol for the review series is registered on PROSPERO as CRD42023266915.

Abstract DC grid fault protection techniques have previously faced challenges such as fixed thresholds, insensitivity to high-resistance faults, and dependency on specific threshold settings. These limitations can lead to elevated fault currents in the grid, particularly affecting multi-modular converters (MMCs) vulnerability to large fault current transients. This paper proposes a novel approach that combines the disjoint-based Bootstrap Aggregating (Bagging) technique and Bayesian optimization (BO) for fault detection in DC grids. Disjoint partitions reduce variance and enhance Ensemble Artificial Neural Network (EANN) performance, while BO optimizes EANN architecture. The proposed approach uses multiple transient periods instead of a fixed time to train the model. Transient periods are segmented into multiple 1 ms intervals, and each interval trains a separate neural network. In this way, a robust local relay is created that does not require high-speed communication systems. Additionally, a discrete wavelet transform (DWT) is applied to select detailed coefficients of the transient fault current, measured at the DC line’s sending terminal for fault protection. EANN is trained in comprehensive offline data that considers noise impact. Simulation results demonstrate the scheme’s ability to detect faults as high as 400 Ω accurately. This makes it a robust, reliable, and effective solution for fault detection on high-voltage direct current (HVDC) transmission lines. Lastly, this research provides the first-ever scientometric analysis of HVDC transmission line fault protection using neural network algorithms, highlighting major research themes and trends. The scientometric analysis was based on a dataset of 136 available research articles from the Scopus database from the last ten years. Therefore, this research provides valuable insights into the use of ANN for HVDC transmission line fault protection.

Abstract Background Patients perceive effective patient-doctor communication as an important metric when evaluating their satisfaction with health systems. Hence, optimal patient-physician communication is fundamental for quality healthcare. High-income countries (HICs) have extensively studied patient-resident communication. However, there is a dearth of similar studies in low- and middle-income countries (LMICs). Therefore, we aimed to explore the current state of and barriers to practicing good patient-resident communication and explore possible solutions to mitigate these challenges at one of the largest Academic Medical Centers in an LMIC. Methods This study employed an exploratory qualitative study design and was conducted at the Aga Khan University Hospital in Pakistan. Through purposive maximum variation sampling, 60 healthcare workers from diverse cohorts, including attendings, fellows, residents, and medical students, participated in eight focus group discussions. Results We identified three key themes from the data: Status-quo of residents’ communication skills and learning (Poor verbal and non-verbal communication, inadequate training programs, and variable sources of learning), Barriers to effective communication (Institutional barriers such as lack of designated counselling spaces, lack of resident insight regarding effective communication and deficits in intra-team communication), and the need for developing a communication skills curriculum (Design, implementation and scaling to other cohorts of healthcare workers). Conclusions Findings from this study show that multifaceted factors are responsible for inadequate patient resident-physician communication, highlighting the need for and importance of developing a formal communication skills training curriculum for residents. These insights can be used to create standardized training for equipping residents with adequate skills for effectively communicating with patients which can improve healthcare service delivery and patient outcomes.

Abstract As Europe integrates more renewable energy resources, notably offshore wind power, into its super meshed grid, the demand for reliable long-distance High Voltage Direct Current (HVDC) transmission systems has surged. This paper addresses the intricacies of HVDC systems built upon Modular Multi-Level Converters (MMCs), especially concerning the rapid rise of DC fault currents. We propose a novel fault identification and classification for DC transmission lines only by employing Long Short-Term Memory (LSTM) networks integrated with Discrete Wavelet Transform (DWT) for feature extraction. Our LSTM-based algorithm operates effectively under challenging environmental conditions, ensuring high fault resistance detection. A unique three-level relay system with multiple time windows (1 ms, 1.5 ms, and 2 ms) ensures accurate fault detection over large distances. Bayesian Optimization is employed for hyperparameter tuning, streamlining the model’s training process. The study shows that our proposed framework exhibits 100% resilience against external faults and disturbances, achieving an average recognition accuracy rate of 99.04% in diverse testing scenarios. Unlike traditional schemes that rely on multiple manual thresholds, our approach utilizes a single intelligently tuned model to detect faults up to 480 ohms, enhancing the efficiency and robustness of DC grid protection.

Abstract The genome of Mycobacterium tuberculosis encodes for a large repertoire of toxin-antitoxin systems. In the present study, MenT3 and MenT4 toxins belonging to MenAT subfamily of TA systems have been functionally characterized. We demonstrate that ectopic expression of these toxins inhibits bacterial growth and this is rescued upon co-expression of their cognate antitoxins. Here, we show that simultaneous deletion of menT3 and menT4 results in enhanced susceptibility of M. tuberculosis upon exposure to oxidative stress and attenuated growth in guinea pigs and mice. We observed reduced expression of transcripts encoding for proteins that are essential or required for intracellular growth in mid-log phase cultures of ΔmenT4ΔT3 compared to parental strain. Further, the transcript levels of proteins involved in efficient bacterial clearance were increased in lung tissues of ΔmenT4ΔT3 infected mice relative to parental strain infected mice. We show that immunization of mice and guinea pigs with ΔmenT4ΔT3 confers significant protection against M. tuberculosis infection. Remarkably, immunization of mice with ΔmenT4ΔT3 results in increased antigen-specific TH1 bias and activated memory T cell response. We conclude that MenT3 and MenT4 are important for M. tuberculosis pathogenicity and strains lacking menT3 and menT4 have the potential to be explored further as vaccine candidates.

Abstract Background There are limited data available, particularly in low- and middle-income countries (LMICs), on the long-term quality of life (QoL) and family functioning of primary caregivers of children and young people (CYPs) affected by primary brain tumors (PBTs). This study aimed to assess the factors associated with the mean change in QoL and family functioning scores of primary caregivers of CYP patients with PBTs 12 months posttreatment. Methods This prospective cohort study enrolled CYPs aged 5–21 years with newly diagnosed PBTs and their primary caregivers. The study was carried out between November 2020 and July 2023. The primary caregivers of CYPs were recruited from two major tertiary care centers in Karachi, Pakistan. The primary caregivers QoL were assessed by the Pediatric Quality of Life Inventory (PedsQL) Family Impact Module. The assessment was undertaken by a psychologist at the time of diagnosis and 12 months posttreatment. The data were analyzed with STATA version 12. Results Forty-eight CYPs with newly diagnosed PBTs and their primary caregivers (46 mothers and 2 fathers) were enrolled. At 12 months posttreatment, 25 (52%) CYPs and their primary caregivers (mothers) were reassessed, and 23 (48%) were lost to follow-up. On multivariable analysis, a significant decrease in mothers’ mean 12-month posttreatment QoL and family functioning scores was associated with CYP having posttreatment seizures (beta= -10.2; 95% CI: -18.4 to -2.0) and with the financial burden associated with the CYP’s illness (beta= -0.3; 95% CI: -0.4 to -0.1). However, in those cases where CYP had higher posttreatment quality of life scores (beta = 0.4; 95% CI = 0.1, 0.6) and posttreatment higher verbal intelligence scores (beta = 0.1; 95% CI = 0.01, 0.3), the mothers’ QoL and family functioning scores were significantly greater. Conclusion We found a significant decrease in QoL of mothers who had a high financial burden and whose CYP had posttreatment seizures. However, those whose CYPs had higher posttreatment verbal intelligence scores and quality of life scores had significantly greater QoL scores. Identification of the factors that influence primary caregivers QoL has the potential to aid in the development of targeted strategies to alleviate stressors and improve the overall quality of life for primary caregivers and their children who are at high risk.

Summary: Contextual memories are critical for survival but must be extinguished when new conditions render them nonproductive. By most accounts, extinction forms a new memory that competes with the original association for control over behavior, but the underlying circuit mechanisms remain largely enigmatic. Here, we demonstrate that extinction of contextual fear conditioning recruits somatostatin interneurons (SST-INs) in the ventral hippocampus. Correspondingly, real-time activity of SST-INs correlates with transitions between immobility and movement, signaling exit from defensive freezing bouts. Optogenetic manipulation of SST-INs but not parvalbumin interneurons (PV-INs) elicits bidirectional changes in freezing that are specific to the context in which extinction was acquired. Finally, similar effects were obtained following extinction of sucrose-based appetitive conditioning, in which SST-IN inhibition triggers relapse to reward seeking. These data suggest that ventral hippocampal SST-INs play a fundamental role in extinction that is independent of affective valence and may be related to their disruption of spontaneous emotional responses.

Introduction: Knee osteoarthritis is a degenerative disease of joints and is the major cause of chronic impairment in older ages. This is the consequence of several years of use accompanied by the effect of wear and tear of bone, joint, and cartilage. Aims & Objectives: To evaluate the quality of life among patients with osteoarthritis actively and non-actively performing religious prayers in district Swat, Pakistan. Place and Duration of Study: The study was conducted at District Swat, from November 2019 to September 2020. Material & Method: A comparative cross-sectional study was conducted among osteoarthritic patients. A pre-tested and validated KOOS questionnaire was administered to osteoarthritic patients (group 1), who had modified their prayer method by using a chair to perform prayers, and compared to another group of osteoarthritic patients (group 2) who were practicing normal praying position. Pain, symptoms, everyday activities, sports and recreation, and knee-related quality of life (QOL) were assessed. SPSS version 22 was used for statistical analysis. P-value ?0.05 was considered significant. Results: The total number of patients in both groups was 800. Among those, 54.8% had a family history of knee pain, 60.4% had bilateral knee problems and 93.4% had no prior knee injuries. Group 1 was found to have more complaints related to the knee as compared to group 2 in all subscales of KOOS. Statistically significant relationship was observed between duration of knee pain, family history, knee problem, and previous knee injury between group 1 and group 2. (P

Purpose To evaluate the current communication skills of resident physicians and identify areas for improvement.Study design Using a cross-sectional design, data from medical students, residents, fellows, and faculty were assimilated at one of the largest academic medical centers in a low-and-middle-income country via a self-administered, validated survey with a 5-point LIKERT scale. One-way ANOVA was used to compare intra-group means, followed by the Bonferroni test, with a p-value

Introduction Older populations, being a unique subset of patients, have poor outcomes for emergency general surgery (EGS). In regions lacking specialized medical coverage for older patients, disparities in healthcare provision lead to poor clinical outcomes. We aimed to identify factors predicting index admission inpatient mortality from EGS among sexagenarians, septuagenarians, and octogenarians.Methods Data of patients aged >60 years with EGS conditions defined by the American Association for the Surgery of Trauma at primary index admission from 2010 to 2019 operated and non-operated at a large South Asian tertiary care hospital were analyzed. The primary outcome was primary index admission inpatient 30-day mortality. Parametric survival regression using Weibull distribution was performed. Factors such as patients’ insurance status and surgical intervention were assessed using adjusted HR and 95% CI with a p-value of

Background: Brain Arteriovenous Malformations (AVMs) located in proximity to eloquent brain regions are associated with poor surgical outcomes, which may be due to higher rates of postoperative neurological deterioration. Current treatment protocols include stereotactic radiosurgery, transarterial embolization, and surgical resection under general anesthesia. Awake Craniotomy (AC) allows intraoperative mapping of eloquent areas to improve post-operative neurologic outcomes. Objectives: We reviewed the current literature reporting surgical outcomes and assessed the feasibility of AC for AVM resection. Methods: The PRISMA guidelines were utilized as a template for the review. Three databases including PubMed, Scopus, and Cochrane Library were searched using a predefined search strategy. After removing duplicates and screening, full texts were analyzed. Outcomes including the extent of resection, intra-operative and post-operative complications, and long-term neurologic outcomes were assessed. Results: 12 studies were included with a total of 122 AVM cases. Spetzler–Martin grading was used for the classification of the AVMs. The asleep–awake–asleep protocol was most commonly used for AC. Complete resection was achieved in all cases except 5. Intraoperative complications included seizures (n = 2) and bleeding (n = 4). Short-term post-operative complications included hemorrhage (n = 3), neurologic dysfunctions including paresis (n = 3), hemiplegia (n = 10), dysphasia/aphasia (n = 6), cranial nerve dysfunction (n = 3), and pulmonary embolism (n = 1). Almost all neurological deficits after surgery gradually improved on subsequent follow-ups. Conclusion: AVMs may shift the anatomical location of eloquent brain areas which may be mapped during AC. All studies recommended AC for the resection of AVMs in close proximity to eloquent areas as mapping during AC identifies the eloquent cortex thus promoting careful tissue handling which may preserve neurologic function and/or predict the postoperative functional status of the patients We, therefore, conclude that AC is a viable modality for AVMs resection near eloquent language and motor areas.

IntroductionInitiated in June 2019, this collaborative effort involved 15 public and private sector hospitals in Pakistan. The primary objective was to enhance the capacity for pediatric neuro-oncology (PNO) care, supported by a My Child Matters/Foundation S grant.MethodsWe aimed to establish and operate Multidisciplinary Tumor Boards (MTBs) on a national scale, covering 76% of the population (185.7 million people). In response to the COVID-19 pandemic, MTBs transitioned to videoconferencing. Fifteen hospitals with essential infrastructure participated, holding monthly sessions addressing diagnostic and treatment challenges. Patient cases were anonymized for confidentiality. Educational initiatives, originally planned as in-person events, shifted to a virtual format, enabling continued implementation and collaboration despite pandemic constraints.ResultsA total of 124 meetings were conducted, addressing 545 cases. To augment knowledge, awareness, and expertise, over 40 longitudinal lectures were organized for healthcare professionals engaged in PNO care. Additionally, two symposia with international collaborators and keynote speakers were also held to raise national awareness. The project achieved significant milestones, including the development of standardized national treatment protocols for low-grade glioma, medulloblastoma, and high-grade glioma. Further protocols are currently under development. Notably, Pakistan's first pediatric neuro-oncology fellowship program was launched, producing two graduates and increasing the number of trained pediatric neuro-oncologists in the country to three.DiscussionThe initiative exemplifies the potential for capacity building in PNO within low-middle income countries. Success is attributed to intra-national twinning programs, emphasizing collaborative efforts. Efforts are underway to establish a national case registry for PNO, ensuring a comprehensive and organized approach to monitoring and managing cases. This collaborative initiative, supported by the My Child Matters/Foundation S grant, showcases the success of capacity building in pediatric neuro-oncology in low-middle income countries. The establishment of treatment protocols, fellowship programs, and regional tumor boards highlights the potential for sustainable improvements in PNO care.

The study aimed to synthesize nanoparticles from Viola odorata extract to biodegrade azo-dyes, enabling a circular economy approach to waste management in industries that utilize these dyes. The study utilized UV–visible spectroscopy and scanning electron microscopy (SEM) to confirm the synthesis and analyze the characteristics of the nanoparticles. The stability of the nanoparticles was assessed through the examination of four factors: the impact of NaCl, storage conditions, temperature, and pH. Plant-based nanoparticles were mixed with dye solutions, incubated, and analyzed for dye degradation using UV–Vis spectroscopy. Antibacterial and antifungal activity were assayed by disc diffusion method. UV–Vis spectrum confirms the synthesis of Ag-NPs at 450 nm, Au-NPs 533 nm, Co-NPs 246, Fe-NPs 255 nm. Ag-NPs had an average size of 18.2, Co-NPs 22.86 nm, Au-NPs 14. 9 nm and Fe-NPs 43 nm and all nanoparticles are spherical in shape. The nanoparticles exhibited excellent stability under varying temperature, pH, salt concentrations, and during six-months storage, these stable nanoparticles degraded methyl orange absorbance from 2.7 to 1.5. Methyl red was also degraded and its absorbance decreased from 2.8 to 1.25. The study found that all the synthesized nanoparticles displayed good antibacterial activity against both Gram-negative and Gram-positive bacteria. However, the gold nanoparticles (Au-NPs) demonstrated the highest potency, particularly against Pseudomonas aeruginosa, with an inhibition zone diameter nearly matching that of the commercial antibiotic Streptomycin. Similarly, the antifungal assay revealed that the Au-NPs exhibited the strongest activity against the tested fungal strains compared to the other nanoparticle types.

Abstract Introduction Effective communication is key to a successful patient-doctor interaction and improved healthcare outcomes. However, communication skills training in residency is often subpar, leading to inadequate patient-physician communication. There is a dearth of studies exploring the observations of nurses – key members of healthcare teams with a special vantage point to observe the impact of residents’ communication with patients. Thus, we aimed to gauge the perceptions of nurses regarding residents’ communication skills expertise. Methods This study employed a sequential mixed-methods design, and was conducted at an academic medical center in South Asia. Quantitative data was collected via a REDCap survey using a structured validated questionnaire. Ordinal logistic regression was applied. For qualitative data, In-depth interviews were conducted with nurses using a semi-structured interview guide. Results A total of 193 survey responses were obtained from nurses hailing from various specialties including Family Medicine (n = 16), Surgery (n = 27), Internal Medicine (n = 22), Pediatrics (n = 27), and Obstetrics/Gynecology (n = 93). Nurses rated long working hours, infrastructural deficits, and human failings as the main barriers to effective patient-resident communication. Residents working in in-patient settings were more likely to have inadequate communication skills (P-value = 0.160). Qualitative data analysis of nine in-depth interviews revealed two major themes: existing status-quo of residents’ communication skills (including deficient verbal and non-verbal communication, bias in patient counselling and challenging patients) and recommendations for improving patient-resident communication. Conclusion The findings from this study highlight significant gaps in patient-resident communication from the perception of nurses and identify the need for creating a holistic curriculum for residents to improve patient-physician interaction.

Power generation in the global power sector has recently seen a paradigm shift from centralized bulk generation to distributed generation. In this regard, there are two transmission technologies available: high-voltage alternating current (HVAC) and high-voltage direct current (HVDC). The technical and economic benefits of HVDC transmission technology have enabled many countries to implement it widely for long-distance bulk power transmission, particularly between remote locations and densely populated areas. HVDC technology, however, is still relatively new in Pakistan. Despite this, HVDC technology holds great promise in Pakistan, specifically in utilizing and integrating distributed renewable energy sources with the national grid, as well as enabling cross-border energy trade. This study aims to provide a first-ever scientometric analysis of the HVDC technology field, highlighting key research themes and trends. A correlation is established between HVDC research and its adoption in Pakistan by extracting articles from the Scopus database and analyzing them with the VOS viewer, a modern data analysis tool. The scientometric analysis indicates a minimal contribution from Pakistani authors in the field of HVDC technology as compared to authors of the neighboring nations, highlighting a significant gap in knowledge transfer and technology adoption. Moreover, an overview of HVDC technology is provided, along with a comparison between HVAC and HVDC technologies. Last but not least, Pakistan’s existing and proposed HVDC projects, prospects, and challenges associated with HVDC adoption are discussed.

Abstract Introduction With a growing interest in simulation-based training to develop clinical proficiency, bootcamps have been utilized for imparting basic skills to medical trainees. While considerable research on the topic exists in high income countries, no such neurosurgical teaching standards have been employed in Low- and Middle-Income Countries. Methods We conducted a cross-sectional study to explore the effectiveness of first low-cost, multi-center regional neurosurgery bootcamp in South Asia. Twenty-two participants attended the bootcamp and practiced 12 hands-on skills over the course of 2 days. Burr-holes and craniotomies were done on 3D printed skulls. Lumbar drain insertion was practiced on a purpose-built lumbar puncture mannequin. For laminectomy, we used an in-house designed simulation. The modified Objective Structured Assessment of Technical Skills tool was utilized for skills Assessment. Feedback from faculty and residents was collected via a standard 5-point Likert scale. Results Only one participant (4.55%) had previously attended a neurosurgical skills workshop. Comparison of outcomes on 1st and 3rd attempts of cranial and spinal skills showed a significant improvement in all 14 domains assessed (p

Numerous scientific fields depend on precise solutions, which can be obtained for nonlinear partial differential equations (PDEs) through various techniques. It is important to note that solutions obtained through different approaches can vary. The main objective of this research is to identify novel traveling wave solutions for the (2+1)-dimensional Generalized Hirota–Satsuma–Ito equation (GHSIE). Initially, the reduced form of the GHSIE is derived, and then, using the G′G′+G+A-Expansion method, new exact solutions are obtained including kink and lumps. These solutions depict the dynamics of nonlinear phenomena and are represented graphically as periodically solitary waves.

Abstract There is an urgent need to validate new drug targets and identify small molecules that possess activity against both drug-resistant and drug-sensitive bacteria. The enzymes belonging to amino acid biosynthesis have been shown to be essential for growth in vitro, in vivo and have not been exploited much for the development of anti-tubercular agents. Here, we have identified small molecule inhibitors targeting homoserine acetyl transferase (HSAT, MetX, Rv3341) from M. tuberculosis. MetX catalyses the first committed step in L-methionine and S-adenosyl methionine biosynthesis resulting in the formation of O-acetyl-homoserine. Using CRISPRi approach, we demonstrate that conditional repression of metX resulted in inhibition of M. tuberculosis growth in vitro. We have determined steady state kinetic parameters for the acetylation of L-homoserine by Rv3341. We show that the recombinant enzyme followed Michaelis–Menten kinetics and utilizes both acetyl-CoA and propionyl-CoA as acyl-donors. High-throughput screening of a 2443 compound library resulted in identification of small molecule inhibitors against MetX enzyme from M. tuberculosis. The identified lead compounds inhibited Rv3341 enzymatic activity in a dose dependent manner and were also active against HSAT homolog from S. aureus. Molecular docking of the identified primary hits predicted residues that are essential for their binding in HSAT homologs from M. tuberculosis and S. aureus. ThermoFluor assay demonstrated direct binding of the identified primary hits with HSAT proteins. Few of the identified small molecules were able to inhibit growth of M. tuberculosis and S. aureus in liquid cultures. Taken together, our findings validated HSAT as an attractive target for development of new broad-spectrum anti-bacterial agents that should be effective against drug-resistant bacteria.

Brain metastasis from testicular germ cell tumour (TGCT) is rare and represents only 2% of metastatic brain tumours. Although TGCTs have a good survival rate, the prognosis of brain metastasis is poor. Due to the rarity of the diagnosis, there are limited studies on the topic and a standardized treatment protocol does not exist. Surgical management has long been considered a positive prognostic factor; however, recent studies have investigated the impact of chemotherapy and radiotherapy in these patients. Current literature suggests multiplicity of brain lesions and treatment with chemotherapy or radiotherapy alone can have a poor impact on the prognosis of the disease. However, studies with larger cohorts are required to understand and develop the optimal treatment protocol for patients with brain metastasis from TGCT.

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumour with a poor prognosis. The risk of developing a post-operative infection after craniotomy is the highest in GBM patients. Historical beliefs suggest that post-operative infections render a survival advantage in GBM patients, however recent clinical neurosurgical reports involving large multicentric patient cohorts do not support this claim. Nonetheless, the relationship has not been extensively studied which poses the need for further large, scaled studies to determine the association between post-operative infections and survival benefit in GBM patients. Keywords: Surgical site infections; glioblastoma surgery; survival time.

Recovery after spinal cord injury (SCI) is highly variable, often leaving the victim disabled for life and having to deal with the complications of paraplegia. Stem cell therapy is a potential hope for these patients. Most of the research on use of stem cells for SCI has been on animal models in laboratories. Some recent clinical trials involving human subjects have shown positive outcomes with regards to tissue growth after transplantation, but meaningful functional recovery is yet to be seen. The emergence of lumbar cord simulation is a new approach and the recent identification of recovery organizing interneurons points to a pathway that could integrate neuromodulation with cellular therapy. Keywords: Spinal Cord, Paraplegia, Stem Cell, Transplantation, Interneurons

The emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) in humans, is a primary reason for treatment failure. Currently, only limited options are available for the management of multi-drug resistant TB, warranting the design of novel anti-TB drugs by exploiting newer targets. One of the caseinolytic protease (Clp) machinery components, an unfoldase known as ClpC1, has emerged as a distinct anti-TB drug target owing to its essential role in the pathogen's survival. The naturally occurring cyclic peptides targeting the Mtb ClpC1, exhibit potent antimycobacterial activity. However, the large, complex, and poor synthetic tractability of these peptides limit their clinical application. Identification of small molecule inhibitors of Mtb ClpC1 will be useful for future drug development. Here, we report the discovery of a bisquinoline chemotype from the screening of a small molecule chemical library against Mtb ClpC1. The hit molecule binds with ClpC1 and exhibits dose-dependent inhibition of its enzymatic activity by direct binding. The in vitro growth of Mtb is inhibited by the hit molecule at a minimum inhibitory concentration of 12.5 µM. Investigation of the structure–activity relationship by chemical synthesis underlines the requirement of the two quinoline rings, 9/10 carbon linker, and the importance of basic ring nitrogen for its inhibitory activity. To our knowledge, this is the first report on the systematic analysis of small molecule inhibitors of Mtb ClpC1.

Objective: To ascertain the age and gender differences, treatment, and management of meningiomas across Pakistan. Methods: Data were collected as part of the PBTES, and patients with a histopathological diagnosis of an intracranial meningioma in 2019 that presented at these centres were included in this cohort study sub-analysis. Thirty-two centres participated in the study. Medical students, residents, and faculty collated data from medical records. Results: Our data indicate that meningiomas constitute 15.6% of all intracranial tumours in Pakistan and occur more often in females (236, 55%) than in males. The mean age at diagnosis was 43.7 ± 19.9 years. Meningiomas had a slightly higher preponderance in the right hemisphere of the brain at 203 (47.32%) tumours and 267 (62.2%) of the tumours in the frontal and parietal lobes. We found that 174 (61.3%) of all meningiomas diagnosed in Pakistan in 2019 were grade I tumours, which was also the most commonly occurring tumour grade. Adjuvant chemoradiotherapy for meningiomas was rarely observed in Pakistan. Conclusion: The PBTES reveals a low hospital-based incidence of meningiomas in 2019 when compared to the incidence in high-income countries but found evidence similar to those of other LMICs. Tumour characteristics, such as location, grading and surgical procedures, were similar to global literature. Keywords: Meningioma, Chemoradiotherapy, Brain Neoplasms, Epidemiology, Gender traits. Continue...

Objective: To provide information about brain tumour epidemiology in Pakistan and potential associated risk factors due to family, medical and social characteristics. Methods: A retrospective cross-sectional nationwide study was designed by the Pakistan Society of Neuro-oncology, to include patients diagnosed with brain tumours in Pakistan retrospectively, from January 1, 2019- December 31, 2019. The study intended to involve data from all age groups for all brain tumour cases, irrespective of histopathology which would determine the national prevalence and incidence of these tumours. Results: A total of 2750 brain tumour cases were recorded, of which 1897 (69%) were diagnosed in the public sector. MRIs were a more common radiological study compared to CT scans. Gliomas were the most common tumours 778 (28.29%), while pineal tumours were the least common 19 (0.69%). The median age at diagnosis for males was 36 (24-49), while the median age at diagnosis for females was 37 (24-48). Hypertension was the most common co-morbidity in patients diagnosed with a brain tumour, 524 (51.89%), and smoking was the most frequent social behaviour, 355 (62.02%). Findings indicate a low metastasis frequency and few females seeking care. Conclusion: The PBTES and the PBTC have presented an opportunity and platform for hospitals and health professionals to work together to strengthen cancer care health systems, ensure implementation of treatment guidelines and conduct regular cancer registration. Keywords: brain neoplasms, registries, retrospective studies, epidemiology, Neuro-oncological surgery. Continue...

Objective: Malignant disease diagnosis brings great psychological suffering to the patient, and the sickness might have catastrophic ramifications for the relatives. The Objective of this study is to assess influence of cancer news on quality of life of patient's families. Methodology: This study was prospective cohort study conducted at the oncology department of a tertiary care Hospital, Pakistan for the duration of one year. The quality of life was assessed as per pre-defined questionnaire both from two first degree relatives at each clinical visit during treatment every week and every month for six months after completion of treatment. Data analysis was done by employing SPSS version 21. Results: 180 family members were included. QOL of family members was 1.54±0.57 (p=0.001). Anxiety/depression score of the family members was 1.67±0.64 while in control group it was 1.50±0.64 (p=0.031). The EQ VAS score in control group was 66.5±16.7 whereas in caregivers group, it was 71.3±18.8 (P=0.023). Stress was observed in 98 (54.44%) participants in caregivers group. Moderate-severe depression was observed in 45(25%) vs 21(11.67%) participants in caregivers vs control group, respectively (p=0.041) Conclusion: Our findings reveal that family caregivers of cancer patients face mental health issues and a decline in health-related quality of life. To reduce the effect of caring on the mental health and health related quality of life of family caregivers in Pakistan, culturally suitable caregiver support programs are required.

Objective: Methotrexate was first used in 1947 as a chemotherapeutic drug in the treatment of acute lymphoblastic leukemia (ALL). Methotrexate has been extensively explored as an anticancer drug since that time. High dose methotrexate is a term used for doses above 1000mg/m2. The objective of this study is to determine efficacy of Furosemide in methotrexate clearance in patients treated with high dose methotrexate. Methodology: It was a prospective cohort study carried out at the Oncology department of a tertiary care hospital, Pakistan for a period of one year. Total 80 patients were enrolled and all received daily hydration of at least 5L along with urine alkalization with sodium-bicarbonate and calcium rescue as per protocol. All patients were given Furosemide 40 mg three times a day. Methotrexate levels were monitored every 24 hours to follow its clearance. Data analysis was done by using IBM SPSS version 24. Results: The mean (SD) hospital stay in the current study was 4 (±1) days. Frequency of delayed methotrexate clearance was observed in 16 (20%) patients. The mean (SD) time of methotrexate clearance was 4 (±1) days. Renal injury was observed in 8 (10%) subjects, electrolyte imbalance in 12 (15%) subjects, and transaminitis in 11 (13.75%) subjects while mucositis was observed in 8 (10%) subjects. Conclusion: Our study concludes that furosemide is effective in methotrexate clearance in patients treated with high dose methotrexate. The use of furosemide reduces the cost and hospital stay. As furosemide is cheaper and easily available so it can be used easily in the methotrexate clearance.

Meningiomas are one of the most common primary brain tumours, and seizures are a common presenting symptom. Complete tumour resection results in seizure freedom in up to 90% patients. The use of AEDs in these patients is inconsistent, and current evidence shows that they do not have any benefit in long-term seizure prevention after resection. Tumour histology, location, surrounding oedema, recurrence and post-operative complications are important risk factors for having post-operative seizures. Keywords: Brain tumour, Meningioma, Seizure, Anti-epileptic drugs. Continue...

Intraventricular tumours are relatively uncommon among all brain tumours, and non-enhancing lesions, mostly subependymoma, are even less frequently reported. Select cases of subependymoma can show variable contrast enhancement as well. Gross total surgical resection is recommended for treating these lesions, with no significant role of adjuvant chemotherapy or radiotherapy. Keywords: Intraventricular tumors, Subependymoma, Non-enhancing lesions.

With the ever-increasing economic development and population growth in Pakistan, there is an unprecedented increase in demand for electricity. On the other hand, using fossil fuels for the generation of electricity is leading to severe environmental pollution. To solve the above-mentioned problems, the use of renewable energy resources (RES) is gaining considerable attention recently. Ample solar energy resources and vast wastelands make Pakistan an ideal country for the development of solar thermal power. Amongst the available solar power technologies, the concentrated solar power (CSP) system is potentially low cost and has no environmental impact. This paper aims to analyze the prospect of electricity generation using various technologies for concentrated solar power systems in Pakistan.

Stereotactic radiosurgery (SRS) is a choice of treatment for pituitary adenomas (PA), particularly for residual or recurrent disease, apart from surgery. It has a progression free survival and endocrine remission rate comparable to surgery, with fewer side effects, making it an ideal tool for dealing with PA. In this review, we have discussed the role of SRS for primary as well as post-operative residual/ recurrent PA, and have assessed its safety and outcomes. Keywords: Pituitary adenoma, Stereotactic Radiosurgery, SRS, Gamma Knife Radiosurgery.

Background: Intraoperative neurophysiology, high magnification microscopes, and ultrasonic aspirators are considered essential aid for the safe resection of intramedullary spinal cord tumors (IMSCTs). Most centers in developing countries such as Pakistan still lack these facilities. The purpose of this study was to review the management of IMSCTs at our hospital and to determine factors associated with the outcomes of surgery. Methods: This was a retrospective review of medical records of adult patients undergoing surgery for IMSCT over 12 years. The institutional ethical review committee approved this study. Data were collected regarding demographics, clinical and radiological features, and surgical details. Modified McCormick Scale was used to grade patients’ neurological status at admission, discharge, and followup. Statistical analysis was performed using the Statistical Package for Social Sciences version 22. Results: Forty three cases were reviewed. Mean age was 33.8 ± 15.1 years whereas median follow-up was 5 months (range: 0.25–96 months). Most patients had ependymoma (n = 16; 73%). Cervical region was the most commonly involved (n = 15; 34.9%). Gross total resection (GTR) was achieved in 30 cases (69.8%). The preoperative McCormick grade was significantly associated with follow-up McCormick grade (P value = 0.002). Eight patients (18.6%) underwent intraoperative electrophysiological monitoring, out of which GTR was achieved in all cases, and none had disease progression or recurrence. Ten patients received postoperative radiotherapy. Thirty five patients (81.4%) had progression free survival at last follow-up. Conclusions: We achieved a GTR rate of 68.9% for IMSCTs with limited resources. In few cases, where intraoperative electrophysiology was used, the rate of GTR was 100%. Preoperative neurological status was associated with better postoperative McCormick score. [ABSTRACT FROM AUTHOR]

Internet of Things enabled smart grid (SG) is one of the most advanced technologies, which plays a key role in maintaining a balance between demand and supply by implementing demand response (DR) program. In SG, the main focus of the researchers is on home energy management (HEM) system, which is called demand side management. Appliance scheduling is an integral part of HEM system as it manages energy demand according to supply, by automatically controlling the appliances and shifting the load from peak to off peak hours. In this paper, the comparative performance of HEM controller embedded with heuristic algorithms, such as harmony search algorithm, enhanced differential evolution, and harmony search differential evolution, is evaluated. The integration of renewable energy source (RES) in SG makes the performance of HEM system more efficient. The electricity consumption in peak hours usually creates peaks and increases the cost but integration of RES makes the electricity consumer able to use the appliances in the peak hours. We formulate our problem using multiple knapsack theory that the maximum capacity of the consumer of electricity must be in the range, which is bearable for consumer with respect to electricity bill. Feasible regions are computed to validate the formulated problem. Finally, simulation of the proposed techniques is conducted in MATLAB to validate the performance of proposed scheduling algorithms in terms of cost, peak-to-average ratio, and waiting time minimization.

The increasing incident rates of drug-resistant tuberculosis (DR-TB) is a global health concern and has been further complicated by the emergence of extensive and total drug-resistant strains. Identification of new chemical entities which are compatible with first-line TB drugs, possess activity against DR-, and metabolically less active bacteria is required to tackle this epidemic. Here, we have performed phenotypic screening of a small molecule library against Mycobacterium bovis BCG and identified 24 scaffolds that exhibited MIC99 values of at least 2.5 μM. The most potent small molecule identified in our study was a nitroso containing pyrazole derivative, NSC 18725. We observed a significant reduction in viable bacilli load of starved Mycobacterium tuberculosis upon exposure to NSC 18725. The action of NSC 18725 was “synergistic” with isoniazid (INH) and “additive” with other drugs in our checkerboard assays. Structure-activity relationship (SAR) studies of the parent compound revealed that pyrazole derivatives without a functional group at fourth position lacked anti-mycobacterial activity in vitro. The derivative with para-chlorophenyl substitution at the first position of the pyrazole ring was the most active scaffold. We also demonstrate that NSC 18725 is able to induce autophagy in differentiated THP-1 macrophages. The induction of autophagy by NSC 18725 is the major mechanism for the killing of intracellular slow and fast-growing mycobacteria. Taken together, these observations support the identification of NSC 18725 as an antimycobacterial compound, which synergizes with INH, is active against non-replicative mycobacteria and induces autophagy in macrophages.

Objective: To compare the technique of paramedian with midline approach of subarachnoid block in terms of number of attempts and frequency of success rate in elderly patients undergoing elective lower body surgeries. Study Design: Randomized controlled trial. Place and Duration of Study: This study was carried out at Anaesthesia department of Combined Military Hospital Lahore. Six months from Jan 2014 to Jun 2014. Material and Methods: One hundred and seventy elderly patients were scheduled for lower body surgery, using spinal anaesthesia. They were randomized to either Midline approach (n=85) or Paramedian approach (n=85) by lottery method. The outcome measures number of attempts and success rate were noted in both groups and analyzed using SPSS version 18. Results: The successful block in first attempt was 95.3% in Paramedian group and 58.8% in Midline group. Mean number of attempts in paramedian group was 1.24 ± 0.52 as compared to 1.95 ± 0.97 in midline group. A p-value

One of the technical challenges that needs to be addressed for the future of the multi-terminal high voltage direct current (M-HVDC) grid is DC fault isolation. In this regard, HVDC circuit breakers (DCCBs), particularly hybrid circuit breakers (H-DCCBs), are paramount. The H-DCCB, proposed by the ABB, has the potential to ensure a reliable and safer grid operation, mainly due to its millisecond-level current interruption capability and lower on-state losses as compared to electromechanical and solid-state based DCCBs. This paper aims to study and evaluate the operational parameters, e.g., electrical, and thermal stresses on the IGBT valves and energy absorbed by the surge arrestors within H-DCCB during different DC fault scenarios. A comprehensive set of modeling requirements matching with operational conditions are developed. A meshed four-terminal HVDC test bench consisting of twelve H-DCCBs is designed in PSCAD/EMTDC to study the impacts of the M-HVDC grid on the operational parameters of H-DCCB. Thus, the system under study is tested for different current interruption scenarios under a (i) low impedance fault current and (ii) high impedance fault current. Both grid-level and self-level protection strategies are implemented for each type of DC fault.