Search

Muhammad Amir,1,2 Zeeshan Feroz,2,3 Anwar Ejaz Beg2 1Pharmacy Services, Aga Khan University Hospital, Karachi, Pakistan; 2Faculty of Pharmacy, Ziauddin University, Karachi, Pakistan; 3Department of Basic Sciences, King Saud Bin Abdulaziz University, Riyadh, Saudi Arabia Abstract: This paper presents a practice-based conceptual (theoretical) model to address medication adherence. The study reviews literature for different rationales of medication adherence and its associated factors. It also reviews the interventions involved in improving medication adherence and its effect. It is known that many interventions applied have not received great success owing to the fact that they have not been employed in regular clinical practice. Furthermore, models or theories utilized for different interventions were based on patient perspective only. The model presented in the paper is based on health care professionals’ perspective, with an aim to be employed in clinical practice. The model framework is based on five premises on the basis of which the two dynamics, patient and health care professional, work. The model is presented with a graphical representation and exemplary procedural framework. It is also compared to other related procedural models. It is suggested that using such a model will allow medication adherence as an integral part of health care outcomes. Keywords: medication adherence, practice model, health care professional, theoretical concept, pharmacy practice

BACKGROUND: Frontotemporal dementia (FTD) represents a collection of neurobehavioral and neurocognitive syndromes that are associated with a significant degree of clinical, pathological, and genetic heterogeneity. Such heterogeneity hinders the identification of effective biomarkers, preventing effective targeted recruitment of participants in clinical trials for developing potential interventions and treatments. In the present study, we aim to automatically differentiate patients with three clinical phenotypes of FTD, behavioral-variant FTD (bvFTD), semantic variant PPA (svPPA), and nonfluent variant PPA (nfvPPA), based on their structural MRI by training a deep neural network (DNN). METHODS: Data from 277 FTD patients (173 bvFTD, 63 nfvPPA, and 41 svPPA) recruited from two multi-site neuroimaging datasets: the Frontotemporal Lobar Degeneration Neuroimaging Initiative and the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration databases. Raw T1-weighted MRI data were preprocessed and parcellated into patch-based ROIs, with cortical thickness and volume features extracted and harmonized to control the confounding effects of sex, age, total intracranial volume, cohort, and scanner difference. A multi-type parallel feature embedding framework was trained to classify three FTD subtypes with a weighted cross-entropy loss function used to account for unbalanced sample sizes. Feature visualization was achieved through post-hoc analysis using an integrated gradient approach. RESULTS: The proposed differential diagnosis framework achieved a mean balanced accuracy of 0.80 for bvFTD, 0.82 for nfvPPA, 0.89 for svPPA, and an overall balanced accuracy of 0.84. Feature importance maps showed more localized differential patterns among different FTD subtypes compared to groupwise statistical mapping. CONCLUSION: In this study, we demonstrated the efficiency and effectiveness of using explainable deep-learning-based parallel feature embedding and visualization framework on MRI-derived multi-type structural patterns to differentiate three clinically defined subphenotypes of FTD: bvFTD, nfvPPA, and svPPA, which could help with the identification of at-risk populations for early and precise diagnosis for intervention planning.

In this study, 3D printing filaments were produced from hemp hurd fibre-reinforced polylactide (PLA) composites. Hemp hurd microfibres were obtained through alkaline digestion followed by a bleaching treatment and were used to produce PLA-based composites with 20–40 wt% fibre content for fused deposition modelling. Tensile testing of 3D printed composites revealed a gradual increase of Young's modulus with the addition of fibres, reaching a maximum of 7.1 GPa for the 40 wt% composite - a two-fold increase to neat PLA. However, tensile strength was only improved for the 20 wt% formulation, with an increase of 8% in comparison with neat PLA. Nevertheless, the thermo-mechanical properties of the composites were significantly enhanced with the addition of fibres. In addition, physical objects were printed from the recycled filaments to assess their recyclability and printability. It was found that the recycled filaments maintained comparable mechanical properties and printability after three recycling cycles.

Abstract Type-1 diabetes (T1D) is an autoimmune disorder characterized by impaired insulin release by islet β cells. It has been shown that proinflammatory cytokines released during the disease can exacerbate the condition, while anti-inflammatory cytokines offer protection. This study analyzed the clinical role of interleukin (IL)-6, -8, -10, and vitamin D levels in T1D patients compared to healthy controls. The levels of IL-6, IL-8, IL-10, and vitamin D in the participants’ serum samples were analyzed using ELISA. The findings showed that T1D patients had significantly increased levels (p

Cardiovascular disease (CVD) and diabetes mellitus (DM) are the pressing global health issue, with advanced glycation end products (AGEs) playing a crucial role in its development. AGEs are harmful compounds formed through chronic exposure to elevated blood glucose levels and oxidative stress, both of which are prevalent in diabetes mellitus. These molecules have detrimental effects on vascular function, inflammation, and oxidative stress, exacerbating CVD progression. Conventional strategies for managing AGEs are often limited by side effects and insufficient efficacy, driving the need for alternative approaches. This review investigates the intricate relationship between AGEs, diabetes mellitus, and CVD, with a focus on the therapeutic potential of natural products-particularly phenolic compounds. The review explores how AGEs contribute to the pathogenesis of diabetes-related complications and their impact on cardiovascular health. It examines the molecular mechanisms underlying AGE formation and the inhibitory effects of various natural compounds on this process. Additionally, the review assesses preclinical and clinical evidence supporting the efficacy of these natural agents in mitigating AGE-induced damage. By highlighting the significant role of AGEs in diabetes and CVD, the study underscores the potential of natural products to counteract AGE accumulation. It provides an in-depth analysis of AGE biochemistry, their sources, and the effects of different natural products on AGE formation. The review concludes by emphasizing the promise of natural compounds in reducing oxidative stress and inflammation, and thereby lowering the risk of cardiovascular complications associated with diabetes. This comprehensive overview advocates for the integration of natural products into therapeutic strategies for managing AGE-mediated cardiovascular and diabetic conditions.

Introduction: Adolescent girls and young women of childbearing age are the main populations affected by endocrinopathy known as polycystic ovarian syndrome (PCOS). It is especially important to take into account whether clinical and biochemical signs of hyperandrogenism are present in female patients. In maintaining metabolic homeostasis, leptin is crucial. According to research, vitamin D deficiency may play a role in the pathophysiology of PCOS by contributing to insulin resistance, inflammation, dyslipidaemia, and obesity, which are all conditions linked to the syndrome. In this study, leptin and vitamin D3 levels will be measured in order to determine how each relates to the aetiology of PCOS. Materials and Methods: Hundred young women were allocated into two groups, 50 women with PCOS (diagnosed on the basis of revised Rotterdam criteria for PCOS), taken as a study group, and 50 healthy women with no PCOS as control group. Blood samples were collected and tested for hormonal parameters. Results: Between the two groups, there were no appreciable variations in demographic traits. Study groups were found to have considerably higher serum leptin levels than control groups. The study group’s vitamin D3 levels were found to be lower than those of the control group. Conclusion: Patients with PCOS are a special population with distinctive hormonal profiles that differ from typical profiles in healthy populations. Comparing PCOS to healthy individuals, leptin levels were higher while vitamin D3 levels were lower. It is necessary to conduct more extensive research on the involvement of leptin and vitamin D3 in the aetiology of PCOS.

Abstract Centrin1 gene deleted Leishmania donovani parasite (LdCen1 −/− ) was developed and extensively tested experimentally as an intracellular stage-specific attenuated and immunoprotective live parasite vaccine candidate ex vivo using human PBMCs and in vivo in animals. Here we report manufacturing and pre-clinical evaluation of current Good-Laboratory Practice (cGLP) grade LdCen1 −/− parasites, as a prerequisite before proceeding with clinical trials. We screened three batches of LdCen1 −/− parasites manufactured in bioreactors under cGLP conditions, for their consistency in genetic stability, attenuation, and safety. One such batch was preclinically tested using human PBMCs and animals (hamsters and dogs) for its safety and protective immunogenicity. The immunogenicity of the CGLP grade LdCen1 −/− parasites was similar to one grown under laboratory conditions. The cGLP grade LdCen1 −/− parasites were found to be safe and non-toxic in hamsters and dogs even at 3 times the anticipated vaccine dose. When PBMCs from healed visceral leishmaniasis (VL) cases were infected with cGLP LdCen1 −/− , there was a significant increase in the stimulation of cytokines that contribute to protective responses against VL. This effect, measured by multiplex ELISA, was greater than that observed in PBMCs from healthy individuals. These results suggest that cGLP grade LdCen1 −/− manufactured under cGMP complaint conditions can be suitable for future clinical trials.

Sediment accumulation on the bed of open sewers and drains reduces hydraulic efficiency and can cause localized flooding. Slotted invert traps installed underneath the bed of open sewers and drains can eliminate sediment build-up by catching sediment load. Previous three-dimensional (3D) computational studies have examined the particle trapping performance of invert traps of different shapes and depths under varied sediment and flow conditions, considering particles as spheres. For two-dimensional and 3D numerical modeling, researchers assumed the lid geometry to be a thin line and a plane, respectively. In this 3D numerical study, the particle trapping efficiency of a slotted irregular hexagonal invert trap fitted at the flume bottom was examined by incorporating the particle shape factor of non-spherical sewage solid particles and the thicknesses of upstream and downstream lids over the trap in the discrete phase model of the ANSYS Fluent 2020 R1 software. The volume of fluid (VOF) and the realizable k–ε turbulence models were used to predict the velocity field. The two-dimensional particle image velocimetry (PIV) was used to measure the velocity field inside the invert trap. The results showed that the thicknesses of upstream and downstream lids affected the velocity field and turbulent kinetic energy at all flow depths. The joint impact of the particle shape factor and lid thickness on the trap efficiency was significant. When both the lid thickness and particle shape factor were considered in the numerical modeling, trap efficiencies were underestimated, with relative errors of −8.66% to −0.65% in comparison to the experimental values of Mohsin and Kaushal (2017). They were also lower than the values predicted by Mohsin and Kaushal (2017), which showed an overall overestimation with errors of −2.3% to 17.4%.

Background Hydroxychloroquine (HCQ) has proved ineffective in treating patients hospitalised with Coronavirus Disease 2019 (COVID-19), but uncertainty remains over its safety and efficacy in chemoprevention. Previous chemoprevention randomised controlled trials (RCTs) did not individually show benefit of HCQ against COVID-19 and, although meta-analysis did suggest clinical benefit, guidelines recommend against its use. Methods and findings Healthy adult participants from the healthcare setting, and later from the community, were enrolled in 26 centres in 11 countries to a double-blind, placebo-controlled, randomised trial of COVID-19 chemoprevention. HCQ was evaluated in Europe and Africa, and chloroquine (CQ) was evaluated in Asia, (both base equivalent of 155 mg once daily). The primary endpoint was symptomatic COVID-19, confirmed by PCR or seroconversion during the 3-month follow-up period. The secondary and tertiary endpoints were: asymptomatic laboratory-confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection; severity of COVID-19 symptoms; all-cause PCR-confirmed symptomatic acute respiratory illness (including SARS-CoV-2 infection); participant reported number of workdays lost; genetic and baseline biochemical markers associated with symptomatic COVID-19, respiratory illness and disease severity (not reported here); and health economic analyses of HCQ and CQ prophylaxis on costs and quality of life measures (not reported here). The primary and safety analyses were conducted in the intention-to-treat (ITT) population. Recruitment of 40,000 (20,000 HCQ arm, 20,000 CQ arm) participants was planned but was not possible because of protracted delays resulting from controversies over efficacy and adverse events with HCQ use, vaccine rollout in some countries, and other factors. Between 29 April 2020 and 10 March 2022, 4,652 participants (46% females) were enrolled (HCQ/CQ n = 2,320; placebo n = 2,332). The median (IQR) age was 29 (23 to 39) years. SARS-CoV-2 infections (symptomatic and asymptomatic) occurred in 1,071 (23%) participants. For the primary endpoint the incidence of symptomatic COVID-19 was 240/2,320 in the HCQ/CQ versus 284/2,332 in the placebo arms (risk ratio (RR) 0.85 [95% confidence interval, 0.72 to 1.00; p = 0.05]). For the secondary and tertiary outcomes asymptomatic SARS-CoV-2 infections occurred in 11.5% of HCQ/CQ recipients and 12.0% of placebo recipients: RR: 0.96 (95% CI, 0.82 to 1.12; p = 0.6). There were no differences in the severity of symptoms between the groups and no severe illnesses. HCQ/CQ chemoprevention was associated with fewer PCR-confirmed all-cause respiratory infections (predominantly SARS-CoV-2): RR 0.61 (95% CI, 0.42 to 0.88; p = 0.009) and fewer days lost to work because of illness: 104 days per 1,000 participants over 90 days (95% CI, 12 to 199 days; p < 0.001). The prespecified meta-analysis of all published pre-exposure RCTs indicates that HCQ/CQ prophylaxis provided a moderate protective benefit against symptomatic COVID-19: RR 0.80 (95% CI, 0.71 to 0.91). Both drugs were well tolerated with no drug-related serious adverse events (SAEs). Study limitations include the smaller than planned study size, the relatively low number of PCR-confirmed infections, and the lower comparative accuracy of serology endpoints (in particular, the adapted dried blood spot method) compared to the PCR endpoint. The COPCOV trial was registered with ClinicalTrials.gov; number NCT04303507. Interpretation In this large placebo-controlled, double-blind randomised trial, HCQ and CQ were safe and well tolerated in COVID-19 chemoprevention, and there was evidence of moderate protective benefit in a meta-analysis including this trial and similar RCTs. Trial registration ClinicalTrials.gov NCT04303507; ISRCTN Registry ISRCTN10207947., Author(s): William H. K. Schilling 1,2,*, Mavuto Mukaka 1,2, James J. Callery 1,2, Martin J. Llewelyn 3,4, Cintia V. Cruz 1,2, Mehul Dhorda 1,2, Thatsanun Ngernseng 1, Naomi Waithira 1,2, [...]

This study aims to provide an extensive overview of the consequences of heat source and thermal radiation on blood flow in stenosed arteries through Casson fluid. We examine the behaviour of an unsteady non-Newtonian fluid under oscillatory Darcy flow. This analysis explores the impact of blood flow in the stenosed arteries on the momentum and energy profiles of the Casson fluid. In addition, this study examines a parametric analysis to illustrate the impact of the Nusselt number and Casson parameter. Higher values of the thermal radiation and Casson-Viscous parameters result in enhanced velocity fields. The Brinkman model accurately represents the resistance to flow caused by the porous material, known as Darcy resistance. The inner space of the coronary artery generates cholesterol-rich fatty plaques and blood clots that block the artery, simulating the diseased condition of blood circulation in this study. We employ a set of non-dimensional variables to convert the governing equations of the current flow into dimensionless partial differential equations. Analytical methods have derived a solution for the studied problem. The discovery is pertinent to the natural circulation of blood through coronary arteries, which are highly porous. A particular artery pathology creates a permeable structure within the arterial lumen. The current study demonstrates that blood flow may be manipulated by adjusting the intensity of the external magnetic field, while the temperature of the blood can be managed by either increasing or decreasing its thermal conductivity. The graphical representation demonstrates the impact of different physical parameters on velocity, temperature, and concentration profiles. The significant results of the current studies are that, the fluid velocity diminishes with rising magnetic and Biot numbers but exhibits an increase when considering the Darcy number and Hall parameter. There is a gentle increase in the wall shear stress as the Casson parameter (β) increases from 0.1 to 0.3. For β = 0.3, the percentage change along the axial direction (x) is more pronounced. This is because the wall shear stress is proportional to the number of Casson parameters.

Introduction: The translation of gene expression profiles of SCLC to clinical testing remains relatively unexplored. In this study, gene expression variations in SCLC were evaluated to identify potential biomarkers. Methods: RNA expression profiling was performed on 44 tumor samples from 35 patients diagnosed with SCLC using the clinically validated RNA Salah Targeted Expression Panel (RNA STEP). RNA sequencing (RNA-Seq) and immunohistochemistry were performed on two different SCLC cohorts, and correlation analyses were performed for the ASCL1, NEUROD1, POU2F3, and YAP1 genes and their corresponding proteins. RNA STEP and RNA-Seq results were evaluated for gene expression profiles and heterogeneity between SCLC primary and metastatic sites. RNA STEP gene expression profiles of independent SCLC samples (n = 35) were compared with lung adenocarcinoma (n = 160) and squamous cell carcinoma results (n = 25). Results: The RNA STEP results were highly correlated with RNA-Seq and immunohistochemistry results. The dominant transcription regulator by RNA STEP was ASCL1 in 74.2% of the samples, NEUROD1 in 20%, and POU2F3 in 2.9%. The ASCL1, NEUROD1, and POU2F3 gene expression profiles were heterogeneous between primary and metastatic sites. SCLCs displayed markedly high expression for targetable genes DLL3, EZH2, TERT, and RET. SCLCs were found to have relatively colder immune profiles than lung adenocarcinomas and squamous cell carcinomas, characterized by lower expression of HLA genes, immune cell, and immune checkpoint genes, except the LAG3 gene. Conclusions: Clinical-grade SCLC RNA expression profiling has value for SCLC subtyping, design of clinical trials, and identification of patients for trials and potential targeted therapy.

Single agent immune checkpoint inhibitors have been ineffective for patients with advanced stage and recurrent high grade serous ovarian cancer (HGSOC). Using pre-clinical models of HGSOC, we evaluated the anti-tumor and immune stimulatory effects of an oncolytic adenovirus, MEM-288. This conditionally replicative virus encodes a modified membrane stable CD40L and IFNβ. We demonstrated this virus successfully infects HGSOC cell lines and primary human ascites samples in vitro. We evaluated the anti-tumor and immunostimulatory activity in vivo in immune competent mouse models. Intraperitoneal delivery of MEM-288 decreased ascites and solid tumor burden compared to controls, and treatment generated a systemic anti-tumor immune response. The tumor microenvironment had a higher proportion of anti-tumor macrophages and decreased markers of angiogenesis. MEM-288 is a promising immunotherapy agent in HGSOC, with further pre-clinical studies required to understand the mechanism of action in the peritoneal microenvironment and clinical activity in combination with other therapies.

Repositioning of FDA approved/clinical phase drugs has recently opened a new opportunity for rapid approval of drugs, as it shortens the overall process of drug discovery and development. In previous studies, we predicted the possibility of better activity profiles of flavopiridol, the FDA approved orphan drug with better fit value 2.79 using a common feature pharmacophore model for anti-adipogenic compounds (CFMPA). The present study aimed to investigate the effect of flavopiridol on adipocyte differentiation and to determine the underlying mechanism. Flavopiridol inhibited adipocyte differentiation in different cell models like 3T3-L1, C3H10T1/2, and hMSCs at 150 nM. Flavopiridol was around 135 times more potent than its parent molecule rohitukine. The effect was mediated through down-regulation of key transcription factors of adipogenesis i.e. Peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), and their downstream targets, including adipocyte protein −2 (aP2) and fatty acid synthase (FAS). Further, results revealed that flavopiridol arrested the cell cycle in G1/S phase during mitotic clonal expansion by suppressing cell cycle regulatory proteins i.e. Cyclins and CDKs. Flavopiridol inhibited insulin-stimulated signalling in the early phase of adipocyte differentiation by downregulation of AKT/mTOR pathway. In addition, flavopiridol improved mitochondrial function in terms of increased oxygen consumption rate (OCR) in mature adipocytes. In the mouse model of diet-induced obesity, flavopiridol attenuated obesity-associated adipose tissue inflammation and improved serum lipid profile, glucose tolerance as well as insulin sensitivity. In conclusion, the FDA approved drug flavopiridol could be placed as a potential drug candidate for the treatment of cancer and obesity comorbid patients.

Local scour around bridge piers is the common cause of undermining of bridge foundation. Many researchers have studied local scour around bridge pier in finer sediment bed. The literature survey reveals a limited information is available on scour around a group of bridge piers with and without collar founded in gravel bed. Keeping this in view, an attempt is made to examine experimentally the efficacy of the collar around a group of three piers placed in a staggered triangular arrangement in the gravel bed of 3 mm effective size. The data on temporal variation of scour depth, scour hole characteristics, and areal extent of scour hole were collected. The collected experimental results infer very prominent information to the bridge engineers. The obtained results on equilibrium scour depth and areal extent of scour help in knowing the extent up to which bridge pier protection can be provided against scour. It is found that at longitudinal pier spacing (Z) equals to 8.45 times the pier diameter (b), the equilibrium scour depth at nose of the piers was maximum than that of at other pier spacing. At pier spacing Z/b > 8.45, the equilibrium scour depth at downstream pier without collar decreases with increasing pier spacing and reaches to minimum at Z/b = 40. At pier spacing 8.45 10. The present study reveals that bridge piers without collar became free of mutual interference effect on local scour at centre-to-centre (c/c) pier spacing of 60 times the pier diameter. It is worth mentioning that for piers with collar, the effect of mutual interference vanished at c/c longitudinal pier spacing of 20 times the pier diameter. The results show that additional shielding of collar makes the piers free from mutual interference effect at lesser spacing than the pier group without collar. This concludes that the present investigation is very useful when limited space is available between the existing and newly proposed bridges.

Background: Globally, the mortality of non-cardiac surgery patients within the first month is increasing. Monitoring troponin-I levels aids in early mortality risk identification. Hence, the objective of this study was to determine the association between increased postoperative troponin-I levels to 90-day mortality in non-cardiac surgery patients. Methods: This prospective longitudinal study was conducted at Liaquat National Hospital’s general surgery department from June to December 2018. A total of 188 patients aged 40-70 years receiving a general or regional anesthetic, and undergoing emergency/elective surgery with a ≥2 days hospital stays, a procedure time of ≥2 hours, or blood loss of more than 300ml were recruited using a non-probability consecutive sampling technique. Troponin-I levels were assessed 6 to 12 hours post-surgery, followed by a 90-day phone-based mortality check. Data was analyzed using SPSS v.22. The chi-square test and Fisher’s exact test were applied with a p-value

The current study is concerned with Rusafa side of Baghdad city, which extends on 362 square kilometres and is inhabited by 3738371 people. It suffers from population growth, which led to decline in municipal services and rising of land surface temperature (LST) during the summer season. The current study aims to assess the spatial and temporal variation of LST using different dated satellite images of Landsat 4, 7 and 8 at path 168 and raw 037 during July 16, 1989, April 25, 2000, April 26, 2006, and May 31, 2016. Eight analysis models which were built using ERDAS 2014 software are used to calculate the LST parameters; while the land use/land cover (LULC) types are classified using ENVI v.5.3 software. The maximum surface temperature recorded at barren lands are between 26 and 41°C, while at vegetation cover ranging from 25 to 34°C and an inverse correlation are recorded between LST and NDVI ranging from -0.5 to -0.81. The built-up area was increased by 23%, whereas open spaces and vegetation cover are decreased by 16% and 6% respectively all that consequently will make the environment of the study area prone to be warmer.

A study on the neutron production from single and double gas puff Z-pinches on the CESZAR linear transformer driver with ∼0.45 MA current and 170 ns rise time is presented. Total neutron yield measurements made with a LaBr activation detector are compared for three configurations, using a double nozzle setup. When a single, hollow, deuterium gas shell was used, reliable implosions could only be attained at higher load mass than the optimal value to match implosion time with the driver rise time, with neutron yields of ∼106 per pulse. The use of a double gas puff configuration with a deuterium center jet allowed a reduction in the shell density and operation closer to machine-matched conditions, recording up to (4.1 ± 0.3) × 107 neutrons/pulse when either Kr or D2 was used in the shell. For a comparable mass and implosion time, using a higher atomic-number gas in the outer shell results in more unstable plasma surface and smaller plasma radius at the location of instability bubbles, which, however, do not seem to consistently correlate with a higher neutron yield. Comparing implosion dynamics with models and neutron yields with literature scaling suggests that the machine current is not well coupled to the plasma during the final stages of compression. Optimizing current and energy coupling to the pinched plasma is critical to improving performance, particularly in low-impedance drivers. [ABSTRACT FROM AUTHOR]