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Background: Hereditary motor and sensory neuropathy (HMSN) refers to a group of inherited progressive peripheral neuropathies characterized by reduced nerve conduction velocity with chronic segmental demyelination and/or axonal degeneration. HMSN is highly clinically and genetically heterogeneous with multiple inheritance patterns and phenotypic overlap with other inherited neuropathies and neurodegenerative diseases. Due to this high complexity and genetic heterogeneity, this study aimed to elucidate the genetic causes of HMSN in Pakistani families using Whole Exome Sequencing (WES) for variant identification and Sanger sequencing for validation and segregation analysis, facilitating accurate clinical diagnosis. Methods: Families from Khyber Pakhtunkhwa with at least two members showing HMSN symptoms, who had not previously undergone genetic analysis, were included. Referrals for genetic investigations were based on clinical features suggestive of HMSN by local neurologists. WES was performed on affected individuals from each family, with Sanger sequencing used to validate and analyze the segregation of identified variants among family members. Clinical data including age of onset were assessed for variability among affected individuals, and the success rate of genetic diagnosis was compared with existing literature using proportional differences and Cohen's h. Results: WES identified homozygous pathogenic variants in GDAP1 (c.310 + 4 A > G, p.?), SETX (c.5948_5949del, p.(Asn1984Profs*30), IGHMBP2 (c.1591 C > A, p.(Pro531Thr) and NARS1 (c.1633 C > T, p.(Arg545Cys) as causative for HMSN in five out of nine families, consistent with an autosomal recessive inheritance pattern. Additionally, in families with HMSN, a SETX variant was found to cause cerebellar ataxia, while a NARS1 variant was linked to intellectual disability. Based on American College of Medical Genetics and Genomics criteria, the GDAP1 variant is classified as a variant of uncertain significance, while variants in SETX and IGHMBP2 are classified as pathogenic, and the NARS1 variant is classified as likely pathogenic. The age of onset ranged from 1 to 15 years (Mean = 5.13, SD = 3.61), and a genetic diagnosis was achieved in 55.56% of families with HMSN, with small effect sizes compared to previous studies. Conclusions: This study expands the molecular genetic spectrum of HMSN and HMSN plus type neuropathies in Pakistan and facilitates accurate diagnosis, genetic counseling, and clinical management for affected families. [ABSTRACT FROM AUTHOR]

Background: Hereditary Spastic Paraplegias (HSPs) and Hereditary Cerebellar Ataxias (HCAs) are progressive neurodegenerative disorders encompassing a spectrum of neurogenetic conditions with significant overlaps of clinical features. Spastic ataxias are a group of conditions that have features of both cerebellar ataxia and spasticity, and these conditions are frequently clinically challenging to distinguish. Accurate genetic diagnosis is crucial but challenging, particularly in resource-limited settings. This study aims to investigate the genetic basis of HSPs and HCAs in Pakistani families. Methods: Families from Khyber Pakhtunkhwa with at least two members showing HSP or HCA phenotypes, and who had not previously been analyzed genetically, were included. Families were referred for genetic analysis by local neurologists based on the proband's clinical features and signs of a potential genetic neurodegenerative disorder. Whole Exome Sequencing (WES) and Sanger sequencing were then used to identify and validate genetic variants, and to analyze variant segregation within families to determine inheritance patterns. The mean age of onset and standard deviation were calculated to assess variability among affected individuals, and the success rate was compared with literature reports using differences in proportions and Cohen's h. Results: Pathogenic variants associated with these conditions were identified in five of eight families, segregating according to autosomal recessive inheritance. These variants included previously reported SACS c.2182 C > T, p.(Arg728*), FA2H c.159_176del, p.(Arg53_Ile58del) and SPG11 c.2146 C > T, p.(Gln716*) variants, and two previously unreported variants in SACS c.2229del, p.(Phe743Leufs*8) and ZFYVE26 c.1926_1941del, p.(Tyr643Metfs*2). Additionally, FA2H and SPG11 variants were found to have recurrent occurrences, suggesting a potential founder effect within the Pakistani population. Onset age among affected individuals ranged from 1 to 14 years (M = 6.23, SD = 3.96). The diagnostic success rate was 62.5%, with moderate effect sizes compared to previous studies. Conclusions: The findings of this study expand the genotypic and phenotypic spectrum of HSPs and HCAs in Pakistan and emphasize the importance of utilizing exome/genome sequencing for accurate diagnosis or support accurate differential diagnosis. This approach can improve genetic counseling and clinical management, addressing the challenges of diagnosing neurodegenerative disorders in resource-limited settings. [ABSTRACT FROM AUTHOR]

Influence of different levels of silicon under a variety of thermal treatment is investigated on the thermophysical behaviour of Al-Si-Cu-Mg automotive alloys. Conventional cast alloys are subjected to T6 heat treatment for age hardening. Hardness values, thermal conductivity along with microstructural observation under different heattreated conditions are well thought-out to comprehend the ageing performance and the precipitation behaviour of the alloys. From these investigational results it is indicated that two successive hardening peaks take place in the aged alloys. Ageing sequence consists of different phases like a supersaturated solid solution, GP zones, intermediate β", intermetallic β', equilibrium β and the Q phase but GP zones and the metastable phases are most likely responsible for these ageing peaks. Thermal conductivity decreases for these precipitates formation during ageing and increases for relieving the internal stress, dissolution of metastable phase and coarsening the precipitation of the alloys. Adding up of Si to the alloy showed earlier ageing peaks with higher intensities intended for its increasing properties of heterogeneous nucleation and diffusion kinetics. After ageing around at 200°C for four hours the alloys offer the height hardness. Microstructural study reveals that eutectic silicon makes the grain boundary coarsen and beyond the eutectic composition the star-shaped blocky primary Si is formed. Subsequent to ageing at 350oC for one hour the alloys reach completely recrystallized state. [ABSTRACT FROM AUTHOR]

Background: Severe sepsis and septic shock are two major causes of death in children with sepsis. The Pediatric risk of mortality (PRISM) score allows for mortality risk assessment in the pediatric ICU. It is institution-independent and can be used within limits to compare different intensive care units. Materials and Methods: It was a prospective observational hospital based study. All patients admitted in the Paediatric Intensive Care Unit between the age group of one month to 14 years who fulfilled the inclusion criteria were prospectively observed and details were recorded in a predesigned proforma. Critical illness severity was estimated with the Paediatric Risk of Mortality (PRISM III-24) score. Results: 30 patients (14 males & 16 females) were included in the study&mortality rate of 40.0% was witnessed.29(96.7%) patients were given pressor support. In terms of outcome, 17(94.4%) of the 18 discharged patients received pressor support and 01(5.6%) of them did not receive any pressor support. On the other hand, all 12 expired patients received pressor support (P=0.406). 25(83.3%) patients required mechanical ventilation. In terms of outcome, 14(77.8%) of the discharged patients required mechanical ventilation while 04(22.2%) of them did not require it. On the other hand, out of 16 patients who expired, 11(91.7%) required mechanical ventilation while 01(8.3%) did not require it (P=0.317). None of the patients, either from the discharged ones or from the expired ones, had a low-risk HsCRP level(<3). The mean PRISM III Score at admission in discharged patients was 20.5±3.65 and the mean PRISM III Score at admission in expired patients was 23.25±1.76 (P=0.01). The mean PRISM III score at 24 hours in discharged patients was 17.33±4.46 and the mean PRISM III score in expired patients was 22.50±1.50 (P=0.001). When analyzed in specificity versus threshold (ROC) curve, PRISM III Score was significant at both time intervals i.e., at admission (P=0.019) and at 24 hours (P=0.003). Conclusion:. [ABSTRACT FROM AUTHOR]

Self-compacting mortar (SCM) has superior workability and long-term durable performance compared to traditional mortar. The strength of SCM, including both its compressive and flexural strengths, is a crucial property that is determined by appropriate curing conditions and mix design parameters. In the context of materials science, predicting the strength of SCM is challenging because of multiple influencing factors. This study employed machine learning techniques to establish SCM strength prediction models. Based on ten different input parameters, the strength of SCM specimens were predicted using two different types of hybrid machine learning (HML) models, namely Extreme Gradient Boosting (XGBoost) and the Random Forest (RF) algorithm. HML models were trained and tested by experimental data from 320 test specimens. In addition, the Bayesian optimization method was utilized to fine tune the hyperparameters of the employed algorithms, and cross-validation was employed to partition the database into multiple folds for a more thorough exploration of the hyperparameter space while providing a more accurate assessment of the model's predictive power. The results show that both HML models can successfully predict the SCM strength values with high accuracy, and the Bo-XGB model demonstrated higher accuracy (R2 = 0.96 for training and R2 = 0.91 for testing phases) for predicting flexural strength with low error. In terms of compressive strength prediction, the employed BO-RF model performed very well, with R2 = 0.96 for train and R2 = 0.88 testing stages with minor errors. Moreover, the SHAP algorithm, permutation importance and leave-one-out importance score were used for sensitivity analysis to explain the prediction process and interpret the governing input variable parameters of the proposed HML models. Finally, the outcomes of this study might be applied to guide the future mix design of SCM specimens. [ABSTRACT FROM AUTHOR]

Horizontal directional drilling (HDD) is a widely used trenchless method for underground utility connections. The associated ground settlement triggered by HDD depends on the size, types, and surface texture of pipe, diameter of borehole, and soil conditions. The present study investigates the surface settlement due to the construction of a 1067 mm diameter HDD, which will replace an existing sewer siphon under the SR-60 highway in Chino, California using empirical, and numerical methods. Based on the results obtained from the subsurface investigation, an empirical analysis was conducted first. followed by numerical modeling of the HDD using PLAXIS 2D software. A careful comparison between two different methods indicated closer values of surface settlement between the empirical method (7.3 mm) and the numerical modeling (4.6 mm). In addition, the shape of surface settlement and horizontal settlement curves for the empirical and numerical methods was found to be similar. The minor discrepancy between the two methods resulted as the numerical model can host several soil layers whereas the empirical equation can use only one type of soil. Finally, a parametric study was conducted to evaluate the effect of borehole cover depth, size, and soil parameters on surface settlement. It was observed that soil strength parameters yielded a greater effect on surface movement, whereas modulus of elasticity has a relatively smaller influence with zero contribution from Poisson's ratio. [ABSTRACT FROM AUTHOR]

Pesticides are widely used to control weeds and pests in agricultural settings but harm non-target aquatic organisms. In this study, our objective was to evaluate the effect of short-term exposure (one week) to environmentally relevant concentrations of pesticides mixture (low concentration: 0.4 μg/l atrazine, 0.5 μg/l Roundup®, and 0.5 μg/l 2,4-D; high concentration: 0.8 μg/l atrazine, 1 μg/l Roundup®, and 1 μg/l 2,4-D) on tissue architecture, body fluid conditions, and 3-nitrotyrosine protein (NTP) and Na+/K+-ATPase, expressions in tissues of American oyster (Crassostrea virginica) under controlled laboratory conditions. Histological analysis demonstrated the atrophy in the gills and digestive glands of oysters exposed to pesticides mixture. Periodic acid-Schiff (PAS) staining showed the number of hemocytes in connective tissue increased in low- and high-concentration pesticides exposure groups. However, pesticides treatment significantly (P < 0.05) decreased the amount of mucous secretion in the gills and digestive glands of oysters. The extrapallial fluid (i.e., body fluid) protein concentrations and glucose levels were dropped significantly (P < 0.05) in oysters exposed to high-concentration pesticides exposure groups. Moreover, immunohistochemical analysis showed significant upregulations of NTP and Na+/K+-ATPase expressions in the gills and digestive glands in pesticides exposure groups. Our results suggest that exposure to environmentally relevant pesticides mixture causes morphological changes in tissues and alters body fluid conditions and NTP and Na+/K+-ATPase expressions in tissues, which may lead to impaired physiological functions in oysters. [Display omitted] • Pesticides are widely used to control weeds and pests in agricultural settings. • Aquatic environments are becoming increasingly inundated by pesticides. • Pesticides harm non-target aquatic organisms. • Pesticides altered the morphology of gills and digestive glands of oysters. • Pesticides induced nitrative stress and Na+/K+-ATPase expression in oysters. [ABSTRACT FROM AUTHOR]

The penetration of microwave power inside a human head model is improved by employing a dielectric loaded rectangular waveguide as the transmission source. A multi-layer reflection model is investigated to evaluate the combined material characteristics of different lossy human head tissues at 2.45 GHz. A waveguide loaded with a calculated permittivity of 3.62 is shown to maximise the microwave power penetration at the desired frequency. A Quartz (SiO2) loaded rectangular waveguide fed by a microstrip antenna is designed to validate the power penetration improvement inside an inhomogeneous human head phantom. A measured 1.33 dB power penetration increment is observed for the dielectric loaded waveguide over a standard rectangular waveguide at 50 mm inside the head, with an 81.9% reduction in the size of the transmission source. [ABSTRACT FROM AUTHOR]

Oral cancer has become serious health issues. It is owing to a variety of factors including poor hygiene, tobacco usage, chewing tobacco, smoking, and others. Along with surgery and chemotherapy, the most common treatments include radiation therapy and chemotherapy. Patients with cancer may experience oral toxic effects as a result of antineoplastic therapy such as radiotherapy and chemotherapy. A variety of factors influence radiation, including the oral mucosa’s fast cell turnover rate, the richness and complexity of the oral microbiota, and soft tissue stress during normal mouth function. The present literature review is for awareness regarding the main oral manifestation secondary to post cancer therapy. [ABSTRACT FROM AUTHOR]

We propose a periodically modulated metasurface (MTS) capable of producing two-sided electromagnetic (EM) beams with frequency-controlled beam reconfiguration. The beam-forming functionality is realized through the leaky-wave (LW) conditions of the periodic structure, and the beam reconfiguration at quadrature azimuth angle is triggered by switching between the two operating frequencies. The MTS is formed using a periodic homogeneous array of split ring resonators (SRRs) with anisotropic characteristics. The EM bandgap (EBG) properties and LW conditions of the individual SRRs are combined to produce both beam-forming and beam-reconfiguration functionalities. The subwavelength SRR unit cells are designed such that they satisfy LW theory at 1.8 GHz to form a two-sided beam along azimuth angles 0° and 180° and create a complete EBG at 2.6 GHz to form a two-sided beam along angles 90° and 270° at 2.6 GHz. Both the TE and TM mode responses of the individual SRRs are taken into consideration during the design process. The MTS structure is synthesized and evaluated using full-wave EM simulator and is validated with the experimental results. [ABSTRACT FROM AUTHOR]

The use of the Internet of Things (IoT) is steadily increasing in a wide range of applications. Among these applications, safety and security are some of the prominent applications. Through surveillance systems, we can restrict access to our premises and thus secure our assets. Nowadays face detection and recognition enabled surveillance systems are available in the market, which can detect faces from video frames captured using IP cameras, and then recognize those faces by comparing them with existing databases. However, higher prices and low accuracy are impeding the large scale deployment of those systems. In this paper, we have proposed a generic architecture for face detection and recognition system from real-time video frames that have been captured through IP cameras and processed using low-cost IoT devices by utilizing Cloud computing services. We have selected two IoT platforms: Eclipse Mosquitto IoT broker and Kaa IoT middleware to implement our proposed architecture. The face detection part is deployed in the IoT devices and the computation-intensive task, i.e., face recognition is carried out in backend Cloud servers. We have executed our experiments in two different Cloud infrastructures: Core Cloud and Edge Cloud and measured the total processing time in different scenarios. The experimental results show that the performance of the Mosquitto broker in terms of total processing time is better than Kaa middleware. Total processing time can be further reduced by deploying a face recognition application from Core Cloud to Edge Cloud. Furthermore, the k-nearest neighbor algorithm shows promising results compared to other face recognition algorithms. [ABSTRACT FROM AUTHOR]

An anisotropic impedance surface based on electromagnetic bandgap (EBG) theory is proposed to produce reconfigurable dual-beam radiation through surface-wave (SW) lensing by controlling SW propagation across the surface-to-air interface. The reconfiguration of the lensing effect is triggered by switching between 4.0- and 4.5-GHz frequencies, utilizing the anisotropy of the impedance surface created from two mutually exclusive EBGs along the two orthogonal spaces. The bandgaps are formed by a periodic arrangement of two different split-ring resonators (SRRs) with bandgaps at around 4.0 and 4.5 GHz along the orthogonal $y$ - and $x$ -axes, respectively, producing a strong axially symmetric anisotropy. As a result, a surface-bound wave, i.e., both transverse electric (TE) and transverse magnetic (TM), faces asymmetric propagation reluctance toward these two directions one of which is very high compared to the other at frequencies around the individual bandgaps of the unit cells. The proposed impedance surface is designed and simulated using commercial electromagnetic simulation software and then fabricated and measured to validate the model. [ABSTRACT FROM AUTHOR]

A compact 3-D antenna for microwave medical diagnosis is presented. The antenna is matched with an inhomogeneous human head allowing higher signal penetration so as to obtain more meaningful data reflected from inside the brain. Utilizing a folded inverted F-like structure and a slot-loaded ground plane, the antenna is a compact $0.23\,\,\lambda \times 0.23 \,\,\lambda \times 0.04 \,\,\lambda $ in size with respect to the lowest operating frequency. The antenna is backed with a rectangular cavity to minimize sidelobe and backlobe radiation. The cavity and folded antenna configuration achieve a highly directional radiation pattern toward the head with a front-to-back ratio of more than 17 dB. A curved inhomogeneous human head phantom is fabricated to validate the antenna performance for medical diagnosis applications. An operational frequency band from 1 to 1.7 GHz is achieved with the antenna attached to the surface of the phantom. Less than 0.0147 W/kg SAR is achieved throughout the operating frequency range, which is lower than the state of the art for comparable antennas. The salient characteristics of the proposed antenna make it a suitable candidate for microwave diagnosis of the human head. [ABSTRACT FROM AUTHOR]

This paper presents a custom made small rover based surveying, mapping and building information modeling solution. Majority of the commercially available mobile surveying systems are larger in size which restricts their maneuverability in the targeted indoor vicinities. Furthermore their functional cost is unaffordable for low budget projects belonging to developing markets. Keeping in view these challenges, an economical indigenous rover based scanning and mapping system has developed using orthogonal integration of two low cost RPLidar A1 laser scanners. All the instrumentation of the rover has been interfaced with Robot Operating System (ROS) for online processing and recording of all sensorial data. The ROS based pose and map estimations of the rover have performed using Simultaneous Localization and Mapping (SLAM) technique. The perceived class 1 laser scans data belonging to distinct vicinities with variable reflective properties have been successfully tested and validated for required structural modeling. Systematically the recorded scans have been used in offline mode to generate the 3D point cloud map of the surveyed environment. Later the structural planes extraction from the point cloud data has been done using Random Sampling and Consensus (RANSAC) technique. Finally the 2D floor plan and 3D building model have been developed using point cloud processing in appropriate software. Multiple interiors of existing buildings and under construction indoor sites have been scanned, mapped and modelled as presented in this paper. In addition, the validation of the as-built models have been performed by comparing with the actual architecture design of the surveyed buildings. In comparison to available surveying solutions present in the local market, the developed system has been found faster, accurate and user friendly to produce more enhanced structural results with minute details. [ABSTRACT FROM AUTHOR]

Postharvest losses in fruits and vegetables pose a key challenge to the global horticulture industry. Improved storage stability of horticultural commodities through irradiation is a technological intervention which has greater compliance over more than 60 foods and food products. The present study was intended to explore the effect of γ-irradiation doses on the postharvest quality of fresh guava fruits stored under ambient (temperature 20 ± 2 °C, RH 85%) conditions. Various storage specific quality attributes including physiological weight loss, respiration rate (CO2), ethylene estimation, ripening index, fruit firmness, ascorbic acid, nutraceutical potential, and enzyme kinetics were evaluated during postharvest storage at four days of interval. The results indicated that the fruits irradiated at doses (0.8 kGy and 1.0 kGy) exhibited significant reduction in physiological parameters in contrast with untreated fruit samples. Firmness, total phenolic compounds, flavonoids, and radical scavenging activity were successfully retained in irradiated fruit samples up to twenty days of storage. The respiration and ethylene production rates were suppressed in irradiated guava fruits compared to control. Moreover, it has also been discovered that the fruits exposed to 1.0 kGy had considerably decreased the polyphenol oxidase (PPO) activity compared to nonirradiated fruits, thus resulting in lowering the enzymatic browning. Aside from that, irradiation guava fruits had considerably enhanced antioxidant enzyme activity (P ≤ 0.05) in terms of catalase, peroxidase, and superoxide dismutase. In conclusion, the study revealed that γ -rays irradiation doses up to 1.0 kGy might be considered effective to improve the postharvest storage of native guava fruits variety with intact nutritional attributes. [ABSTRACT FROM AUTHOR]

Pre-eclampsia is a vascular disorder of pregnancy where anti-angiogenic factors, systemic inflammation and oxidative stress predominate, but none can claim to cause pre-eclampsia. This review provides an alternative to the 'two-stage model' of pre-eclampsia in which abnormal spiral arteries modification leads to placental hypoxia, oxidative stress and aberrant maternal systemic inflammation. Very high maternal soluble fms-like tyrosine kinase-1 (s Flt-1 also known as s VEGFR) and very low placenta growth factor ( PlGF) are unique to pre-eclampsia; however, abnormal spiral arteries and excessive inflammation are also prevalent in other placental disorders. Metaphorically speaking, pregnancy can be viewed as a car with an accelerator and brakes, where inflammation, oxidative stress and an imbalance in the angiogenic milieu act as the 'accelerator'. The 'braking system' includes the protective pathways of haem oxygenase 1 (also referred as Hmox1 or HO-1) and cystathionine- γ-lyase (also known as CSE or Cth), which generate carbon monoxide ( CO) and hydrogen sulphide ( H2S) respectively. The failure in these pathways (brakes) results in the pregnancy going out of control and the system crashing. Put simply, pre-eclampsia is an accelerator-brake defect disorder. CO and H2S hold great promise because of their unique ability to suppress the anti-angiogenic factors s Flt-1 and soluble endoglin as well as to promote PlGF and endothelial NOS activity. The key to finding a cure lies in the identification of cheap, safe and effective drugs that induce the braking system to keep the pregnancy vehicle on track past the finishing line. Linked Articles This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit [ABSTRACT FROM AUTHOR]

This paper provides a comprehensive review of travel-time budget (TTB) studies in the literature for about the past four decades. Starting with the concept of TTBs, it discusses both the studies that support the existence of TTB and also those that deem the concept to be unfounded. Sociodemographic variables and their relation to TTB are also discussed briefly. However, as past studies use different data sources, survey techniques, and methodology for analysis, cross comparison of studies is not possible. Most importantly, the underlying cause of the regularity that is found at an aggregate level is still not known. The idea of TTB is important because, if it exists, it would mean that the total time spent on travelling per person per day will remain unchanged in spite of all improvements to transport. TTB has immense implications for transport policies and it is usually ignored. The paper also explores the available theoretical explanation of this concept, past research gaps and new analysis potentials. Recent directions in TTB studies are also discussed together with the potential use of multiday multiyear panel data in TTB research to explore the phenomenon better than before. [ABSTRACT FROM PUBLISHER]

Abstract: Alzheimer's disease (AD) is the most common form of dementia, with over 37 million sufferers worldwide and a global cost of over $600 billion. There is currently no cure for AD and no reliable method of diagnosis other than post-mortem brain examination. The development of a point-of-care test for AD is an urgent requirement in order to provide earlier diagnosis and, thus, useful therapeutic intervention. Here, we present a novel, label-free impedimetric biosensor for the specific detection of amyloid-beta oligomers (AβO), which are the primary neurotoxic species in AD. AβO have been proposed as the best biomarker for AD and levels of AβO in the blood have been found to correlate with cerebrospinal fluid load. The biorecognition element of our biosensor is a fragment of the cellular prion protein (PrPC, residues 95–110), a highly expressed synaptic protein which mediates the neuronal binding and toxicity of AβO. During the layer-by-layer sensor construction, biotinylated PrPC (95–110) was attached via a biotin/NeutrAvidin bridge to polymer-functionalised gold screen-printed electrodes. Electrochemical impedance spectroscopy (EIS), cyclic voltammetry and scanning electron microscopy were used to validate biosensor assembly and functionality. EIS was employed for biosensor interrogation in the presence of Aβ oligomers or monomers. The biosensor was specific for the detection of synthetic AβO and gave a linear response, without significant detection of monomeric Aβ, down to an equivalent AβO concentration of ~0.5pM. The biosensor was also able to detect natural, cell-derived AβO present in conditioned medium. The eventual commercialisation of this biosensor system could allow for the early diagnosis and disease monitoring of AD. [Copyright &y& Elsevier]

Abstract: Heme oxygenase (Hmox) is an endogenous system that offers protection against placental cytotoxic damage associated with preeclampsia. The Hmox1/carbon monoxide (CO) pathway inhibits soluble Flt-1 (sFlt-1) and soluble Endoglin (sEng). More importantly, statins induce Hmox1 and suppress the release of sFlt-1 and sEng; thus, statins and Hmox1 activators are potential novel therapeutic agents for treating preeclampsia. The contribution of the Hmox system to the pathogenesis of preeclampsia has been further indicated by the incidence of preeclampsia being reduced by a third in smokers, who had reduced levels of circulating sFlt-1. Interestingly, preeclamptic women exhale less CO compared with women with healthy pregnancies. Hmox1 is reduced prior to the increase in sFlt-1 as Hmox1 mRNA expression in the trophoblast is decreased in the first trimester in women who go on to develop preeclampsia. Induction of Hmox1 or exposure to CO or bilirubin has been shown to inhibit the release of sFlt-1 and sEng in animal models of preeclampsia. The functional benefit of statins and Hmox1 induction in women with preeclampsia is valid not only because they inhibit sFlt-1 release, but also because statins and Hmox1 are associated with anti-apoptotic, anti-inflammatory, and anti-oxidant properties. The StAmP trial is the first randomized control trial (RCT) evaluating the use of pravastatin to ameliorate severe preeclampsia. This proof-of-concept study will pave the way for future global RCT, the success of which will greatly contribute to achieving the United Nations Millennium Development Goals (MDG4 and MDG5) and offering an affordable and easily accessible therapy for preeclampsia. [Copyright &y& Elsevier]

Streptococcus pyogenes, also known as group A streptococcus (GAS), is a Gram positive human pathogen responsible for invasive and noninvasive human infections with a high incidence rate. Traditional detection methods involve cell culture and PCR, which are limited by long processing times or the need for high cost equipment. Impedance-based electrochemical immunosensors provide an alternative by which precise and rapid quantitative detection of the organism can help with rapid clinical decisions. To bring a biosensor for point-of-care applications to market, strict optimization of each level of construction and operation is required. In this paper, commercial screen-printed gold electrodes have been used to construct polytyramine (Ptyr)-based immunosensors. Biotin tagged whole antibodies against S. pyogenes were conjugated to Ptyr amine group via biotin-NeutrAvidin coupling. Sensors were optimized at each level of construction, particularly for Ptyr electrodeposition and antibody concentration, to optimize signal and specificity. Scanning electron microscopy, fluorescence microscopy, and on-sensor analysis (HRP conjugated enhanced chemiluminescence-based semiquantitative method) to detect Ptyr surface amine and bound antibody were performed as supporting techniques. Cumulative and single shot incubations had shown detection range of 100 to 105 cells per 10 μL and 100 to 104 cells per 10 μL of bacteria in PBS, respectively. Sensors were also able to specifically detect S. pyogenes in 50% (v/v) human saliva, with good selectivity and low cross-reactivity. [ABSTRACT FROM AUTHOR]

The inhibitor kappaB kinase β (IKK β) is a serine-threonine protein kinase that is critically involved in the activation of the transcription factor nuclear factor kappa B (NF-κB) in response to various inflammatory stimuli. IKK β-selective inhibitors could prove useful for the treatment of inflammatory diseases. In the absence of structural information, a ligand-based approach can serve as an alternative to the virtual screening of large databases. We have developed a 3D QSAR pharmacophore model based on 23 IKK β inhibitors with 3 nM ≤ IC ≤ 50000 nM. A four-feature pharmacophore containing a hydrophobic (Hy) feature, two ring aromatic (RA) features, and a hydrogen bond donor (D) feature was constructed. It yielded a correlation coefficient of 0.93 with experimentally determined activity data, and a correlation coefficient of 0.77 with training set activity data. The best hypothesis, Hypo 1, was validated by estimating the activities of 136 compounds in a test set. As well as the correlation analysis and test set activity estimation, a Fisher's validation test was conducted at the 95% confidence level. The pharmacophore model's specificity and selectivity were determined in an exhaustive enrichment study. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Abstract: Pharmacophore modelling, docking and virtual screening have become important tool in drug discovery process. Serotonin 2C (5-HT2C) receptor ligands have got major attention for their therapeutic uses as antidepressant and anorectic agents. Two step pharmacophore and docking based virtual screening was done using 5-HT2C agonists. Two common feature pharmacophore directed virtual hits had submicromolar activity. Refined pharmacophore with excluded volumes was constructed and combined with homology model based docking. Best hit from this virtual screening showed IC50 of 20.1nM. Similarity search of this hit compound resulted more active ligand with 7.8nM activity. [Copyright &y& Elsevier]

Differential splicing of the flt-1 mRNA generates soluble variant of vascular endothelial growth factor (VEGF) receptor-1 (sVEGFR-1, also known as sFlt-1). The action of VEGF is antagonized by sVEGFR-1. Soluble VEGFR-1 binds to VEGF with a high affinity and therefore works to modulate VEGF and VEGF signaling pathway. In this study, the authors tested the hypothesis that VEGF-mediated endothelial cell angiogenesis is tightly modulated by the release of sVEGFR-1 and placental expression of sVEGFR-1 is upregulated by hypoxia. Immunolocalization studies showed progressively intense staining for sVEGFR-1 and VEGF in the trophoblast of placental villous explants throughout gestation. Endothelial cell migration studies using a modified Boyden's chamber showed a significant increase in cell migration in response to VEGF that was significantly attenuated in the presence of exogenous sVEGFR-1. Furthermore, stimulation of endothelial cells with VEGF led to a dose-dependent increase in the release of sVEGFR-1 as determined by enzyme-linked immunosorbent assay (ELISA). Exposure of normal placental villous explants to hypoxia (1% pO 2 ) increased trophoblast expression of sVEGFR-1 when compared with tissue normoxia (5% pO 2 ). In addition, conditioned media from hypoxia treated placental villous explants induced a significant increase in endothelial cell migration that was significantly reduced in presence of sVEGFR-1. Our study demonstrates that hypoxia positively regulates sVEGFR-1 protein expression in ex vivo trophoblasts, which control VEGF-driven angiogenesis. [ABSTRACT FROM AUTHOR]

[Display omitted] Recently developed medicated dressings target either bacterial or fungal infection only, which is not effective for the treatment of mixed infections common in diabetic foot ulcers (DFUs). This study aimed to develop advanced bioactive alginate-based dressings (films and wafers) to deliver therapeutically relevant doses of ciprofloxacin (CIP) and fluconazole (FLU) to target mixed bacterial and fungal infections in DFUs. The alginate compatibility with the drugs was confirmed by SEM, XRD, FTIR and texture analysis, while the medicated wafers showed better fluid handling properties than the films in the presence of simulated wound fluid. The dressings showed initial fast release of FLU followed by sustained release of CIP which completely eradicated E. coli , S. aureus , P. aeruginosa and reduced fungal load (C. albicans) by 10-fold within 24 h. Moreover, the medicated dressings were biocompatible (>70% cell viability over 72 h) with human primary adult keratinocytes and in-vitro scratch assay showed 65–68% wound closure within 7 days. [ABSTRACT FROM AUTHOR]

Examines the effect of mitogenic concentrations of basic fibroblast growth factor (bFGF) on the activation of phospholipase D (PLD). Effect of the activation of protein kinase C (PKC) on bFGF-induced PLD activation; Mitogenic activity of bFGF in human umbilical vascular endothelial (HUVE) cells; Mitogenesis; Fibroblast growth factor.

Objective: To evaluate total mechanical gastroesophageal anastomosis in patients with carcinoma of esophagus. Study Design: Cross sectional study. Place and Duration of Study: Department of Surgery, Bolan Medical University, from Jan 2020 to Jun 2021. Methodology: Total of 75 patients were included consecutively in this observational cross sectional study involving patients diagnosed with esophageal cancer and awaiting to undergo esophagiectomy with mechanical anastomosis in-between 18 to 60 years and were ASA I and II were included. Patients that were ASA III or IV and having any systemic disorder and those that refused to participate were excluded. SPSS version 23.0 was used for data analysis keeping p-value <0.05 as significant. Results: Mean age of patients was 58.31 ± 6.2 years wherein 42(56%) males and 33(44%) females. 29 (38.7%) of patients were ASA I while 46 (61.3%) were ASA II. Mean operative time of patients was 240 ± 65.2 minutes while mean blood loss was 205 ± 32.3 ml. Regarding anastomotic leakage, minor (type I) leakage was observed in 05(6.7%) of patients while major (type II or III) leakage was seen in 03(4%) of patients. Anastomotic dilatation, stricture formation and death were reported in 01(1.33%) patient each. Conclusion: Total mechanical gastro-esophageal anastomosis was found to have safe, less time consuming and with minimal post-operative anastomotic leakage or stricture formation and morbidity. [ABSTRACT FROM AUTHOR]

Background: Epilepsy, a challenging neurological condition, is often present with comorbidities that significantly impact diagnosis and management. In the Pakistani population, where financial limitations and geographical challenges hinder access to advanced diagnostic methods, understanding the genetic underpinnings of epilepsy and its associated conditions becomes crucial. Methods: This study investigated four distinct Pakistani families, each presenting with epilepsy and a spectrum of comorbidities, using a combination of whole exome sequencing (WES) and Sanger sequencing. The epileptic patients were prescribed multiple antiseizure medications (ASMs), yet their seizures persist, indicating the challenging nature of ASM-resistant epilepsy. Results: Identified genetic variants contributed to a diverse range of clinical phenotypes. In the family 1, which presented with epilepsy, developmental delay (DD), sleep disturbance, and aggressive behavior, a homozygous splice site variant, c.1339–6 C > T, in the COL18A1 gene was detected. The family 2 exhibited epilepsy, intellectual disability (ID), DD, and anxiety phenotypes, a homozygous missense variant, c.344T > A (p. Val115Glu), in the UFSP2 gene was identified. In family 3, which displayed epilepsy, ataxia, ID, DD, and speech impediment, a novel homozygous frameshift variant, c.1926_1941del (p. Tyr643MetfsX2), in the ZFYVE26 gene was found. Lastly, family 4 was presented with epilepsy, ID, DD, deafness, drooling, speech impediment, hypotonia, and a weak cry. A homozygous missense variant, c.1208 C > A (p. Ala403Glu), in the ATP13A2 gene was identified. Conclusion: This study highlights the genetic heterogeneity in ASM-resistant epilepsy and comorbidities among Pakistani families, emphasizing the importance of genotype-phenotype correlation and the necessity for expanded genetic testing in complex clinical cases. [ABSTRACT FROM AUTHOR]

The use of travelling surface acoustic waves (TSAW) in a microfluidic system provides a powerful tool for the manipulation of particles and cells. In a TSAW driven system, acoustophoretic effects can cause suspended micro-objects to display three distinct responses: (1) swirling, driven by acoustic streaming forces, (2) migration, driven by acoustic radiation forces and (3) patterning in a spatially periodic manner, resulting from diffraction effects. Whilst the first two phenomena have been widely discussed in the literature, the periodic patterning induced by TSAW has only recently been reported and is yet to be fully elucidated. In particular, more in-depth understanding of the size-dependant nature of this effect and the factors involved are required. Herein, we present an experimental and numerical study of the transition in acoustophoretic behaviour of particles influenced by relative dominance of these three mechanisms and characterise it based on particle diameter, channel height, frequency and intensity of the TSAW driven microfluidic system. This study will enable better understanding of the performance of TSAW sorters and allow the development of TSAW systems for particle collection and patterning. [ABSTRACT FROM AUTHOR]

Opinion. Discusses John Kingdom and Peter Kaufmann's challenging of the idea of placental hypoxia. Requirements of a successful placentation; Requirements for molecular confirmation of Kingdom and Kaufmann's work; Groups to be studied for confirmation.

The exact aetiology of preeclampsia is unknown, but there is a good association with an imbalance in angiogenic growth factors and abnormal placentation [1] . Hydrogen sulphide (H 2 S), a gaseous messenger produced mainly by cystathionine γ -lyase (CSE), is pro-angiogenic vasodilator [2,3] . We hypothesized that a reduction in CSE activity may alter the angiogenic balance in pregnancy and induce abnormal placentation and maternal hypertension. Plasma levels of H 2 S were significantly decreased in preeclamptic women ( p < 0.01), which was associated with reduced CSE message and protein expression in human placenta as determined by real-time PCR and immunohistochemistry. Inhibition of CSE activity by DL-propargylglycine (PAG) in first trimester (8–12 weeks gestation) human placental explants had reduced placenta growth factor (PlGF) production as assessed by ELISA and inhibited trophoblast invasion in vitro. Endothelial CSE knockdown by siRNA transfection increased the endogenous release of soluble fms-Like tyrosine kinase-1 (sFlt-1) and soluble endoglin, (sEng) from human umbilical vein endothelial cells while adenoviral-mediated CSE overexpression inhibited their release. Administration of PAG to pregnant mice induced hypertension, liver damage, and promoted abnormal labyrinth vascularisation in the placenta and decreased fetal growth. Finally, a slow releasing, H 2 S-generating compound, GYY4137, inhibited circulating sFlt-1 and sEng levels and restored fetal growth that was compromised by PAG-treatment demonstrating that the effect of CSE inhibitor was due to inhibition of H 2 S production. These results imply that endogenous H 2 S is required for healthy placental vasculature and a decrease in of CSE/H 2 S activity may contribute to the pathogenesis of preeclampsia. [ABSTRACT FROM AUTHOR]

MicroRNAs are small, noncoding RNA molecules that regulate target gene expression in the posttranscriptional level. Unlike siRNA, microRNAs are “fine-tuners” rather than “switches” in the regulation of gene expression; thus they play key roles in maintaining tissue homeostasis. The aberrant microRNA expression is implicated in the disease process. To date, numerous studies have demonstrated the regulatory roles of microRNAs in various pathophysiological conditions. In contrast, the study of microRNA in pregnancy and its associated complications, such as preeclampsia (PE), fetal growth restriction (FGR), and preterm labor, is a young field. Over the last decade, the knowledge of pregnancy-related microRNAs has increased and the molecular mechanisms by which microRNAs regulate pregnancy or its associated complications are emerging. In this review, we focus on the recent advances in the research of pregnancy-related microRNAs, especially their function in pregnancy-associated complications and the potential clinical applications. Here microRNAs that associate with pregnancy are classified as placenta-specific, placenta-associated, placenta-derived circulating, and uterine microRNA according to their localization and origin. MicroRNAs offer a great potential for developing diagnostic and therapeutic targets in pregnancy-related disorders. [ABSTRACT FROM AUTHOR]

Highway slopes constructed with highly plastic clay soils undergo shrink-swell cycles during the wet-dry season, which usually soften the soil and may cause failure a few years following construction. There are two major wet-dry cycles in Texas, where summer to early fall is categorized as the dry period, and late fall to spring is categorized as the wet period. During this study, the failure of a highway slope located in Fort Worth, Texas was investigated, and the effect of rainfall on the slope failure was evaluated. The failure of the slope was investigated using soil test borings, geophysical testing, laboratory testing, slope stability analysis, and unsaturated flow analysis. The site investigation included sample collections from different depths of borings, determination of the soil index properties, and various shear strength testing to determine soil strength parameters. The obtained test results were further utilized in slope stability and flow analyses using the finite element method (FEM) in PLAXIS. The study indicated that both a fully-softened condition and rainfall were responsible for the slope failure. The fully-softened condition provided a factor of safety of 1.46, whereas the perched water condition after rainfall provided a nearly failing factor of safety of 1.05. [ABSTRACT FROM AUTHOR]

Abstract: The incidence of preeclampsia is reduced by a third in smokers, but not in snuff users. Soluble Flt-1 (sFlt-1) and soluble endoglin (sEng) are increased prior to the clinical onset of preeclampsia. Animals exposed to high circulating levels of sFlt-1 and sEng elicit severe preeclampsia-like symptoms. Smokers have reduced circulating sFlt-1 and cigarette smoke extract decreases sFlt-1 release from placental villous explants. An anti-inflammatory enzyme, heme oxygenase-1 (HO-1) and its metabolite carbon monoxide (CO), inhibit sFlt-1 and sEng release. Women with preeclampsia exhale less CO than women with normal pregnancies and HO expression decreases as the severity of preeclampsia increases. In contrast, sFlt-1 levels increase with increasing severity. More importantly, chorionic villous sampling from women at eleven weeks gestation shows that HO-1 mRNA expression is decreased in women who go on to develop preeclampsia. Collectively, these facts provide compelling evidence to support the proposition that the pathogenesis of preeclampsia is largely due to loss of HO activity. This results in an increase in inflammation and excessive elevation of the two key anti-angiogenic factors responsible for the clinical signs of preeclampsia. These findings provide strong evidence for a protective role of HO-1 in pregnancy and identify HO as a target for the treatment of preeclampsia. The cardiovascular drugs, statins, stimulate HO-1 expression and inhibit sFlt-1 release in vivo and in vitro, thus, they have the potential to ameliorate early onset preeclampsia. The StAmP trial is underway to address this and if positive, its outcome will lead to the very first therapeutic intervention to prolong affected pregnancies. [ABSTRACT FROM AUTHOR]

Objective: To compare outcomes of side-to-side staple versus hand-sewn esophago-gastric anastomosis in esophagectomy patients with carcinoma of esophagus after subtotal esophagectomy along with gastric tube reconstruction. Study Design: Retrospective cross-sectional study. Place and Duration of Study: Lady Reading Hospital, Peshawar Pakistan, from July 2019 to June 2020. Methodology: After ethical approval, medical records of patients that underwent stapled/hand sewn gastro esophageal anastomosis due to carcinoma esophagus were included. Inoperable Ca esophagus and with thoracic anastomosis were excluded. Each anastomotic technique was applied on 50 patients randomly. The variables of study included demographic, anastomotic leak, anastomotic stricture, operative time, and other complications. All the cases were followed up for 1 year. SPSS version 26.0 was used for data analysis. Result: From 100 patients, 56 were males and 34 females. Age ranged from 15 to 80 years with mean age of 48.5 and 51.1 respectively in two groups. In 42 cases tumor was present in lower end, middle third in 30 and middle lower third of gastro esophageal junction in 28 cases. Histo-pathologically 58 cases were adenocarcinoma, 31 squamous cell carcinoma and 11 adeno squamous carcinoma. The anastomosis time in group I was 6.8±.22 minutes while in group II was 13.2±1.71 minutes (p0.04). None of the patients in group I, having stapled anastomosis were found to have anastomotic leakage or stricture formation after 1 year of follow up while 04 patients in group II were reported to have anastomotic leakage and 06 patients had anastomotic stricture formation (p-<0.01). Conclusion: Side by side stapled anastomosis technique was far superior to hand-sewn technique in terms of the time taken for anastomosis to be completed and patient outcomes (anastomotic leakage and stricture formation). [ABSTRACT FROM AUTHOR]

Background and Aims: Decreasing mortality in sick and ventilated neonates is an endeavor of all neonatologists. To reduce the high mortality in this group of neonates, identifi cation of risk factors is important. This study was undertaken to fi nd out the indications of ventilation and complications in ventilated neonates and also study possible predictors of outcome. Subjects: Age <1-month; mechanically ventilated; not having suspected metabolic disorders or congenital anomalies; excluding postoperative patients. Methods: Neonates consecutively put on mechanical ventilation during the study period (October 2011 to November 2013) enrolled. Primary disease of the neonates along with complications present listed. Clinical and laboratory parameters analyzed to fi nd the predictors of mortality. Results: Total 300 neonates were ventilated. 52% were male. Mean age, weight, and gestational age were 21 ± 62 h, 2320 ± 846.2 g, and 35.2 ± 4.9 weeks, respectively. 130 (43%) neonates died. Respiratory distress syndrome (RDS) (31.1%), sepsis (22.7%), and birth asphyxia (18%) were the most common indications for ventilation. Mortality in ventilated patients with sepsis, pneumonia, RDS or birth asphyxia was 64.7%, 60%, 44.6%, and 33.3%, respectively. Weight <2500 g, gestation <34 weeks, initial pH <7.1, presence of sepsis, apnea, shock, pulmonary hemorrhage, hypoglycemia, neutropenia, and thrombocytopenia were signifi cantly associated with mortality (P < 0.05). Resuscitation at birth, seizures, intra ventricular hemorrhage, pneumothorax, ventilator-associated pneumonia, PO2, or PCO2 did not have a signifi cant association with mortality. On logistic regression, gestation <34 weeks, initial pH <7.1, pulmonary hemorrhage, or shock were independently signifi cant predictors of mortality. Conclusions: Weight <2500 g, gestation <34 weeks, initial arterial pH <7.1, shock, pulmonary hemorrhage, apnea, hypoglycemia, neutropenia, and thrombocytopenia were signifi cant predictors of mortality in ventilated neonates. [ABSTRACT FROM AUTHOR]

This paper presents the comparative evaluation of multiple compact and lightweight 2D laser scanners for their possible backpack based scanning and mapping applications. These scanners include Hokuyo URG-04LX, Slamtec RPLidar A1-M8 and Hokuyo UTM-30LX-EW scanners. Since the technical datasheets provide general information and limited working details, this research presents a thorough study on the performance of each scanner related explicitly to indoor mapping operations. A series of scanning experiments have been performed for the characterization of each scanner using statistical analysis. During the testing, all the scanning data has been recorded using Robot Operating System (ROS) and then computed in offline processing. In initial tests, each scanner's drift effect on range measurements has been tested and presented in the relevant section of the paper. In continuation, the effect of various scanning distances on measurement accuracy has been evaluated and discussed. Later the impact of various materials typically found in indoor vicinities and their respective properties of color and smoothness have been tested and provided in the paper. Finally, a Kalman Filtering based mathematical formulation has been utilized to calibrate each scanner and to reduce the measuring uncertainties as observed in various tests for each scanner. [ABSTRACT FROM AUTHOR]

Alkali-activated binders have been widely used as they are low-carbon materials and eco-friendly to environment. Compressive strength (CS) is the most crucial parameter for designing the alkali-activated binder (AAB) concrete. Hence, the accurate prediction of CS becomes the most important when considering the issues like time saving and cost benefits analytical point of view. This study adopted the conventional deep learning (CDL) and hybrid deep learning (HDL) models to enhance the prediction of CS through analyzing the experimental CS data collected from previous research articles. Three CDL models such as CNN, GRU and LSTM, and their hybrid HDL forms like CNN-GRU, CNN-LSTM and LSTM-GRU were employed to predict the CS property. The models were run with 2060 data points including eight input parameters of AAB concrete specimens, where the 70% data points were used for training and 30% for testing phases. It was observed that HDL models showed the better prediction performance than the CDL models, where the hybrid CNN-LSTM model presents the significant accurate prediction of strength property, with R 2 = 0.997, RMSE = 1.45 and R 2 = 0.995, RMSE = 2.24 for training and testing phases, respectively. Moreover, SHAP analysis of CNN-LSTM model exhibits that age of concrete specimens is the main dominant parameter for strength development and cement contents is the second highest contributing issue to strength increment of alkali-activated concrete. These results might be applied in the field of building construction sectors for optimum design of alkali-activated concrete specimens for better strength achievement. • Alkali-activated materials strength is predicted using Deep learning approaches. • Hybrid CNN-LSTM model shows better prediction accuracy. • Parametric analysis is performed with SHAP algorithm. • Uncertainty analysis is done for checking the overfitting of the models. [ABSTRACT FROM AUTHOR]

Colorectal cancer remains one of the leading prevalent cancers in the world and is the fourth most common cause of death from cancer. Unfortunately, the currently utilized chemotherapies fail in selectively targeting cancer cells and cause harm to healthy cells, which results in profound side effects. Researchers are focused on developing anti-cancer targeted medications, which is essential to making them safer, more effective, and more selective and to maximizing their therapeutic benefits. Milk-derived extracellular vesicles (EVs) from camels and cows have attracted much attention as a natural substitute product that effectively suppresses a wide range of tumor cells. This review sheds light on the biogenesis, methods of isolation, characterization, and molecular composition of milk EVs as well as the therapeutic potentials of milk EVs on colorectal cancer. [ABSTRACT FROM AUTHOR]