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Objectives: To determine the incidence of complications [Surgical site infection (SSI), intra-abdominal abscess (IAA), stump leak] related to stump ligation with manual loop of sliding extracorporeal suture knot in laparoscopic appendectomy., Methods: This cohort study was conducted on patients who underwent laparoscopic appendectomy from June 2014 to November 2020 performed by the same surgeon with almost similar technique. Stump was ligated with manual loops, applied by the surgeon or trainee or both (one by surgeon and other by trainee). SSI and IAA were classified according to Centers for Disease Control and Prevention (CDC) criteria., Results: Total 120 patients were included with median (Interquartile range, IQR) age of 24 (19-35) years and male predominance i.e. 81 (67.5%). Median (IQR) for the duration of symptoms, time from presentation to surgery and duration of surgery was 2(1-4) days, 10 (4-15) hours and 60 (44-70) minutes, respectively. SSI was documented in 9(7.5%) patients, managed by wound hygiene and antibiotics. IAA was observed in one(0.8%) patient who required readmission for antibiotics and radiology guided drain placement. No stump leak was observed., Conclusions: Manual endo-loop is a safe, reliable and cost effective technique for stump ligation in LA, and can safely be incorporated into teaching of surgical trainees.

Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide. Ongoing research to develop AD treatments has characterized multiple drug targets including the cholinergic system, amyloid-β peptide, phosphorylated tau, and neuroinflammation. These systems have the potential to interact to either drive or slow AD progression. Promising agents that simultaneously impact many of these drug targets are the AD experimental drug Posiphen and its enantiomer phenserine that, currently, are separately being evaluated in clinical trials. To define the cholinergic component of these agents, the anticholinesterase activities of a ligand dataset comprising Posiphen and primary metabolites ((+)-N1-norPosiphen, (+)-N8-norPosiphen, and (+)-N1,N8-bisnorPosiphen) were characterized and compared to those of the enantiomer phenserine. The "target" dataset involved the human cholinesterase enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Binding interactions between the ligands and targets were analyzed using Autodock 4.2. The computationally determined inhibitory action of these ligands was then compared to ex vivo laboratory-measured values versus human AChE and BChE. While Posiphen lacked AChE inhibitory action, its major and minor metabolites (+)-N1-norPosiphen and (+)-N1,N8-bisnorPosiphen, respectively, possessed modest AChE inhibitory activity, and Posiphen and all metabolites lacked BChE action. Phenserine, as a positive control, demonstrated AChE-selective inhibitory action. In light of AChE inhibitory action deriving from a major and minor Posiphen metabolite, current Posiphen clinical trials in AD and related disorders should additionally evaluate AChE inhibition; particularly if Posiphen should be combined with a known anticholinesterase, since this drug class is clinically approved and the standard of care for AD subjects, and excessive AChE inhibition may impact drug tolerability., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Virus-like particles (VLPs) are nanostructures that possess diverse applications in therapeutics, immunization, and diagnostics. With the recent advancements in biomedical engineering technologies, commercially available VLP-based vaccines are being extensively used to combat infectious diseases, whereas many more are in different stages of development in clinical studies. Because of their desired characteristics in terms of efficacy, safety, and diversity, VLP-based approaches might become more recurrent in the years to come. However, some production and fabrication challenges must be addressed before VLP-based approaches can be widely used in therapeutics. This review offers insight into the recent VLP-based vaccines development, with an emphasis on their characteristics, expression systems, and potential applicability as ideal candidates to combat emerging virulent pathogens. Finally, the potential of VLP-based vaccine as viable and efficient immunizing agents to induce immunity against virulent infectious agents, including, SARS-CoV-2 and protein nanoparticle-based vaccines has been elaborated. Thus, VLP vaccines may serve as an effective alternative to conventional vaccine strategies in combating emerging infectious diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tariq, Batool, Asif, Ali and Abbasi.)

Objective: Microscopic magnetic resonance imaging (µMRI) and polarized light microscopy (PLM) are used to characterize the structural variations at different anatomical locations of femoral cartilage in young rabbits (12-14 weeks old)., Design: Four intact knees were imaged by µMRI at 86 µm resolution. Three small cartilage-bone specimens were harvested from each of 2 femoral medial condyles and imaged by quantitative µMRI (T2 anisotropy) at 9.75 µm resolution ( N = 6). These specimens, as well as the other 2 intact femoral condyles, were used for histology and imaged by quantitative PLM (retardation and angle) at 0.25 µm to 4 µm resolutions., Results: Quantitative MRI relaxation data and PLM fibril data revealed collaboratively distinct topographical variations in both cartilage thickness and its collagen organization in the juvenile joint. Cartilage characteristics from the central location have a 3-zone arcade-like fibril structure and a distinct magic angle effect, commonly seen in mature articular cartilage, while cartilage at the anterior location lacks these characteristics. Overall, the lowest retardation values and isotropic T2 values have been found in the distal femur (trochlear ridge), with predominant parallel fibers with respect to the articular surface. Central cartilage is the thickest (~550 µm), approximately twice as thick as the anterior and posterior locations., Conclusion: Distinctly different characteristics of tissue properties were found in cartilage at different topographical locations on femoral condyle in rabbits. Knowledge of location-specific structural differences in the collagen network over the joint surface can improve the understanding of local mechanobiology and provide insights to tissue engineering and degradation repairs.

Background: Osteoarthritis is a heterogeneous disease of joints that affects mainly older population. Definitive cure of osteoarthritis is still undiscovered. This study was designed to evaluate and compare the chondroprotective effects of hyaluronic acid and triamcinolone in murine model of osteoarthritis., Methods: This Laboratory based experimental study was carried out in Pharmacology Department, Army Medical College Rawalpindi, from April-June 2019. Osteoarthritis was induced by medial menisectomy and anterior cruciate ligament resectioning of knee joints of twenty-four rats which were then divided into three groups with eight rats in each. Group I, II and III were named control, hyaluronic acid and triamcinolone groups respectively, which were given intra-articular injections of these drugs once weekly for four consecutive weeks and then gait pattern was scored. Animals were sacrificed thereafter and samples were collected for histopathological analysis., Results: Comparison of gait score of control, hyaluronic acid and triamcinolone groups exhibited a p value of <0.01 while intergroup comparison between group I and II, group I and III and group II and III depicted p-value of <0.001, 0.016 and 0.003 respectively. Likewise, collective histopathological analysis of the three groups showed p-value of <0.01 while intergroup comparison of group I and II, group I and III and group II and III showed p-value of <0.001 for all., Conclusions: Comparison of control group with treatment groups proved chondroprotective effects of hyaluronic acid and triamcinolone. Additionally, hyaluronic acid proved to provide better chondroprotection as compared to triamcinolone.

Objective This trial aimed to evaluate the safety and efficacy of pre-exposure prophylaxis (PrEP) with various hydroxychloroquine (HCQ) doses against a placebo among healthcare personnel (HCP) with high-risk exposure to coronavirus disease 2019 (COVID 19). Methods A phase II, randomized, placebo-controlled trial was conducted including 200 subjects with no active or past severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (antibody testing and reverse transcription-polymerase chain reaction (RT-PCR) were taken at the time of enrollment). Subjects of experimental groups one to three received HCQ in various doses and the control group received a placebo. The study outcomes in terms of safety and efficacy were monitored. Participants exhibiting COVID-19 symptoms were tested for SARS-CoV-2 during the study and by the end of week 12 with RT-PCR or serology testing (COVID-19 IgM/IgG antibody testing). Results Out of the total participants, 146 reported exposure to a confirmed COVID-19 case in the first month, and 192 were exposed by week 12 of the study. Moreover, the precautionary use of personal protective equipment (PPE) significantly varied; initially more than 80% of the exposed HCPs were not ensuring PPE being used by the patients treated by them, which gradually developed over time. Mild treatment-related side effects were observed among the interventional and placebo arm patients. There was no significant clinical benefit of PrEP with HCQ as compared to placebo (p>0.05). Conclusion It is concluded that the PrEP HCQ does not significantly prevent COVID-19 among high-risk HCPs., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Syed et al.)

Cognitive impairments such as dementia are considered the biggest challenges for public health. Benzodiazepines are often prescribed for treatment of anxiety disorder but they are associated with elevated risk of dementia. The present study has been designed to evaluate the neuroprotective effect of telmisartan and metformin on diazepam-induced cognitive dysfunction in mice. Piracetam was used as an established nootropic agent. Mice were divided into 8 groups, group1; control group which received normal saline. groups 2, 3 and 4 were received telmisartan 0.3 mg/kg/day, metformin 100 mg/kg/day and piracetam 200 mg/kg/day respectively. group 5; DZP group that injected with diazepam 2.5 mg/kg, groups 6, 7 and 8 were received diazepam 2.5 mg/kg + telmisartan 0.3 mg/kg/day, metformin 100 mg/kg/day and piracetam 200 mg/kg/day respectively. All drugs were administrated for 15 successive days. Cognitive skills of the animals were examined with Elevated plus maze and Passive Shock Avoidance tests. Investigations of oxidative stress markers were performed. Gene expression levels of TNF-α, NFκB, Caspase 3 and AMPK were analyzed using RT-PCR. Histological and immunohistochemical techniques were performed in hippocampus using H&E, cresyl violet stain, anti GFAP and anti COX-2 immunostain. The study revealed that administration of diazepam increased initial and retention transfer latency as well as it decreased step down latency that means it caused memory impairment. There was a significant increase in hippocampal expression levels of TNF-α, NFκB, and Caspase 3 and downregulation of AMPK expression levels associated with increased neurodegeneration, astrocytes activation and COX-2 immunohistochemical staining. This study indicates that diazepam caused a decline in cognitive function depending on hippocampal activity. Telmisartan, a common antihypertensive agent and metformin, a traditional antidiabetic drug improved this cognitive dysfunction through their anti-oxidant and anti-inflammatory effect as they decreased initial and retention transfer latency as well as it increased step down latency. Also they decreased TNF-α, NFκB, and Caspase 3 and upregulated AMPK expression, moreover they ameliorated the hippocampal morphological alterations, GFAP and COX-2 immunoexpression., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: In order to appreciate the roles articular cartilage of sesamoid bones and sesamoid fibrocartilage play in anatomy and pathology, the articular cartilage of the patella ( n = 4) and suprapatella ( n = 4) (a sesamoid fibrocartilage) of 12 to 14 weeks old New Zealand rabbits were studied qualitatively and quantitatively., Design/method: The intact knee joints and block specimens from the joints were imaged using microscopic magnetic resonance imaging (µMRI) at a 97.6-µm pixel resolution for the former and 19.5-µm resolution for the latter. Histological sections were made out of the µMRI-imaged specimens, which were imaged using polarized light microscopy (PLM) at 0.25-, 1-, and 4-µm pixel resolutions., Results: The patella cartilage varied in thickness across the medial to lateral ends of the sesamoid bone with the central medial aspect slightly thicker than the lateral aspect. The suprapatella fibrocartilage decreased proximally away from the knee joint. Quantitative results of patellar cartilage showed strong dependence of fiber orientation with the tissue depth. Three histological zones can be clearly observed, which are similar to articular cartilage from other large animals. The sesamoid fibrocartilage has one thin surface layer (10 µm thick) of parallel-arranged structured fibers followed immediately by the majority of random fibers in bulk tissue. T2 relaxation time anisotropy was observed in the patellar cartilage but not in the bulk fibrocartilage., Conclusion: Given the different functions of these 2 different types of cartilages in joint motion, these quantitative results will be beneficial to future studies of joint diseases using rabbits as the animal model.

Background: Community pharmacists are one of the most accessible healthcare practitioners worldwide and their services are used by a large proportion of the population. Expanding the roles of community pharmacists could contribute to reducing pressure on general health practice and other areas of the health services. This research aimed to evaluate the contribution of community pharmacists in the provision of public health services and to investigate the perceived barriers for the provision of these services in Saudi Arabia., Materials and Methods: This study followed a cross-sectional design using an online anonymous self-administered questionnaire. The study took place in Asir region, Saudi Arabia, between September 2019 and February 2020. A convenience sampling strategy was used to select and recruit the study participants. The questionnaire was adapted from previous research and involved three sections: demographics, involvement in public health services and barriers for practising public health roles., Results: The total number of respondents was 193. The proportion of respondents who reported that they were "very involved" or "involved" in each service was 61.7% for weight management, 60.6% for sexual health, 57.5% for healthy eating, 53.4% for physical activity promotion, 51.3% for dental health, 46.1% for smoking cessation, 39.4% for screening for diabetes, 35.7% for screening for hypertension, 31.1% for alcohol dependence and drug misuse counselling, 30.6% for screening for dyslipidaemia, and 21.8% for vaccination and immunisation. Most of the barriers in the current research were rated as having low relevance to the provision of public health services., Conclusion: Findings in the current research suggest that community pharmacists in Asir region have varying levels of involvement in public health roles. Further research needs to be undertaken to understand the barriers to the provision of public health services and what strategies would be beneficial for enhancing the public health role of community pharmacists in Saudi Arabia., (© 2021 John Wiley & Sons Ltd.)

The perturbation of nicotinic cholinergic receptors is thought to underlie many neurodegenerative and neuropsychiatric disorders, such as Alzheimer's and schizophrenia. We previously identified that the tumor suppressor gene, MEN1 , regulates both the expression and synaptic targeting of α7 nAChRs in the mouse hippocampal neurons in vitro. Here we sought to determine whether the α7 nAChRs gene expression reciprocally regulates the expression of menin, the protein encoded by the MEN1 gene, and if this interplay impacts learning and memory. We demonstrate here that α7 nAChRs knockdown (KD) both in in vitro and in vivo, initially upregulated and then subsequently downregulated menin expression. Exogenous expression of menin using an AAV transduction approach rescued α7 nAChRs KD mediated functional and behavioral deficits specifically in hippocampal (CA1) neurons. These effects involved the modulation of the α7 nAChR subunit expression and functional clustering at the synaptic sites. Our data thus demonstrates a novel and important interplay between the MEN1 gene and the α7 nAChRs in regulating hippocampal-dependent learning and memory.

Global data, including those from Saudi Arabia, that examined public knowledge, attitudes, and practices (KAP) toward hepatitis E virus (HEV) are limited. This study examined KAP levels of the general population in Saudi Arabia toward HEV. A cross-sectional study was conducted among 768 participants. An Arabic electronic questionnaire that contained demographic data and had 35 questions was used to measure KAP of the participants concerning HEV. Collected data were analyzed at a significance level of 0.05. A total of 768 individuals participated in the study, of whom 16.3% (N = 125) were males and 83.7% (N = 643) were females. Study subjects were 18 years and above. Most of the participants were Saudi citizens (95.6%; N = 734), and from Western Saudi Arabia (76.4%; N = 587). Thirty-four percent (N = 261) of the participants had not heard of HEV, and 48% were aware that yellowish skin or eyes are the most important sign of hepatitis. The level of participants' knowledge about HEV was low (39.5%). However, positive attitudes and practices were apparent and tended to aim at how to avoid becoming infected with HEV. In conclusion, the level of HEV-related knowledge among the participants was low, and their practices and attitudes were aimed at avoiding HEV infection. Awareness campaigns are required to increase the public's HEV-related knowledge.

Objectives: The design of peptide-based vaccines for cancer is a promising immunotherapy that can induce a cancer-specific cytotoxic response in tumor cells., Methods: Herein, we used the immunoinformatic approach in designing a multi-epitope vaccine targeting G-protein coupled receptor 87 (GPCR-87), cystine/glutamate transporter (SLC7A11), Immunoglobulin binding protein 1 (IGBP1), and thioredoxin domain-containing protein 5 (TXNDC5), which can potentially contribute to NSCLC. The MHC-I and MHC-II epitopes selected for the fusion construct were evaluated for their antigenic and non-allergenic natures via VaxiJen and AllerTop., Results: A total of five epitopes, four class-I (FIFYLKNIV, CRYTSVLFY, RYLKVVKPF, and RQAKIQRYK), and one class-II (NQVRGYPTLLWFRDG), having combined USA population coverage of 100%, were used to make ten possible multi-epitope fusion constructs. In these constructs, PADRE, a universal T-helper epitope, and RSO9, a TLR4 agonist, were fused as adjuvants. The molecular docking analysis revealed that two constructs were showing significant binding affinities toward HLA -A*02:01, the most prevalent HLA allele in USA. Moreover, MD simulations marked one construct as a promising therapeutic candidate., Conclusion: The multi-epitope vaccine constructs designed using immunogenic, and non-allergenic peptides of NSCLS tumor-associated proteins are likely to pose significant therapeutic efficacies in cancer immunotherapy due to their high binding affinities toward HLA molecules.

Objectives: The aim of this study was to determine the prevalence of infection, genotypes and risk factors for human papillomavirus (HPV) among men who have sex with men (MSM) and transgender women living with and without HIV in Pakistan. Anal infection with HPV is very common worldwide among MSM, particularly among MSM living with HIV. The high prevalence of HIV among MSM and male-to-female transgendered individuals in Pakistan is a significant health concern since access to screening and health-seeking is often delayed in this stigmatised key population., Design: This cross-sectional study was conducted between March 2016 and November 2017., Participants, Setting and Data Collection: This study recruited MSM and transgender-women who self-reported to have had anal sex in the last 6 months, and were at least 18 years of age, from the sexual health and antiretroviral therapy centres. Structured questionnaires were administered, and blood samples were obtained to confirm HIV status. Anal swabs were collected for HPV-DNA detection and typing., Main Outcome Measures: The primary outcome was the prevalence of 'HPV-DNA infection'. The prevalence ratios (PR) were calculated using Cox proportional hazard model algorithms to analyse the association between exposure variables and HPV-infection., Results: Complete data were available for 298 MSM and transgender women (HIV +n=131; HIV-n=167). The overall HPV-DNA prevalence was 65.1% and was higher in participants living with HIV as compared with HIV-negative (87% vs 48%; χ 2 p≤0.001). Likewise, 28.9% of participants living with HIV were infected with two or more than two types of HPV as compared with 18.8% participants without HIV(χ 2 p≤0.001). The most frequent HPV type was HPV6/11 (46.9%), followed by HPV16 (35.1%), HPV18 (23.2%) and HPV35 (21.1%). HIV status (PR 2.81, 95% CI 2.16 to 3.82) and never condom use (PR 3.08, 95% CI 1.69 to 5.60)) were independently associated with prevalence of 'anal-HPV16 infection' when adjusting for confounding for age, other sexual and behavioural factors, for example, smoking and alcohol consumption., Conclusion: High prevalence of HPV indicates a substantial future risk of anal cancer in Pakistani MSM and transgender women, and particularly in those living with HIV. Current findings support anal Pap-smear HPV screening for this particular group and vaccination efforts for future generations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Fagonia indica is a rich source of pharmacologically active compounds. The variation in the metabolites of interest is one of the major issues in wild plants due to different environmental factors. The addition of chemical elicitors is one of the effective strategies to trigger the biosynthetic pathways for the release of a higher quantity of bioactive compounds. Therefore, this study was designed to investigate the effects of chemical elicitors, aluminum chloride (AlCl 3 ) and cadmium chloride (CdCl 2 ), on the biosynthesis of secondary metabolites, biomass, and the antioxidant system in callus cultures of F. indica . Among various treatments applied, AlCl 3 (0.1 mM concentration) improved the highest in biomass accumulation (fresh weight (FW): 404.72 g/L) as compared to the control (FW: 269.85 g/L). The exposure of cultures to AlCl 3 (0.01 mM) enhanced the accumulation of secondary metabolites, and the total phenolic contents (TPCs: 7.74 mg/g DW) and total flavonoid contents (TFCs: 1.07 mg/g DW) were higher than those of cultures exposed to CdCl 2 (0.01 mM) with content levels (TPC: 5.60 and TFC: 0.97 mg/g) as compared to the control (TPC: 4.16 and TFC: 0.42 mg/g DW). Likewise, AlCl 3 and CdCl 2 also promoted the free radical scavenging activity (FRSA; 89.4% and 90%, respectively) at a concentration of 0.01 mM, as compared to the control (65.48%). For instance, the quantification of metabolites via high-performance liquid chromatography (HPLC) revealed an optimum production of myricetin (1.20 mg/g), apigenin (0.83 mg/g), isorhamnetin (0.70 mg/g), and kaempferol (0.64 mg/g). Cultures grown in the presence of AlCl 3 triggered higher quantities of secondary metabolites than those grown in the presence of CdCl 2 (0.79, 0.74, 0.57, and 0.67 mg/g). Moreover, AlCl 3 at 0.1 mM enhanced the biosynthesis of superoxide dismutase (SOD: 0.08 nM/min/mg-FW) and peroxidase enzymes (POD: 2.37 nM/min/mg-FW), while CdCl 2 resulted in an SOD activity up to 0.06 nM/min/mg-FW and POD: 2.72 nM/min/mg-FW. From these results, it is clear that AlCl 3 is a better elicitor in terms of a higher and uniform productivity of biomass, secondary cell products, and antioxidant enzymes compared to CdCl 2 and the control. It is possible to scale the current strategy to a bioreactor for a higher productivity of metabolites of interest for various pharmaceutical industries.

Loquat [Eriobotrya japonica (Thunb.) Lindl.] is an important fruit crop in Pakistan; however, a constant decline in its production is noted due biotic and abiotic stresses, particularly disease infestation. Fungal pathogens are the major disease-causing agents; therefore, their identification is necessary for devising management options. This study explored Taxila, Wah-Cantt, Tret, Chatar, Murree, Kalar-Kahar, Choa-Saidan-Shah and Khan-Pur districts in the Punjab and Khyber Paktoon Khawa (KPK) provinces of Pakistan to explore the diversity of fungal pathogens associated with loquat. The samples were collected from these districts and their microscopic characterizations were accomplished for reliable identification. Alternaria alternata, Curvularia lunata, Lasiodiplodia theobromae, Aspergilus flavis, Botrytis cinerea, Chaetomium globosum, Pestalotiopsis mangiferae and Phomopsis sp. were the fungal pathogens infesting loquat in the study area. The isolates of A. alternata and C. lunata were isolated from leaf spots and fruit rot, while the isolates of L. theobromae were associated with twig dieback. The remaining pathogens were allied with fruit rot. The nucleotide evidence of internal transcribed spacer (ITS) regions (ITS1, 5.8S, and ITS2) were computed from all the pathogens and submitted in the database of National Center for Biotechnology Information (NCBI). For multigene analysis, beta-tubulin (BT) gene and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) regions were explored for A. alternata and C. lunata isolates, respectively. The virulence scales of leaf spots, fruit rot, and twig dieback diseases of loquat were developed for the first time through this study. It is the first comprehensive study with morpho-molecular identification, and newly developed virulence scales of the fungal pathogens associated with loquat, which improves the understanding of these destructive diseases., Competing Interests: The authors have declared that no competing interests exist.

Gastric cancer (G.C) is one of the most lethal cancer types worldwide. Current treatment requires surgery along with chemotherapy, which causes obstacles for speedy recovery. The discovery of novel drugs is needed for better treatment of G.C with minimum side effects. Latcripin-7A (LP-7A) is a newly discovered peptide extracted from Lentinula edodes. It is recently studied for its anti-cancer activity. In this study, LP-7A was modeled using a phyre2 server. Anti-proliferation effects of LP-7A on G.C cells were examined via CCK-8, colony formation, and morphology assay. Apoptosis of LP-7A treated G.C cells was evaluated via Hoechst Stain, western blot and flow cytometry. Autophagy was assessed via acridine orange staining and western blot. The cell cycle was assessed via flow cytometry assay and western blot. Pathway was studied via western blot and STRING database. Anti-migratory effects of LP-7A treated G.C cells were analyzed via wound healing, western blot, and migration and invasion assay. LP-7A effectively inhibited the growth of G.C cells by inhibiting the PI3K/Akt/mTOR pathway. G.C cells treated with LP-7A arrested the cell cycle at the G1 phase, contributing to the inhibition of migration and invasion. Furthermore, LP-7A induced apoptosis and autophagy in gastric cancer cells. These results indicated that LP-7A is a promising anti-cancer agent. It affected the proliferation and growth of G.C cells (SGC-7901 and BGC-823) by inducing apoptosis, autophagy, and inhibiting cell cycle at the G1 phase in G.C cells., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Silicon (Si) and hydrogen sulfide (H 2 S) are known to enhance plant defense against multiple stresses. Current study was conducted to investigate the application of Si and H 2 S alone as well as in combination, improved physiological resilience of wheat plants to drought stress (DS) and pathogen-Puccinia triticina (Pt) infection. We aimed to increase the wheat plant growth and to enhance the DS tolerance and Pt resistance with the concurrent applications of H 2 S and Si. In the first experiment, we selected the best growth enhancing concentration of H 2 S (0.3 mM) and Si (6 mM) to further investigate their tolerance and resistance potential in the pot experiment under DS and pathogen infection conditions. The obtained results reveal that DS has further increased the susceptibility of wheat plants to leaf rust pathogen infection while, the sole application of Si and the simultaneous exogenous treatments of H 2 S + Si enhanced the plant growth, decreased disease incidence, and significantly improved tolerance and defense mechanisms of wheat under individual and interactive stress conditions. The exogenous treatment of H 2 S + Si improved the growth criteria, photosynthetic pigments, osmoprotectants, and defense related enzyme activities. The same treatment also reinforced the endogenous H 2 S, Si, ABA and SA contents while decreased the disease incidence and oxidative stress indicators under individual and combined stress conditions. Overall, results from this study presents the influence of combined drought and P. triticina stress in wheat and reveal the beneficial impacts of concurrent exogenous treatment of H 2 S + Si to mitigate the drought and pathogen (P. triticina) induced adverse effects., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Infertility is a multifactorial and polygenic disease. A vast majority of infertility is still unexplained despite modern diagnostic techniques. Oxidative stress is considered a factor for male infertility but etiology in terms of functional gene polymorphism and experimental studies on human subjects is scarcely reported. The aim of the study was to investigate the status of three antioxidant enzymes; catalase, superoxide dismutase (SOD), and glutathione reduced (GSH) in clinically diagnosed infertile males and find the potential association of CAT gene variant in the promoter region -21 A/T (rs7943316). The study consisted of 55 clinically diagnosed infertile males and 50 non-infertile volunteers. The activity of antioxidant enzymes was measured through a spectrophotometer. Polymerase chain reaction-restriction fragment length polymorphism was performed for genotyping of single-nucleotide polymorphism. Catalase enzyme activity was significantly decreased while SOD and GSH were substantially increased (p ≤ 0.01) in infertile men in comparison to non-infertile. CAT gene variant rs7943316 had shown significant association in dominant, recessive model and allelic frequencies. The study concludes that rs7943316 has a substantial role in male infertility. The outcome of the study may help in resolving idiopathic infertility cases and may help in evolving novel diagnostic and therapeutic approaches. Other variants of CAT and antioxidant genes are suggested to ascertain further insight., (© 2021 Wiley Periodicals LLC.)

Avian colibacillosis caused by the zoonotic pathogen Escherichia coli is a common bacterial infection that causes major losses in the poultry sector. Extracts of different medicinal plants and antibiotics have been used against poultry bacterial pathogens. However, overuse of antibiotics and extracts against pathogenic strains leads to the proliferation of multi-drug resistant bacteria . Due to their environmentally friendly nature, nanotechnology and beneficial bacterial strains can be used as effective strategies against poultry infections. Green synthesis of zinc oxide nanoparticles (ZnO-NPs) from Eucalyptus globulus leaves was carried out in this study. Their characterization was done by UV-vis spectroscopy, X-ray diffraction (XRD), and Fourier transmission infrared spectroscopy (FT-IR) which confirmed their synthesis, structure, and size. In vitro, antimicrobial activities of plant leaf extract, ZnO-NPs, and plant growth-promoting rhizobacteria (PGPR) were checked against E. coli using well diffusion as well as disc diffusion method. Results proved that the antimicrobial activity of ZnO-NPs and PGPR strains was more enhanced when compared to eucalyptus leaf extract at 36 h. The maximum relative inhibition shown by ZnO-NPs, PGPR strains and eucalyptus leaf extracts was 88%, 67% and 58%, respectively. The effectiveness of ZnO-NPs was also increased with an increase in particle dose and treatment time. The 90 mg/ml of ZnO-NPs was more effective . PGPR strains from all over the tested strains, Pseudomonas sp . (HY8N) exhibited a strong antagonism against the E. coli strain as compared to other PGPR strains used in this study. However, combined application of PGPR ( Pseudomonas sp . (HY8N)) and ZnO-NPs augment antagonistic effects and showed maximum 69% antagonism. The study intends to investigate the binding affinity of ZnO-NPs with the suitable receptor of the bacterial pathogen by in silico methods. The binding site conformations showed that the ligand ZnO binds with conserved binding site of penicillin-binding protein 6 (PBP 6) receptor. According to the interactions, ZnO-NPs form the same interaction pattern with respect to other reported ligands, hence it can play a significant role in the inhibition of PBP 6. This research also found that combining ZnO-NPs with Pseudomonas sp. (HY8N) was a novel and effective technique for treating pathogenic bacteria, including multidrug-resistant bacteria., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Groups marginalized and/or isolated by minority status-including transgender individuals-are at significant risk for loneliness and diminished quality of life (QoL), effects that can be mitigated to some extent by coping styles. In this study, we examined the relationships among coping styles, loneliness, and QoL outcomes in a marginalized but understudied gender minority group, namely, 200 transgender individuals living in communities in an emerging/developing non-Western geo-cultural region of South-Central Asia (Pakistan), comparing them against a reference group of 100 heterosexual cisgender individuals. Results indicated strong relationships among coping styles, loneliness, and QoL in both transgender and cisgender groups. Moderating variable analysis revealed that coping skills-whether adaptive or maladaptive-help explain differences in loneliness and QoL not only between trans- and cis-gender individuals, but also within just the transgender group. The implications of these findings for intervention strategies to improve QoL among transgender populations are discussed, with reference to both the specific context within Pakistan and the larger context of transgender marginalization within many developing/emerging countries.

Allelochemicals are secondary metabolites which are not edible and can be used as growth regulators and bio-herbicides. The goal of current study was to assess allelopathic ability of Lantana camara (Sage-plant) flowers against weeds viz. Avena fatua (Wild oat), Euphorbia helioscopia (Sun-spurge), Chenopodium album (Goosefoot), Phalaris minor (Canary-grass), and Rumex dentatus (Knotweed). Bioassay analysis of three methanolic fractions of the Combi flash from L. camara was performed at 50%, 75% and 100% concentration using germination percentage parameters, inhibition of plumule and radicle size. The fraction II of Combi flash strongly suppressed all weeds with negligible effect on T. aestivum . Gas chromatography-mass spectroscopy was conducted for the fraction, and isolated compounds were used to perform bioassays. From fraction II GC-MS detected four methyl esters of allelopathic fatty acid viz. Methyl oleate, methyl palmitate, methyl stearate and methyl linoleate. The evaluation of physiological effects of the bioassay revealed substantial suppression of chlorophyll, antioxidant enzymes (superoxide, dismutase peroxidase) and protein material in all weeds by methyl palmitate. Bioassay activity and study of physiological parameters revealed that the effective bio-herbicidal compound in Lantana camara flowers is methyl palmitate. This is the first time that methyl palmitate (a fatty acid methyl ester) has been related to herbicidal activity in L. camara flowers. It is proposed that field studies based on hormesis research and the mechanism of action of this compound be carried out., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Background: Chemotherapeutic drugs cause severe toxicities if administered unprotected, without proper targeting, and controlled release. In this study, we developed topotecan- (TPT-) loaded solid lipid nanoparticles (SLNs) for their chemotherapeutic effect against colorectal cancer. The TPT-SLNs were further incorporated into a thermoresponsive hydrogel system (TRHS) (TPT-SLNs-TRHS) to ensure control release and reduce toxicity of the drug. Microemulsion technique and cold method were, respectively, used to develop TPT-SLNs and TPT-SLNs-TRHS. Particle size, polydispersive index (PDI), and incorporation efficiency (IE) of the TPT-SLNs were determined. Similarly, gelation time, gel strength, and bioadhesive force studies of the TPT-SLNs-TRHS were performed. Additionally, in vitro release and pharmacokinetic and antitumour evaluations of the formulation were done., Results: TPT-SLNs have uniformly distributed particles with mean size in nanorange (174 nm) and IE of ~90%. TPT-SLNs-TRHS demonstrated suitable gelation properties upon administration into the rat's rectum. Moreover, drug release was exhibited in a control manner over an extended period of time for the incorporated TPT. Pharmacokinetic studies showed enhanced bioavailability of the TPT with improved plasma concentration and AUC. Further, it showed significantly enhanced antitumour effect in tumour-bearing mice as compared to the test formulations., Conclusion: It can be concluded that SLNs incorporated in TRHS could be a potential source of the antitumour drug delivery with better control of the drug release and no toxicity., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 R. Xing et al.)

High energy-density supercapacitors (SCs) with long operating life, cost-effective, and competitive cycling performance is attracted great research attention to competing in the requirements of the modern age. However, despite these benefits, SC hampers inadequate rate-capability and structural deterioration, which primarily affects its commercialization. Herein, ultra-thin two-dimensional (2D) ZnCo 2 O 4 nanosheets are in situ anchored on the conductive surface of nickel foam (denoted as ZCO@NF) by hydrothermal process. The binder-free ZCO@NF is employed as an electrode for SCs and shows impressive charge storage properties. ZCO@NF electrode exhibited a high capacitance of 1250 (750) and 733 F g -1 (440 C g -1 ) at 2.5 and 20 A g -1 , respectively, demonstrating the outstanding rate-capability of 58.6% even at 8 times larger current density. Furthermore, the ZCO@NF electrode exhibits admirable capacitance retention of 96.5% after 10 000 cycles. This impressive performance of the ZCO@NF electrode is attributed to the high surface area which gives a short distance for ion/electron transfer, a high conductivity with extensive electroactive cities, and strong structural stability. The binder-free approach provides a strong relationship between the current collector and the active material, which turns into improved electrochemical operation as an electrode material for SCs., (© 2021 IOP Publishing Ltd.)

Background: Hypercalcemia is a common electrolyte abnormality presenting with a variety of symptoms. The common causes are primary hyperparathyroidism and malignancy associated with hypercalcemia. However, iatrogenic hypercalcemia with the overzealous use of vitamin D has now emerged as another important cause of hypercalcemia over the past decade., Objective: This study aims to evaluate the causes of hypercalcemia, management strategies, and outcomes in patients admitted with hypercalcemia in a tertiary care hospital.  Method: It is a retrospective study done at Aga Khan University Hospital (AKUH), Karachi after taking approval from the ethical review committee (ERC). Data were gathered about all patients admitted from 1st   January 2008 to 31st   December 2018. A total of 1142 patients were included in the study and their calcium levels were noted. Along with demographic details, data pertaining to their diagnosis and all investigations done to evaluate the causes of hypercalcemia were noted in a pre-defined questionnaire., Results: A total of 814 patients having hypercalcemia were included in the final analysis and their mean age was 60.8 ± 14.1 years. Male and female patients were 45.4% and 54.6%, respectively, and their mean hospital stay was 6.2 ± 5.8 days. The most common cause of hypercalcemia was malignant solid tumors (49.1%), followed by hematological malignancy (16.5%), hyperparathyroidism (10.9%), definite vitamin D toxicity (8%), chronic kidney disease (4.9%), chronic granulomatous diseases (4.7%), and probable vitamin D toxicity (3.5%). The oral cavity carcinoma (17.7%) was the most common solid tumor associated with hypercalcemia. Amongst hematological malignancy, multiple myeloma (14.4%) was the most common one. Out of 814 patients admitted with hypercalcemia, 601 (74%) patients recovered from hypercalcemia, while mortality was observed in 129 (16%) patients. Of those who expired, 110 (85.3%) had malignancy either solid tumor or hematological., Conclusion: Malignancy is the most common cause of hypercalcemia in admitted patients. The knowledge of hypercalcemia's causes is of great importance so that targeted investigations can be done. Not only will it minimize the cost burden and shorten the hospitalization of patients; it will also help the physicians to decide the appropriate management accordingly. Moreover, vitamin D toxicity was also observed in a significant number of patients which highlights the common practice of using higher doses of vitamin D by physicians., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Banu et al.)

Introduction: Over 800 000 people die due to suicide each year and suicide presents a huge psychological, economic and social burden for individuals, communities and countries as a whole. Low-income and middle-income countries (LMICs) are disproportionately affected by suicide. The strongest risk factor for suicide is a previous suicide attempt, and other types of self-harm have been found to be robust predictors of suicidal behaviour. An approach that brings together multiple sectors, including education, labour, business, law, politics and the media is crucial to tackling suicide and self-harm. The WHO highlights that evaluations of the knowledge and attitudes that priority groups, not only healthcare staff, have of mental health and suicidal behaviour are key to suicide prevention strategies. The aim of this systematic review is to examine the knowledge, attitudes and experiences different stakeholders in LMICs have of self-harm and suicide., Methods and Analysis: MEDLINE, Embase, PsycINFO, CINAHL, BNI, Social Sciences and Cochrane Library will be searched. Reviewers working independently of each other will screen search results, select studies for inclusion, extract and check extracted data, and rate the quality of the studies using the Strengthening the Reporting of Observational studies in Epidemiology and Critical Appraisals Skills Programme checklists. In anticipation of heterogeneity, a narrative synthesis of quantitative studies will be provided and metaethnography will be used to synthesise qualitative studies., Ethics and Dissemination: Ethical approval is not required. A report will be provided for the funding body, and the systematic review will be submitted for publication in a high-impact, peer-reviewed, open access journal. Results will also be disseminated at conferences, seminars, congresses and symposia, and to relevant stakeholders., Prospero Registration Number: CRD42019135323., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Aim: This study is a longitudinal multicenter study which aims to find the prevalence, the demographic data, survival and mortality rates of patients with systemic lupus erythematosus (SLE) in Oman., Method: All Omani patients, pediatrics and adults diagnosed with SLE, who fulfill either the 1997 American College of Rheumatology or Systemic Lupus International Collaborating Clinics classifications criteria for SLE were included from January 2006 till February 2020., Results: In total 1160 patients were included in this cohort. Data analysis showed that patient's ages ranged from 2-82 years with female predominance and female-to-male ratio of 7:1 (87.7% female,12.3% male). The mean prevalence of SLE among different age groups was 38.8 (range 5-63 per 100 000 inhabitants). The mortality rate was found to be 5%. Male patients had significantly higher mortality rate than females (7.6% vs 5.4%, P value = .04). Sepsis was the commonest cause of mortality (34%). The coexistence of systemic sclerosis correlates significantly with death (P = .002). Survival analysis in our data showed 5, 10, 20, 40-year survival rates of 100%, 100%, 99% and 90% respectively for antinuclear antibody (ANA) positive patients and lower survival rate for ANA negative patients with 5,10, 20, 40-year survival rates of 100, 99%, 99% and 75%, respectively., Conclusion: This study showed that the mean prevalence of SLE in Oman to be 38.8 (range 5-63) per 100 000 inhabitants. The 40-year survival rate among patients with positive ANA was found to be 90%, while patients with negative ANA had worse survival outcomes., (© 2021 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Menin, a product of MEN1 (multiple endocrine neoplasia type 1) gene is an important regulator of tissue development and maintenance; its perturbation results in multiple tumors-primarily of the endocrine tissue. Despite its abundance in the developing central nervous system (CNS), our understanding of menin's role remains limited. Recently, we discovered menin to play an important role in cholinergic synaptogenesis in the CNS, whereas others have shown its involvement in learning, memory, depression and apoptosis. For menin to play these important roles in the CNS, its expression patterns must be corroborated with other components of the synaptic machinery imbedded in the learning and memory centers; this, however, remains to be established. Here, we report on the spatio-temporal expression patterns of menin, which we found to exhibit dynamic distribution in the murine brain from early development, postnatal period to a fully-grown adult mouse brain. We demonstrate here that menin expression is initially widespread in the brain during early embryonic stages, albeit with lower intensity, as determined by immunohistochemistry and gene expression. With the progression of development, however, menin expression became highly localized to learning, memory and cognition centers in the CNS. In addition to menin expression patterns throughout development, we provide the first direct evidence for its co-expression with nicotinic acetylcholine, glutamate and GABA (gamma aminobutyric acid) receptors-concomitant with the expression of both postsynaptic (postsynaptic density protein PSD-95) and presynaptic (synaptotagamin) proteins. This study is thus the first to provide detailed analysis of spatio-temporal patterns of menin expression from initial CNS development to adulthood. When taken together with previously published studies, our data underscore menin's importance in the cholinergic neuronal network assembly underlying learning, memory and cognition.

Background: Improper use of asthma inhalers is one of the potential factors of poor asthma control among children. This study aimed to assess the proper handling of asthma inhalers and asthma control in addition to factors influencing them among pediatric patients who self-administer their inhalers., Methods: A cross-sectional study was conducted in Jordan from February 2019 to February 2020. All eligible pediatric patients with asthma attending outpatient settings were approached. The inhalation technique was assessed according to a standard checklist, and asthma control was assessed using the Asthma Control Test., Results: A total of 150 patients were included in this study. A metered dose inhaler (MDI) was the most commonly used inhaler device (89.4%) which was used appropriately by only 13.4% of participants. Whereas, appropriate use of Turbohaler and Diskus was reported by 38.5% and 28.9%, respectively. The higher level of parental knowledge was associated with higher number of correct MDI steps (OR = 1.066; 95% CI = 1.010-1.125; p = .020) and less reported errors in critical steps (OR = 0.949; 95% CI = 0.900-0.999; p = .047). Higher level of both parental education and pediatric average stigma score (less stigmatized) were associated with better asthma control ([OR = 5.181; 95% CI = 1.238-21.677; p = .024], [OR = 2.825; 95% CI = 1.420-5.619; p = .003], respectively)., Conclusion: Continuous education on appropriate inhaler self-administration for asthmatic children is highly recommended. Clinical pharmacists play a major role toward improving the administration of inhalers through patient training and counseling., (© 2021 Wiley Periodicals LLC.)

Currently, the whole world is facing the coronavirus disease-19 pandemic. As of now, approximately 0.15 million people around the globe are infected with the novel coronavirus. In the last decade, two strains of the coronavirus family, severe acute respiratory syndrome-related coronavirus and Middle East respiratory syndrome coronavirus, also resulted in epidemics in south Asian and the Middle Eastern countries with high mortality rate. This scenario demands the development of a putative vaccine which may provide immunity against all current and new evolving coronavirus strains. In this study, we designed an epitope-based vaccine using an immunoinformatic approach. This vaccine may protect against all coronavirus strains. The vaccine is developed by considering the geographical distribution of coronavirus strains and host genetics (Chinese population). Nine experimentally validated epitopes sequences from coronavirus strains were used to derive the variants considering the conservancy in all strains. Further, the binding affinities of all derived variants were checked with most abundant human leukocyte antigen alleles in the Chinese population. Three major histocompatibility complex (MHC) Class I epitopes from spike glycoprotein and nucleoprotein showed sufficient binding while one MHC Class II epitope from spike glycoprotein was found to be an effective binder. A cocktail of these epitopes gave more than 95% population coverage in the Chinese population. Moreover, molecular dynamics simulation supported the aforementioned predictions. Further, in vivo studies are needed to confirm the immunogenic potential of these vaccines., (© 2021 The Societies and John Wiley & Sons Australia, Ltd.)

Sox2 is one of the core transcription factors maintaining the embryonic stem cells (ES) pluripotency and, also indispensable for cellular reprogramming. However, limited data is available about the DNA methylation of pluripotency genes during lineage-specific differentiations. This study investigated the DNA methylation of Sox2 regulatory region 2 (SRR2) during directed differentiation of mouse ES into neural lineage. ES cells were first grown to form embryoid bodies in suspension which were then dissociated, and cultured in defined medium to promote neural differentiation. Typical neuronal morphology together with the up-regulation of Pax6, neuroepithelial stem cell intermediate filament and β-tubulin III and, down-regulation of pluripotency genes Oct4, Nanog and Sox2 showed the existence of neural phenotype in cells undergoing differentiation. Three CpGs in the core enhancer region of neural-specific SRR2 were individually investigated by direct DNA sequencing post-bisulfite treatment and, found to be unmethylated in differentiated cells at time-points chosen for analysis. This analysis does not limit the possibility of methylation at other CpG sites than those profiled here and/or transient methylation. Hence, similar analyses exploring the DNA methylation at other regions of the Sox2 gene could unravel the onset and transitions of epigenetic signatures influencing the outcome of differentiation pathways and neural development. The data presented here shows that in vitro neural differentiation of embryonic stem cells can be employed to study and characterize molecular regulatory mechanisms governing neurogenesis by applying diverse pharmacological and toxicological agents., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Batool, Kayani, Valis and Kuca.)

COVID-19 spread rapidly and jeopardised the physicians with not only treatment but also with limited resources and new working style. This study aimed to investigate the experience of physicians in Pakistan as frontline workers for the treatment of COVID-19 patients. The study employed a qualitative design and used Haas's adaptation of Colaizzi method for analysis. The respondents for the interview were selected based on purposive sampling and only those physicians were contacted who were treating COVID-19 patients in Lahore, Pakistan. The results of the study revealed many challenges faced by Pakistani physicians which included physical and psychological stress due to the treatment of COVID-19 patients. Moreover, infrastructural flaws have added in the vulnerabilities of the physicians. In developing countries, the fight is much harder for physicians as evidenced by their first-hand experience. The policymakers in developing countries especially in Pakistan can direct policies facilitating physicians to reduce their physical and psychological stress as well as increasing resources for the treatment of COVID-19 patients., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2021 Wajiha Haq, Fareyha Said, Sidrah Batool, Hafiz Muhammad Awais.)

Objective: The purpose of this study was to develop novel carbopol-based miltefosine-loaded transfersomal gel (HePCTG) for the treatment of cutaneous leishmaniasis (CL) via efficient targeting of leishmania infected macrophages., Methods: Miltefosine-loaded transfersomes (HePCT) were prepared by ethanol injection method followed by their incorporation into carbopol gel to form HePCTG. The prepared HePCT were assessed for physicochemical properties including mean particle size, polydispersity index, zeta potential, entrapment efficiency, morphology, and deformability. Similarly, HePCTG was evaluated for physiochemical and rheological attributes. The in vitro release, skin permeation, skin irritation, anti-leishmanial activity, and in vivo efficacy in BALB/c mice against infected macrophages were also performed for HePCT., Results: The optimized HePCT displayed a particle size of 168 nm with entrapment efficiency of 92%. HePCTG showed suitable viscosity, pH, and sustained release of the incorporated drug. Furthermore, HePCT and HePCTG demonstrated higher skin permeation than drug solution. The results of macrophage uptake study indicated improved drug intake by passive diffusion. The lower half maximal inhibitory concentration value, selectivity index and higher 50% cytotoxic concentration  value of HePCT compared to that of HePC solution demonstrated the improved anti-leishmanial efficacy and non-toxicity of the formulation. This was further confirmed by the notable reduction in parasite load and lesion size observed in in vivo anti-leishmanial study., Conclusion: It can be stated that the formulated HePCTG can effectively be used for the treatment of CL.

Anesthetics are deemed necessary for all major surgical procedures. However, they have also been found to exert neurotoxic effects when tested on various experimental models, but the underlying mechanisms remain unknown. Earlier studies have implicated mitochondrial fragmentation as a potential target of anesthetic-induced toxicity, although clinical strategies to protect their structure and function remain sparse. Here, we sought to determine if preserving mitochondrial networks with a non-toxic, short-life synthetic peptide-P110, would protect cortical neurons against both inhalational and intravenous anesthetic-induced neurotoxicity. This study provides the first direct and comparative account of three key anesthetics (desflurane, propofol, and ketamine) when used under identical conditions, and demonstrates their impact on neonatal, rat cortical neuronal viability, neurite outgrowth and synaptic assembly. Furthermore, we discovered that inhibiting Fis1-mediated mitochondrial fission reverses anesthetic-induced aberrations in an agent-specific manner. This study underscores the importance of designing mitigation strategies invoking mitochondria-mediated protection from anesthetic-induced toxicity in both animals and humans.

Background: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive inherited disorder with distinctive clinical feature such as obesity, degeneration of retina, polydactyly, and renal abnormalities. The study was aimed at finding out the disease-causing variant/s in patients exhibiting clinical features of BBS., Methods: The identification of disease-causing variant was done by using whole exome sequencing on Illumina HiSeq 4000 platform involving the SeqCap EZ Exome v3 kit (Roche NimbleGen). The identified variant was further validated by Sanger sequencing., Results: WES revealed a novel homozygous missense mutation (NM&#95;031885: c.443A>T:p.N148I) in exon 3 of the BBS2 gene. Sanger sequencing confirmed this variant as homozygous in both affected subjects and heterozygous in obligate parents, demonstrating autosomal recessive inheritance pattern. To the best of our knowledge, this variant was not present in literature and all publically available databases. The candidate variant is predicted to be pathogenic by a set of in-silico softwares., Conclusion: Clinical and genetic spectrum of BBS and BBS-like disorders is not completely defined in the Pakistani as well as in Kashmiri population. Therefore, more comprehensive genetic studies are required to gain insights into genotype-phenotype associations to facilitate carrier screening and genetic counseling of families with such disorders., Competing Interests: The authors have no conflict of interest to declare., (Copyright © 2021 Ghazanfar Ali et al.)

Background: Community acquired pneumonia is a commonly presenting respiratory tract infection around the world. Its treatment is problematic at times because of diversity of infecting organisms and change in susceptibility pattern to commonly prescribed antimicrobials., Methods: This was a single centred prospective cross sectional study. About 165 patients diagnosed with community acquired pneumonia were included and blood samples, sputum samples were taken for culture sensitivity and antimicrobial susceptibility., Results: Of the 165 patients (43% males and 57% females), 77 (46.6%) patients tested positive for bacterial pathogens out of a total of 165. The most common pathogen was Streptococcus pneumonia (34%) followed on by Hemophilus influenza (16%), Staphylococcus aureus (13%) Klebsiella (12%), Pseudomonas aeruginosa (10%), Legionella (6%), Eschericha coli (5%) and Proteus mirabilis (2%). The sensitivity pattern of all 77 bacterial isolates was high for cephalosporins (ceftriaxone, 81%; ceftazidime, 80%), penicillins (amoxicillin/sulbactam, 70%), quinolones (levofloxacin, 74%) and aminoglycosides (amikacin, 80.5%). The sensitivity to macrolides (azithromycin, 59.7%; clarithromycin, 53.2%) and tetracycline's (55.8%) is somewhat intermediate and low for ampicillin (42.8%) and cotrimoxazole (51.9%)., Conclusion: The decreased susceptibility to macrolides and tetracyclines is a matter of concern and judicious use of antimicrobials should be done to prevent further rates of resistance., (© 2020 John Wiley & Sons Ltd.)

Aims: To determine the prevalence of inflammatory back pain (IBP) and radiographic axial spondyloarthritis (SpA) in a semi-urban community of Lahore, Pakistan., Methods: This cross-sectional household survey was designed as per the Community Oriented Program for the Control of Rheumatic Diseases (COPCORD) model. In Phase 1, the subjects were interviewed for musculoskeletal (MSK) pain in the last 7 days by clinical assistants. In Phase 2, physiotherapists identified subjects with spinal/back pain and interviewed for Assessment in Spondyloarthritis International Working Group (ASAS) criteria for IBP. In Phase 3 subjects having IBP or chronic back pain (CBP) with an age at onset ≤45 years, were assessed and further investigated., Results: A total of 4922 subjects with a mean age of 35.3 ± 14.5 years, including 2770 (56%) women were surveyed in Phase 1. MSK pain in last 7 days was reported by 1407 (28.6%) of whom 1034 (21%) had spinal pain. The ASAS criteria for IBP were met in 329 (6.7%, 95% CI 6.0-7.0). In Phase 3, 222 with IBP and 83 having CBP with age at onset ≤45 years were evaluated. Out of this total of 305, 144 (2.9%) were confirmed to have IBP by rheumatologists as per at least 1 of the 3 criteria. ASAS criteria were met in 107 (2.2%, 95% CI 1.8-2.6). ASAS criteria for radiographic axial SpA were met in 47 (1%, 95% CI 0.7-1.3) of the surveyed population., Conclusion: Inflammatory back pain was reported in 6.7% by physiotherapists, confirmed in 3% by rheumatologists. The prevalence of radiographic axial SpA was 1%., (© 2020 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

A series of new derivatives of 4-(2-chloroethyl)morpholine hydrochloride (5) were efficiently synthesized. Briefly, different aromatic organic acids (1a-f) were refluxed to acquire respective esters (2a-f) using conc. H 2 SO 4 as catalyst. The esters were subjected to nucleophillic substitution by monohydrated hydrazine to acquire hydrazides (3a-f). The hydrazides were cyclized with CS2 in the presence of KOH to yield corresponding oxadiazoles (4a-f). Finally, the derivatives, 6a-f, were prepared by reacting oxadiazoles (4a-f) with 5 using NaH as activator. Structures of all the derivatives were elucidated through 1D-NMR EI-MS and IR spectral data. All these molecules were subjected to antibacterial and hemolytic activities and showed good antibacterial and hemolytic potential relative to the reference standards.

Background: Bistorta amplexicaulis of the genus Polygonum (Polygonaceae) has been reported for its antioxidant and anticancer activities. However, the low cellular uptake of the compounds in its extract limits its therapeutic application., Objectives: The present study aimed at developing a nanoliposomal carrier system for B. amplexicaulis extracts for improved cellular uptake, thus resulting in enhanced anticancer activity., Methods: Ultra Pressure Liquid Chromatography (UPLC) was used to identify major compounds in the plant extract. Nanoliposomes (NLs) were prepared by employing a thin-film rehydration method using DPPC, PEG2000DSPE and cholesterol, followed by characterization through several parameters. In vitro screening was performed against breast cancer cell line (MCF-7) and Hepatocellular carcinoma cell line (HepG-2) using MTT-assay. Raw extract and nanoliposomes were tested on Human Umbilical Vein Endothelial Cells (HUVEC). Moreover, molecular docking was performed to validate the data obtained through wet lab., Results: The UHPLC method identified gallic acid, caffeic acid, chlorogenic acid and catechin as the major compounds in the extract. The NLs with a size ranging between 140-155 nm, zeta potential -16.9 to -19.8 mV and good polydispersity index of < 0.1 were prepared, with a high encapsulation efficiency of 81%. The MTT assay showed significantly (p > 0.05) high uptake and cytotoxicity of NLs as compared to the plant extract. Moreover, reduced toxicity against HUVEC cells was observed as compared to the extract. Also, the docking of identified compounds suggested a favorable interaction with the SH2 domain of both STAT3 and STAT5., Conclusion: Overall, the results suggest NLs as a potential platform that could be developed for the improved intracellular delivery of plant extract, thus increasing the therapeutic outcomes., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The present study was conducted to get more information about the genome and locate the taxonomic position of Schizothorax niger in Schizothoracinae through mitochondrial 13 protein-coding genes (PCGs). These PCGs for S. niger were found to be 11409 bps in length ranging from 165 (ATPase 8) to 1824 bps (NADH dehydrogenase subunit 5) and encode 3801 amino acids. In these PCGs, 4 genes overlap on the similar strands, while one shown on the opposite one: ATPase 6+8 and NADH dehydrogenase subunit 4+4L overlap by 7 nucleotides. Similarly, ND5-ND6 overlap by 4 nucleotides, while ATP6 and COIII overlap by 1 nucleotide. Similarly, four commonly used amino acids in S. niger were Leu (15.6 %), Ile (10.12 %), Thr (8.12 %), and Ala (8.7 %). The results presented that COII, COIII, NDI, ND4L, and Cytb had substantial amino acid conservation as compared to the COI gene. Through phylogenetic analysis, it was observed that S. niger is closely linked with S. progastus , S. labiatus , S. plagiostomus , and S. nepalensis with high bootstrap values. The present study provided more genomic data to know the diversity of the mitochondrial genome and its molecular evolution in Schizothoracinae., Competing Interests: The authors alone are responsible for the content and writing of the paper. The authors report no conflicts of interest., (Copyright © 2020 Tasleem Akhtar et al.)

Background and Objectives: Organophosphate (OPs) anticholinesterases are one of the main groups of pesticides used in agriculture. Harmful effects of OPs on health have been attributed primarily for irreversible inhibition of acetylcholinesterase (AChE) at nerve synapse. However, studies have shown that inhibition of AChE alone cannot explain all the maladies encountered in prolonged exposure to OPs. Predisposition to population heterogeneity and irregularities in various biochemicals like paraoxonases and inflammatory biochemicals are the possible affects of OPs long term exposure that may lead to sequels of diseases and are less addressed in literature. The study was aimed to assess the cholinergic enzymes (AChE and BChE), PON1, and inflammatory markers (IL1β, IL6, TNFα, CRP, Apo AI, Apo B) and determine the toxicogenetics association of PON1 gene (rs 662 and rs 85456) to chronically OPs exposed groups from Pakistan and Cameroon., Materials and Methods: AChE, BChE and PON1 were measured by colorimetric method using spectrophotometry. Inflammatory markers were determined by Elisa assay. PCR-restriction fragment length polymorphism (PCR-RFLP) using salting out method was employed for SNP genotyping., Results: The results revealed the significant (p ≤ 0.05) inhibition of cholinergic enzymes PON 1 was found to be 6.91 ng/mL±1.03 and 2.84 ng/mL±1.40 (mean ± SD) in Pakistan and Cameroon groups respectively. IL6, TNFα, CRP were increased and Apo AI was less while Apo B was increased in OP exposed groups in both population groups. SNPs analysis of PON1 showed significant differences in allelic and genotype frequencies of OPs exposed and non-exposed groups., Conclusions: PON1 was noticeably less in Cameroonian than Pakistani, albeit both groups have significant decrease in PON1 actity. In addition, the study concludes that OPs induce low grade inflammation, an aetiology of many diseases. Selected PON1 SNPs analysis showed a significant toxicogenetics association with OPs exposure marker enzymes. The results of this study may help in regulation of usage of OPs anticholinesterases in different populations. The study will further open new avenues in toxicogenetic and exploration of SNPs based strategies on organophosphate intoxication., (Copyright © 2020 Elsevier Inc. All rights reserved.)

There are many factors of methodological origin that influence the measurement of optical properties of the entire circulatory system which consists of blood as the basic component. The basic idea of this review article is to provide the optical properties of the circulatory system with all those factors of influence that have been employed in biomedical optics for different applications. We begin with the available optical properties, i.e., absorption, scattering and, reduced scattering coefficient, in general for any tissue inside the human body and prominent scattering theories (e.g., light, X-rays, neutrons) that are helpful in this regard. We have reviewed and compiled already available formulas and their respective available data for different human tissues for these optical properties. Then we have descended to the blood composition and to different scattering techniques available in the literature to study scattering and light propagation inside blood. We have reviewed both computational and theoretical scattering techniques.

Organophosphates (OP) are a major agrochemical. The application of OP pesticides is expected to increase multifold in the coming decades. The etiology of diabetic diseases is attributed to multiple factors including OP pesticide exposure. The present study investigates pancreatic dysregulation with respect to exocrine enzymes and diabesity in groups of Pakistani and Cameroonian people exposed to a mixture of OP pesticides. Nine hundred and four OP exposed individuals were enrolled for this cross-sectional study after due consent and approval from an ethical review committee. Pesticides' residues were measured by GC-MS spectrometry. Cholinergic enzymes were measured by Elman's method. Serum glucose, insulin, serum amylase, lipase, and triglyceride were measured by spectrophotometry and ELISA; HOMA-IR was determined in OP exposed and non-exposed participants. Stata 15 and R 3.2.0 software were used for statistical analysis of the data. Malathion, chlorpyrifos, and parathion residues were evident in plasma samples. RBC-acetylcholinesterase was significantly depressed in OP exposed groups. In both population samples, investigated pancreatic functions were found to be statistically significantly more dysregulated than non-exposed. OP exposure indicated risk of diabetes and insulin, glycaemia, adiponectin, triglycerides, and TNF-α dysregulations. The study concludes that both OP exposed population groups exhibited a mixture of OP residues and pancreatic dysregulation, although the effect was more pronounced in the Cameroonian population. In addition, serum lipase has a positive correlation with OP exposure and diabetes and may be suggested as an alternate/additional diagnostic marker for diabesity under OP exposure. However, screening of other environmental co-factors with OP for pancreatic dysregulation is suggested., (Copyright © 2020 Leonel Javeres, Raza, Judith, Anwar, Habib, Batool and Nurulain.)

Background Caustic ingestion continues to be a significant problem worldwide especially in developing countries and particularly in the age group of under six years. Ingestion of caustic substances is a medical emergency in both the adult and pediatric population and is associated with high morbidity and mortality. The ingestion of caustic substances induces an extensive spectrum of injuries to the aerodigestive tract, which includes extensive necrosis and perforation of the esophagus and stomach. Objectives The main aims were to determine upper and lower esophageal injuries associated with corrosive intake and to compare esophageal injury with age and gender. Rationale Once we'll find the extent and severity of esophageal injury associated with corrosive intake within 24 hours, we'll be able to manage the case timely and to limit further complications and disabilities. Materials and Methods This descriptive cross-sectional study was conducted on 150 patients who presented with corrosive ingestion and underwent urgent endoscopic evaluation. Data were collected using self-designed pro forma. Endoscopic findings were classified according to the Zargar classification. A descriptive analysis of study variables was performed using SPSS v.21.0 (IBM Corp., Armonk, NY, USA). The chi-square test was used, and a p-value of less than 0.05 was considered statistically significant. Results Out of 150 patients under study, 103 (68.7%) were females and 47 (31.3%) were males. The most prevalent age group presenting with corrosive intake was found to be between 21 and 34 years of age (43.3%) in both genders. The most common part of the esophagus prone to corrosive insult is the upper esophagus (99.3%), whereas, regarding severity, the lower esophagus has more severe injuries (predominant being stage 2B, i.e., 32%). There are no statistically significant differences in esophageal injuries in different age groups (upper esophageal injury: 0.319; lower esophageal injury: 0.696) and genders (upper esophageal injury: 0.769; lower esophageal injury: 0.752).  Conclusions Most of the patients under study belong to the female gender and teen and younger age group. The predominant upper esophageal injury as a result of corrosive intake is stage 0 injury, and the least common is found to be stage 1 injury. The predominant lower esophageal injury as a result of corrosive intake is stage 2B injury, whereas the least common is found to be stage 4 injury., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Ain et al.)

Background: To determine staining expression of CK5\6 in healthy oral mucosa and various grades of oral dysplasia and to find out possible association of CK5\6 expression in dysplastic transformation of clinically normal oral mucosa to various grades of oral dysplasia., Methods: This cross-sectional descriptive study was done at Al-Tibri Medical College and Hospital and Dow University of Health Sciences, Karachi from March 2018 to November 2018. It included 120 diagnosed paraffin embedded tissue samples of normal oral mucosa and various grades of oral epithelial dysplastic lesions. Patient's data was reviewed for age, gender and tobacco habits. For immunohistochemistry CK5\6 staining was performed on all the samples. Immunohistochemical evaluation was done by observing the staining expression of CK5\6 on various oral dysplastic samples on the basis of staining intensity. The compiled data was statistically analyzed by using Chi-square. p-values of <0.05 were considered to be significant., Results: All of the 60/60 (100%) oral dysplastic cases were moderately to strongly positive for CK5\6. Gradual increase in staining intensity for CK5\6 was observed with increasing grades of dysplasia. We found highly significant association of CK5\6 immunopositivity in transformation of normal mucosa to various grades oral dysplastic lesions., Conclusions: CK5\6 can be used as reliable adjuvant marker for the early dysplastic transformation of oral mucosain tobacco users, before it progresses to oral squamous cell carcinoma (OSCC).

Background: Diabetes mellitus is the metabolic state which has shown a persistent global rise in numbers. It is therefore necessary to closely assess all aspects of this state. Sleep quality and diabetic control have a relation where both can affect each other. Therefore, we aim to study the quality of sleep and factors affecting it in our diabetic population. The objective of the study was the identification of quality of sleep and factors affecting it in the diabetic and non diabetic adult population., Methods: In this comparative cross sectional study quality of sleep was evaluated in all the patients through the Pittsburgh Sleep Quality Index. Statistical analysis was conducted with the SPSS-23., Results: The total number of study participants were 250 adults (18 years and above), where 125 were diabetics, while 125 were non diabetics. In Diabetic group, the total number of patients with impaired sleep was 65 (52%). In non-diabetic group, impaired sleep was found in 70 (56%) individuals. The mean age of diabetics was 55.2±11.6 years and non-diabetics was 37.23±12.017 years. Prevalence of restless leg syndrome and depression among diabetics was 33 (26.4%) and 30 (24.0%) respectively and in nondiabetic was 20 (16.0%) and 63 (50.4%). Impaired sleep quality was associated with the use of cell phones before going to bed (p-value: 0.01) and watching television until late at night in both groups. Impaired sleep is seen more commonly in uncontrolled DM (RR:1.462 and CI: 0.531 to 4.025)., Conclusions: Impaired sleep and uncontrolled DM has a direct relation and the prevalence of Restless leg syndrome (RLS) is higher in Diabetics. Addressing the factors impairing sleep can improve sleep quality and have beneficial effects on the sufferers from this metabolic state.

Whitlockite, being the second most abundant bio-mineral in living bone, finds huge applications in tissue regeneration and implants and its synthesis into its pure form has remained a challenge. Although precipitation of whitlockite phase has been reported recently in many publications, effects of various parameters to control such phase as well as conditions for the bulk preparation of this extremely important bio-mineral have not been investigated so far. In this work, we report the precipitation of pure whitlockite phase using common precursors. As reported in the literature, whitlockite is stable in a narrow pH range, therefore; optimization of pH for the stabilization of whitlockite phase has been investigated. Additionally, in order to narrow down the optimum conditions for the whitlockite precipitation, effect of temperature and heating conditions has also been studied. The obtained solids were characterized using powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, scanning electron microscopy (SEM) and thermogravimetric analysis (TGA). From PXRD analysis, it was observed that heating the precursor's mixture at 100 °C with subsequent aging at the optimized pH resulted in the precipitation of pure whitlockite phase. These results were further confirmed by TGA, SEM and Raman spectroscopy analysis and it was confirmed that the conditions reported here favor whitlockite precipitation without formation of any secondary phase. These reaction conditions were further confirmed by changing all the parameters like aging, heating time, feed rate of precursors one by one. From PXRD analysis of these samples, it was concluded that not only pH but temperature, heating time, aging time and feed rate effect simultaneously on the precipitation of pure whitlockite phase and a subtle change in any of these parameters could lead to the formation of undesired stable secondary calcium phosphate phases.

In this case report, we present a novel presentation of acute epiglottitis in a patient with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) who presented to the emergency room in extremis and respiratory failure requiring emergent cricothyrotomy. Epiglottitis has become less common since the introduction and widespread use of the Haemophilus influenzae type B (Hib) vaccine. This reduction in cases has shifted demographics of the disease from the pediatric population towards adults with comorbid conditions. Interestingly there is a high degree of overlap between many of the comorbidities between epiglottitis and COVID-19. The novel severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), also referred to as coronavirus disease 19 (COVID-19), has been reported to affect the gastrointestinal tract and neural tissue and has been implicated in necrotizing encephalitis. We report the first known case of the novel SARS-CoV-2 virus presenting with acute epiglottitis., (Published by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author(s) 2020.)