Publications by authors named "Muhammad Saeed"

372 Publications

Facile Synthesis and In Vitro Activity of -Substituted 1,2-Benzisothiazol-3(2)-ones against Dengue Virus NS2BNS3 Protease.

Pathogens 2021 Apr 12;10(4). Epub 2021 Apr 12.

Institut für Virologie und Immunbiologie, Versbacher Straße 7, 97078 Würzburg, Germany.

Several new -substituted 1,2-benzisothiazol-3(2)-ones (BITs) were synthesised through a facile synthetic route for testing their anti-dengue protease inhibition. Contrary to the conventional multistep synthesis, we achieved structurally diverse BITs with excellent yields using a two-step, one-pot reaction strategy. All the synthesised compounds were prescreened for drug-like properties using the online Swiss Absorption, Distribution, Metabolism and Elimination (SwissADME) model, indicating their favourable pharmaceutical properties. Thus, the synthesised BITs were tested for inhibitory activity against the recombinant dengue virus serotype-2 (DENV-2) NS2BNS3 protease. Dose-response experiments and computational docking analyses revealed that several BITs bind to the protease in the vicinity of the catalytic triad with IC values in the micromolar range. The DENV2 infection assay showed that two BITs, 2-(2-chlorophenyl)benzo[d]isothiazol-3(2)-one and 2-(2,6-dichlorophenyl)benzo[]isothiazol-3(2)-one, could suppress DENV replication and virus infectivity. These results indicate the potential of BITs for developing new anti-dengue therapeutics.
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http://dx.doi.org/10.3390/pathogens10040464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070447PMC
April 2021

Association of Non-Hodgkin lymphoma risk with CYP1A1, GSTM1 and GSTT1 gene variants, in tobacco addicted patients of Pashtun ethnicity of Khyber Pakhtunkhwa, Pakistan.

Pak J Pharm Sci 2020 Nov;33(6):2617-2624

Department of Zoology, University of Peshawar, Peshawar, Pakistan.

The current study determines the possible antitumor and immunomodulatory effects of thymosin against the in vivo and in vitro growth of tumor-derived cell line in mice. Peritoneal phagocytes count, Ehrlich ascites tumor (EAT) cells, T- lymphocytes, and B- lymphocytes activities were determined. In addition, serum level of interleukin 2 (IL-2) and liver functions were measured. In animal testing, thymosin at doses of 0.50 and 1mg activated the phagocytic function of macrophages, as well as T- and B- cell function. Thymosin caused a marked shortage in the proliferation of EAT cells in the peritoneal fluid with dose 0.50g as compared with that of the corresponding control group. Furthermore, treatment with thymosin caused effectively elevate in serum level of IL-2, on the contrary reduce in serum levels of ALT, AST and total proteins. The size of solid Ehrlich tumor was significantly decreased, as measured morphologically with the doses 0.50 and 1 mg (P<0.01). These results confirmed that many biological activities attributed to thymosin and is as an adjuvant for immune enhancement.
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November 2020

GeneXpert Technology for the diagnosis of HIV-associated tuberculosis: Is scale-up worth it?

Open Life Sci 2020 30;15(1):458-465. Epub 2020 Jun 30.

Department of Pathology, Allama Iqbal Medical College, Lahore, Punjab, 54590, Pakistan.

Recent evaluations of the GeneXpert MTB/RIF assay for the simultaneous detection of and drug resistance in less than 2 h have stimulated tremendous enthusiasm. This is the breakthrough that tuberculosis (TB) control has been waiting for. In this (retrospective review) case study, sputum samples from strongly suspected pulmonary tuberculosis patients were collected and assessed for the GeneXpert MTB/RIF assay for diagnosing TB and drug resistance in comparison with other tests, including Ziehl-Neelsen smear and Löwenstein-Jensen test. Of 3,784 cases, 5.7% (216/3,784) were human immunodeficiency virus (HIV)-positive and TB co-infected patients. In diagnosing HIV-positive and TB co-infected cases, the sensitivity and specificity of GeneXpert were 76.4% and 100%. While in HIV-negative and TB suspected cases, the sensitivity and specificity were 95.6% and 100%. This new test represents a major milestone for global TB diagnosis and care. It also represents new hope for the millions of people who are at the highest risk of TB and drug-resistant disease. GeneXpert is World Health Organization-endorsed technology representing the gold standard for TB testing despite attaining less sensitivity for HIV and TB co-infected patients as compared to HIV-negative patients.
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http://dx.doi.org/10.1515/biol-2020-0052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874587PMC
June 2020

Arsenic uptake and toxicity in wheat (Triticum aestivum L.): A review of multi-omics approaches to identify tolerance mechanisms.

Food Chem 2021 Sep 18;355:129607. Epub 2021 Mar 18.

Environmental Health and Ecotoxicology Laboratory, Department of Environmental Sciences, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan. Electronic address:

Arsenic (As) due to its widespread has become a primary concern for sustainable food production, especially in Southeast Asian countries. In that context, the present review presented a comprehensive detail of the available literature marking an assortment of As-induced impacts on wheat. The conclusive findings of past research suggest that As tends to grossly affect the germination, elongation, biomass, grain yield, and induce oxidative stress. Several human studies are suggestive of higher cancer risks (>1 × 10) due to the ingestion of wheat grains. However, the body of proof is limited and the scarcity of information limited understanding about tolerance mechanism in wheat against As. Therefore, the paper provided a reference from tolerance mechanism based studies in other crops like rice and maize. The generated knowledge of arsenomics would pave the way for plant breeders to develop resistant varieties for As to ensure sustainable food production.
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http://dx.doi.org/10.1016/j.foodchem.2021.129607DOI Listing
September 2021

Migrated PEG balloon causing acute pancreatitis.

BMJ Case Rep 2021 Apr 1;14(4). Epub 2021 Apr 1.

Gastroenterology, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK.

Percutaneous endoscopic gastrostomy (PEG) is a common procedure for an unsafe swallow or inability to maintain oral nutrition. When a PEG tube needs replacement, a balloon gastrostomy tube is usually placed through the same, well formed and mature tract without endoscopy. We present a patient with a rare complication related to the balloon gastrostomy tube, to raise awareness and minimise the risk of this complication in the future. A 67-year-old female patient presented to the emergency department with severe abdominal pain and vomiting. Her gastrostomy feeding tube displaced inwards, up to the feeding-balloon ports complex. After investigations, she was diagnosed with acute pancreatitis. MR cholangiopancreatography (MRCP) confirmed features of this and, interestingly, an inflated gastrostomy balloon could be seen abutting the major and minor ampullae. The patient confirmed that the PEG tube had been changed to a balloon gastrostomy tube some time ago, but the external fixation plate (external bumper) had been loose lately, with the tube repeatedly moving inwards. She admitted that, 1 day before admission, the PEG tube had receded into the stomach and could not be pulled out with a gentle tug. After reviewing the MRCP images, the balloon was deflated, and the tube retracted. Once correctly placed, the balloon was reinflated, and her symptoms improved over the next 2 days.
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http://dx.doi.org/10.1136/bcr-2020-240605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021578PMC
April 2021

Schiff-Based Metal Complexes of Lamotrigine: Design, Synthesis, Characterization, and Biological Evaluation.

ACS Omega 2021 Mar 15;6(11):7719-7730. Epub 2021 Mar 15.

Department of Chemistry and Chemical Engineering, Syed Babar Ali School of Science and Engineering, Lahore University of Management Science, Lahore 54792, Pakistan.

In the current study, a series of Schiff base derivatives of lamotrigine are complexed with zinc, copper, silver, and tin and characterized by spectroscopic techniques and biological assays. Docking analyses revealed six complexes with favorable binding interactions, which were further subjected to anticancer activity. The complexes and displayed the most potent antiproliferative activity against MCF-7 cell lines with an IC value of 11.9 ± 0.27 and 12.0 ± 0.14 μM, respectively, as compared with the standard doxorubicin with an IC value of 0.90 ± 0.14 μM. anticonvulsant activities of the compounds were evaluated by the subcutaneous pentylenetetrazole model and neurotoxic activities by the minimal motor impairment model. The neurotoxicity of targeted compounds was measured using the rotating rod (ROT) method. Computational studies were carried out using the reported crystal structures of multidrug-resistant protein (PDB-ID: 2KAV) and dihydrofolate reductase (PDB-ID: 3GHW), indicating that the compound showed significant interactions at the voltage-gated sodium ion channel in the brain and at dihydrofolate reductase enzyme in the breast. Certain metal complexes of Schiff base ligands (e.g., ) were found to possess the most potent anticancer, anticonvulsant, and neurotoxic potential than lamotrigine alone.
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http://dx.doi.org/10.1021/acsomega.1c00027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992179PMC
March 2021

Arthroscopic Simulation: The Future of Surgical Training: A Systematic Review.

JBJS Rev 2021 Mar 22;9(3). Epub 2021 Mar 22.

Practice Plus Group Hospital, Somerset, United Kingdom.

Background: Arthroscopic simulation has rapidly evolved recently with the introduction of higher-fidelity simulation models, such as virtual reality simulators, which provide trainees an environment to practice skills without causing undue harm to patients. Simulation training also offers a uniform approach to learn surgical skills with immediate feedback. The aim of this article is to review the recent research investigating the use of arthroscopy simulators in training and the teaching of surgical skills.

Methods: A systematic review of the Embase, MEDLINE, and Cochrane Library databases for English-language articles published before December 2019 was conducted. The search terms included arthroscopy or arthroscopic in combination with simulation or simulator.

Results: We identified a total of 44 relevant studies involving benchtop or virtually simulated ankle, knee, shoulder, and hip arthroscopy environments. The majority of these studies demonstrated construct and transfer validity; considerably fewer studies demonstrated content and face validity.

Conclusions: Our review indicates that there is a considerable evidence base regarding the use of arthroscopy simulators for training purposes. Further work should focus on the development of a more uniform simulator training course that can be compared with current intraoperative training in large-scale trials with long-term follow-up at tertiary centers.
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http://dx.doi.org/10.2106/JBJS.RVW.20.00076DOI Listing
March 2021

Synthesis and characterization of ZnO decorated reduced graphene oxide (ZnO-rGO) and evaluation of its photocatalytic activity toward photodegradation of methylene blue.

Environ Sci Pollut Res Int 2021 Mar 20. Epub 2021 Mar 20.

College of Chemical and Materials Engineering, Beijing Institute of Petrochemical Technology, Beijing, China.

Photocatalytic treatment is one of the techniques used for the treatment of dyes-contaminated wastewater. It is important to develop an effective visible-light-driven catalyst for the treatment of dyes-contaminated wastewater. This study reports the synthesis of ZnO-reduced graphene oxide catalyst for the degradation of methylene blue. Graphene oxide was prepared by Hammer and Offeman process, while ZnO-rGO (1:1) was prepared by the chemical reduction method. The prepared ZnO-rGO composite was characterized by XRD, TEM, SEM, UV-Vis, DRS, N adsorption-desorption, FTIR, and XPS analyses. The photocatalytic activity was evaluated by photodegradation of methylene blue solution under irradiation. It was found that ZnO-rGO is capable of removing the dye from water and achieved the highest dye degradation efficiency of ~99% within 60 min. Furthermore, the ZnO-rGO was recycled in degradation experiments without any loss in its catalytic performance. The reaction kinetics was described in terms of the Langmuir-Hinshelwood mechanism, one of the kinetics mechanisms of surface catalyzed reaction. 36.2 and 13.1 kJ/mol were calculated as the apparent and true activation energy for photodegradation of methylene blue respectively.
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http://dx.doi.org/10.1007/s11356-021-13520-6DOI Listing
March 2021

Evaluation of the anti-diarrheal effects of the whole plant extracts of Roxb in pigeons.

Toxicol Rep 2021 23;8:395-404. Epub 2021 Feb 23.

Department of Chemistry, The University of Jordan, Amman, 11942, Jordan.

Background: (dodder) belonging to the family Convolvulaceae has many ethno-medicinal uses such as antidiarrheal and antiemetic. This plant has been employed to treat diarrhea, where the antidiarrheal use of this plant is well established in different communities around the world without scientific bases. In addition, the antibacterial, anthelmintic, anticholinergic, and antihistaminic effects of this parasitic vine are partly responsible for the folkloric antidiarrheal use of this plant. In the present study, the antidiarrheal activity was evaluated in pigeons () using the juice (JCR), aqueous (CRAE), and methanol (CRME) extracts.

Methods: The antidiarrheal effect of was evaluated using different reported research models, with few modifications. In pigeons, diarrhea was induced by administration of castor oil (6 mL/kg, PO), ampicillin (250 mg/kg, IP), magnesium sulfate (2 gm/kg, PO), and cisplatin (6 mg/kg, IV). In these experiments, loperamide (2 mg/kg, IM) was used as a positive control, whereas JCR (1 mL/kg (1%) and 1 mL/kg (2%), CRAE (50, 100 and 200 mg/kg) and CRME (50, 100 and 200 mg/kg) were administered intramuscularly at different doses into each pigeon in the test groups.

Results: In addition to cisplatin-induced diarrhea, all paradigms tested gave significant results ( < 0.01). The JCR, at different doses, exhibited a significant ( < 0.01) a dose-dependent antidiarrheal effect on both the frequency and the onset of diarrhea. Similarly, CRAE and CRME, at doses of 100 and 200 mg/kg, showed considerable ( < 0.001) inhibition against the onset and frequency of diarrhea. On the other hand, JCR, CRAE, and CRME exerted significant effects ( < 0.001) on the percentage inhibition (PI) of diarrhea and gastrointestinal charcoal transit in a dose-dependent manner. In this respect, the maximum PI ( < 0.01) of JCR, CRAE, and CRME in different experimental paradigms was 43.13, 49.14, and 55.99 %, respectively.

Conclusions: Taken all together, results from this study reveal that the juice, aqueous, and methanol extract of exhibit significant anti-motility and anti-secretory potential. These findings may explain the medicinal use of folk medicine as an antidiarrheal medicinal plant.
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http://dx.doi.org/10.1016/j.toxrep.2021.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921875PMC
February 2021

Inflammation, immunity and potential target therapy of SARS-COV-2: A total scale analysis review.

Food Chem Toxicol 2021 Apr 25;150:112087. Epub 2021 Feb 25.

Department of Breeding and Genetics, Faculty of Animal Production and Technology, Cholistan University of Veterinary and Animal Sciences-63100, Bahawalpur, Pakistan. Electronic address:

Coronavirus disease-19 (COVID-19) is a complex disease that causes illness ranging from mild to severe respiratory problems. It is caused by a novel coronavirus SARS-CoV-2 (Severe acute respiratory syndrome coronavirus-2) that is an enveloped positive-sense single-stranded RNA (+ssRNA) virus belongs to coronavirus CoV family. It has a fast-spreading potential worldwide, which leads to high mortality regardless of lows death rates. Now some vaccines or a specific drug are approved but not available for every country for disease prevention and/or treatment. Therefore, it is a high demand to identify the known drugs and test them as a possible therapeutic approach. In this critical situation, one or more of these drugs may represent the only option to treat or reduce the severity of the disease, until some specific drugs or vaccines will be developed and/or approved for everyone in this pandemic. In this updated review, the available repurpose immunotherapeutic treatment strategies are highlighted, elucidating the crosstalk between the immune system and SARS-CoV-2. Despite the reasonable data availability, the effectiveness and safety of these drugs against SARS-CoV-2 needs further studies and validations aiming for a better clinical outcome.
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http://dx.doi.org/10.1016/j.fct.2021.112087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905385PMC
April 2021

The nexus of sectoral-based CO emissions and fiscal policy instruments in the light of Belt and Road Initiative.

Environ Sci Pollut Res Int 2021 Feb 24. Epub 2021 Feb 24.

National University of Computer and Emerging Sciences (FAST), Islamabad, Pakistan.

Climate change due to global warming is becoming a major global issue over the past few decades. The emission of carbon dioxide (CO) and other greenhouse gasses cause global warming. Most carbon emissions come from energy sectors, whereas transportation, industrial, and residential sectors are among the chief contributors. The present study investigates the effect of fiscal policy instruments, economic development, and foreign direct investment (FDI) on the sectoral emissions in Belt and Road Initiative (BRI) countries. The data used in this study is taken from the World Development Indicators (WDI) for the period between 2000 and 2018. Dynamic ordinary least squares (DOLS) and fully modified ordinary least squares (FMOLS) have been used to analyze the long-run impact of fiscal policy instruments, economic development, and FDI on CO emissions from transportation, energy, and industrial sectors. Furthermore, the pairwise Dumitrescu and Hurlin panel causality test was used to authorize the causal relationship among the variables under consideration. The results reveal that fiscal policy instruments, per capita gross domestic product, FDI, and CO emissions show a strong correlation in the industrial, electrical, and transportation sectors. Furthermore, it is shown that public spending is a more reliable tool to reduce CO emissions in the transportation and industrial sectors in the BRI region. This study provides useful information for policy-makers on taking preventive and corrective measures to reduce CO emissions in different sectors and promote sustainable development.
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http://dx.doi.org/10.1007/s11356-021-13040-3DOI Listing
February 2021

Influence of Graphene Oxide Contents on Mechanical Behavior of Polyurethane Composites Fabricated with Different Diisocyanates.

Polymers (Basel) 2021 Jan 30;13(3). Epub 2021 Jan 30.

Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan.

The exceptional behavior of graphene has not yet been entirely implicit in the polymer matrix. To explore this fact in the present work, two series of Polyurethan (PU) composites were synthesized. The structural modification was observed by the use of two different diisocyanate of methylene diisocyanate (MDI) and hexamethylene diisocyanate (HMDI) in hydroxylterminated polybutadiene (HTPB) by using I,4 Butane diol (BD) as the chain extender. The variation in hard segment up to 25 (wt.%) in both series led to significant changes in the mechanical behavior of graphene oxide (GO) induced composites. Both series were prepared by an in situ polymerization process. Fourier transform infrared (FTIR) analysis showed a peak in the region of 1700 cm, which confirmed the conversion of the NCO group into urethane linkages. Thermal gravimetric analysis (TGA) revealed a thermal stability up to 450 °C @ 90% weight loss. The swelling behavior showed the optimum uptake of 30% of water and 40% of dimethyl sulfoxide (DMSO) with aliphatic diisocyanate. The values of storage modulus (), complex modulus (), and compliance complex (D*) were observed up to 7 MPa, 8 Mpa, and 0.7 MPa, respectively. The degree of entanglement () values were calculated from DMA and were found in the range of 1.7 × 10 (mol/m). Phase segregation of PU was observed by scanning electron microscopy (SEM), elucidating the morphology of composites.
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http://dx.doi.org/10.3390/polym13030444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866525PMC
January 2021

An Insight Into COVID-19: A 21st Century Disaster and Its Relation to Immunocompetence and Food Antioxidants.

Front Vet Sci 2020 13;7:586637. Epub 2021 Jan 13.

Department of Microbiology, University of Veterinary and Animal Sciences, Lahore, Pakistan.

Coronavirus Disease 2019 (COVID-19) ranks third in terms of fatal coronavirus diseases threatening public health, coming after SARS-CoV (severe acute respiratory syndrome coronavirus), and MERS-CoV (Middle East respiratory syndrome coronavirus). SARS-CoV-2 (severe acute respiratory syndrome coronavirus type 2) causes COVID-19. On January 30, 2020, the World Health Organization (WHO) announced that the current outbreak of COVID-19 is the sixth global health emergency. As of December 3, 2020, 64 million people worldwide have been affected by this malaise, and the global economy has experienced a loss of more than $1 trillion. SARS-CoV-2 is a positive-sense single-stranded RNA virus belonging to the genus. The high nucleotide sequence identity of SARS-CoV-2 with the BatCoV RaTG13 genome has indicated that bats could be the possible host of SARS-CoV-2. SARS-CoV-2 penetrates the host cell via binding its spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor, which is similar to the mechanisms of SARS-CoV and MERS-CoV. COVID-19 can spread from person to person via respiratory droplets and airborne and contaminated fomites. Moreover, it poses a significant risk to smokers, the elderly, immunocompromised people, and those with preexisting comorbidities. Two main approaches are used to control viral infections, namely, vaccination, and biosecurity. Studies to analyze the antigenicity and immunogenicity of SARS-CoV-2 vaccine candidates are underway, and few vaccines may be available in the near future. In the current situation, the Human Biosecurity Emergency (HBE) may be the only way to cope effectively with the novel SARS-CoV-2 strain. Here, we summarize current knowledge on the origin of COVID-19 as well as its epidemiological relationship with humans and animals, genomic resemblance, immunopathogenesis, clinical-laboratory signs, diagnosis, control and prevention, and treatment. Moreover, we discuss the interventional effects of various nutrients on COVID-19 in detail. However, multiple possibilities are explored to fight COVID-19, and the greatest efforts targeted toward finding an effective vaccine in the near future. Furthermore, antioxidants, polyphenols, and flavonoids, both synthetic and natural, could play a crucial role in the fight against COVID-19.
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http://dx.doi.org/10.3389/fvets.2020.586637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838355PMC
January 2021

Synthesis and Characterization of Co-ZnO and Evaluation of Its Photocatalytic Activity for Photodegradation of Methyl Orange.

ACS Omega 2021 Jan 5;6(2):1426-1435. Epub 2021 Jan 5.

Department of Chemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan.

Photocatalysis is one of the techniques used for the eradication of organic pollutants from wastewater. In this study, Co-ZnO was tested as a photocatalyst for the degradation of methyl orange under irradiation of visible light. Co-ZnO loaded with 5%, 10%, and 15% Co was prepared by the precipitation method. The advanced techniques including X-ray diffraction, X-ray photoelectron spectroscopy, diffuse reflectance UV-visible spectroscopy, photoelectrochemical measurements, temperature-programmed desorption, photoluminescence, and fluorescence spectroscopy related to OH measurements were used for characterization of prepared Co-ZnO. Experiments showed that 10% Co-ZnO was a highly efficient catalyst for the photodegradation of methyl orange as compared to ZnO. The enhanced photocatalytic activity of Co-ZnO is attributed to the implantation of Co which inhibits the electron-hole recombination. A 100 mg/L solution of methyl orange dye was completely degraded within 130 min. The reaction kinetics has been described in terms of the Eley-Rideal mechanism.
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http://dx.doi.org/10.1021/acsomega.0c05092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818618PMC
January 2021

The role of HDAC11 in obesity-related metabolic disorders: A critical review.

J Cell Physiol 2021 Jan 22. Epub 2021 Jan 22.

Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China.

At present, metabolic diseases, such as obesity and diabetes, have become the world's top health threats. These diseases are closely related to the abnormal development and function of adipocytes and metabolic inflammation associated with obesity. Histone deacetylase 11 (HDAC11), with a relatively unique structure and function in the HDAC family, plays a vital role in regulating cell growth, migration, and cell death. Currently, research on new key regulatory functions of HDAC11 in metabolic homeostasis is receiving more and more attention, and HDAC11 has also become a potential therapeutic target in the treatment of obesity and obesity-related diseases. Here, we summarized the latest literature on the role of HDAC11 in regulating the progress of obesity-related metabolic disorders.
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http://dx.doi.org/10.1002/jcp.30286DOI Listing
January 2021

A unique case of multiple calvarial hemangiomas with one large symplastic hemangioma.

BMC Neurol 2021 Jan 19;21(1):29. Epub 2021 Jan 19.

Department of Medical Genetics, Umm-Al-Qura University, Makkah, Saudi Arabia.

Background: Symplastic hemangioma is a benign superficial abnormal buildup of blood vessels, with morphological features which can mimic a pseudo malignancy. A few cases have been reported in the literature. We report here, a unique case of calvarial symplastic hemangioma, which is the first case in the calvarial region.

Case Presentation: A 29-year-old male patient, with a left occipital calvarial mass since childhood, that gradually increased in size with age, was associated with recurrent epileptic fits controlled by Levetiracetam (Keppra), with no history of trauma. He presented to the emergency room with a recent headache, vomiting, frequent epileptic fits and a decrease in the level of consciousness 1 day prior to admission. A CT scan showed three diploic, expansile, variable sized lytic lesions with a sunburst appearance; two that were biparietal, and one that was left occipital, which were all suggestive of calvarial hemangiomas. However, the large intracranial soft tissue content, within the hemorrhage of the occipital lesion was concerning. The patient had refused surgery over the years; however, after the last severe presentation, he finally agreed to treatment. The two adjacent, left parietal and occipital lesions were treated satisfactorily using preoperative embolization, surgical resection, and cranioplasty. Histopathology revealed cavernous hemangiomas, in addition to symplastic hemangioma (pseudo malignancy features) on top at the occipital lesion. The right parietal lesion was not within the surgical field; therefore, it was left untouched for follow-up.

Conclusions: Histopathology and radiology examinations confirmed the diagnosis as symplastic hemangioma, on top of a pre-existing cavernous hemangioma. To the best of our knowledge, this is the first case of a calvarial symplastic hemangioma, which we report here.
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http://dx.doi.org/10.1186/s12883-021-02053-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814591PMC
January 2021

Rise in temperature causes decreased fitness and higher extinction risks in endemic frogs at high altitude forested wetlands in northern Pakistan.

J Therm Biol 2021 Jan 14;95:102809. Epub 2020 Dec 14.

Poultry Research Institute Punjab, Rawalpindi, Pakistan.

The larvae of some amphibian species grow and develop more slowly at lower temperature and attain larger body size at the end of metamorphosis, but this is not true for all amphibians. We have for the first time provided empirical data by using a combination of field and lab-based studies with a robust sample size (360 adults, 1000 tadpoles) for Hazara Torrent Frog (Allopaa hazarensis) and Murree Hills Frog (Nanorana vicina). In this study, we examined how tadpoles responded to different temperatures through metamorphosis, body size, developmental complications or deformities, fitness and survival. We found that the tadpoles of A. hazarensis and N. vicina showed the same response to elevated temperatures under laboratory conditions including faster metamorphosis, reduction in the body size, more frequent developmental complications or deformities such as edema and tail kinks, lower fitness and higher mortality at elevated temperatures (>26 °C). The comparison of thermal sensitivity between the two species showed that N. vicina was more sensitive to higher temperatures. Pakistan has been experiencing changes in climatic patterns, and the ecosystems in northern Pakistan are losing biodiversity due to increasing temperature, frequency of drought and intensity of floods. It is feared that these frogs may experience local extinction in future. Our findings contribute to filling the information gap regarding impacts of temperature increase on biodiversity of high altitude forested montane ecosystems and is an important contribution to future studies associating biodiversity and climate change.
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http://dx.doi.org/10.1016/j.jtherbio.2020.102809DOI Listing
January 2021

Systematic Review: Study of the Prescribing Pattern of Antibiotics in Outpatients and Emergency Departments in the Gulf Region.

Front Pharmacol 2020 15;11:585051. Epub 2020 Dec 15.

College of Pharmacy, Gulf Medical University, Ajman, United Arab Emirates.

To study the prescribing pattern of antibiotics in outpatients and emergency departments in the Gulf region. To compare the appropriateness of prescriptions and antibiotics commonly prescribed for respiratory tract infection. The search was limited to the years 2008-2020, and articles had to be in English. Articles were searched from various resources and evaluated using PRISMA. Forty-one articles were selected and screened, and in the end, 17 articles were included in the study. All articles were selected from the gulf region of six countries: UAE, Saudi Arabia, Qatar, Oman, Yemen, and Bahrain. Only primary literature were included. Inpatient and literature from other countries outside the gulf region were excluded. Penicillins, cephalosporins, and macrolides are highly useful antibiotics for respiratory tract infections. Ceftriaxone IV is recommended in acute respiratory tract infection if therapy with penicillin fails. Most of the antibiotic prescriptions in Gulf countries are inappropriate. Inappropriate antibiotic prescribing in the gulf region varies from place to place and reaches a maximum of 80%. Antibiotics may be prescribed with the wrong dosage or frequency and inappropriate guidelines. Penicillins are prescribed at about 50-60%; the most common penicillins prescribed are amoxicillin and co-amoxiclave. Cephalosporins are prescribed at about 30%, and the most common are third-generation. Macrolides are prescribed at about 17-20%, and the most common macrolides are azithromycin and clarithromycin. Fluoroquinolones are prescribed at about 10-12%, of which levofloxacin and ciprofloxacin are more commonly prescribed with metronidazole at 10%. It is suggested that the antibiotic-prescribing pattern in outpatient and emergency departments in the Gulf region are highly inappropriate and need improvement through education, following guidelines, annual vaccination, and stewardship programs; the most prescribed antibiotic is amoxicillin/co-amoxiclave, and the most often encountered infection in outpatients is acute respiratory tract infection.
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http://dx.doi.org/10.3389/fphar.2020.585051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786364PMC
December 2020

Therapeutic approach for global myocardial injury using bone marrow-derived mesenchymal stem cells by cardiac support device in rats.

Biomed Microdevices 2021 Jan 8;23(1). Epub 2021 Jan 8.

Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, School of Pharmacy, Nanjing, Jiangsu Province, 211198, People's Republic of China.

Bone marrow-derived mesenchymal stem cells (BMSCs) have been considered a promising therapeutic approach to cardiovascular disease. This study intends to compare the effect of BMSCs through a standard active cardiac support device (ASD) and intravenous injection on global myocardial injury induced by isoproterenol. BMSCs were cultured in vitro, and the transplanted cells were labeled with a fluorescent dye CM-Dil. Isoproterenol (ISO) was injected into the rats; 2 weeks later, the labeled cells were transplanted into ISO-induced heart-jury rats through the tail vein or ASD device for 5 days. The rats were sacrificed on the first day, the third day, and the fifth day after transplantation to observe the distribution of cells in the myocardium by fluorescence microscopy. The hemodynamic indexes of the left ventricle were measured before sacrificing. H&E staining and Masson's trichrome staining were used to evaluate the cardiac histopathology. In the ASD groups, after 3 days of transplantation, there were a large number of BMSCs on the epicardial surface, and after 5 days of transplantation, BMSCs were widely distributed in the ventricular muscle. But in the intravenous injection group, there were no labeled-BMSCs distributed. In the ASD + BMSCs-three days treated group and ASD + BMSCs -five days-treated group, left ventricular systolic pressure (LVSP), the maximum rate of left ventricular pressure rise (+dP/dt), the maximum rate of left ventricular pressure decline (-dP/dt) increased compared with model group and intravenous injection group (P < 0.05). By giving BMSCs through ASD device, cells can rapidly and widely distribute in the myocardium and significantly improve heart function.
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http://dx.doi.org/10.1007/s10544-020-00538-9DOI Listing
January 2021

Biological Regulatory Network (BRN) Analysis and Molecular Docking Simulations to Probe the Modulation of IPR Mediated Ca Signaling in Cancer.

Genes (Basel) 2020 Dec 29;12(1). Epub 2020 Dec 29.

Research Center for Modeling and Simulation (RCMS), National University of Sciences and Technology (NUST), Academic-I Building, H-12 Islamabad 44000, Pakistan.

Inositol trisphosphate receptor (IPR) mediated Ca signaling is essential in determining the cell fate by regulating numerous cellular processes, including cell division and cell death. Despite extensive studies about the characterization of IPR in cancer, the underlying molecular mechanism initiating the cell proliferation and apoptosis remained enigmatic. Moreover, in cancer, the modulation of IPR in downstream signaling pathways, which control oncogenesis and cancer progression, is not well characterized. Here, we constructed a biological regulatory network (BRN), and describe the remodeling of IPR mediated Ca signaling as a central key that controls the cellular processes in cancer. Moreover, we summarize how the inhibition of IPR affects the deregulated cell proliferation and cell death in cancer cells and results in the initiation of pro-survival responses in resistance of cell death in normal cells. Further, we also investigated the role of stereo-specificity of IP molecule and its analogs in binding with the IP receptor. Molecular docking simulations showed that the hydroxyl group at R position along with the phosphate group at R position in conformation is more favorable for IP interactions. Additionally, Arg-266 and Arg-510 showed π-π and hydrogen bond interactions and Ser-278 forms hydrogen bond interactions with the IP binding site. Thus, they are identified as crucial for the binding of antagonists.
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http://dx.doi.org/10.3390/genes12010034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823498PMC
December 2020

Cytomegalovirus pancreatitis in an immunocompetent patient.

IDCases 2020 18;22:e00932. Epub 2020 Aug 18.

Division of Transplant Surgery, Department of Surgery, Augusta University Medical Center, Augusta, GA, United States.

(CMV) is a double-stranded DNA virus, which infects a large portion of the adult population. In immunocompetent patients, it typically is asymptomatic or manifests as mild and self-limiting flu-like illness symptoms, whereas in immunocompromised patients, CMV can cause significant disease. Herein we report an unusual case of CMV pancreatitis in an immunocompetent 75-year-old female. Patient developed severe significant pancreatic necrosis that failed non-operative management, and ultimately underwent pancreatic necrosectomy. Later on, she developed three spontaneous gastric perforations. The first two perforations were managed operatively, but after the third perforation family decided not to undergo another operation. The CMV pancreatitis diagnosis was based on pancreatic histopathology and confirms by a prompt response to ganciclovir. Patient was promptly started on intravenous (IV) ganciclovir which resulted in clinical recovery and she remained asymptomatic more than one-year post op. This is a rare case of CMV pancreatitis with gastric perforations in an immunocompetent patient. High degree of suspicion and appropriate treatment are important for such clinical scenarios.
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http://dx.doi.org/10.1016/j.idcr.2020.e00932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708617PMC
August 2020

Antinociceptive and Anti-inflammatory like effects of Berberis baluchistanica.

Curr Mol Pharmacol 2020 Dec 4. Epub 2020 Dec 4.

Department of Pharmacy, University of Malakand, Dir. Pakistan.

Background: Numerous therapeutic agents are in clinical practice for the treatment of inflammatory and painful conditions, but their applications has been challenged by various side /toxic effects. Therefore, new effective and safe therapies are most warrant, for which medicinal plant could be a significant alternative. Berberis baluchistanica has traditionally been used as analgesic and antiinflammatory without any scientific background.

Objective: The current study was designed to evaluate the analgesic and antiinflammatory like effects of extract B. baluchistanica in animal models.

Methods: For the study of antinociceptive effect, an of extract of B. baluchistanica (100, 200 and 300 mg/kg i.p.), were tested in acetic acid induced writhing and formalin tests. while for the antiinflammatory action, carrageenan induced paw edema, cotton pellet induced granuloma and xylene induced ear edema tests were used.

Results: The results showed significant dose dependent antinociceptive effect of extract of B. baluchistanica in acetic acid induced writhing and formalin induced flinching behavior tests. However, the effect was strongly antagonized by the injection of naloxone, suggesting the expression via opioidergic receptors. Similarly, strong antiinflammatory action was illustrated in carrageenan induced paw edema, cotton pellet induced granuloma and xylene induced ear edema tests and thus provided evidence for the versatile phytochemical nature of its phytochemical.

Conclusions: In short, it is concluded that the extract of B. baluchistanica exhibited significant antinociceptive and antiinflammatory effects in animal models. It is, therefore, further detail studies on the efficacy and safety as well as on the phytochemical investigation are required to ascertain its clinical uses.
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http://dx.doi.org/10.2174/1874467213666201204153045DOI Listing
December 2020

Muricazine, a new hydrazine derivative from L. with antioxidant, lipoxygenase and urease inhibitory activities.

Nat Prod Res 2020 Dec 7:1-6. Epub 2020 Dec 7.

Institute of Chemical Sciences, University of Peshawar, Peshawar, Pakistan.

L., an important member of family Ranunculaceae upon submission to phytochemical studies, led to the isolation of a novel natural hydrazine derivative, muricazine (). Chemical structure of the compound was established with the aid of advanced spectroscopic techniques. It was evaluated for antioxidant, lipoxygenase, and urease (jack-bean) inhibitory activities. Results suggested that compound could scavenge the DPPH free radical (42.1 ± 0.12 M) to a great extent as compared to the standard (40.6 ± 0.91 M). However, it showed moderate inhibitory potential against lipoxygenase (65.2 ± 0.45 M) and urease (54.8 ± 0.23 M) enzymes.
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http://dx.doi.org/10.1080/14786419.2020.1855169DOI Listing
December 2020

Biotechnological approaches to the production of plant-derived promising anticancer agents: An update and overview.

Biomed Pharmacother 2020 Dec 1;132:110918. Epub 2020 Nov 1.

Department of Human Anatomy, Medical College of Qinghai University, Xining, 810000,P.R China. Electronic address:

The plant kingdom is a rich source of bioactive compounds, many of which have been used since pre-history for their therapeutic properties to treat a range of illnesses. These metabolites have recently attracted attention to their antineoplastic activities to treat various cancers relying on different mechanisms. Some of these molecules are glycosides, which have proven useful as anti-cancer agents, namely podophyllotoxin (PPT) anaryltetralin lignan or alkaloids. There are three primary forms of alkaloids, such as indole alkaloids (vincristine and vinblastine from Catharanthus roseus), quinoline alkaloid (camptothecin from Camptotheca acuminata), and diterpenoid alkaloid (taxol and it's analogous from Taxus and Corylus species). This review considers various plant biotechnology approaches used to enhance the production of these anticancer molecules in different species. In this regard, many in vitro culture techniques such as stimulation of suspension culture and hairy roots are being used to investigate the effects of plant growth regulators and elicitors on various explants.
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http://dx.doi.org/10.1016/j.biopha.2020.110918DOI Listing
December 2020

Synthetic flavonoids as potential antiviral agents against SARS-CoV-2 main protease.

J Biomol Struct Dyn 2020 Nov 30:1-12. Epub 2020 Nov 30.

Department of Chemistry and Chemical Engineering, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences, Lahore, Pakistan.

The COVID-19 pandemic has claimed more than a million lives worldwide within a short time span. Due to the unavailability of specific antiviral drugs or vaccine, the infections are causing panic both in general public and among healthcare providers. Therefore, an urgent discovery and development of effective antiviral drug for the treatment of COVID-19 is highly desired. Targeting the main protease (M) of the causative agent, SARS-CoV-2 has great potential for drug discovery and drug repurposing efforts. Published crystal structures of SARS-CoV-2 M further facilitated investigations for discovering new inhibitors against M. The present study aimed to screen several libraries of synthetic flavonoids and benzisothiazolinones as potential SARS-CoV-2 M inhibitors using methods. The short-listed compounds after virtual screening were filtered through SwissADME modeling tool to remove molecules with unfavorable pharmacokinetics and medicinal properties. The drug-like molecules were further subjected to iterative docking for the identification of top binders of SARS-CoV-2 M. Finally, molecular dynamic (MD) simulations and binding free energy calculations were performed for the evaluation of the dynamic behavior, stability of protein-ligand complex, and binding affinity, resulting in the identification of thioflavonol, as a potential inhibitor of M. The computational studies further revealed the binding of close to catalytic dyad and interactions with conserved residues in the S1 subsite of the substrate binding site. Our study demonstrated that synthetic analogs of flavonoids, particularly thioflavonols, have a strong tendency to inhibit the main protease M, and thereby inhibit the reproduction of SARS-CoV-2. Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1850359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754928PMC
November 2020

Frequency domain analysis of resilient consensus in multi-agent systems subject to an integrity attack.

ISA Trans 2021 May 20;111:156-170. Epub 2020 Nov 20.

Department of Automation, Shanghai Jiaotong University, Shanghai 200240, PR China. Electronic address:

Unmanned systems like autonomous surface vessels are being enhanced with the communication infrastructure to improve their reliability, efficiency and sustainability. Regardless of the significance advantages, their open communication network and connectivity renders these systems to a variety of cyber-attacks. This paper considers the resilient consensus problem of multi-agent systems (MASs) under an integrity attack. Unlike the existing works in the time domain, a resilient consensus controller is designed and analyzed for MASs in the frequency domain. To this end, analysis and modeling of MASs under the integrity attacks (MU-IA) are addressed in the frequency domain in which each agent is a linear continuous system with an input time delay. A resilient H controller is proposed to tackle the tampering of information due to an integrity attack. The proposed H controller is designed based on an internal stability method for performance tracking and robustness of the MU-IA. A significant strength of this scheme is that the current approach does not enforce any limit on the number of agents or neighboring agents under the integrity attacks. A quantitative tuning method is used to trade off the nominal performance and robustness of the MU-IA. Simulation results show the effectiveness of the proposed control strategy.
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http://dx.doi.org/10.1016/j.isatra.2020.11.014DOI Listing
May 2021

Effect of Y50H and S187G substitutions on thermostability and exonuclease activity of TK1646 from Thermococcus kodakarensis.

Protein Expr Purif 2021 Mar 26;179:105799. Epub 2020 Nov 26.

School of Biological Sciences, University of the Punjab, Lahore, Pakistan. Electronic address:

TK1646 is a highly thermostable single strand specific 3'-5' exonuclease. Exonucleases play important role in maintaining the genome integrity at elevated temperatures. Therefore, it is important to examine the factors contributing to thermostability of these exonucleases. In this study we report on production, purification and characterization of S187G and Y50H mutants of TK1646, focusing on the factors leading to thermostability of TK1646. Characterization of the recombinant proteins indicated that these substitutions did not drastically affect the catalysis of single stranded DNA. However, both of these substitutions reduced the thermostability of the recombinant proteins. Half-lives of Y50H and S187G mutants were 95 and 155 min, respectively, at 100 °C in comparison to 180 min of the wild type. Bioinformatics analysis indicated an increase in solvent accessibility of the mutated residues and disruption of hydrogens bonds. Molecular modelling and superimposition of the 3D structures of the mutants and the wild type demonstrated that one of the active site residues, Glu145, was shifted away from the metal ion in both the mutants which may be responsible for the decrease in catalytic activity. Compact secondary structure, hydrophobicity and hydrogen bonding might be the major factors contributing to the thermostability of TK1646.
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http://dx.doi.org/10.1016/j.pep.2020.105799DOI Listing
March 2021

Prevalence of inflammatory back pain and radiographic axial spondyloarthritis in a semi-urban community of Lahore, Pakistan.

Int J Rheum Dis 2021 Feb 27;24(2):207-215. Epub 2020 Nov 27.

Department of Rheumatology, Gulab Devi Teaching Hospital, Al-Aleem Medical College, Lahore, Pakistan.

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%.
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http://dx.doi.org/10.1111/1756-185X.14030DOI Listing
February 2021

In-Vitro Assessment Of The Therapeutic Potential Of Polymyxins And Tigecycline Against Multidrugresistant Acinetobacter Isolates From Infected Wounds.

J Ayub Med Coll Abbottabad 2020 Oct-Dec;32(4):459-464

Department of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Pakistan.

Background: The incidence of multidrug-resistant (MDR), extreme drug resistant (XDR), and pan drug-resistant (PDR) Acinetobacter are increasing throughout the world. The therapeutic management and control of Acinetobacter are difficult due to the emergence of drug resistance and its enduring capacity to survive in the environment. The present study was designed to appraise the efficacy of Polymyxins and Tigecycline against multidrugresistant Acinetobacter isolates from surgical and burn wounds.

Methods: During the study, the specimens were collected from various types of wounds from inpatients and outpatients of the tertiary care hospitals of Lahore, Pakistan in 2017 and 2018. The bacterial pathogens were isolated and identified using standard microbiological procedures and molecular confirmation of Acinetobacter species was examined by PCR using specific primers. The antibiotic susceptibility profiling of Acinetobacter isolates was studied against 18 antibiotics as per Clinical and Laboratory Standards Institute (CLSI) guidelines.

Results: The Acinetobacter isolates demonstrated extreme resistance especially to ampicillin/sulbactam, piperacillin/tazobactam, cephalosporins, carbapenems, fluoroquinolones, and aminoglycosides. However, the colistin, polymyxin, and tigecycline remained the most effective antimicrobial agents against Acinetobacter isolates.

Conclusions: The results highlight the extent of drug resistance and therapeutic potential of Polymyxins and Tigecycline for wound infections caused by MDR and XDR Acinetobacter species. The wiser use of antimicrobials, incessant surveillance of antimicrobial resistance, and stringent adherence to infection control guidelines are critical to reducing major outbreaks in the future.
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January 2021

Factors associated with disease severity and mortality among patients with COVID-19: A systematic review and meta-analysis.

PLoS One 2020 18;15(11):e0241541. Epub 2020 Nov 18.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.

Background: Understanding the factors associated with disease severity and mortality in Coronavirus disease (COVID-19) is imperative to effectively triage patients. We performed a systematic review to determine the demographic, clinical, laboratory and radiological factors associated with severity and mortality in COVID-19.

Methods: We searched PubMed, Embase and WHO database for English language articles from inception until May 8, 2020. We included Observational studies with direct comparison of clinical characteristics between a) patients who died and those who survived or b) patients with severe disease and those without severe disease. Data extraction and quality assessment were performed by two authors independently.

Results: Among 15680 articles from the literature search, 109 articles were included in the analysis. The risk of mortality was higher in patients with increasing age, male gender (RR 1.45, 95%CI 1.23-1.71), dyspnea (RR 2.55, 95%CI 1.88-2.46), diabetes (RR 1.59, 95%CI 1.41-1.78), hypertension (RR 1.90, 95%CI 1.69-2.15). Congestive heart failure (OR 4.76, 95%CI 1.34-16.97), hilar lymphadenopathy (OR 8.34, 95%CI 2.57-27.08), bilateral lung involvement (OR 4.86, 95%CI 3.19-7.39) and reticular pattern (OR 5.54, 95%CI 1.24-24.67) were associated with severe disease. Clinically relevant cut-offs for leukocytosis(>10.0 x109/L), lymphopenia(< 1.1 x109/L), elevated C-reactive protein(>100mg/L), LDH(>250U/L) and D-dimer(>1mg/L) had higher odds of severe disease and greater risk of mortality.

Conclusion: Knowledge of the factors associated of disease severity and mortality identified in our study may assist in clinical decision-making and critical-care resource allocation for patients with COVID-19.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241541PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673562PMC
December 2020