24 research outputs found
Respiratory syndromes among pilgrims: assessment of Health status and interventions to alleviate respiratory Symptoms
Background: Acute respiratory symptoms are the commonest problems faced by
pilgrims in Makkah. They could result from overcrowding, physical exhaustion and
anxiety. The hot-dry atmospheric air exacerbates the problems.
Objectives: The aim of the study was to determine the occurrence of acute respiratory
symptoms among Malaysian hall pilgrims
Methodology: A cross-sectional study was conducted amongst two thousands
Malaysian pilgrims. Survey forms were distributed at Madinatul-hullaj, Jeddah where
pilgrims stay on transit before returning to Malaysia. Response to the survey was on
voluntary basis. The results were analysed using STAT A version 9.0. The denominator
was the number of completed survey forms.
Results: 394 pilgrims completed and returned the survey forms; 219 males and 173
were females [2 persons did not state their gender]. Only two (0.5%) pilgrims were
younger than 10 years and 51 (13.0%) were above 61 years of age. A large majority
received influenza vaccination 278 (72.4%). The common underlying diseases were
diabetes 48 (12.2%), asthma 35 (8.9%), prolonged cough 34 (8.6%) and rhinitis 28
(7.1 %). In descending order the occurrence of symptoms and their respective 95%
confidence intervals were: cough 91.3% (88.0-93.7), runny nose 79.2% (74.9-82.9), sore
throat 57.1% (52.1 -61.9) and fever 59.1% (54.2-63.9). Only 3.6% (2.2-5.9) of pilgrims
did not suffer from any of these symptoms. Majority had more than two symptoms and
longer than 2 weeks duration. The Malaysian hall pilgrims who had single symptom were
9.3% (6.8-12.6), two symptoms 23.7% (19.7-28.1), three symptoms 25.4% (21.4-30.0),
and four symptoms 36.5% (31.9-41.4). Only 1.5% (0. 7-3.3) had had hospitalization due
to their illness.
Conclusion: Acute respiratory symptoms were remarkably common among Malaysian
hall pilgrims. The interventional measures to reduce the" morbidity of respiratory related
symptoms should be carried out in future Hall seasons
Nosocomial acinetobacter bacteraemia in HUSM
Acinetoliacter ''IPP is a known nosocomial pathogen causing a wide range of clinical diseases such as pneumonia,
wound infeCti_On·and ·bloodstream infections (Bsn. The clinical outcomes of acinetobacter BSI were compared to
· other gram negative infections. The crude mortality ofacinetobacter BSI was 47.2%, which was signitlcantly greater
than other gfafn .. negative BSI. We found that patients treated in intensive care units (ICU), who had longer ICU
stays, who preSented with shock or coagulopathy, had prior exposure to carbapenems, had mechanical ventilation,
were on a ventilator tbr longer periods, had a nasogastric tube, had an arterial catheter or had parenteral nutrition at a
significantly greatei- risk of mortality due to acinetobacter BSL Patients presenting with septic shock or having a
central venous catheter were independently at higher risk for mortality. Appropriateness of therapy reduced the
mortality attributes of acinetobacter BSJ but did not significantly reduce crude mortality in acinetobacter BSJ
patients. This study shows the importance of preventing acinetobacter BSI and the appropriate use of antimicrobial
agents to reduce mortality
Structural Evaluation of the Spike Glycoprotein Variants on SARS-CoV-2 Transmission and Immune Evasion
From MDPI via Jisc Publications RouterHistory: accepted 2021-07-07, pub-electronic 2021-07-10Publication status: PublishedFunder: Universiti Sains Malaysia; Grant(s): 1001/PPSP/8012382Abstract: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents significant social, economic and political challenges worldwide. SARS-CoV-2 has caused over 3.5 million deaths since late 2019. Mutations in the spike (S) glycoprotein are of particular concern because it harbours the domain which recognises the angiotensin-converting enzyme 2 (ACE2) receptor and is the target for neutralising antibodies. Mutations in the S protein may induce alterations in the surface spike structures, changing the conformational B-cell epitopes and leading to a potential reduction in vaccine efficacy. Here, we summarise how the more important variants of SARS-CoV-2, which include cluster 5, lineages B.1.1.7 (Alpha variant), B.1.351 (Beta), P.1 (B.1.1.28/Gamma), B.1.427/B.1.429 (Epsilon), B.1.526 (Iota) and B.1.617.2 (Delta) confer mutations in their respective spike proteins which enhance viral fitness by improving binding affinity to the ACE2 receptor and lead to an increase in infectivity and transmission. We further discuss how these spike protein mutations provide resistance against immune responses, either acquired naturally or induced by vaccination. This information will be valuable in guiding the development of vaccines and other therapeutics for protection against the ongoing coronavirus disease 2019 (COVID-19) pandemic
Diagnostic accuracy of rapid antigen test kits for detecting SARS-CoV-2:a systematic review and meta-analysis of 17,171 suspected COVID-19 patients
Early diagnosis is still as crucial as the initial stage of the COVID-19 pandemic. As RT-PCR sometimes is not feasible in developing nations or rural areas, health professionals may use a rapid antigen test (RAT) to lessen the load of diagnosis. However, the efficacy of RAT is yet to be investigated thoroughly. Hence, we tried to evaluate the overall performance of RAT in SARS-CoV-2 diagnosis. Based on our PROSPERO registered protocol (CRD42021231432), we searched online databases (i.e., PubMed, Google Scholar, Scopus, and Web of Science) and analysed overall pooled specificity and sensitivity of RAT along with study quality, publication bias, heterogeneity and more. The overall pooled specificity and sensitivity of RAT were detected as 99.4% (95% CI: 99.1–99.8; I2 = 90%) and 68.4% (95% CI: 60.8–75.9; I2 = 98%), respectively. In subgroup analyses, nasopharyngeal specimens and symptomatic patient’s samples were more sensitive in RAT, while cycle threshold (Ct) values were found to have an inverse relationship with sensitivity. In the European and American populations, RAT showed better performance. Although the sensitivity of RAT is yet to be improved, it could still be an alternative in places with poor laboratory set up. Nevertheless, the negative samples of RAT can be re-tested using RT-PCR to reduce false negative results
Pharmacodynamics of Polymyxins and Their Combinations with Carbapenems against Multidrug-Resistant Klebsiella pneumoniae
Emergence of
antibiotic-resistant bacteria and dearth of new chemical agents in the
antibiotics development pipeline present a major medical challenge. The
Infectious Diseases Society of America (IDSA) launched the “Bad Bugs, No Drugs”
campaign in 2004 to bring attention to the USA policy makers on this unmet
medical need. In the 2000s, the global spread of <i>Klebsiella pneumoniae
</i>carbapenemase and New Delhi metallo-β-lactamase-producing <i>Enterobacteriaceae</i>
(mainly <i>K. pneumoniae</i>) significantly further reduced the choice of antibiotics
in the clinic as these pathogens are usually resistant to almost all clinically
available antibiotics except polymyxins.<br> <br>
Polymyxins were discovered more than fifty years ago and had
never been subjected to modern drug discovery procedures until recently. Two
polymyxins are available for clinical use, polymyxin B and colistin (polymyxin
E). Polymyxins were ignored from clinical practice from the 1970s due to
toxicity and availability of ‘safer’ antibiotics. With no new antibiotic
candidate against Gram-negative bacteria in near future, there is an urgent
need to optimize the use and understand the mechanism of activity of polymyxins
to prolong its therapeutic utility.<br> <br>
In the first experimental chapter of this thesis, the
antibacterial activity of colistin-doripenem combination regimens against MDR
<i>K. pneumoniae</i> was examined in an <i>in vitro</i> one-compartment pharmacokinetic/pharmacodynamic
(PK/PD) model. The colistin-doripenem combination at clinically achievable
concentrations substantially increased bacterial killing against
colistin-susceptible and -heteroresistant isolates at both low and high initial
inocula. Emergence of colistin-resistant subpopulations in colistin-susceptible
and -heteroresistant isolates was generally eliminated by combination regimens.<br> <br>
In the second experimental chapter of the thesis, the mode of
action of polymyxins was investigated. The activity of polymyxins and their
analogues were examined for their ability to inhibit the type II NADH-quinone
oxidoreductases (NDH-2) in the respiratory chains of Gram-negative bacteria.
Polymyxin B and colistin inhibited the NDH-2 activity in a concentration-dependent
manner using inner membrane preparations of <i>K. pneumoniae </i>(colistin-susceptible
and resistant variants), <i>Escherichia coli</i> and <i>Acin</i><i></i><i>etobacter baumannii.</i> These
findings suggest that a novel secondary mode of action of polymyxins involves
the inhibition of bacterial respiratory enzymes in the Gram-negative bacterial
inner membrane.<br> <br>
In the third experimental chapter, the surface components of
polymyxin-susceptible and resistant variants of <i>K. pneumoniae</i> were examined by
a number of biophysical tests. Comparing to the polymyxin-susceptible parent
strain, the polymyxin-resistant variant displayed lower negative surface
charges, greater outer membrane permeability and less sensitivity to the lytic
action of lysozyme and sodium deoxycholate after colistin exposure. The binding
affinity of polymyxin B and colistin to LPS purified from wild type was higher
than the binding to LPS from the resistant variant. Taken together, a secondary
mechanism of polymyxin resistance is believed due to diminished initial electrostatic
contacts with the outer membrane that led to reduced killing activity.<br> <br>
In the fourth experimental chapter of this thesis, the uptake
of polymyxins by live <i>K. pneumoniae</i> cells was observed under time-lapse laser
scanning confocal microscopy using a novel polymyxin-dansyl probe that
possessed native antibacterial activity. The polymyxin probe initially
accumulated in the outer membrane and subsequently penetrated the inner
membrane and finally entered into the cytoplasm. These findings indicated this
platform can be employed for the discovery of novel polymyxin-like lipopeptides
with efficacy against polymyxin-resistant strains.<br> <br>
Lastly, colistin-doripenem combinations were examined in a
non-neutropaenic <i>K. pneumoniae</i> bacteremic mouse model to simultaneously examine
bactericidal and endotoxin neutralization effects. Beside the susceptible
reference isolate, the efficacy of colistin-carbapenem combination was
evaluated for the first time against globally disseminated NDM-1-producer
carbapenem-resistant isolate in an animal model. The combination therapy
resulted in lower bacterial counts against both isolates, compared to colistin
or doripenem monotherapy. Significant lower endotoxin level was observed in
mice treated with colistin-doripenem combination therapy against the
NDM-1-producer, compared to the control or any monotherapy groups. Against the
NDM-1-producer this combination therapy led to significant lower TNF levels
compared to the untreated control. These findings demonstrated that the
colistin-doripenem combination is useful for the treatment of sepsis caused by
NDM-1-producing <i>K. pneumoniae.<br> </i><br>
In summary, this thesis provides novel information on the
optimal use and the mechanism of activity of polymyxins against <i>K. pneumoniae.</i>
Colistin-doripenem combination was synergistic and able to suppress the
emergence of polymyxin resistance in MDR <i>K. pneumoniae</i> infections. In
non-neutropenic bacteraemic mice caused by an NDM-1-producer
carbapenem-resistant <i>K. pneumoniae,</i> a significant reduction was evident in the
bacterial load and endotoxin activity after treatment with colistin-doripenem
combination. This study provides important information on the strategies to
maximise the efficacy of polymyxins. This thesis is also the first to report the
inhibition of NDH-2 respiratory enzymes in Gram-negative by polymyxins,
supported by the microscopic observation of accumulation and penetration of the
native polymyxin-like probe in the cell membrane. This secondary target of
polymyxins is still vulnerable in polymyxin-resistant <i>K. pneumoniae</i> strains;
therefore, it can be exploited for the development of new lipopeptide
antibiotics targeting polymyxin-resistant bacteria
In Silico Molecular Characterization of Human TMPRSS2 Protease Polymorphic Variants and Associated SARS-CoV-2 Susceptibility
The 2019 coronavirus disease (COVID-19) pandemic continues to challenge health care systems worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for the cause of global pandemic. Type 2 transmembrane serine protease (TMPRSS2) is important in the cell entry and spread of SARS-CoV-2 and plays a crucial role in the proteolytic cleavage of SARS-CoV-2 spike (S) glycoprotein. Here, using reported structural data, we analyzed the molecular complex of TMPRSS2 and the S glycoprotein and further examined intermolecular interactions of natural TMPRSS2 polymorphic variants. We identified several TMPRSS2 variants that could possibly alter host susceptibility to the SARS-CoV-2 infection. Molecular docking analysis revealed that G462D/G462S variants were predicted to be protective variants, whereas Q438E and S339F variants were predicted to increase susceptibility. In addition, we examined intermolecular interactions between TMPRSS2 and its two potential serine protease inhibitors, camostat mesylate and nafamostat. Further, we investigated the effect of TMPRSS2 variants on these interactions. Our structural analysis revealed that G462D, C297S and S460R variants had possibly altered the interactions with the protease inhibitors. Our results identified important TMPRSS2 variations that could be useful to develop high affinity and personalized drugs for treating COVID-19 patients
Structural Insights into Substrate Binding and Antibiotic Inhibition of Enterobacterial Penicillin-Binding Protein 6
Shigella sonnei remains the second most common cause of shigellosis in young children and is now increasingly dominant across developing countries. The global emergence of drug resistance has become a main burden in the treatment of S. sonnei infections and β-lactam antibiotics, such as pivmecillinam and ceftriaxone, are recommended to be used as second-line treatment. They work by inhibiting the biosynthesis of the peptidoglycan layer of bacterial cell walls, in which the final transpeptidation step is facilitated by penicillin-binding proteins (PBPs). In this study, using protein homology modelling, we modelled the structure of PBP6 from S. sonnei and comprehensively examined the molecular interactions between PBP6 and its pentapeptide substrate and two antibiotic inhibitors. The docked complex of S. sonnei PBP6 with pentapeptides showed that the substrate bound to the active site groove of the DD-carboxypeptidase domain, via hydrogen bonding interactions with the residues S79, V80, Q101, G144, D146 and R240, in close proximity to the catalytic nucleophile S36 for the nucleophilic attack. Two residues, R240 and T208, were found to be important in ligand recognition and binding, where they formed strong hydrogen bonds with the substrate and β-lactams, respectively. Our results provide valuable information on the molecular interactions essential for ligand recognition and catalysis by PBP6. Understanding these interactions will be helpful in the development of effective drugs to treat S. sonnei infections