Epidemiology of tuberculosis in Saudi Arabia following the implementation of end tuberculosis strategy: Analysis of the surveillance data 2015-2019.

OBJECTIVES: To analyze the evolution of tuberculosis (TB) epidemiology in Saudi Arabia in the 5 years following the implementation of the end-TB Strategy. METHODS: A retrospective analysis of surveillance data, reported by the national tuberculosis control program from 2015-2019, was carried out. The annual incidence and the percentage of yearly changes were calculated and compared to the World Health Organization (WHO) milestones, which anticipate a 4-5% annual decline. Additionally, various other epidemiological indicators of TB were examined. RESULTS: The national TB incidence declined from 10.55% per 100,000 in 2015 to 8.76% per 100,000 in 2019, aligning with the WHO's 2019 milestone estimated between 8.59-8.96% per 100,000. While Makkah Region (40.3%) and Riyadh (24.6%) accounted for the majority of cases, Jazan region consistently exhibited the highest incidence throughout the study period. Demographic features shifted towards a younger age category, male, and native dominance. There was a consistent decrease in resistance and intermediate sensitivity to all first-line anti-TB drugs, associated with a substantial decrease in both polydrug resistance (from 4.7-1.9%; p<0.001) and multidrug resistance (from 4.4-2.4%; p=0.008). CONCLUSION: The figures of TB incidence TB in Saudi Arabia between 2015-2019 has met the WHO end-TB milestones, predicting successful progress toward the 2035 goal.

Repurposing of antibacterial compounds for suppression of Mycobacterium tuberculosis dormancy reactivation by targeting resuscitation-promoting factors B.

Tuberculosis infection has always been a global concern for public health, and the mortality rate has increased tremendously every year. The ability of the resuscitation Mycobacterium tuberculosis (Mtb) from the dormant state is one of the major reasons for the epidemic spread of tuberculosis infection, especially latent tuberculosis infection (LTBI). The element that encourages resuscitation, RpfB (resuscitation-promoting factors B), is mostly in charge of bringing Mtb out of slumber. This reason makes RpfB a promising target for developing tuberculosis drugs because of the effects of latent tuberculosis. Therefore, this work was executed using a computational three-level screening of the Selleckhem antibiotics database consisting of 462 antibiotics against the ligand binding region of the RpfB protein, followed by an estimation of binding free energy for ideal identification and confirmation of potential RpfB inhibitor. Subsequently, three antibiotic drug molecules, i.e., Amikacin hydrate (-66.87 kcal/mol), Isepamicin sulphate (-60.8 kcal/mol), and Bekanamycin (-46.89 kcal/mol), were selected on the basis of their binding free energy value for further computational studies in comparison to reference ligand, 4-benzoyl-2-nitrophenyl thiocyanate (NPT7). Based on the intermolecular interaction profiling, 200 ns molecular dynamic simulation (MD), post-simulation analysis and principal component analysis (PCA), the selected antibiotics showed substantial stability with the RpfB protein compared to the NPT7 inhibitor. Conclusively based on the computational results, the preferred drugs can be potent inhibitors of the RpfB protein, which can be further validated using in vivo research and in vitro enzyme inhibition to understand their therapeutic activity against tuberculosis infection.Communicated by Ramaswamy H. Sarma.

Impact of diabetes mellitus and co-morbidities on mortality in patients with COVID-19: A single-center retrospective study.

OBJECTIVES: To describe the effect of diabetes mellitus (DM) on clinical outcomes of patients admitted with COVID-19 infection. METHODS: We carried out a single center, observational, retrospective study. We included adult patients with laboratory-confirmed diagnosis of COVID-19 admitted to a tertiary hospital in Jeddah, Saudi Arabia, from April 2020 to December 2020. Electronic medical records were reviewed for demographics, clinical status, hospital course, and outcome; and they were compared between the patients with or without DM. RESULTS: Out of 198 patients included in the study, 86 (43.4%) were diabetic and 112 (56.5%) were non-diabetic. Majority of the patients were males 139 (70.2%) with a mean age of 54.14±14.89 years. In-hospital mortality rate was higher in diabetic patients than in non-diabetic patients (40 vs. 32; p=0.011). The most common comorbidity was hypertension (n=95, 48%) followed by ischemic heart disease (n=35, 17.7%), chronic kidney disease (n=17, 9.6%), and bronchial asthma (n=10, 5.1%). CONCLUSION: The risk of SARS-CoV-2 infection is higher among diabetic patients; particularly, those with preexisting co-morbidities or geriatric patients. Diabetic patients are prone to a severe clinical course of COVID-19 and a significantly higher mortality rate.

Exploration of Microbially Derived Natural Compounds against Monkeypox Virus as Viral Core Cysteine Proteinase Inhibitors.

Monkeypox virus (MPXV) is a member of the Orthopoxvirus genus and the Poxviridae family, which instigated a rising epidemic called monkeypox disease. Proteinases are majorly engaged in viral propagation by catalyzing the cleavage of precursor polyproteins. Therefore, proteinase is essential for monkeypox and a critical drug target. In this study, high-throughput virtual screening (HTVS) and molecular dynamics simulation were applied to detect the potential natural compounds against the proteinase of the monkeypox virus. Here, 32,552 natural products were screened, and the top five compounds were selected after implementing the HTVS and molecular docking protocols in series. Gallicynoic Acid F showed the minimum binding score of -10.56 kcal/mole in the extra precision scoring method, which reflected the highest binding with the protein. The top five compounds showed binding scores ≤-8.98 kcal/mole. These compound complexes were tested under 100 ns molecular dynamics simulation, and Vaccinol M showed the most stable and consistent RMSD trend in the range of 2 Å to 3 Å. Later, MM/GBSA binding free energy and principal component analysis were performed on the top five compounds to validate the stability of selected compound complexes. Moreover, the ligands Gallicynoic Acid F and H2-Erythro-Neopterin showed the lowest binding free energies of -61.42 kcal/mol and -61.09 kcal/mol, respectively. Compared to the native ligand TTP-6171 (ΔGBind = -53.86 kcal/mol), these two compounds showed preferable binding free energy, suggesting inhibitory application against MPXV proteinase. This study proposed natural molecules as a therapeutic solution to control monkeypox disease.

Glycosylated Flavonoid Compounds as Potent CYP121 Inhibitors of Mycobacterium tuberculosis.

Due to the concerning rise in the number of multiple- and prolonged-drug-resistant (MDR and XDR) Mycobacterium tuberculosis (Mtb) strains, unprecedented demand has been created to design and develop novel therapeutic drugs with higher efficacy and safety. In this study, with a focused view on implementing an in silico drug design pipeline, a diverse set of glycosylated flavonoids were screened against the Mtb cytochrome-P450 enzyme 121 (CYP121), which is established as an approved drug target for the treatment of Mtb infection. A total of 148 glycosylated flavonoids were screened using structure-based virtual screening against the crystallized ligand, i.e., the L44 inhibitor, binding pocket in the Mtb CYP121 protein. Following this, only the top six compounds with the highest binding scores (kcal/mol) were considered for further intermolecular interaction and dynamic stability using 100 ns classical molecular dynamics simulation. These results suggested a considerable number of hydrogen and hydrophobic interactions and thermodynamic stability in comparison to the reference complex, i.e., the CYP121-L44 inhibitor. Furthermore, binding free energy via the MMGBSA method conducted on the last 10 ns interval of MD simulation trajectories revealed the substantial affinity of glycosylated compounds with Mtb CYP121 protein against reference complex. Notably, both the docked poses and residual energy decomposition via the MMGBSA method demonstrated the essential role of active residues in the interactions with glycosylated compounds by comparison with the reference complex. Collectively, this study demonstrates the viability of these screened glycosylated flavonoids as potential inhibitors of Mtb CYP121 for further experimental validation to develop a therapy for the treatment of drug-resistant Mtb strains.

Assessment of the new World Health Organization's dengue classification for predicting severity of illness and level of healthcare required.

The objective of this study was to assess the validity of the new dengue classification proposed by the World Health Organization (WHO) in 2009 and to develop pragmatic guidelines for case triage and management. This retrospective study involved 357 laboratory-confirmed cases of dengue infection diagnosed at King Abdulaziz University Hospital, Jeddah, Saudi Arabia over a 4-year period from 2014 to 2017. The sensitivity of the new classification for identifying severe cases was limited (65%) but higher than the old one (30%). It had a higher sensitivity for identifying patients who needed advanced healthcare compared to the old one (72% versus 32%, respectively). We propose adding decompensation of chronic diseases and thrombocytopenia-related bleeding to the category of severe dengue in the new classification. This modification improves sensitivity from 72% to 98% for identifying patients who need advanced healthcare without altering specificity (97%). It also improves sensitivity in predicting severe outcomes from 32% to 88%. In conclusion, the new classification had a low sensitivity for identifying patients needing advanced care and for predicting morbidity and mortality. We propose to include decompensation of chronic diseases and thrombocytopenia-related bleeding to the category of severe dengue in the new classification to improve the sensitivity of predicting cases requiring advanced care.

Development and validation of different indirect ELISAs for MERS-CoV serological testing.

Since 2012, MERS-CoV has caused up to 2220 cases and 790 deaths in 27 countries with Saudi Arabia being the most affected country with ~83.1% of the cases and ~38.8% local death rate. Current serological assays such as microneutralization (MN), plaque reduction neutralization, immunofluorescence, protein microarray or pseudoparticle neutralization assays rely on handling of live MERS-CoV in high containment laboratories or need for expensive and special equipment and reagents and highly trained personnel which represent a technical hurdle for most laboratories in resource-limited MERS-CoV endemic countries. Here, we developed, compared and evaluated three different indirect ELISAs based on MERS-CoV nucleocapsid protein (N), spike (S) ectodomain (amino acids 1-1297) and S1 subunit (amino acids 1-725) and compared them with MN assay. The developed ELISAs were evaluated using large number of confirmed seropositive (79 samples) and seronegative (274 samples) MERS-CoV human serum samples. Both rS1- and rS-ELISAs maintained high sensitivity and specificity (≥90%) across a wider range of OD values compared to rN-ELISA. Moreover, rS1- and rS-based ELISAs showed better agreement and correlation with MN assay in contrast to rN-ELISA. Collectively, our data demonstrate that rS1-ELISA and rS-ELISA are more reliable than rN-ELISA and represent a suitable choice for seroepidemiological testing and surveillance in MERS-CoV endemic regions.

Simulation-based training in Ebola Personal Protective Equipment for healthcare workers: Experience from King Abdulaziz University Hospital in Saudi Arabia.

BACKGROUND: Millions of Muslims from across the world gather annually to perform pilgrimage. This can import unusual communicable diseases such as Ebola. Communicable diseases with a high risk of mortality necessitate special training to master the required competency to avert transmission of infections. The efficacy of simulation-based training (SBT) has been shown in such circumstances. OBJECTIVE: We sought to develop an SBT program in Ebola Personal Protective Equipment (PPE) for all healthcare workers (HCWs). METHODS: We conducted a quasi-experimental study at the clinical skills and simulation center at the King Abdulaziz University. An interdisciplinary committee was formed to develop this program in three stages. Pre-intervention: Needs assessment "Diagnostic drill"; we conducted in-situ simulation in the emergency department (ED). High-fidelity simulator (HFS) was used as a suspected Ebola case to assess HCWs' competency of PPE. We used a checklist that was developed in accordance with the national and international guidelines. We then conducted "Train the Trainer in Ebola PPE" course to develop potential instructors. INTERVENTION: PPE competency SBT courses. This involved focusing on trainees to be skilled in Ebola PPE and becoming trained observers using skill stations and Ebola scenario with HFS, followed by debriefing. All courses gathered participants' evaluations, pre, and post-tests. Post-intervention: In-situ simulation in the ED two months later that was similar to the diagnostic drill. RESULTS: Pre-intervention: 7 HCWs were involved in the drill, the average score was 37% of the checklist items. For train the trainer, 19 potential PPE instructors attended the program; of them, 65% were female and 35% male, and 6 were physicians and 13 nurses. Average pre and post-tests scores were 72% and 86%, respectively. INTERVENTION: 10 PPE courses that were attended by 179 HCWs; of them, 67% were female and 33% male, and 52 were physicians, 112 nurses, and 15 others. Pre and posttests were 67% (57-75%) and 85% (81-91%), respectively, with a p-value<0.01. Post-intervention: Post Program drill's average score was 86% of the checklist items (37% in diagnostic drill). CONCLUSIONS: Using SBT could be an effective method of developing competent HCWs in Ebola PPE.

Genetic characterization and diversity of circulating influenza A/H1N1pdm09 viruses isolated in Jeddah, Saudi Arabia between 2014 and 2015.

The emerged influenza A/H1N1pdm09 viruses have replaced the previously circulating seasonal H1N1 viruses. The close antigenic properties of these viruses to the 1918 H1N1 pandemic viruses and their post-pandemic evolution pattern could further enhance their adaptation and pathogenicity in humans representing a major public health threat. Given that data on the dynamics and evolution of these viruses in Saudi Arabia is sparse we investigated the genetic diversity of circulating influenza A/H1N1pdm09 viruses from Jeddah, Saudi Arabia, by analyzing 39 full genomes from isolates obtained between 2014-2015, from patients with varying symptoms. Phylogenetic analysis of all gene segments and concatenated genomes showed similar topologies and co-circulation of clades 6b, 6b.1 and 6b.2, with clade 6b.1 being the most predominate since 2015. Most viruses were more closely related to the vaccine strain (Michigan/45/2015) recommended for the 2017/2018 season, than to the California/07/2009 strain. Low sequence variability was observed in the haemagglutinin protein compared to the neuraminidase protein. Resistance to neuraminidase inhibitors was limited as only one isolate had the H275Y substitution. Interestingly, two isolates had short PA-X proteins of 206 amino acids compared to the 232 amino acid protein found in most influenza A/H1N1pdm09 viruses. Together, the co-circulation of several clades and the predominance of clade 6b.1, despite its low circulation in Asia in 2015, suggests multiple introductions most probably during the mass gathering events of Hajj and Umrah. Jeddah represents the main port of entry to the holy cities of Makkah and Al-Madinah, emphasizing the need for vigilant surveillance in the kingdom.

Viral Infection and Obesity: Current Status and Future Prospective.

BACKGROUND: The association of pathogenic viruses with obesity has now been well-known in both human and animals. Globally, human obesity has become a serious problem leading to the emergence of multiple lifethreatening diseases. Adenoviruses contribute a significant role in the induction of obesity by affecting various pathways. Due to impaired immunity, obese individuals are more prone to nosocomial infections leading to complications of obesity. In contrast, several other important factors contributing to human obesity are known. METHODS: Currently, many published reports showed strong evidence of the role and linkage of Ad36 infection in human obesity. The Ad36 pathogenesis effect on the hepatic steatosis reduces leptin gene expression, reduced antibody response in vaccination, reduces immune system, insulin sensitivity, increases glucose uptake, activates the lipogenic and pro-inflammatory pathways in adipose tissue increases the level of Macrophage Chemo attractant Protein-1 leading chronic inflammation and affect lipid metabolism. RESULTS: The E4-ORF1 gene of Ad36 play an important role in the induction of adipogenesis and regulation of adipocyte differentiation and also known to activate the sensitizing effect of insulin. The use of E4-ORF1gene as a ligand to develop new drugs against diabetes and the prevention of Ad36 infection by an effective vaccination will attract researchers and open new area of research in the field of obesity and obesity-related multiple diseases. CONCLUSION: Therefore, the identification and management of important contributory factors by identifying the regulation of adipocyte differentiation leading to a chronic condition like adipogenesis and insulin resistance resulting in obesity is an urgent requirement globally for human health.

A stepwise introduction of a successful antimicrobial stewardship program. Experience from a tertiary care university hospital in Western, Saudi Arabia.

OBJECTIVES: To analyze and evaluate the safety and cost-effectiveness of a gradually-implemented antimicrobial stewardship programs (ASP) in a tertiary care center. METHODS: Prospective data were collected from an ASP that was gradually introduced between April 2012 and December 2013 in 6 hospital departments, over successive periods of 3 months each. A multidisciplinary team supervised antibiotic use and regulated pharmacy dispensations of a list of restricted antimicrobials (RAs). Indicators were prospectively monitored and included hospital mortality as the safety indicator; incidence of multi-drug resistance (MDR) infections as the effectiveness indicator, RA cost savings as the cost-effectiveness indicator and RA consumption indicated the process implementation. RESULTS: Between 2012 and 2014, dispensations of RAs decreased by 67% and prescriptions by 75%; no increase in mortality rate was observed. Microbiologically, there was a decreasing trend of incidence across all monitored infections, but this was only significant for Acinetobacter baumannii (p=0.007). Cost analysis showed a decrease in expenditure for RAs, with an average monthly saving of up to 326,020USD. CONCLUSIONS: Stepwise implementation of ASPs is a safe and cost-effective strategy for improving antibiotic prescribing practice and to reduce multi-drug resistance.