Exploring optimal drug targets through subtractive proteomics analysis and pangenomic insights for tailored drug design in tuberculosis.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, ranks among the top causes of global human mortality, as reported by the World Health Organization's 2022 TB report. The prevalence of M. tuberculosis strains that are multiple and extensive-drug resistant represents a significant barrier to TB eradication. Fortunately, having many completely sequenced M. tuberculosis genomes available has made it possible to investigate the species pangenome, conduct a pan-phylogenetic investigation, and find potential new drug targets. The 442 complete genome dataset was used to estimate the pangenome of M. tuberculosis. This study involved phylogenomic classification and in-depth analyses. Sequential filters were applied to the conserved core genome containing 2754 proteins. These filters assessed non-human homology, virulence, essentiality, physiochemical properties, and pathway analysis. Through these intensive filtering approaches, promising broad-spectrum therapeutic targets were identified. These targets were docked with FDA-approved compounds readily available on the ZINC database. Selected highly ranked ligands with inhibitory potential include dihydroergotamine and abiraterone acetate. The effectiveness of the ligands has been supported by molecular dynamics simulation of the ligand-protein complexes, instilling optimism that the identified lead compounds may serve as a robust basis for the development of safe and efficient drugs for TB treatment, subject to further lead optimization and subsequent experimental validation.

Household COVID-19 secondary attack rate and associated determinants in Pakistan; A retrospective cohort study.

BACKGROUND: COVID-19 household transmissibility remains unclear in Pakistan. To understand the dynamics of Severe Acute Respiratory Syndrome Coronavirus disease epidemiology, this study estimated Secondary Attack Rate (SAR) among household and close contacts of index cases in Pakistan using a statistical transmission model. METHODOLOGY: A retrospective cohort study was conducted using an inclusive contact tracing dataset from the provinces of Punjab and Khyber-Pakhtunkhwa to estimate SAR. We considered the probability of an infected person transmitting the infection to close contacts regardless of residential addresses. This means that close contacts were identified irrespective of their relationship with the index case. We assessed demographic determinants of COVID-19 infectivity and transmissibility. For this purpose based on evolving evidence, and as CDC recommends fully vaccinated people get tested 5-7 days after close contact with a person with suspected or confirmed COVID-19. Therefore we followed the same procedure in the close contacts for secondary infection. FINDINGS: During the study period from 15th May 2020 to 15th Jan 2021, a total of 339 (33.9%) index cases were studied from 1000 cases initially notified. Among close contact groups (n = 739), households were identified with an assumed mean incubation period of 8.2+4.3 days and a maximum incubation period of 15 days. SAR estimated here is among the household contacts. 117 secondary cases from 739 household contacts, with SAR 11.1% (95% CI 9.0-13.6). All together (240) SAR achieved was 32.48% (95% CI; 29.12-37.87) for symptomatic and confirmed cases. The potential risk factors for SAR identified here included; old age group (>45 years of age), male (gender), household members >5, and residency in urban areas and for index cases high age group. Overall local reproductive number (R) based on the observed household contact frequencies for index/primary cases was 0.9 (95% CI 0.47-1.21) in Khyber Pakhtunkhwa and 1.3 (95% CI 0.73-1.56) in Punjab. CONCLUSIONS: SAR estimated here was high especially in the second phase of the COVID-19 pandemic in Pakistan. The results highlight the need to adopt rigorous preventive measures to cut the chain of viral transmission and prevent another wave of COVID-19.

Triggering receptor expressed on myeloid cells-1 (TREM-1) inhibition in atherosclerosis.

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a transmembrane protein expressed on endothelial cells, white blood cells, smooth muscle cells and platelets. TREM-1 plays an important role in innate immunity. TREM-1 activation pathways are implicated both in sepsis and in non-infectious inflammatory conditions, including atherosclerosis. TREM-1 enhances the subendothelial lipid accumulation and expression of pro-inflammatory cytokines and matrix-degrading enzymes, thereby promoting inflammation and plaque destabilization. TREM-1 inhibitors attenuate the inflammatory process in the atherosclerotic plaque, leading to plaque stabilization. This review focuses on the role of TREM-1 in the pathophysiology of atherosclerosis and the effects of TREM-1 inhibition in the natural history of the disease.

Rational use of Computed Tomography Scan head in the Emergency Department of a high volume tertiary care public sector hospital.

OBJECTIVE: To emphasize the rational use of Computed Tomography (CT) head in emergency department (ED) of a high volume tertiary care hospital. METHODS: This retrospective observational study was conducted in Radiology Department of Medical Teaching Institute Lady Reading Hospital (MTI-LRH), Peshawar, Pakistan from November 1st 2017 to 31st January 2018. Patients of all ages and both genders presenting to the emergency department with post traumatic and non-traumatic indications for emergency CT head scan were included in the study. The imaging was performed on GE 16 multi slice Optima CT system. The imaging protocol included slice thickness of 3-5mm, non-contrast study for cases of head trauma or suspected stroke. Where needed intravenous contrast was administered e.g. to exclude meningitis in patients presenting with severe headache. Patients undergoing CT examination for regions of the body other than head and brain were excluded from the study as their number was insignificant. Reporting was done on PACS and results analyzed using latest SPSS version. RESULTS: Out of 4284 CT scans performed in emergency department 90.8% were CT head (3893). Among 3893 CT scan head done in ED, 2581 cases were reported normal (66.29%), while 1312 cases had positive findings (33.7%), including post traumatic and non-traumatic. CONCLUSION: Misuse of CT head is common especially in an emergency setting. Emergency physicians should be encouraged to obtain a detailed history and perform a thorough physical examination with reference to internationally standardized guidelines, while ordering CT scan.

Infective endocarditis complicated by splenic rupture and fatal intra-abdominal haemorrhage.

This case report describes a rare presentation of Streptococcus mitis endocarditis of the aortic and mitral valves, complicated by spontaneous splenic rupture due to splenic infarction, which led to massive intra-abdominal bleeding and ultimately death.