A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,864 COVID-19 cases (713 with severe and 1,151 with mild disease) and 15,033 ancestry-matched population controls across 4 independent COVID-19 biobanks. We tested whether rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only 1 rare pLOF mutation across these genes among 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We found no evidence of association of rare LOF variants in the 13 candidate genes with severe COVID-19 outcomes.

Pregnancy termination consecutively for three or more times during the first trimester is termed as Recurrent pregnancy loss (RPL). In addition to the abnormal karyotype, heavy metal induced oxidative damage may contribute as prominent etiological factor in pregnancy termination. Oxidative stress is considered crucial in etiology underlying RPL with altered antioxidant status and subsequent DNA damage. The current case controlled study investigated Total antioxidant capacity (TAC), DNA damage (8OHdG) and heavy metals in RPL group (n = 30) and the women with successful pregnancies and no cases of miscarriage as control group (30 women). Heavy metals -Antimony (Sb) and Arsenic (As) were measured by Inductively Coupled Plasma Mass spectrophotometry (ICP-MS). There was significant decrease in levels of TAC in RPL group compared to healthy pregnant women (P < 0.05). On contrary, elevated levels of As and Sb were observed in RPL group with subsequent increase in the levels of 8OHdG (P < 0.001); indicating extensive DNA damage in these patients. Furthermore, increased levels of As and Sb in RPL group were positively correlated with 8OHdG and negatively with total antioxidant capacity. The outcome of the study provides clear insight of the role of metal induced oxidative stress that plays a vital role in the pathophysiology underlying RPL.

Pseudomonas aeruginosa is a multidrug-resistant pathogen known for chronic infections, mainly due to biofilm formation. This study aimed to explore the potential repurposing of 5-fluorouracil (5-FU), an anticancer drug, to treat P. aeruginosa infections. Firstly, we investigated the inhibitory effects of 5-FU on bacterial growth using the microdilution method. Secondly, the impact of 5-FU on biofilm formation and disassembly was assessed via biofilm biomass measurements with the crystal violet staining method and confocal microscopy analyses. Lastly, the potential synergy between 5-FU and the antibiotics gentamicin and meropenem was evaluated using a checkerboard assay. Results revealed that 5-FU inhibited bacterial growth in a dose-dependent manner, with 100% inhibition observed at concentrations of 25 µg/mL and higher. Also, 70% and 100% reductions in biofilm biomass were demonstrated at concentrations of 12 and 100 µg/mL, respectively. Controversy, these higher concentrations unexpectedly increased biofilm biomass in pre-formed biofilms. Synergistic interactions were observed between 5-FU and gentamicin in both growth inhibition (FICI 0.31) and biofilm inhibition (ZIP 14.1), while no synergy was found with meropenem. These findings highlight the potential of 5-FU as an adjunctive therapy for P. aeruginosa infections, especially in combination with gentamicin. However, further research is required to address 5-FU limitations against mature biofilms.

Background: Dystrophic Epidermolysis bullosa (DEB) is a rare, severe subtype of epidermolysis bullosa (EB), characterized by blisters and miliary rashes of the skin. Dystrophic EB (DEB) includes variants inherited both in an autosomal-dominant or autosomal-recessive manner. Recessive dystrophic EB (RDEB) is divided into many subtypes and prevails as a result of biallelic genetic mutations in COL7A1 gene encoding type VII collagen, a major stabilizing molecule of the dermo-epidermal junction. The blister formation is mainly due to the variable structural and functional impairment of anchoring fibrils in VII collagen (COLVII), responsible for the adhesion of the epidermis to the dermis. Method: Three Pakistani families (A, B and C) affected with congenital dystrophic epidermolysis bullosa were recruited in the present study. The whole-exome sequencing (WES) approach was utilized for the detection of the pathogenic sequence variants in probands. The segregation of these variants in other participants was confirmed by Sanger sequencing. Results: This study identified a novel missense variant c.7034G>A, p. Gly2345Asp in exon 91, a novel Frameshift mutation c.385del (p. His129MetfsTer18) in a homozygous form in exon no 3, and a previously known nonsense variation (c.1573 C>T; p. Arg525Ter) in exon 12 of COL7A1 gene in families A, B, and C, respectively, as causative mutations responsible for dystrophic epidermolysis bullosa in these families. Conclusion: Our study validates the involvement of the COL7A1 gene in the etiology of dystrophic epidermolysis bullosa. It further expands the COL7A1 gene mutation database and provides an additional scientific basis for diagnosis, genetic counseling, and prognosis purposes for EB patients.