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Distal arthrogryposis type 5D (DA5D) is clinically characterized by knee extension contractures, distal joint contractures, clubfoot, micrognathia, ptosis, and scoliosis. We report nine affected individuals from eight unrelated Indian families with DA5D. Although the overall musculoskeletal phenotype is not very distinct from other distal arthrogryposis, the presence of fixed knee extension contractures with or without scoliosis could be an important early pointer to DA5D. We also report a possible founder variant in ECEL1 along with four novel variants and further expand the genotypic spectrum of DA5D. [ABSTRACT FROM AUTHOR]

To analyse published evidence on the economic evaluation of risk‐based screening (RBS), a full systematic literature review was conducted. After a quality appraisal, we compared the cost‐effectiveness of risk‐based strategies (low‐risk, medium‐risk and high‐risk) with no screening and age‐based screening. Studies were also analysed for modelling, risk stratification methods, input parameters, data sources and harms and benefits. The 10 modelling papers analysed were based on screening performance of film‐based mammography (FBM) (three); digital mammography (DM) and FBM (two); DM alone (three); DM, ultrasound (US) and magnetic resonance imaging (one) and DM and US (one). Seven studies did not include the cost of risk‐stratification, and one did not consider the cost of diagnosis. Disutility was incorporated in only six studies (one for screening and five for diagnosis). None of the studies reported disutility of risk‐stratification (being considered as high‐risk). Risk‐stratification methods varied from only breast density (BD) to the combination of familial risk, genetic susceptibility, lifestyle, previous biopsies, Jewish ancestry and reproductive history. Less or no screening in low‐risk women and more frequent mammography screening in high‐risk women was more cost‐effective compared to no screening and age‐based screening. High‐risk women screened annually yielded a higher mortality rate reduction and more quality‐adjusted life years at the expense of higher cost and false positives. RBS can be cost effective compared to the alternatives. However, heterogeneity among risk‐stratification methods, input parameters, and weaknesses in the methodologies hinder the derivation of robust conclusions. Therefore, further studies are warranted to assess newer technologies and innovative risk‐stratification methods. What's new? Most countries have set up population‐based mammography screening programmes based on women's age. However, the potential psychosocial harms, over‐diagnosis, and increased costs together with the growing understanding of breast cancer risk factors have led researchers to seek alternative screening paradigms. This full systematic literature review compares the cost effectiveness of risk‐based screening with no screening and age‐based screening in the general population. The findings suggest that risk‐based screening can be an economically efficient alternative and could potentially substitute current breast cancer screening programmes. Moreover, the review identifies several limitations that negatively impact the studies' methodological robustness and proposes possible solutions. [ABSTRACT FROM AUTHOR]

A series of benzimidazole‐derived–furanones (4a–l) were synthesized, characterized, and explored for their in vitro anticancer activities. The pharmacokinetic parameters assessed revealed that all the compounds followed the Lipinski's rule of five, making them potential drug candidates. Further, the results of anticancer activity revealed that (E)‐5‐(1H‐benzo[d]imidazol‐2‐yl)‐3‐(3,4,5‐trimethoxybenzylidene)furan‐2(3H)‐one (4a), was active against A549, MCF7, and DU145 with an IC50 values of 10.4 ± 0.39, 11.1 ± 0.43, and 10.7 ± 0.19 μM, respectively. While another compound (E)‐5‐(1H‐benzo[d]imidazol‐2‐yl)‐3‐([5‐phenyl]furan‐2‐yl)furan‐2(3H)‐one (4k) also exhibited good activity against A549, MCF7, and DU145 with IC50 values of 11.4 ± 0.39, 9.1 ± 0.43, and 12.7 ± 0.19 μM, respectively. Doxorubicin was used as the standard drug. Further, molecular docking studies were carried out to provide binding mode into the binding sites of vascular endothelial growth factor receptor (VEGFR). Docking scores and binding energies corroborated well with the results of experimental anticancer activity. Pharmacokinetic (ADME) parameters of the potent derivatives were also found to be in an acceptable range. The benzimidazole‐furanonone conjugates seem to be a potential source for the further development of potent cytotoxic agents. [ABSTRACT FROM AUTHOR]

We report herein one-pot synthesis and the antibacterial and antitubercular activities of 2,5-disubstituted-1,3,4-oxadiazole compounds obtained by hybridization of a well-known antitubercular agent isoniazid ( INH) with four broad-spectrum antibiotics belonging to fluoroquinolone ( FQ) class. The work is aimed at designing and developing potential antimicrobial agents having synergistic action due to the coupling of INH and FQ through the biologically active 1,3,4-oxadiazole nucleus. The synthesized compounds are expected to have low toxicity as compared to INH due to the absence of free hydrazide group in the chemical structure of the prepared derivatives. The antibacterial activities of the 1,3,4 oxadiazole derivatives were also tested against several Gram-positive and Gram-negative pathogenic bacterial strains. The antitubercular activity was evaluated against M. tuberculosis H37Rv strain, and the results were compared with that of the positive control INH. The title compounds showed excellent antimicrobial and promising antitubercular activity in comparison to the parent fluoroquinolones and INH, respectively. [ABSTRACT FROM AUTHOR]

A number of pyridazinone derivatives bearing substituted benzylidene and heterocyclic/aromatic rings at 4th and 6th positions, respectively were synthesized in good to moderate yields and screened for antioxidant activity. Antioxidant activity of pyridazinone derivatives was evaluated by using several in vitro radical scavenging methods such as 1,1-diphenylpicrylhydrazyl (DPPH), hydrogen peroxide (H2O2), nitric oxide (NO), reducing power, and metal chelating assay etc. Molegro virtual docker software was used to study the binding affinity of the title compounds with the xanthine oxidoreductase enzyme. Amongst the tested compounds, 5a, 5d, 5g & 5j were found to exhibit excellent antioxidant activity at par with the positive control, ascorbic acid. The molecular docking studies of these compounds demonstrated a good selectivity profile with xanthine oxidoreductase receptors. A preliminary study of the structural-activity relationship showed that the presence of electron withdrawing group and heterocyclic ring on pyridazinone nucleus are associated with the best potency and selectivity profile. It could be proposed that xanthine oxidoreductase receptor may be involved in observed antioxidant activity of pyridazinone derivatives bearing aromatic ring and benzylidene substituents and thus the synthesized compounds are worthy of further exploration. [ABSTRACT FROM AUTHOR]