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Objective To assess the effects of COVID-19 vaccines in women before or during pregnancy on SARS-CoV-2 infection-related, pregnancy, offspring and reactogenicity outcomes.Design Systematic review and meta-analysis.Data sources Major databases between December 2019 and January 2023.Study selection Nine pairs of reviewers contributed to study selection. We included test-negative designs, comparative cohorts and randomised trials on effects of COVID-19 vaccines on infection-related and pregnancy outcomes. Non-comparative cohort studies reporting reactogenicity outcomes were also included.Quality assessment, data extraction and analysis Two reviewers independently assessed study quality and extracted data. We undertook random-effects meta-analysis and reported findings as HRs, risk ratios (RRs), ORs or rates with 95% CIs.Results Sixty-seven studies (1 813 947 women) were included. Overall, in test-negative design studies, pregnant women fully vaccinated with any COVID-19 vaccine had 61% reduced odds of SARS-CoV-2 infection during pregnancy (OR 0.39, 95% CI 0.21 to 0.75; 4 studies, 23 927 women; I2=87.2%) and 94% reduced odds of hospital admission (OR 0.06, 95% CI 0.01 to 0.71; 2 studies, 868 women; I2=92%). In adjusted cohort studies, the risk of hypertensive disorders in pregnancy was reduced by 12% (RR 0.88, 95% CI 0.82 to 0.92; 2 studies; 115 085 women), while caesarean section was reduced by 9% (OR 0.91, 95% CI 0.85 to 0.98; 6 studies; 30 192 women). We observed an 8% reduction in the risk of neonatal intensive care unit admission (RR 0.92, 95% CI 0.87 to 0.97; 2 studies; 54 569 women) in babies born to vaccinated versus not vaccinated women. In general, vaccination during pregnancy was not associated with increased risk of adverse pregnancy or perinatal outcomes. Pain at the injection site was the most common side effect reported (77%, 95% CI 52% to 94%; 11 studies; 27 195 women).Conclusion COVID-19 vaccines are effective in preventing SARS-CoV-2 infection and related complications in pregnant women.PROSPERO registration number CRD42020178076.

Introduction The prevalence of COVID-19 and its impact varied between countries and regions. Pregnant women are at high risk of COVID-19 complications compared with non-pregnant women. The magnitude of variations, if any, in SARS-CoV-2 infection rates and its health outcomes among pregnant women by geographical regions and country’s income level is not known.Methods We performed a random-effects meta-analysis as part of the ongoing PregCOV-19 living systematic review (December 2019 to April 2021). We included cohort studies on pregnant women with COVID-19 reporting maternal (mortality, intensive care admission and preterm birth) and offspring (mortality, stillbirth, neonatal intensive care admission) outcomes and grouped them by World Bank geographical region and income level. We reported results as proportions with 95% confidence intervals (CI).Results We included 311 studies (2 003 724 pregnant women, 57 countries). The rates of SARS-CoV-2 infection in pregnant women varied significantly by region (p

Abstract Background Various normalisation techniques have been developed in the context of microarray analysis to try to correct expression measurements for experimental bias and random fluctuations. Major techniques include: total intensity normalisation; intensity dependent normalisation; and variance stabilising normalisation. The aim of this paper is to discuss the impact of normalisation techniques for two-channel array technology on the process of identification of differentially expressed genes. Results Through three precise simulation plans, we quantify the impact of normalisations: (a) on the sensitivity and specificity of a specified test statistic for the identification of deregulated genes, (b) on the gene ranking induced by the statistic. Conclusion Although we found a limited difference of sensitivities and specificities for the test after each normalisation, the study highlights a strong impact in terms of gene ranking agreement, resulting in different levels of agreement between competing normalisations. However, we show that the combination of two normalisations, such as glog and lowess, that handle different aspects of microarray data, is able to outperform other individual techniques.

We used in vitro selection to identify DNAzymes that acylate the exocyclic nucleobase amines of cytidine, guanosine, and adenosine in DNA oligonucleotides. The acyl donor was the 2,3,5,6-tetrafluorophenyl ester (TFPE) of a 5'-carboxyl oligonucleotide. Yields are as high as >95 % in 6 h. Several of the N-acylation DNAzymes are catalytically active with RNA rather than DNA oligonucleotide substrates, and eight of nine DNAzymes for modifying C are site-specific (>95 %) for one particular substrate nucleotide. These findings expand the catalytic ability of DNA to include site-specific N-acylation of oligonucleotide nucleobases. Future efforts will investigate the DNA and RNA substrate sequence generality of DNAzymes for oligonucleotide nucleobase N-acylation, toward a universal approach for site-specific oligonucleotide modification., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Conjugate vaccines prepared with the cross-reactive material 197 (CRM 197 ) carrier protein have been successful in the clinic and are of great interest in the field of immunotherapy. One route to preparing peptide-CRM 197 conjugate vaccines involves an activation-conjugation strategy, effectively coupling lysine residues on the protein to cysteine thiolate groups on the peptide of interest using a heterobifunctional linker as an activation agent. This method has been found to result in two distinct populations of conjugates, believed to be the result of a conformational change of CRM 197 during preparation. This report explores the factors that lead to this conformational change, pointing to a model in which the unintentional alkylation of histidine-21 by the activating agent promotes the "opening" of the monomeric protein. This exposes a new set of lysine residues that are modified by additional activation agents. Subsequent peptide ligation to these sites results in the two conformers. This is the first time that a specific chemical modification is demonstrated to induce a defined conformational change for this carrier protein. Importantly, alternative conditions and reagents have been found to minimize this effect, improving the conformational homogeneity of peptide-CRM 197 conjugates.

1-Ethyl-3-(3-(dimethylamino)propyl)carbodiimide (EDC) bioconjugations have been utilized in preparing variants for medical research. While there have been advances in optimizing the reaction for aqueous applications, there has been limited focus toward identifying conditions and side reactions that interfere with product formation. We present a systematic investigation of EDC/N-hydroxysulfosuccinimide (sNHS)-mediated bioconjugations on carboxylated peptides and small proteins. We identified yet-to-be-reported side products arising from both the reagents and substrates. Model peptides used in this study illustrate particular substrates are more susceptible to side reactions than others. From our studies, we found that bioconjugations are more efficient with high concentrations of amine nucleophile but not sNHS. Performing bioconjugations on a model affibody protein show that the trends established with model peptides hold for more complex systems.

Infection is the most common factor that leads to dental titanium implant failure. Antibacterial implant surfaces based on nano-scale modifications of the titanium appear as an attractive strategy for control of peri-implantitis. In the present work, the preparation and antibacterial properties of a novel composite coating for titanium based on nanoporous silica and silver nanoparticles are presented. Starch-capped silver nanoparticles (AgNPs) were synthesized and then incorporated into sol-gel based solution system. The AgNP-doped nanoporous silica coatings were prepared on titanium surface using a combined sol-gel and evaporation-induced self-assembly (EISA) method. The coating nanostructure was characterized by XRD, SEM-EDX, and HR-TEM. Antibacterial activity was evaluated against Aggregatibacter actinomycetemcomitans, a representative pathogen of dental peri-implantitis. Colony-forming units (CFUs) were counted within the biofilm and at the planktonic state. Biofilm development was quantified using crystal violet staining and viability of adherent bacteria was confirmed with the Live/Dead fluorescence assay. Silica-based composite coating containing AgNPs (AgNP/NSC) was prepared on titanium surface by direct incorporation of AgNP suspension into the sol-gel system. The self-assembly technique enabled the spontaneous formation of a highly ordered nanoporosity in the coating structure, which is a desired property for osseointegration aspects of titanium implant surface. AgNP/NSC coating produces a strong antibacterial effect on titanium surface by not only killing the adherent bacteria but also reducing the extent of biofilm formation. Biofilm survival is reduced by more than 70% on the AgNP/NSC-modified titanium surface, compared to the control. This antibacterial effect was verified for up to 7 days of incubation. The long-term antibacterial activity exhibited by the nanostructured AgNP/NSC-titanium surface against A. actinomycetemcomitans suggests that this type of nano-scale surface modification is a promissory strategy to control infections associated with dental implant rehabilitation., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Mediastinal sarcoidal reaction in follow up for seminoma. Testicular germ cell tumors constitute a model for curable neoplasia. Long-term complications are well-known and follow-up includes not only awareness of relapse, but also of the development of secondary tumors and treatment sequelae. In the last two decades, an increase in sarcoidosis incidence has been described in cured patients, who at follow-up present lung nodules or mediastinal lymph nodes. A 28 year-old patient who, on clinical follow up of a semi-nomatous tumor, presented mediastinal lymph nodes on CT scan and chest x-ray, without evidence of disease in pelvis or abdomen is presented. His other testicle was normal and he had negative tumor markers. Because of this rare presentation, a mediastinoscopy was performed and sarcoidosis like reaction was diagnosed. During follow-up of patients with testicular germ cell tumors, the presence of mediastinal lymph nodes requires a histological diagnosis and sarcoidosis should be considered as differential diagnosis.

A novel series of substituted N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-N-(3-phenoxyphenyl)-trifluoro-3-amino-2-propanols is described which potently and reversibly inhibit cholesteryl ester transfer protein (CETP). Starting from the initial lead 1, various substituents were introduced into the 3-phenoxyaniline group to optimize the relative activity for inhibition of the CETP-mediated transfer of [3H]-cholesteryl ester from HDL donor particles to LDL acceptor particles either in buffer or in human serum. The better inhibitors in the buffer assay clustered among compounds in which the phenoxy group was substituted at the 3, 4, or 5 positions. In general, small lipophilic alkyl, haloalkyl, haloalkoxy, and halogen moieties increased potency relative to 1, while analogues containing electron-donating or hydrogen bond accepting groups exhibited lower potency. Compounds with polar or strong electron-withdrawing groups also displayed lower potency. Replacement of the phenoxy ring in 1 with either simple aliphatic or cycloalkyl ethers as well as basic heteroaryloxy groups led to reduced potency. From the better compounds, a representative series 4a-i was prepared as the chirally pure R(+) enantiomers, and from these, the 4-chloro-3-ethylphenoxy analogue was identified as a potent inhibitor of CETP activity in buffer (4a, IC50 0.77 nM, 59 nM in human serum). The simple R(+) enantiomer 4a represents the most potent acyclic CETP inhibitor reported. The chiral synthesis and biochemical characterization of 4a are reported along with its preliminary pharmacological assessment in animals.

A novel series of substituted N-benzyl-N-phenyl-trifluoro-3-amino-2-propanols are described that reversibly inhibit cholesteryl ester transfer protein (CETP). Starting with screening lead 22, various structural features were explored with respect to inhibition of the CETP-mediated transfer of [(3)H]cholesterol from high-density cholesterol donor particles to low-density cholesterol acceptor particles. The free hydroxyl group of the propanol was required for high potency, since acylation or alkylation reduced activity. High inhibitory potency was also associated with 3-ether moieties in the aniline ring, and the highest potencies were exhibited by 3-phenoxyaniline analogues. Activity was substantially reduced by oxidation or substitution in the methylene of the benzylic group, implying that the benzyl ring orientation was important for activity. In the benzylic group, substitution at the 3-position was preferred over either the 2- or the 4-positions. Highest potencies were observed with inhibitors in which the 3-benzylic substituent had the potential to adopt an out of plane orientation with respect to the phenyl ring. The best 3-benzylic substituents were OCF(2)CF(2)H (42, IC(50) 0.14 microM in buffer, 5.6 microM in human serum), cyclopentyl (39), 3-iso-propoxy (27), SCF(3) (67), and C(CF(3))(2)OH (36). Separation of 42 into its enantiomers unexpectedly showed that the minor R(+) enantiomer 1a was 40-fold more potent (IC(50) 0.02 microM in buffer, 0.6 microM in human serum) than the major S(-) enantiomer 1b, demonstrating that the R-chirality at the propanol 2-position is key to high potency in this series. The R(+) enantiomer 1a represents the first reported acyclic CETP inhibitor with submicromolar potency in plasma. A chiral synthesis of 1a is reported.

A series of novel N,N-disubstituted trifluoro-3-amino-2-propanols has been prepared as potent inhibitors of cholesteryl ester transfer protein (CETP). Modifying the aromatic 3-tetrafluoroethoxy group in the lead molecule 1a with various heteroaryl moieties produced new 2-furyl analogues 2a,b with submicromolar potency in vitro.

Continued development around our ETA-selective endothelin (ET) antagonist 1 (CI-1020) has led to the synthesis of analogues with improved aqueous solubility profiles. Poor solubility characteristics displayed by 1 required a complex buffered formulation in order to conduct iv studies. To overcome the use of specific iv formulations for preclinical studies on additional drug candidates, analogues with improved aqueous solubility were desired. Several analogues were synthesized with substitution patterns that allowed for the formation of either acid or base addition salts. These derivatives had dramatically improved aqueous solubility. In addition, these analogues retained equivalent or improved ETA receptor selectivity and antagonist potency, versus 1, both in vitro and in vivo. Compound 29, which contains as a substituent the sodium salt of a sulfonic acid, has an ETA IC50 = 0.38 nM, ETA selectivity of 4200-fold, and ETA functional activity of KB = 7.8, all of which are similar or superior to those of 1. Compound 29 also has vastly superior aqueous solubility and solubility duration, compared to 1. Furthermore, 29 after iv infusion displays improved activity to 1 in preventing acute hypoxia-induced pulmonary hypertension in rats with an ED50 = 0.3 microg/kg/h.

A series of bi-aryl pyridine carboxylic acids has been prepared and evaluated as inhibitors of ECE-1. The analogs were prepared by Pd catalyzed cross couplings of halogenated pyridines with heteroaryl organo-boranes, -tinate or -zincate derivatives.

Objective: We estimated hepatitis B virus (HBV) and hepatitis C virus (HCV) sexual transmission among homosexual men., Methods: Two hundred twenty-eight homosexually active men attending two clinical centers and presenting no risk factors except for sexual exposure were interviewed, and a blood sample was drawn. HBV marker test was performed using enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay, and HCV was tested using ELISA-2 and recombinant immunoblot assay-2., Results: HBV and HCV infection prevalence rates were 34.4% and 12.7%, respectively. Using logistic regression analysis including sexual exposure and controlling for confounders, we found that anal receptive intercourse (odds ratio [OR] = 4.01; 95% confidence interval [CI] = 1.34-11.94), duration of homosexuality (OR = 3.43; 95% CI = 1.29-9.12), insertive anilingus (OR = 2.02; 95% CI = 1.06-3.87), and sexually transmitted diseases (OR = 1.87; 95% CI = 1.00-3.47) were independently associated with the risk of HBV sexual transmission. We did not find any association between sexual behavior and HCV transmission., Conclusions: Sexual behavior is a plausible explanatory factor of HBV sexual transmission among homosexual men. Further evidence is needed to elucidate the occurrence and the efficiency of HCV sexual transmission in the absence of other risk factors.