Prenatal and Birth Care of Roma Women.

BACKGROUND: The reproductive health of Roma women has been poorly studied. It is important to determine the follow-up care received by Roma women from pregnancy to the first postpartum visit, together with neonatal outcomes, to improve prenatal care and maternal-child outcomes. OBJECTIVE: The aim of this study was to examine differences in prenatal care and maternal-infant outcomes between Roma and non-Roma women. METHODS: A retrospective longitudinal study was conducted in 122 pregnant women (28 Roma and 94 non-Roma women) recruited from seven primary care centers in three districts of Asturias (Spain). Sociodemographic variables, prenatal control, birth characteristics, feeding, and neonatal outcomes (gestational age, weight, and APGAR [appearance, pulse, grimace, activity, and respiration]) were collected from the electronic medical records. Prenatal care was assessed using three indices: the Kessner index, the Modified Adequacy of Prenatal Care Utilization Spanish Index, and an ad hoc index that considered adherence to the recommendations for pregnant women in Spain. RESULTS: Compared with non-Roma women, advanced maternal age (≥35 years) and primigravida were less common among Roma women. Roma women visited the dentist less often, smoked more, and underwent group B streptococcus screening less frequently. No differences were found in the number of prenatal visits between Roma and non-Roma women. Consequently, there were no differences between the Kessner index and the Modified Adequacy of Prenatal Care Utilization Spanish Index. Using the ad hoc index, the non-Roma women more frequently had adequate prenatal visits. There were no differences in birth characteristics, type of feeding, and neonatal outcomes. DISCUSSION: Overall, prenatal care was slightly worse in Roma women; however, this did not imply worse neonatal health outcomes. Both study groups had similar birth characteristics and immediate puerperium, including feeding.

Limitación auditiva y fragilidad social en hombres y mujeres mayores / Hearing loss and social frailty in older men and women

Objetivo: Explorar la asociación entre la limitación auditiva y la fragilidad social en una muestra de personas mayores de España. Método: Estudio transversal con una muestra de 445 personas (190 hombres y 255 mujeres) de 65 y más años de edad no institucionalizadas, reclutadas de centros de atención primaria en España. La limitación auditiva se determinó de forma autoinformada utilizando tres preguntas. Se consideró que existía fragilidad social cuando la persona presentó dos o más de las siguientes condiciones: vivir solo/a, ausencia de persona que brinde ayuda, contacto infrecuente con la familia, contacto infrecuente con amistades, falta de confidente y falta de ayuda para las actividades cotidianas en los últimos 3 meses. Para estudiar la asociación entre la limitación auditiva y la fragilidad social se realizaron modelos de regresión logística ajustados por posibles factores de confusión, incluyendo la presencia de fragilidad física. Resultados: La edad media de los/las participantes fue de 76,2 años (77,5 años para las mujeres). El 54,4% presentaban limitación auditiva y el 23,2% fueron considerados/as frágiles sociales. La limitación auditiva se asoció con la fragilidad social ( odds ratio ajustada [ORa]=1,78; intervalo de confianza del 95% [IC95%]: 1,043,06). No obstante, la asociación fue dependiente del sexo (p de interacción=0,041) y en los análisis estratificados la asociación solo se halló en las mujeres (ORa=3,21; IC95%: 1,447,17).Conclusiones: La limitación auditiva se asoció con fragilidad social en las mujeres, pero no en los hombres. Se precisan estudios longitudinales que confirmen esta asociación y ayuden a entender el efecto diferencial del sexo. (AU)

Objective: To explore the association between hearing loss and social frailty in a sample of Spanish older adults recruited from primary health care network.Method: Crosssectional study on a sample of 445 noninstitutionalized adults aged 65 or more years (190 men and 255 women), recruited from primary care centers in Spain. Three selfreported hearing impairment questions were used to assess hearing loss. Social frailty was deemed to exist when the person presented two or more of the following conditions: living alone, absence of a person to provide help, infrequent contact with family, infrequent contact with friends, lack of confident and lack of help for daily activities in the last 3 months. To study the association between hearing loss and social frailty we used logistic regression models adjusted for potential confounders, including physical frailty. Results: The mean age of participants was 76.2 years (77.5 years for women). More than half of the participants (54.4%) reported hearing loss and the frequency of social frailty was 23.2%. Hearing loss was associated with social frailty (adjusted odds ratio [aOR]=1.78; 95% confidence interval [95%CI]: 1.043.06). However, the association was sexdependent (p for interaction=0.041). In stratified analysis, the association was only found in women (aOR=3.21; 95%CI: 1.447.17). Conclusions: Hearing loss was associated with social frailty in women, but not in men. Longitudinal studies are needed to confirm this association and to understand the differential effect of gender. (AU)

Interaction Mode of the Novel Monobactam AIC499 Targeting Penicillin Binding Protein 3 of Gram-Negative Bacteria.

Novel antimicrobial strategies are urgently required because of the rising threat of multi drug resistant bacterial strains and the infections caused by them. Among the available target structures, the so-called penicillin binding proteins are of particular interest, owing to their good accessibility in the periplasmic space, and the lack of homologous proteins in humans, reducing the risk of side effects of potential drugs. In this report, we focus on the interaction of the innovative ß-lactam antibiotic AIC499 with penicillin binding protein 3 (PBP3) from Escherichia coli and Pseudomonas aeruginosa. This recently developed monobactam displays broad antimicrobial activity, against Gram-negative strains, and improved resistance to most classes of ß-lactamases. By analyzing crystal structures of the respective complexes, we were able to explore the binding mode of AIC499 to its target proteins. In addition, the apo structures determined for PBP3, from P. aeruginosa and the catalytic transpeptidase domain of the E. coli orthologue, provide new insights into the dynamics of these proteins and the impact of drug binding.

Discovery of Pyrrolidine-2,3-diones as Novel Inhibitors of P. aeruginosa PBP3.

The alarming threat of the spread of multidrug resistant bacteria currently leaves clinicians with very limited options to combat infections, especially those from Gram-negative bacteria. Hence, innovative strategies to deliver the next generation of antibacterials are urgently needed. Penicillin binding proteins (PBPs) are proven targets inhibited by ß-lactam antibiotics. To discover novel, non-ß-lactam inhibitors against PBP3 of Pseudomonas aeruginosa, we optimised a fluorescence assay based on a well-known thioester artificial substrate and performed a target screening using a focused protease-targeted library of 2455 compounds, which led to the identification of pyrrolidine-2,3-dione as a potential scaffold to inhibit the PBP3 target. Further chemical optimisation using a one-pot three-component reaction protocol delivered compounds with excellent target inhibition, initial antibacterial activities against P. aeruginosa and no apparent cytotoxicity. Our investigation revealed the key structural features; for instance, 3-hydroxyl group (R2) and a heteroaryl group (R1) appended to the N-pyrroldine-2,3-dione via methylene linker required for target inhibition. Overall, the discovery of the pyrrolidine-2,3-dione class of inhibitors of PBP3 brings opportunities to target multidrug-resistant bacterial strains and calls for further optimisation to improve antibacterial activity against P. aeruginosa.

Correction: Freischem et al. Interaction Mode of the Novel Monobactam AIC499 Targeting Penicillin Binding Protein 3 of Gram-Negative Bacteria. Biomolecules 2021, 11, 1057.

In the original article [...].

[Hearing loss and social frailty in older men and women]. / Limitación auditiva y fragilidad social en hombres y mujeres mayores.

OBJECTIVE: To explore the association between hearing loss and social frailty in a sample of Spanish older adults recruited from primary health care network. METHOD: Cross-sectional study on a sample of 445 non-institutionalized adults aged 65 or more years (190 men and 255 women), recruited from primary care centers in Spain. Three self-reported hearing impairment questions were used to assess hearing loss. Social frailty was deemed to exist when the person presented two or more of the following conditions: living alone, absence of a person to provide help, infrequent contact with family, infrequent contact with friends, lack of confident and lack of help for daily activities in the last 3 months. To study the association between hearing loss and social frailty we used logistic regression models adjusted for potential confounders, including physical frailty. RESULTS: The mean age of participants was 76.2 years (77.5 years for women). More than half of the participants (54.4%) reported hearing loss and the frequency of social frailty was 23.2%. Hearing loss was associated with social frailty (adjusted odds ratio [aOR]=1.78; 95% confidence interval [95%CI]: 1.04-3.06). However, the association was sex-dependent (p for interaction=0.041). In stratified analysis, the association was only found in women (aOR=3.21; 95%CI: 1.44-7.17). CONCLUSIONS: Hearing loss was associated with social frailty in women, but not in men. Longitudinal studies are needed to confirm this association and to understand the differential effect of gender.

Reversible regulation of conjugation of Bacillus subtilis plasmid pLS20 by the quorum sensing peptide responsive anti-repressor RappLS20.

Quorum sensing plays crucial roles in bacterial communication including in the process of conjugation, which has large economical and health-related impacts by spreading antibiotic resistance. The conjugative Bacillus subtilis plasmid pLS20 uses quorum sensing to determine when to activate the conjugation genes. The main conjugation promoter, Pc, is by default repressed by a regulator RcopLS20 involving DNA looping. A plasmid-encoded signalling peptide, Phr*pLS20, inactivates the anti-repressor of RcopLS20, named RappLS20, which belongs to the large group of RRNPP family of regulatory proteins. Here we show that DNA looping occurs through interactions between two RcopLS20 tetramers, each bound to an operator site. We determined the relative promoter strengths for all the promoters involved in synthesizing the regulatory proteins of the conjugation genes, and constructed an in vivo system uncoupling these regulatory genes to show that RappLS20 is sufficient for activating conjugation in vivo. We also show that RappLS20 actively detaches RcopLS20 from DNA by preferentially acting on the RcopLS20 molecules involved in DNA looping, resulting in sequestration but not inactivation of RcopLS20. Finally, results presented here in combination with our previous results show that activation of conjugation inhibits competence and competence development inhibits conjugation, indicating that both processes are mutually exclusive.

Exploring the SAR of the ß-Ketoacyl-ACP Synthase Inhibitor GSK3011724A and Optimization around a Genotoxic Metabolite.

In the course of optimizing a novel indazole sulfonamide series that inhibits ß-ketoacyl-ACP synthase (KasA) of Mycobacterium tuberculosis, a mutagenic aniline metabolite was identified. Further lead optimization efforts were therefore dedicated to eliminating this critical liability by removing the embedded aniline moiety or modifying its steric or electronic environment. While the narrow SAR space against the target ultimately rendered this goal unsuccessful, key structural knowledge around the binding site of this underexplored target for TB was generated to inform future discovery efforts.

Draft Genome Sequences of Sporulation-Impaired Bacillus pumilus Strain NRS576 and Its Native Plasmid p576.

Bacillus pumilus spores can cause foodborne poisonings. B. pumilus strain NRS576 forms spores with a very reduced efficiency due to the presence of a plasmid, named p576. Here, we report the genome sequence of strain B. pumilus NRS576 and its plasmid p576.

Easy-To-Synthesize Spirocyclic Compounds Possess Remarkable in Vivo Activity against Mycobacterium tuberculosis.

Society urgently needs new, effective medicines for the treatment of tuberculosis. To kick-start the required hit-to-lead campaigns, the libraries of pharmaceutical companies have recently been evaluated for starting points. The GlaxoSmithKline (GSK) library yielded many high-quality hits, and the associated data were placed in the public domain to stimulate engagement by the wider community. One such series, the spiro compounds, are described here. The compounds were explored by a combination of traditional in-house research and open source methods. The series benefits from a particularly simple structure and a short associated synthetic chemistry route. Many members of the series displayed striking potency and low toxicity, and highly promising in vivo activity in a mouse model was confirmed with one of the analogues. Ultimately the series was discontinued due to concerns over safety, but the associated data remain public domain, empowering others to resume the series if the perceived deficiencies can be overcome.

Novel inhibitors of Mycobacterium tuberculosis GuaB2 identified by a target based high-throughput phenotypic screen.

High-throughput phenotypic screens have re-emerged as screening tools in antibiotic discovery. The advent of such technologies has rapidly accelerated the identification of 'hit' compounds. A pre-requisite to medicinal chemistry optimisation programmes required to improve the drug-like properties of a 'hit' molecule is identification of its mode of action. Herein, we have combined phenotypic screening with a biased target-specific screen. The inosine monophosphate dehydrogenase (IMPDH) protein GuaB2 has been identified as a drugable target in Mycobacterium tuberculosis, however previously identified compounds lack the desired characteristics necessary for further development into lead-like molecules. This study has identified 7 new chemical series from a high-throughput resistance-based phenotypic screen using Mycobacterium bovis BCG over-expressing GuaB2. Hit compounds were identified in a single shot high-throughput screen, validated by dose response and subjected to further biochemical analysis. The compounds were also assessed using molecular docking experiments, providing a platform for their further optimisation using medicinal chemistry. This work demonstrates the versatility and potential of GuaB2 as an anti-tubercular drug target.