Structural basis of Cfr-mediated antimicrobial resistance and mechanisms to evade it.

The bacterial ribosome is an essential drug target as many clinically important antibiotics bind and inhibit its functional centers. The catalytic peptidyl transferase center (PTC) is targeted by the broadest array of inhibitors belonging to several chemical classes. One of the most abundant and clinically prevalent resistance mechanisms to PTC-acting drugs in Gram-positive bacteria is C8-methylation of the universally conserved A2503 nucleobase by Cfr methylase in 23S ribosomal RNA. Despite its clinical importance, a sufficient understanding of the molecular mechanisms underlying Cfr-mediated resistance is currently lacking. Here, we report a set of high-resolution structures of the Cfr-modified 70S ribosome containing aminoacyl- and peptidyl-transfer RNAs. These structures reveal an allosteric rearrangement of nucleotide A2062 upon Cfr-mediated methylation of A2503 that likely contributes to the reduced potency of some PTC inhibitors. Additionally, we provide the structural bases behind two distinct mechanisms of engaging the Cfr-methylated ribosome by the antibiotics iboxamycin and tylosin.

Ten-Year Outcome After Supracricoid Partial Laryngectomy in cT3M0 Laryngeal Squamous Cell Carcinoma-A STROBE Analysis.

OBJECTIVES: The aim of this study was to document 10-year outcomes after supracricoid partial laryngectomy (SCPL) in selected cT3M0 laryngeal squamous cell carcinoma (SCC) patients. METHODS: This real-life retrospective observational study analyzed an inception cohort of 168 patients with isolated, untreated, selected cT3M0 laryngeal SCC, that were consecutively managed by SCPL during the period 1973-2013, and followed up until death or for a minimum of 10 years in 92% of cases at a single French academic and tertiary referral care center. Prior induction chemotherapy, arytenoid cartilage removal, level II-IV neck dissection, and postoperative radiation therapy were performed on 148, 77, 136, and 27 patients, respectively. The main objective was to determine 10-year actuarial local control and laryngeal preservation estimates. Secondary objectives included 10-year actuarial survival and cause-of-death analysis, and assessment of correlations between endpoints and clinical variables. The significance threshold was set at p < 0.005. RESULTS: Ten-year actuarial local control, laryngeal preservation, and survival estimates were 90%, 85%, and 52%, respectively. Salvage treatment resulted in an overall 99% local control rate. Metachronous second primary cancer, intercurrent disease without evidence of SCC, SCPL-related death, and uncontrolled local recurrence accounted for 31%, 26%, 7%, and 2% of causes of death. On univariate analysis, overall local recurrence and laryngeal preservation rates varied significantly, from 5% to 54% and 90% to 46% when resection margins were R0 and R1, respectively. CONCLUSION: The present study highlighted successful 10-year outcomes after SCPL, providing further evidence in favor of its integration into the conservative armamentarium for endolaryngeal cT3 SCC. LEVEL OF EVIDENCE: 4 Laryngoscope, 2024.

Coding definitions of participant religious, non-religious and spiritual beliefs in the Avon Longitudinal Study of Parents & Children (ALSPAC).

Mainstream religious beliefs and behaviours have been shown to have positive effects on health and well-being, but there has been increasing secularisation in the West over time. With concurrent increases in those stating they have no religion (the 'nones') there are increasing numbers now describing themselves as humanist, 'spiritual but not religious' or who have sought alternative forms of belief. Others have formed their own beliefs using elements of different belief systems. This trend is reflected in ALSPAC data with larger proportions considering themselves as 'nones', agnostic or atheist, and about 3% of parent participants consistently stating they had 'other' beliefs. The main aim of this paper is to describe the coding of the Christian denominations, world religions, non-mainstream beliefs (NMB) and non-religious groups derived from the text-based data collected from the original mother and partner cohorts (G0). This spans a period of ~28 years from pregnancy onwards. We also describe the coding of text-based responses from their offspring (G1) collected at ages 27+ and 29+. The creation of this coded data will enable researchers to compare between the Christian denominations and/or other belief groups taken from two generations alongside the rich resource of physical and mental health, behavioural and social data that exists within ALSPAC.

Maternal prenatal paracetamol ingestion and scholastic attainments of the offspring.

Background: Fetal exposure to paracetamol (acetaminophen) has been shown to be associated with asthma and other atopic disorders, as well as behavioural problems including hyperactivity, in childhood. However, there is little information on scholastic abilities among children exposed to paracetamol in pregnancy. Objectives: To determine whether there are any differences in scholastic abilities among the offspring of women who ingested paracetamol during pregnancy compared with non-exposed children. Methods: Mothers enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) had recorded the frequency with which they had taken the medication over two time periods during pregnancy: i) the first 18 weeks and ii) 18-32 weeks. The offspring have been followed up ever since. For this study we use as outcomes: a) 14 tests of ability at reading and 2 of spelling using the study's tests and the national education system test results; b) 6 of mathematical abilities including tests of arithmetic and mathematical reasoning, and c) 1 of scientific understanding. Multiple regression was used, adjusting for 15 different exposures including reasons for taking the medication as well as demographic features. Results: Almost all unadjusted and adjusted mean differences were negative (i.e., those exposed to maternal intake of paracetamol did less well), but negative associations for exposures between 18 and 32 weeks of gestation were much more evident than for exposures earlier in pregnancy. Of the later exposures, after adjustment, 12 of the 23 scholastic tests were associated with prenatal exposure to paracetamol at p < 0.05. These negative effects were found in the girls (12 tests at p < 0.05) but not boys (0 tests at p < 0.05). Conclusion: Evidence from this longitudinal study suggests that maternal exposure to paracetamol is associated with disadvantages to the offspring in scholastic abilities such as mathematics and reading at secondary school ages. This raises the question as to whether there are longer-lasting effects on educational attainment from age 15 years onwards, including at university level. Clearly these results should be tested in other settings, but meanwhile they add to a growing accumulation of known adverse effects of exposure to paracetamol in pregnancy.

The mother during pregnancy and the puerperium: Detailed data abstracted from the clinical obstetric records of ALSPAC pregnancies.

Background: When the Avon Longitudinal Study of Parents and Children (ALSPAC) was planned, it was assumed that the clinical obstetric data would be easily accessible from the newly developed National Health Service computerised 'STORK' system. Pilot studies, however, showed that, although fairly accurate in regard to aspects of labour and delivery, it was, at the time (1990-2), inadequate for identifying the full antenatal and postnatal details of clinical complications and treatments of the women in the Study. Methods: A scheme was therefore developed to train research staff to find and abstract relevant details from clinical records onto proformas designed for the purpose. Extracting such data proved very time consuming (up to six hours for complicated pregnancies) and consequently expensive. Funding for the enterprise was obtained piecemeal using specific focussed grants to extract data for subsamples of the Study, including a random sample to serve as controls. Results: To date, detailed records have been completed for 8369 pregnancies, and a further 5336 (13,705 in total) have complete details on specific prenatal areas, including serial measures of maternal blood pressure, proteinuria and weight. In this Data Note we describe the information abstracted from the obstetric medical records concerning the mother during pregnancy, labour, delivery and the first two weeks of the puerperium. Information abstracted relating to the fetus (including fetal monitoring, presentation, method of delivery) and neonate (signs of asphyxia, resuscitation, treatment and well-being) have been described in a further Data Note. Conclusions: These data add depth to ALSPAC concerning ways in which the signs and symptoms, procedures and treatments of the mother prenatally, intrapartum and postnatally, may impact on the long-term health and development of both mother and child. They augment the data collected from the mothers' questionnaires (described elsewhere) and the 'STORK' digital hospital data.