In silico gepotidacin target mining among 33 213 global Neisseria gonorrhoeae genomes from 1928 to 2023 combined with gepotidacin MIC testing of 22 gonococcal isolates with different GyrA and ParC substitutions.

OBJECTIVES: The novel dual-target triazaacenaphthylene, gepotidacin, recently showed promising results in its Phase III randomized controlled trial for the treatment of gonorrhoea. We investigated alterations in the gepotidacin GyrA and ParC targets in gonococci by in silico mining of publicly available global genomes (n = 33 213) and determined gepotidacin MICs in isolates with GyrA A92 alterations combined with other GyrA and/or ParC alterations. METHODS: We examined gonococcal gyrA and parC alleles available at the European Nucleotide Archive. MICs were determined using the agar dilution method (gepotidacin) or Etest (four antimicrobials). Models of DNA gyrase and topoisomerase IV were obtained from AlphaFold and used to model gepotidacin in the binding site. RESULTS: GyrA A92 alterations were identified in 0.24% of genomes: GyrA A92P/S/V + S91F + D95Y/A/N (0.208%), A92P + S91F (0.024%) and A92P (0.003%), but no A92T (previously associated with gepotidacin resistance) was found. ParC D86 alterations were found in 10.6% of genomes: ParC D86N/G (10.5%), D86N + S87I (0.051%), D86N + S88P (0.012%) and D86G + E91G (0.003%). One isolate had GyrA A92P + ParC D86N alterations, but remained susceptible to gepotidacin (MIC = 0.125 mg/L). No GyrA plus ParC alterations resulted in a gepotidacin MIC > 4 mg/L. Modelling of gepotidacin binding to GyrA A92/A92T/A92P suggested that gepotidacin resistance due to GyrA A92T might be linked to the formation of a new polar contact with DNA. CONCLUSIONS: In silico mining of 33 213 global gonococcal genomes (isolates from 1928 to 2023) showed that A92 is highly conserved in GyrA, while alterations in D86 of ParC are common. No GyrA plus ParC alterations caused gepotidacin resistance. MIC determination and genomic surveillance of potential antimicrobial resistance determinants are imperative.

Needs for re-intervention on restored teeth in adults: a practice-based study.

OBJECTIVES: Evaluate the need for re-intervention on dental coronal restorations in adults seen in a network of general dental practitioners (ReCOL).  MATERIALS AND METHODS: This observational, cross-sectional, multicenter study involved 40 practitioners and 400 patients. Coronal restoration failures (needing re-intervention for unsatisfactory outcomes) were assessed with a simplified rating scale of seven criteria from the FDI World Dental Federation. The oral health status, the risk factors, and Oral Health Impact Profile-14 were also examined. Previous restoration characteristics (extent, technique, material) were analyzed according to the need for re-intervention (yes/no), the age group, and the risk profile. Qualitative variables were compared between "re-intervention" and "no re-intervention" group using Fisher exact test. RESULTS: The need for re-intervention was estimated at 74% (95% CI: 70; 79); it increased with age (49 to 90%), unfavorable risk profile (82 vs. 62%), and extent of the filling (32, 39, 44, and 44% on 1, 2, 3 surfaces, and crowns, respectively). More posterior than anterior teeth were restored (median per patient: 6 vs. 1) or needed re-intervention (median per patient: 1 vs. 0). CONCLUSIONS: The needs for re-intervention in adults are still high within a context of ever-changing materials and techniques, simplified and rationalized decision-makings, and demands for patient involvement. CLINICAL RELEVANCE: Meeting these needs requires the following: (i) consensus definitions and assessment methods for "failure" and (ii) reliable feedbacks on materials, procedures, and satisfaction. Building large and detailed databases fed by networks of motivated practitioners will help analyzing complex success/failure data by artificial intelligence and guiding treatment and research.

Understanding the potential role of whole genome sequencing (WGS) in managing patients with gonorrhoea: A systematic review of WGS use on human pathogens in individual patient care.

OBJECTIVES: The utility of whole genome sequencing (WGS) to inform sexually transmitted infection (STI) patient management is unclear. Timely WGS data might support clinical management of STIs by characterising epidemiological links and antimicrobial resistance profiles. We conducted a systematic review of clinical application of WGS to any human pathogen that may be transposable to gonorrhoea. METHODS: We searched six databases for articles published between 01/01/2010-06/02/2023 that reported on real/near real-time human pathogen WGS to inform clinical intervention. All article types from all settings were included. Findings were analysed using narrative synthesis. RESULTS: We identified 12,179 articles, of which eight reported applications to inform tuberculosis (n = 7) and gonorrhoea (n = 1) clinical patient management. WGS data were successfully used as an adjunct to clinical and epidemiological data to enhance contact-tracing (n = 2), inform antimicrobial therapy (n = 5) and identify cross-contamination (n = 1). WGS identified gonorrhoea transmission chains that were not established via partner notification. Future applications could include insights into pathogen exposure detected within sexual networks for targeted patient management. CONCLUSIONS: While there was some evidence of WGS use to provide individualised tuberculosis and gonorrhoea treatment, the eight identified studies contained few participants. Future research should focus on testing WGS intervention effectiveness and examining ethical considerations of STI WGS use.

A French study of cocaine intoxication/exposure in children (2010-2020).

BACKGROUND AND OBJECTIVE: In the European Union, the record of cocaine-related seizures indicates an expanding supply. The purity has also been increasing. The health impact of these trends remains poorly documented, in particular, the changes and clinical manifestations of intoxication in young children. We attempted to evaluate the trend in French pediatric admissions for cocaine intoxication/exposure over an 11-year period (2010-2020). METHODS: A retrospective, national, multicenter, study of a pediatric cohort. All children less than 15 years of age admitted to a tertiary-level pediatric emergency unit for proven cocaine intoxication (compatible symptoms and positive toxicological screening) during the reference period were included. RESULTS: Seventy-four children were included. Forty-six percent were less than 6 years old. Annual admissions increased by a factor of 8 over 11 years (+700%) and 57% of all cases were admitted in the last two years. The main clinical signs were neurologic (59%) followed by cardiovascular symptoms (34%). Twelve patients were transferred to the pediatric intensive care unit. Factors significantly associated with the risk of being transferred to the pediatric intensive care unit were initial admission to the pediatric resuscitation area (P < 0.001), respiratory impairment (P < 0.01), mydriasis (P < 0.01), cardiovascular symptoms (P = 0.014), age of less than 2 years (P = 0.014). Blood and/or urine toxicological screening isolated eighteen other substances besides cocaine in 46 children (66%). CONCLUSION: Children are collateral victims of the changing trends in cocaine availability, use and purity. Admissions of intoxicated children to pediatric emergency departments are more frequent and there is an increase in severe presentations. Therefore, this is a growing public health concern.

The PAICE suite reveals circadian posttranscriptional timing of noncoding RNAs and spliceosome components in Mus musculus macrophages.

Circadian rhythms broadly regulate physiological functions by tuning oscillations in the levels of mRNAs and proteins to the 24-h day/night cycle. Globally assessing which mRNAs and proteins are timed by the clock necessitates accurate recognition of oscillations in RNA and protein data, particularly in large omics data sets. Tools that employ fixed-amplitude models have previously been used to positive effect. However, the recognition of amplitude change in circadian oscillations required a new generation of analytical software to enhance the identification of these oscillations. To address this gap, we created the Pipeline for Amplitude Integration of Circadian Exploration suite. Here, we demonstrate the Pipeline for Amplitude Integration of Circadian Exploration suite's increased utility to detect circadian trends through the joint modeling of the Mus musculus macrophage transcriptome and proteome. Our enhanced detection confirmed extensive circadian posttranscriptional regulation in macrophages but highlighted that some of the reported discrepancy between mRNA and protein oscillations was due to noise in data. We further applied the Pipeline for Amplitude Integration of Circadian Exploration suite to investigate the circadian timing of noncoding RNAs, documenting extensive circadian timing of long noncoding RNAs and small nuclear RNAs, which control the recognition of mRNA in the spliceosome complex. By tracking oscillating spliceosome complex proteins using the PAICE suite, we noted that the clock broadly regulates the spliceosome, particularly the major spliceosome complex. As most of the above-noted rhythms had damped amplitude changes in their oscillations, this work highlights the importance of the PAICE suite in the thorough enumeration of oscillations in omics-scale datasets.

Quantification of carious pathogens in the interdental microbiota of young caries-free adults.

BACKGROUND: The majority of caries lesions in adults occur on the proximal tooth surfaces of the posterior teeth. A comprehensive study of the composition of the oral microbiota is fundamental for a better understanding of the etiology of interdental caries. METHODS: Twenty-five caries-free subjects (20-35 years old) were enrolled in the study. The interdental biofilm of four interdental sites were collected. The real-time polymerase chain reaction (PCR) methodology were used to quantify (i) the following bacteria: Streptococcus spp., Streptococcus mutans, Lactobacillus spp., Enterococcus spp., and Enterococcus faecalis; (ii) the fungus Candida albicans; and (iii) total bacteria. RESULTS: Streptococcus spp. was the most abundant species, followed by Lactobacillus spp. and Enterococcus spp. Streptococcus spp. and Lactobacillus spp. were detected at all tested sites and Enterococcus spp. at 99% of sites. S. mutans was detected at only 28% of the tested sites and C. albicans was detected at 11% of sites. E. faecalis was never detected. In 54.5% of the biofilm inhabited by C. albicans, S. mutans was present. Moreover, 28% of the ID sites co-expressed S. mutans and Lactobacillus spp. The studied pathogens were organized into two correlated groups of species. Strikingly, the fungus C. albicans and the bacteria Enterococcus spp. cluster together, whereas Streptococcus spp., S. mutans and Lactobacillus spp. form one distinct cluster. CONCLUSION: The interdental biofilm of young caries-free adults is comprised of pathogens that are able to induce interproximal caries. That several of these pathogens are implicated in heart disease or other systemic diseases is an argument for the disruption of interdental biofilms using daily oral hygiene.

Control of chaos in nonlinear systems with time-periodic coefficients.

In this study, some techniques for the control of chaotic nonlinear systems with periodic coefficients are presented. First, chaos is eliminated from a given range of the system parameters by driving the system to a desired periodic orbit or to a fixed point using a full-state feedback. One has to deal with the same mathematical problem in the event when an autonomous system exhibiting chaos is desired to be driven to a periodic orbit. This is achieved by employing either a linear or a nonlinear control technique. In the linear method, a linear full-state feedback controller is designed by symbolic computation. The nonlinear technique is based on the idea of feedback linearization. A set of coordinate transformation is introduced, which leads to an equivalent linear system that can be controlled by known methods. Our second idea is to delay the onset of chaos beyond a given parameter range by a purely nonlinear control strategy that employs local bifurcation analysis of time-periodic systems. In this method, nonlinear properties of post-bifurcation dynamics, such as stability or rate of growth of a limit set, are modified by a nonlinear state feedback control. The control strategies are illustrated through examples. All methods are general in the sense that they can be applied to systems with no restrictions on the size of the periodic terms.

Incidência da sindrome pré-menstrual na prática de esportes / Incidence of pre-menstrual syndrome in sports practice

Apesar do grande aumento do número de mulheres no esporte, é escassa a literatura sobre aspectos anatômicos, psicológicos e principalmente hormonais que afetam o desempenho das mulheres praticantes de exercício físico. Embora existam muitas pesquisas relatando como o exercício afeta a menstruação, são poucos os estudos de como o ciclo menstrual interfere no desempenho feminino. A maioria dos estudos cita a relação do desempenho e o ciclo menstrual, mas não leva em consideração as alterações do ciclo, as moléstias perimenstruais (MPM)(1). OBJETIVO: Observar a incidência e a frequência dos sintomas da síndrome pré-menstrual em atletas. CASUÍSTICA E MÉTODOS: Em 31 atletas de handebol em idade fértil foi aplicado um diário de sintomas pré-menstruais(2) por um período de três meses consecutivos. RESULTADOS: A prevalência de SPM em atletas foi de 71 por cento, sendo o sintoma mais relatado o de irritabilidade, em 86,4 por cento das atletas, seguidos de mudanças de humor (77,3 por cento) e cólicas (72,7 por cento); 59 por cento das atletas indicaram algum outro sintoma no período pré-menstrual. CONCLUSÕES: Observou-se alta prevalência de SPM em atletas.

Despite the increasing number of women who practice physical exercise, there are still few reports concerned with anatomy, psychology and mainly hormones that could affect their performance. Although there is a multitude of articles about the effects of physical exercise in menstruation, only a few of them report how this function interferes in women's performance. The association physical exercise - menstruation has been studied but without considering the changes during the cycle, the perimenstrual symptoms. Therefore, the aim of this article was to investigate the incidence and periodicity of pre-menstrual symptoms in athletes. A daily questionnaire was applied with the aim to follow the pre-menstrual symptoms during a period of 3 consecutive months. The population of the study was composed by 31 female athletes in fertile age. RESULTS: The prevalence of PMS in athletes was of 71 percent and the mainly reported symptoms were irritability (86.5 percent), mood swings (77.3 percent) and cramps (72.7 percent). Other symptoms were reported by 59 percent of the athletes during the pre-menstrual period. CONCLUSION: Our data show a high prevalence of PMS among athletes.