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Abstract Objective The aim of this study was to identify and analyze the gender breakdown of first authorship contributing to the most‐cited papers in the field of otolaryngology, with a goal of identifying trends in gender representation in publishing. Methods The top 150 most‐cited papers were identified using the Science Citation Index of the Institute for Scientific Information. Among the first authors, gender, h‐index, percentage of first, last, and corresponding authorship positions, total publications, and citations were analyzed. Results The majority of papers were in the English language, from the United States, of clinical nature, and on otologic topics. Eighty‐one percent of papers (n = 122) had men who were first authors, although there was no difference in h‐index score, authorship position, number of publications, citations, and average citations/year between men and women first authors. Upon subgroup analysis by decade (1950s–2010s), there was no difference in the number of articles by women first authors (P = 0.11); however, there was a statistically significant increase in the percentage of women authors (P = 0.001) in papers published later compared to those published earlier. Conclusions While a promising number of women otolaryngologists are publishing high‐powered articles, future initiatives to promote academic inclusivity of women should be considered.

Objective: Several clinical practice guidelines have been produced and disseminated for the evaluation of a neck mass. However, to date, the quality and methodologic rigor of these clinical practice guidelines have not been appraised. Therefore, this study set out to identify and assess the methodologic quality of national and international guidelines for the evaluation and management of neck masses in adults. Methods: We conducted a comprehensive search of EMBASE, MEDLINE/PubMed, SCOPUS and grey literature sources until September 2020. The quality of these guidelines was assessed by four reviewers using the Appraisal of Guidelines for Research and Evaluation, 2nd edition (AGREE II). Domain scores were considered acceptable quality if they scored >60%, and Intraclass Correlation Coefficients (ICC) were calculated to assess agreement among the appraisers. Results: Seven guidelines were assessed for evaluation. Among these, only the American Academy of Otolaryngology (AAO), Cancer Care Manitoba (CCMB), and the American Society of Clinical Oncology (ASCO) achieved an overall rating of “high”. The remaining four guidelines achieved ratings of either “average” or “low”. The “Scope and Purpose” domain achieved the highest mean score (94.4% ± 5.0%), and lowest was “Applicability” (51.5% ± 29.2%). ICC analysis showed substantial to very good agreement across all domains (0.75–0.98). Conclusion: These findings highlight the variability in methodologic quality of guidelines for the evaluation and management of adult neck mass. The results from this analysis highlight the need to improve guidelines development process for this topic and may guide the selection and use of these guidelines in clinical practice.

Abstract Objective Enhanced recovery after surgery (ERAS) protocols are patient‐centered, evidence‐based pathways designed to reduce complications, promote recovery, and improve outcomes following surgery. These protocols have been successfully applied for the management of head and neck cancer, but relatively few studies have investigated the applicability of these pathways for other outpatient procedures in otolaryngology. Our goal was to perform a systematic review of available evidence reporting the utility of ERAS protocols for the management of patients undergoing outpatient otolaryngology operations. Methods A systematic literature review was conducted using MEDLINE, EMBASE, SCOPUS, and gray literature. We identified studies that evaluated ERAS protocols among patients undergoing otologic, laryngeal, nasal/sinus, pediatric, and general otolaryngology operations. We assessed the outcomes and ERAS components across protocols as well as the study design and limitations. Results A total of eight studies fulfilled the inclusion criteria and were included in the analysis. Types of procedures evaluated with ERAS protocols included tonsillectomy and adenoidectomy, functional endoscopic sinus surgery, tympanoplasty and mastoidectomy, and septoplasty. A reduction in postoperative length of stay and hospital costs was reported in two and three studies, respectively. Comparative studies between ERAS and control groups showed persistent improvement in pre‐ and postoperative anxiety and pain levels, without an increase in postoperative complications and readmission rates. Conclusions A limited number of studies discuss implementation of ERAS protocols for outpatient operations in otolaryngology. These clinical pathways appear promising for these procedures as they may reduce length of stay, decrease costs, and improve pain and anxiety postoperatively.

Abstract Enhanced recovery after surgery (ERAS) protocols have been developed in numerous surgical specialties as a means of systematically improving patient recovery, functional outcomes, cost savings, and resource utilization. Such multidisciplinary initiatives seek to minimize variability in several aspects of perioperative patient care, helping to reduce inpatient length of hospital stay, complications, and the overall resource and financial burden of surgical care. Head and neck oncology patients stand to benefit from the implementation of comprehensive ERAS protocols, as these patients have complex medical needs that may dramatically impact multiple aspects of their recovery, including breathing, eating, nutrition, pain, speech, swallowing, and communication. Implementing ERAS protocols for head and neck cancer patients may present unique challenges, and require significant interdisciplinary coordination and collaboration. We therefore sought to provide a comprehensive guide to the planning and institution of such ERAS systems at institutions undertaking care of head and neck cancer patients. Key elements to consider in the implementation of successful ERAS protocols for this population include organizing a team consisting of frontline leaders such as nursing staff, medical specialists, and associated health professionals; designing interventions based on systematically evaluated, high‐quality literature; and instituting a clear methodology for regularly updating protocols and auditing the success or potential limitations of a given intervention. Potential obstacles to the success of ERAS interventions for head and neck cancer patients include challenges in systematically tracking progress of the protocol, as well as resource limitations in a given health system.

Abstract The emergence of SARS-CoV-2/2019 novel coronavirus (COVID-19) has created a global pandemic with no approved treatments or vaccines. Many treatments have already been administered to COVID-19 patients but have not been systematically evaluated. We performed a systematic literature review to identify all treatments reported to be administered to COVID-19 patients and to assess time to clinically meaningful response for treatments with sufficient data. We searched PubMed, BioRxiv, MedRxiv, and ChinaXiv for articles reporting treatments for COVID-19 patients published between 1 December 2019 and 27 March 2020. Data were analyzed descriptively. Of the 2706 articles identified, 155 studies met the inclusion criteria, comprising 9152 patients. The cohort was 45.4% female and 98.3% hospitalized, and mean (SD) age was 44.4 years (SD 21.0). The most frequently administered drug classes were antivirals, antibiotics, and corticosteroids, and of the 115 reported drugs, the most frequently administered was combination lopinavir/ritonavir, which was associated with a time to clinically meaningful response (complete symptom resolution or hospital discharge) of 11.7 (1.09) days. There were insufficient data to compare across treatments. Many treatments have been administered to the first 9152 reported cases of COVID-19. These data serve as the basis for an open-source registry of all reported treatments given to COVID-19 patients at www.CDCN.org/CORONA . Further work is needed to prioritize drugs for investigation in well-controlled clinical trials and treatment protocols.

Preservation of the meniscus has been shown to influence the progression of degenerative changes of the knee. As more meniscus is preserved, the propensity for development of osteoarthritis is lessened. Surgical treatment of a torn discoid meniscus has typically been a subtotal meniscectomy or partial meniscectomy. Similar to tears of a normal meniscus, partial meniscectomy compared with subtotal meniscectomy of the discoid meniscus confers better long-term results. With the abnormal morphology predisposing the discoid meniscus to tearing, several characteristic tear patterns can be observed—the horizontal tear being commonly encountered. We present a technique that not only creates a more normal morphology of a discoid meniscus but also preserves the tissue by using an all-inside, intrameniscal repair technique. This technique restores the central rim of the meniscus in the setting of a horizontal cleavage plane, thus restoring a more normal meniscus morphology.

Given the prevalence of anterior cruciate ligament (ACL) tears in young athletes, it is essential to elucidate and illustrate surgical interventions that return the most favorable outcomes. Although most ACL injuries are full-thickness tears, occasionally either the anteromedial (AM) or posterolateral (PL) bundle is torn in isolation, allowing consideration of an ACL reconstruction or augmentation. Because the ACL-deficient knee has been shown to exhibit less proprioceptive feedback, the preservation of the intact bundle may offer an inherent component of stability. After arthroscopy has confirmed a partial ACL tear, the decision to augment the intact bundle can be made. The technique is adapted from principles of the double-bundle reconstruction such that the graft follows the path of either the native AM bundle or the native PL bundle, depending on the location of the partial tear. We present our surgical technique for ACL AM bundle augmentation with PL bundle reconstruction using a semitendinosus tendon autograft.

Quadriceps tendon rupture is an uncommon injury that usually occurs in middle-aged and elderly men with a history of chronic illnesses. We report the case of a 17-year-old healthy adolescent male baseball player who sustained this injury as a result of sudden deceleration in his left knee. He initially reported to the emergency department and then presented to our practice, where he was diagnosed with a quadriceps tendon tear. Preoperatively, he was unable to perform a single straight-leg raise. During surgical repair, the free edge of the quadriceps tendon was mobilized and anchored into the superior pole of the patella, followed by sutures to ensure reinforcement of the quadriceps footprint. His postoperative course progressed normally, demonstrating full range of motion at 3 months and return to team training at 5 months. Unlike previously reported quadriceps tendon ruptures in adolescents, to our knowledge, this is the first report of a patient who sustained such an injury without previous trauma to his knee or quadriceps mechanism. It is possible that weakened tendon integrity from repeated microtrauma during training combined with the sudden weight change distribution may have resulted in the injury. As urgent surgical intervention is necessary to ensure efficient recovery and return to sport, the sports medicine practitioner must remain educated and vigilant on caring for these patients.

Abstract In recent decades, fishing fleets and effort have grown in aggregate throughout the waters of lower-income coastal countries, much of which is carried out by vessels registered in higher-income countries. Fisheries access arrangements (FAAs) underpin this key trend in ocean fisheries and have their origins in UNCLOS’s promise to establish resource ownership as a mechanism to increase benefits to newly independent coastal and island states. Coastal states use FAAs to permit a foreign state, firm, or industry association to fish within its waters. This paper provides a conceptual approach for understanding FAAs across the global ocean and for exploring their potential to deliver on the promise of UNCLOS. Illustrated with the findings from multiple case studies, we advance understanding of FAAs by developing a geopolitical-economy of access that attends to the combination of contingent and context-specific economic, ecologic, and geopolitical forces that shape the terms, conditions and practices of the FAAs shaping this persistent phenomenon of higher-income industrial fleets fishing throughout lower-income countries’ waters.

Following the release of large language models in the late 2010s, the backers of this new type of artificial intelligence (AI) publicly affirmed that the technology is controversial and harmful to society. This situation sets contemporary AI apart from 20th-century controversies about technnoscience, such as nuclear power and genetically modified (GM) foods, and disrupts established assumptions concerning public controversies as occasions for technological democracy. In particular, it challenges the idea that such controversies enable inclusion and collective processes of problem definition (‘problematisation’) across societal domains. In this paper, we show how social research can contribute to addressing this challenge of AI controversies by adopting a distinctive methodology of controversy analysis: controversy elicitation. This approach actively selects, qualifies and evaluates controversies in terms of their capacity to problematise AI across the science and non-science binary. We describe our implementation of this approach in a participatory study of recent AI controversies, conducted through consultation with UK experts in AI and society. Combining an online questionnaire, social media analysis and a participatory workshop, our study suggests that civil society actors have developed distinctive strategies of problematisation that counter the strategic affirmation of AI’s controversiality by its proponents and which centre on the public mobilisation of AI-related incidents: demonstrations of bias, accidents and walkouts. Crucially, this emphasis on ‘AI frictions’ does not result in the fragmentation of AI controversies, but rather enables the articulation of AI as a ‘super-controversy’: the explication of connections between technical propositions, situated troubles and structural problems in society (discrimination, inequalities and corporate power).

Background: The use of diuretics is extremely common in infants cared for in neonatal wards, despite the lack of proven efficacy for many conditions. The main objective of this study was to assess the rate of diuretics exposure in a multicenter French cohort. The secondary objectives were to describe the evolution of this exposure over time, the indications, the prescription practices, and the exposure rates among centers.Methods: An observational study was conducted in 40 Level 3 French neonatal intensive care units using the same computerized order-entry system. Neonates hospitalized between January 2017 to December 2021 with a corrected age between 24 and 44 weeks of gestation at admission were eligible.Results: A total of 86,032 patients were included. The exposure rate was 8.5%, more specifically 29.4% for children born at < 32 weeks of gestation and 3.7% for neonates born at term. There was no significant variation over the study period, but the exposure ranged from 2.4% to 26.5% depending on the center. The main drugs prescribed were furosemide, spironolactone and dopamine with a diuretic purpose. The main indications were “fluid retention,” and to a lesser extent “bronchopulmonary dysplasia” and “post-transfusion.” For furosemide, the first exposure occurred in mean at 16.5 (±17.8) days of life, mean duration of exposure was 6.2 (±9.5) days, and the cumulative dose was in mean 10.7 (23.9) mg/kg.Conclusion: Diuretic prescription practices vary between centers. The administration of these drugs is often non-evidence based, doses and duration of treatment easily exceed toxic thresholds.

Abstract To curb HIV infection rate in Tanzania, antiretroviral therapy (ART) has been scaled up since 2006, and in 2019, the country shifted to regimen including dolutegravir as a default first line. We assessed the success of ART and the contribution of HIV drug resistance (HIVDR) to unsuppressed viral loads. Between February and May 2023 a cross-sectional survey with random sampling was conducted in the six clinics in an urban cohort in Dar es Salaam. Patients with unsuppresed viral loads (local criteria viral load (VL) ≥ 1000 copies/mL) were tested for HIVDR mutations using the WHO adapted protocol for plasma samples. Mutations were interpreted using the Stanford HIVDR database. In total 600 individuals participated in this survey, the majority were female (76.83%), mean age ( $$\pm$$ ± standard deviation) was 44.0 ( $$\pm$$ ± 11.6) years. The median duration on ART (interquartile range) was 6.5 (3.9–10.2) years. Approximately 99% were receiving tenofovir + lamivudine + dolutegravir as a fixed dose combination. VL testing was successful in 99.67% (598/600) of survey patients and only 33 had VL ≥ 1000 copies/mL, resulting in a viral suppression level of 94.48% (565/598, 95% CI 92.34–96.17%). For 23 samples, protease and reverse transcriptase (RT) genotyping were successful, with 13 sequences containing RT inhibitor surveillance drug resistance mutations (SDRMs) (56.5%). No SDRM against protease inhibitors were detected. Thirty samples were successfully genotyped for integrase with 3 sequences (10.08%) containing integrase strand transfer inhibitor (INSTI) SDRMs. In samples successfully genotyped in the three genetic regions, 68.18% (16/22) had a genotypic susceptibility score (GSS) ≥ 2.5 for the concurrent regimen, implying factors beyond drug resistance caused the unsuppressed viral load. For five patients, GSS indicated that HIVDR may have caused the unsuppressed viral load. All three patients with INSTI resistance mutations were highly resistant to dolutegravir and accumulated nucleoside and non-nucleoside RT inhibitor HIVDR mutations. Although in this cohort the last 95 UNAIDS target was almost achieved, HIVDR mutations, including INSTIs resistance mutations were detected in HIV-positive individuals taking ART for at least one year. We recommend the design and implementation of high-impact interventions to prevent the increase of HIVDR, failure of dolutegravir and address the non-resistance factors in the study area.

Abstract In all domains of life, transfer RNAs (tRNAs) contain post-transcriptionally sulfur-modified nucleosides such as 2- and 4-thiouridine. We have previously reported that a recombinant [4Fe-4S] cluster-containing bacterial desulfidase (TudS) from an uncultured bacterium catalyzes the desulfuration of 2- and 4-thiouracil via a [4Fe-5S] cluster intermediate. However, the in vivo function of TudS enzymes has remained unclear and direct evidence for substrate binding to the [4Fe-4S] cluster during catalysis was lacking. Here, we provide kinetic evidence that 4-thiouridine-5’-monophosphate rather than sulfurated tRNA, thiouracil, thiouridine or 4-thiouridine-5’-triphosphate is the preferred substrate of TudS. The occurrence of sulfur- and substrate-bound catalytic intermediates was uncovered from the observed switch of the S = 3/2 spin state of the catalytic [4Fe-4S] cluster to a S = 1/2 spin state upon substrate addition. We show that a putative gene product from Pseudomonas putida KT2440 acts as a TudS desulfidase in vivo and conclude that TudS-like enzymes are widespread desulfidases involved in recycling and detoxifying tRNA-derived 4-thiouridine monophosphate nucleosides for RNA synthesis.

Abstract Thiolation of uridine 34 in the anticodon loop of several tRNAs is conserved in the three domains of life and guarantees fidelity of protein translation. U34-tRNA thiolation is catalyzed by a complex of two proteins in the eukaryotic cytosol (named Ctu1/Ctu2 in humans), but by a single NcsA enzyme in archaea. We report here spectroscopic and biochemical experiments showing that NcsA from Methanococcus maripaludis (MmNcsA) is a dimer that binds a [4Fe-4S] cluster, which is required for catalysis. Moreover, the crystal structure of MmNcsA at 2.8 Å resolution shows that the [4Fe-4S] cluster is coordinated by three conserved cysteines only, in each monomer. Extra electron density on the fourth nonprotein-bonded iron most likely locates the binding site for a hydrogenosulfide ligand, in agreement with the [4Fe-4S] cluster being used to bind and activate the sulfur atom of the sulfur donor. Comparison of the crystal structure of MmNcsA with the AlphaFold model of the human Ctu1/Ctu2 complex shows a very close superposition of the catalytic site residues, including the cysteines that coordinate the [4Fe-4S] cluster in MmNcsA. We thus propose that the same mechanism for U34-tRNA thiolation, mediated by a [4Fe-4S]-dependent enzyme, operates in archaea and eukaryotes.

IMPORTANCE:. Acute liver failure (ALF) carries significant morbidity and mortality, for both pediatric and adult patients. Albumin dialysis via the molecular adsorbent recirculating system (MARS) is a form of extracorporeal liver support (ELS) that can reduce hepatic encephalopathy (HE), a main driver of mortality in ALF. However, data on MARS and its benefit on mortality have been inconsistent. OBJECTIVES:. We sought to report our experiences and patient outcomes from the first 2 years of operation of a new ELS program, within an established pediatric liver transplantation center. DESIGN, SETTING, AND PARTICIPANTS:. Retrospective review of outcomes in pediatric and adult patients treated with MARS therapy for ALF, from 2021 to 2022. MAIN OUTCOMES AND MEASURES:. Outcomes included reduction in HE and biochemical markers of ALF after MARS therapy, survival, and transplant-free survival. Comparisons were made via Wilcoxon signed-rank test. RESULTS:. Five pediatric and two adult patients underwent MARS for ALF. Ages ranged from 2 to 29 years. Overall, 21 MARS runs were performed (median 3 runs per patient, 12.4 hr per run [interquartile range, IQR 10.1–17]). Overall survival was 85.7%, and transplant-free survival was 71.4%. There was a statistically significant reduction in HE score with MARS therapy (median 3 [IQR 3–4] to 1 [IQR 0–1], p = 0.03), and in ALF biomarkers including ammonia (256 µL/dL [195–265] to 75 µL/dL [58–101], p = 0.02), aspartate aminotransferase (6,362 U/L [920–8,305] to 212 U/L [72–431], p = 0.02), alanine aminotransferase (8,362 U/L [3,866–9,189] to 953 U/L [437–1,351], p = 0.02), and international normalized ratio (4.5 [3.3–6.7] to 1.3 [1.2–1.4], p = 0.02). CONCLUSIONS AND RELEVANCE:. MARS therapy for ALF was well tolerated by both pediatric and adult patients, and resulted in significant improvement in clinical and biochemical parameters. We demonstrated encouraging overall and transplant-free survival, suggesting that early initiation of MARS with relatively long and frequent cycle times may be of significant benefit to ALF patients, and is worthy of additional study in larger cohorts.

Introdução: As pesquisas qualitativas surgiram para potencializar o estudo dentro das ciências metodológicas, buscando um aprofundamento detalhado e subjetivo nas visões individuais do grupo acerca do objeto de pesquisa. Com a revolução informacional, essas pesquisas também sofreram influências, tornando possível o uso de ferramentas virtuais para a realização de análises. Com a pandemia da SARS-COV-22 e a adoção de lockdowns, artifícios como o Google Meet, Zoom e CAQDAS entraram em evidência. Observou-se, com a adoção dessas, uma maior riqueza, além da compreensão mais aprofundada e completa da temática estudada, fazendo-se crucial seu estudo; Objetivos Refletir sobre as aplicações de metodologias tradicionais e virtuais nas pesquisas qualitativas; Métodos Trata-se de um estudo de caráter qualitativo baseado em uma tese de pesquisa-ação que, através da utilização de recursos metodológicos tradicionais, por meio de obras literárias, música, reuniões e palestra, e também os inovadores, utilizando- se ambientes virtuais, resumos em vídeos e CAQDAS, buscou promover um impulsionamento nas análises reflexivas - de modo on-line e presencial - entre os grupos participantes acerca de um conflito coletivo; Resultados Foi visto que a integração do método tradicional às ferramentas virtuais facilitou o alcance de mais participantes, além de apoiar a comunicação e convite deles, ainda, auxiliou na obtenção e processamento de dados obtidos nos debates realizados. Ademais, observou-se que não houve déficit subjetivo na pluralidade dos discursos e temáticas, posteriormente transcritos e analisados ainda com o uso dessas, aumentando a precisão dos dados; Considerações finais A integração entre a modalidade virtual e presencial mostra-se vantajosa no enriquecimento de debates mais rápidos e sem limites geográficos, não deixando de apresentar um caráter plural e dialético, além de mostrar-se mais eficiente na coleta e registro de dados para análises e discussões.

Background and objectives: Environmental factors influence the development of very preterm infants (VPIs, born at less than 32 weeks of gestation). It is important to identify all potential sources of paraben exposure in these vulnerable infants. We aimed to quantify paraben exposure via drug administration in a cohort of VPI cared for in neonatal intensive care units (NICUs).Methods: A prospective, observational study was carried out over a five-year period in a regional setting (two NICUs using the same computerized order-entry system). The main outcome was exposure to paraben-containing drugs. The secondary outcomes were: time of the first exposure, daily intake, number of infants exceeding paraben acceptable daily intake (ADI: 0–10 mg/kg/d), duration of exposure, and cumulative dose.Results: The cohort consisted of 1,315 VPIs [BW 1129.9 (±360.4) g]. Among them, 85.5% were exposed to paraben-containing drugs. In 40.4% of infants, the first exposure occurred during the second week of life. Mean paraben intake and duration of exposure were, respectively, 2.2 (±1.4) mg/kg/d and 33.1 (±22.3) days. The cumulative paraben intake was 80.3 (±84.6) mg/kg. The ADI was exceeded in 3.5% of exposed infants. Lower GA was associated with higher intake and longer exposure (p < 0.0001). The main molecules involved in paraben exposure were: sodium iron feredetate, paracetamol, furosemide, and sodium bicarbonate + sodium alginate.Conclusion: Commonly used drugs are potential source of parabens, and ADI can be easily exceeded in VPIs cared for in NICUs. Efforts are needed to identify paraben-free alternative formulations for these vulnerable infants.

This paper examines the relevance of the sentence concept to the understanding of three types of implicitness (presupposition, conversational implicatures, irony). Our experimental protocol involved 105 children (aged 6 to 11) and 82 adults who were asked to read short texts composed of a context about some characters and a target sentence conveying one of the three implicit contents. After reading, children and adults had to answer a comprehension yes-no question and indicate the segments from the text that helped them answer the question. Results showed a difference between the three types of implicitness, with presupposition being detected and understood at a subsentential level, whereas implicatures and irony come under extrasentential level requiring the context to be taken into account. Referring to sentence as a unit of meaning does not seem relevant as soon as understanding is not limited to the literal meaning of what is written, but also concerns what is meant by the text.

Background: Postnatal corticosteroids (PC) are widely used in very preterm infants. International reports and national multicenter trials describe a marked variability across countries and inter-sites, in the use of PC. Few information is available on therapeutic indications and prescription characteristics of PC.Aim: The main objective of this study was to describe the exposure to PC in a large cohort of preterm infants born at less than 32 weeks of gestation, according to the prescription data of 41 tertiary-care NICUs in France. Secondary objectives were to describe therapeutic indications, day of life (DOL) of the first exposure, route of administration, duration, cumulative dose for each drug, and differences in exposure rates across centers.Methods: We conducted a prospective observational cohort analysis from January 2017 to December 2021, in 41 French tertiary-care NICUs using the same computerized order-entry system.Results: In total, 13,913 infants [birth weight 1144.8 (±365.6) g] were included. Among them, 3633 (26.1%) were exposed to PC, 21.8% by systemic and 10.1% by inhaled route. Within the study population, 1,992 infants (14.3%) received the first corticosteroid treatment in the first week of life and 1641 (11.8%) after DOL 7. The more frequent indications were prevention and/or treatment of bronchopulmonary dysplasia, and arterial hypotension. Hydrocortisone was the more often prescribed molecule. For systemic PC the first exposure occurred in mean at DOL 9.4 (±13.5), mean duration of treatment was 10.3 (±14.3) days, and the cumulative dose (expressed as the equivalent dose of hydrocortisone) was in median [IQR] 9.0 [5.5–28.8] mg/kg. For inhaled PC, the first exposure occurred in mean at DOL 34.1 (±19.7), and mean duration of treatment 28.5 (±24.4) days. The exposure rate ranged from a minimum of 5% to a maximum of 56% among centers, and significantly increased over the study period (p < 0.0001).Conclusion: In this French cohort of very preterm infants, around one patient out to five was exposed to PC during hospital stay in the NICU. The exposure occurred early, starting from the first week of life. Exposure rate widely varied among centers. Pharmacoepidemiology studies are useful to increase knowledge on corticosteroid utilization patterns in preterm infants.

Abstract Background As Canadian global health researchers who conducted a qualitative study with adults with and without disabilities in Uganda, we obtained ethics approval from four institutional research ethics boards (two in Canada and two in Uganda). In Canada, research ethics boards and researchers follow the research ethics norms of the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS2), and the National Guidelines for Research Involving Humans as Research Participants of Uganda (NGRU) in Uganda. The preparation and implementation of this qualitative research raised specific ethical issues related to research participant privacy and the importance of availability and management of financial resources. Main body Our field experience highlights three main issues for reflection. First, we demonstrate that, in a global health research context, methodological and logistic adjustments were necessary throughout the research implementation process to ensure the protection of study participants’ privacy, especially that of people with disabilities, despite having followed the prescribed Canadian and Ugandan ethics norms. Data collection and management plans were adapted iteratively based on local realities. Second, securing financial support as a key aspect of financial management was critical to ensure privacy through disability-sensitive data collection strategies. Without adequate funding, the recruitment of research participants based on disability type, sex, and region or the hiring of local sign language interpreters would not have been possible. Third, although the TCPS2 and NGRU underscore the significance of participants’ privacy, none of these normative documents clearly express this issue in the context of global health research and disability, nor broadly discuss the ethical issue related to financial availability and management. Conclusions Conducting research in resource limited settings and with study participants with different needs calls for a nuanced and respectful implementation of research ethics in a global health context. We recommend a greater integration in both the TCPS2 and NGRU of global health research, disability, and responsible conduct of research. This integration should also be accompanied by adequate training which can further guide researchers, be they senior, junior, or students, and funding agencies.

Abstract Background Consensus treatment plans have been developed for induction therapy of newly diagnosed proliferative lupus nephritis (LN) in childhood-onset systemic lupus erythematosus. However, patients who do not respond to initial therapy, or who develop renal flare after remission, warrant escalation of treatment. Our objective was to assess current practices of pediatric nephrologists and rheumatologists in North America in treatment of refractory proliferative LN and flare. Methods Members of Childhood Arthritis and Rheumatology Research Alliance (CARRA) and the American Society for Pediatric Nephrology (ASPN) were surveyed in November 2015 to assess therapy choices (other than modifying steroid dosing) and level of agreement between rheumatologists and nephrologists for proliferative LN patients. Two cases were presented: (1) refractory disease after induction treatment with corticosteroid and cyclophosphamide (CYC) and (2) nephritis flare after initial response to treatment. Survey respondents chose treatments for three follow up scenarios for each case that varied by severity of presentation. Treatment options included CYC, mycophenolate mofetil (MMF), rituximab (RTX), and others, alone or in combination. Results Seventy-six respondents from ASPN and foty-one respondents from CARRA represented approximately 15 % of the eligible members from each organization. Treatment choices between nephrologists and rheumatologists were highly variable and received greater than 50 % agreement for an individual treatment choice in only the following 2 of 6 follow up scenarios: 59 % of nephrologists, but only 38 % of rheumatologists, chose increasing dose of MMF in the case of LN refractory to induction therapy with proteinuria, hematuria, and improved serum creatinine. In a follow up scenario showing severe renal flare after achieving remission with induction therapy, 58 % of rheumatologists chose CYC and RTX combination therapy, whereas the top choice for nephrologists (43 %) was CYC alone. Rheumatologists in comparison to nephrologists chose more therapy options that contained RTX in all follow up scenarios except one (p

Objectives: No consensus exists about the doses of analgesics, sedatives, anesthetics, and paralytics used in critically ill neonates. Large-scale, detailed pharmacoepidemiologic studies of prescription practices are a prerequisite to future research. This study aimed to describe the detailed prescriptions of these drug classes in neonates hospitalized in neonatal intensive care units (NICU) from computerized prescription records and to compare prescriptions by gestational age.Materials and Methods: We included all neonates requiring intensive care in 30 French level III units from 2014 through 2020 with a computerized prescription for an analgesic, sedative, anesthetic, or paralytic agent. We described frequencies of prescription, methods of administration, concomitant drug prescriptions, and dosing regimen, and compared them across gestational ages.Results: Among 65,555 neonates, 29,340 (44.8%) were prescribed at least one analgesic (acetaminophen in 37.2% and opioids in 17.8%), sedative (9.8%), anesthetic (8.5%), and/or paralytic agent (1%). Among preterm infants born before 28 weeks, 3,771/4,283 (88.0%) were prescribed at least one of these agents: 69.7% opioids, 41.2% sedatives, 32.5% anesthetics, and 5.8% paralytics. The most frequently prescribed agents were sufentanil (in 10.3% of neonates) and morphine (in 8.0% of neonates) for opioids, midazolam (9.3%) for sedatives, ketamine (5.7%) and propofol (3.3%) for anesthetics. In most neonates, opioids and sedatives were prescribed as continuous infusion, whereas anesthetics were prescribed as single doses. Opioids, sedatives and paralytics were mostly prescribed in association with another agent. Doses varied significantly by gestational age but within a limited range. Gestational age was inversely related to the frequency, cumulative dose and duration of prescriptions. For example, morphine prescriptions showed median (IQR) cumulative doses of 2601 (848–6750) vs. 934 (434–2679) µg/kg and median (IQR) durations of 7 (3–15) vs. 3 (2–5) days in infants born

An ultrasound-assisted extraction method, employing ethanol and water as solvents at low temperature (30 °C) and reduced time (15 min), was proposed to extract bioactive molecules from different cultivars (Magliocco Canino, Magliocco Rosato, Gaglioppo, and Nocera Rosso) of wine lees. All the extract yields were evaluated and their contents of phenolic acids, flavonoids, and total polyphenols were determined by means of colorimetric assays and high-performance liquid chromatography coupled with diode-array detection (HPLC-DAD) and Fourier transform infrared (FTIR) techniques. Radical scavenging assays were performed and the Magliocco Canino extracted with a hydroalcoholic mixture returned the best results both against ABTS (0.451 mg mL−1) and DPPH (0.395 mg mL−1) radicals. The chemometric algorithms principal component analysis (PCA) and partial least square regression (PLS) were used to process the data obtained from all qualitative–quantitative sample determinations with the aim of highlighting data patterns and finding possible correlations between composition and antioxidant features of the different wine lees cultivars and the extraction procedures. Wine lees from Magliocco Canino and Magliocco Rosato were found to be the best vegetable matrices in terms of metabolite content and antioxidant properties. The components extracted with alcoholic or hydroalcoholic solvents, specifically (−)-epigallocatechin gallate, chlorogenic acid, and trans-caftaric acid, were found to be correlated with the antioxidant capacity of the extracts. Multivariate data processing was able to identify the compounds related to the antioxidant features. Two PLS models were optimized by using their concentration levels to predict the IC50 values of the extracts in terms of DPPH and ABTS with high values of correlation coefficient R2, 0.932 and 0.824, respectively, and a prediction error lower than 0.07. Finally, cellular (SH-SY5Y cells) antioxidant assays were performed on the best extract (the hydroalcoholic extract of Magliocco Canino cv) to confirm its biological performance against radical species. All these recorded data strongly outline the aptness of valorizing wine lees as a valuable source of antioxidants.

The presentation of novel coronavirus disease 2019 (COVID-19) in children with kidney disease is largely unknown. We report on 2 children with kidney disease not receiving long-term immunosuppression who were hospitalized due to COVID-19. The first case is an infant with end-stage kidney disease secondary to bilateral cystic dysplastic kidneys and posterior urethral valves receiving peritoneal dialysis, with a history of prematurity previously requiring mechanical ventilation in the neonatal intensive care unit, who presented with fever, hypertension, and emesis. He had no respiratory symptoms and recovered with supportive care. His hypertension was managed well with amlodipine. The second case is a child with steroid-sensitive nephrotic syndrome who presented with a relapse of nephrotic syndrome with concurrent peritonitis and sepsis caused by Streptococcus agalactiae. He was treated with antibiotics and prophylactic anticoagulation therspy. Steroid therapy was initiated after 48 hours of antibiotic therapy. Neither child required mechanical ventilation or developed COVID-19–related multisystem inflammatory syndrome.

Single-wavelength anomalous dispersion (SAD)-phasing using sulfur as the unique anomalous scatterer is a powerful method to solve the phase problem in protein crystallography. However, it is not yet widely used by non-expert crystallographers. We report here the structure determination of the double stranded RNA binding domain of human dihydrouridine synthase using the sulfur-SAD method and highly redundant data collected at 1.8 ​Å (“off-edge”), at which the estimated overall anomalous signal was 1.08%. High multiplicity data were collected on a single crystal rotated along the ϕ or ω axis at different κ angles, with the primary beam intensity being attenuated from 50% to 95%, compared to data collection at 0.98 ​Å, to reduce radiation damage. SHELXD succeeded to locate 14 out 15 sulfur sites only using the data sets recorded with highest beam attenuation, which provided phases sufficient for structure solving. In an attempt to stimulate the use of sulfur-SAD phasing by a broader community of crystallographers, we describe our experimental strategy together with a compilation of previous successful cases, suggesting that sulfur-SAD phasing should be attempted for determining the de novo structure of any protein with average sulfur content diffracting better than 3 ​Å resolution.

The aim of this article is to assess whether the teaching of irony allows students to acquire a certain mastery of ironic processes by knowing not only how to identify them, but also how to interpret them. The examination of fourteen French textbooks, representative of the current teaching in class from 9th to 11th grade, is carried out according to five complementary parameters: the proposed classifications of irony, its defining contents, its forms of expression, the literary texts and the exercises associated with it. A number of pitfalls emerge from this study, such as the emphasis on identification at the expense of interpretation, a lack of stability and continuity in the content exposed and at the notional level, or even a lack of incentive for students to establish links between categorisations, defining contents and forms of expression of irony.

Abstract Background SLE manifestations after ESRD may be underdiagnosed and undertreated, contributing to increased morbidity and mortality. Whether specific symptoms persist after ESRD or a shift towards new manifestations occurs has not been extensively studied, especially in the non-Caucasian patients in the United States. In addition, hydroxychloroquine (HCQ) prescribing patterns post-ESRD have not been described. The objective of this study was to assess lupus activity and HCQ prescribing before and after ESRD development. Knowledge gained from this study may aid in the identification of SLE manifestations and improve medication management post-ESRD. Methods We performed a retrospective cohort study of SLE patients with incident ESRD between 2010 and 2017. SLE-related symptoms, serologic markers of disease activity, and medication use were collected from medical records before and after ESRD development. Results Fifty-nine patients were included in the study. Twenty-five (43%) patients had at least one clinical (non-renal) SLE manifestation documented within 12 months before ESRD. Of them, 11/25 (44%) continued to experience lupus symptoms post-ESRD; 9 patients without clinical or serological activity pre-ESRD developed new symptoms of active SLE. At the last documented visit post-ESRD, 42/59 (71%) patients had one or more clinical or serological markers of lupus activity; only 17/59 (29%) patients achieved clinical and serological remission. Thirty-three of 59 (56%) patients had an active HCQ prescription at the time of ESRD. Twenty-six of the 42 (62%) patients with active SLE manifestations post-ESRD were on HCQ. Patients who continued HCQ post-ESRD were more likely to be followed by a rheumatologist (26 [87%] vs 17 [61%], p = 0.024), had a higher frequency of documented arthritis (10 [32%] vs 1 [4%], p = 0.005), CNS manifestations (6 [20%] vs 1 [4%], p = 0.055), and concurrent immunosuppressive medication use (22 [71%] vs 12 [43%], p = 0.029). Conclusions Lupus activity may persist after the development of ESRD. New onset arthritis, lupus-related rash, CNS manifestations, low complement and elevated anti-dsDNA may develop. HCQ may be underutilized in patients with evidence of active disease pre- and post ESRD. Careful clinical and serological monitoring for signs of active disease and frequent rheumatology follow up is advised in SLE patients both, pre and post-ESRD.

RNase Y is a crucial component of genetic translation, acting as the key enzyme initiating mRNA decay in many Gram-positive bacteria. The N-terminal domain of Bacillus subtilis RNase Y (Nter-BsRNaseY) is thought to interact with various protein partners within a degradosome complex. Bioinformatics and biophysical analysis have previously shown that Nter-BsRNaseY, which is in equilibrium between a monomeric and a dimeric form, displays an elongated fold with a high content of α-helices. Using multidimensional heteronuclear NMR and AlphaFold models, here, we show that the Nter-BsRNaseY dimer is constituted of a long N-terminal parallel coiled-coil structure, linked by a turn to a C-terminal region composed of helices that display either a straight or bent conformation. The structural organization of the N-terminal domain is maintained within the AlphaFold model of the full-length RNase Y, with the turn allowing flexibility between the N- and C-terminal domains. The catalytic domain is globular, with two helices linking the KH and HD modules, followed by the C-terminal region. This latter region, with no function assigned up to now, is most likely involved in the dimerization of B. subtilis RNase Y together with the N-terminal coiled-coil structure.

Objectives In lupus nephritis the pathological diagnosis from tissue retrieved during kidney biopsy drives treatment and management. Despite recent approval of new drugs, complete remission rates remain well under aspirational levels, necessitating identification of new therapeutic targets by greater dissection of the pathways to tissue inflammation and injury. This study assessed the safety of kidney biopsies in patients with SLE enrolled in the Accelerating Medicines Partnership, a consortium formed to molecularly deconstruct nephritis.Methods 475 patients with SLE across 15 clinical sites in the USA consented to obtain tissue for research purposes during a clinically indicated kidney biopsy. Adverse events (AEs) were documented for 30 days following the procedure and were determined to be related or unrelated by all site investigators. Serious AEs were defined according to the National Institutes of Health reporting guidelines.Results 34 patients (7.2%) experienced a procedure-related AE: 30 with haematoma, 2 with jets, 1 with pain and 1 with an arteriovenous fistula. Eighteen (3.8%) experienced a serious AE requiring hospitalisation; four patients (0.8%) required a blood transfusion related to the kidney biopsy. At one site where the number of cores retrieved during the biopsy was recorded, the mean was 3.4 for those who experienced a related AE (n=9) and 3.07 for those who did not experience any AE (n=140). All related AEs resolved.Conclusions Procurement of research tissue should be considered feasible, accompanied by a complication risk likely no greater than that incurred for standard clinical purposes. In the quest for targeted treatments personalised based on molecular findings, enhanced diagnostics beyond histology will likely be required.

In this article, we present the potentials of Google Vision API-based networks for studying online images, covering three important modalities as part of a critical visual methodology: the content of the image itself, its specific ‘audiencing’ through web references (or image metadata), and the sites of image circulation. First, we conceptually and technically define different networks built upon computer vision features: image-label, image-web entities, and image-domain. Second, we present a research protocol diagram that illustrates how to build networks of images and respective descriptions or sites of circulation. Third, we discuss the potentialities of computer vision networks as a research device, stressing their data-relational (trans)formations and interpretative specifics. Three different case studies will be introduced as examples. In conclusion, we argue that such a visual methodology requires critical technical practices accounting for the multiple layers of technical mediation involved.

In this article, we present the potentials of Google Vision API-based networks for studying online images, covering three important modalities as part of a critical visual methodology: the content of the image itself, its specific ‘audiencing’ through web references (or image metadata), and the sites of image circulation. First, we conceptually and technically define different networks built upon computer vision features: image-label, image-web entities, and image-domain. Second, we present a research protocol diagram that illustrates how to build networks of images and respective descriptions or sites of circulation. Third, we discuss the potentialities of computer vision networks as a research device, stressing their data-relational (trans)formations and interpretative specifics. Three different case studies will be introduced as examples. In conclusion, we argue that such a visual methodology requires critical technical practices accounting for the multiple layers of technical mediation involved.

In this article, we present the potentials of Google Vision API-based networks for studying online images, covering three important modalities as part of a critical visual methodology: the content of the image itself, its specific ‘audiencing’ through web references (or image metadata), and the sites of image circulation. First, we conceptually and technically define different networks built upon computer vision features: image-label, image-web entities, and image-domain. Second, we present a research protocol diagram that illustrates how to build networks of images and respective descriptions or sites of circulation. Third, we discuss the potentialities of computer vision networks as a research device, stressing their data-relational (trans)formations and interpretative specifics. Three different case studies will be introduced as examples. In conclusion, we argue that such a visual methodology requires critical technical practices accounting for the multiple layers of technical mediation involved.

In this article, we present the potentials of Google Vision API-based networks for studying online images, covering three important modalities as part of a critical visual methodology: the content of the image itself, its specific ‘audiencing’ through web references (or image metadata), and the sites of image circulation. First, we conceptually and technically define different networks built upon computer vision features: image-label, image-web entities, and image-domain. Second, we present a research protocol diagram that illustrates how to build networks of images and respective descriptions or sites of circulation. Third, we discuss the potentialities of computer vision networks as a research device, stressing their data-relational (trans)formations and interpretative specifics. Three different case studies will be introduced as examples. In conclusion, we argue that such a visual methodology requires critical technical practices accounting for the multiple layers of technical mediation involved.

In this article, we present the potentials of Google Vision API-based networks for studying online images, covering three important modalities as part of a critical visual methodology: the content of the image itself, its specific ‘audiencing’ through web references (or image metadata), and the sites of image circulation. First, we conceptually and technically define different networks built upon computer vision features: image-label, image-web entities, and image-domain. Second, we present a research protocol diagram that illustrates how to build networks of images and respective descriptions or sites of circulation. Third, we discuss the potentialities of computer vision networks as a research device, stressing their data-relational (trans)formations and interpretative specifics. Three different case studies will be introduced as examples. In conclusion, we argue that such a visual methodology requires critical technical practices accounting for the multiple layers of technical mediation involved.

Sesquiterpenes such as leucodin and the labdane-type diterpene manool are natural compounds endowed with remarkably in vitro vasorelaxant and in vivo hypotensive activities. Given their structural similarity with the sesquiterpene lactone (+)-sclareolide, this molecule was selected as a scaffold to develop novel vasoactive agents. Functional, electrophysiology, and molecular dynamics studies were performed. The opening of the five-member lactone ring in the (+)-sclareolide provided a series of labdane-based small molecules, promoting a significant in vitro vasorelaxant effect. Electrophysiology data identified 7 as a CaV1.2 channel blocker and a KCa1.1 channel stimulator. These activities were also confirmed in the intact vascular tissue. The significant antagonism caused by the CaV1.2 channel agonist Bay K 8644 suggested that 7 might interact with the dihydropyridine binding site. Docking and molecular dynamic simulations provided the molecular basis of the CaV1.2 channel blockade and KCa1.1 channel stimulation produced by 7. Finally, 7 reduced coronary perfusion pressure and heart rate, while prolonging conduction and refractoriness of the atrioventricular node, likely because of its Ca2+ antagonism. Taken together, these data indicate that the labdane scaffold represents a valuable starting point for the development of new vasorelaxant agents endowed with negative chronotropic properties and targeting key pathways involved in the pathophysiology of hypertension and ischemic cardiomyopathy.

Introduction: Prescribing antibiotics to newborns is challenging, as excess antibiotics are a risk factor for increased morbidity and mortality. The objective of this study was to describe the evolution of antibiotic exposure over three years in a large network of level 3 neonatal wards where each center is informed yearly of its own results and the results of other centers and has full autonomy to improve its performance.Patients and Methods: This is a prospective, observational study of antibiotics prescriptions over the 2017–2019 period in a network of 23 French level 3 neonatal wards. The network relied on an internal benchmarking program based on a computerized prescription ordering system. Among others, antibiotics exposure, treatment duration, and antibiotics spectrum index were analyzed.Results: The population consisted of 39,971 neonates (51.5% preterm), 44.3% of which were treated with antibiotics. Of the treated patients, 78.5% started their first antibiotic treatment in the first three days of life. Antibiotic exposure rate significantly declined from 2017 to 2019 (from 46.8% to 42.8%, p < 0.0001); this decline was significant in groups with gestational age >26 weeks, but not in the group with extremely low gestational age

Protein farnesylation is a post-translational modification regulated by the ERA1 (Enhanced Response to ABA 1) gene encoding the β-subunit of the protein farnesyltransferase in Arabidopsis. The era1 mutants have been described for over two decades and exhibit severe pleiotropic phenotypes, affecting vegetative and flower development. We further investigated the development and quality of era1 seeds. While the era1 ovary contains numerous ovules, the plant produces fewer seeds but larger and heavier, with higher protein contents and a modified fatty acid distribution. Furthermore, era1 pollen grains show lower germination rates and, at flower opening, the pistils are immature and the ovules require one additional day to complete the embryo sac. Hand pollinated flowers confirmed that pollination is a major obstacle to era1 seed phenotypes, and a near wild-type seed morphology was thus restored. Still, era1 seeds conserved peculiar storage protein contents and altered fatty acid distributions. The multiplicity of era1 phenotypes reflects the diversity of proteins targeted by the farnesyltransferase. Our work highlights the involvement of protein farnesylation in seed development and in the control of traits of agronomic interest.

In pre-hypertension, moderate control of blood pressure (BP) can be obtained by a nutritional approach. The effects of a diet enriched with defatted larvae of the mealworm Tenebrio molitor (Coleoptera: Tenebrionidae) (TM) endowed with ACE inhibitory activity was studied in both spontaneously hypertensive rats (SHR) and in the age-matched normotensive Wistar Kyoto strain. These were fed for 4 weeks with standard laboratory rodent chow supplemented with or without TM or captopril. In SHR, the TM diet caused a significant reduction in BP, heart rate and coronary perfusion pressure, as well as an increase in red blood cell glutathione/glutathione disulphide ratio. Rat brain slices of SHR were more resistant to oxidative stress and contained lower levels of inflammatory cytokines, while vascular and liver enzyme-activities were not affected. These results suggest that TM can be considered a new functional food that can lower BP in vivo and thus control cardiovascular-associated risk factors such as hypertension.

Size Exclusion Chromatography coupled with Multi-Angle Light Scattering (SEC-MALS) is a technique that determines the absolute molar mass (molecular weight) of macromolecules in solution, such as proteins or polymers, by detecting their light scattering intensity. Because SEC-MALS does not rely on the assumption of the globular state of the analyte and the calibration of standards, the molar mass can be obtained for proteins of any shape, as well as for intrinsically disordered proteins and aggregates. Yet, corrections need to be made for samples that absorb light at the wavelength of the MALS laser, such as iron–sulfur [Fe-S] cluster-containing proteins. We analyze several examples of [2Fe-2S] and [4Fe-4S] cluster-containing proteins, for which various corrections were applied to determine the absolute molar mass of both the apo- and holo-forms. Importantly, the determination of the absolute molar mass of the [2Fe-2S]-containing holo-NEET proteins allowed us to ascertain a change in the oligomerization state upon cluster binding and, thus, to highlight one essential function of the cluster.

Abstract Background The use of Next Generation Sequencing such as Whole Genome Sequencing (WGS) is a promising step towards a better understanding and treatment of neurological diseases. WGS can result into unexpected information (incidental findings, IFs), and information with uncertain clinical significance. In the context of a Genome Canada project on ‘Personalized Medicine in the Treatment of Epilepsy’, we intended to address these challenges surveying neurologists’ opinions about the type of results that should be returned, and their professional responsibility toward recontacting patients regarding new discovered mutations. Methods Potential participants were contacted through professional organizations or direct invitations. Results A total of 204 neurologists were recruited. Fifty nine percent indicated that to be conveyed, WGS results should have a demonstrated clinical utility for diagnosis, prognosis or treatment. Yet, 41% deemed appropriate to return results without clinical utility, when they could impact patients’ reproductive decisions, or on patients’ request. Current use of targeted genetic testing and age of patients influenced respondents’ answers. Respondents stated that analysis of genomics data resulting from WGS should be limited to the genes likely to be relevant for the patient’s specific medical condition (69%), so as to limit IFs. Respondents felt responsible to recontact patients and inform them about newly discovered mutations related to the medical condition that triggered the test (75%) for as long as they are following up on the patient (55%). Finally, 53.5% of the respondents felt responsible to recontact and inform patients of clinically significant, newly discovered IFs. Conclusion Our results show the importance of formulating professional guidelines sensitive to the various – and sometimes opposite – viewpoints that may prevail within a same community of practice, as well as flexible so as to be attuned to the characteristics of the neurological conditions that triggered a WGS.

AlphaFold and RoseTTAFold are deep learning-based approaches that predict the structure of proteins from their amino acid sequences. Remarkable success has recently been achieved in the prediction accuracy of not only the fold of the target protein but also the position of its amino acid side chains. In this article, I question the accuracy of these methods to predict iron–sulfur binding sites. I analyze three-dimensional models calculated by AlphaFold and RoseTTAFold of Fe–S–dependent enzymes, for which no structure of a homologous protein has been solved experimentally. In all cases, the amino acids that presumably coordinate the cluster were gathered together and facing each other, which led to a quite accurate model of the Fe–S cluster binding site. Yet, cysteine candidates were often involved in intramolecular disulfide bonds, and the number and identity of the protein amino acids that should ligate the cluster were not always clear. The experimental structure determination of the protein with its Fe–S cluster and in complex with substrate/inhibitor/product is still needed to unambiguously visualize the coordination state of the cluster and understand the conformational changes occurring during catalysis.

Background: Aminoglycosides are the most prescribed antibiotics in neonatal intensive care units (NICU). Reducing exposure to antibiotics in the NICU is highly desirable, particularly through benchmarking methods. Methods: Description of aminoglycosides prescriptions in 23 French NICU using the same computerized system over a 4-year period (2017–2020). A benchmarking program of antibiotics prescription was associated. Results: The population included 53,818 patients. Exposition rates to gentamicin and amikacin were 31.7% (n = 17,049) and 9.1% (n = 4894), respectively. Among neonates exposed to gentamicin, 90.4% of gentamicin and 77.6% of amikacin treatments were started within the 1st week of life. Among neonates exposed to amikacin, 77.6% started amikacin within the 1st week. The average daily dose of gentamicin at first prescription increased over the study period from 3.9 in 2017 to 4.4 mg/kg/d in 2020 (p < 0.0001). Conversely, the corresponding amikacin daily doses decreased from 13.0 in 2017 to 12.3 mg/kg/d in 2020 (p = 0.001). The time interval between the first 2 doses of gentamicin was mainly distributed in 3 values during the first week of life: 49.4% at 24 h, 26.4% at 36 h, and 22.9% at 48 h. At first amikacin prescription, the time interval was distributed in 4 categories: 48% at 24 h, 4.1% at 30 h, 8.5% at 36 h, and 37.1% at 48 h. As compared to literature guidelines, the rates of overdose and underdose in gentamicin (1.5% and 2.7%) and amikacin (0.3% and 1.0%). They significantly decreased for gentamicin over the study period. In multivariate analysis, the factors significantly associated with GENT overdose were the year of admission, prematurity, length of stay, and duration of the treatment. Conclusion: This prescription strategy ensured a low rate of overdose and underdose, and some benefits of the benchmarking program is suggested.

Antimicrobial use (AMU) is one of the major drivers of emerging antimicrobial resistance (AMR). The surveillance of AMU, which is a pillar of AMR stewardship (AMS), helps devise strategies to mitigate AMR. This descriptive, longitudinal retrospective study quantified the trends in human antibiotics utilization between 2010 and 2016 using data on all antibiotics imported for systemic human use into Tanzania’s mainland. Regression and time series analyses were used to establish trends in antibiotics use. A total of 12,073 records for antibiotics were retrieved, totaling 154.51 Defined Daily Doses per 1000 inhabitants per day (DID), with a mean (±standard deviation) of 22.07 (±48.85) DID. The private sector contributed 93.76% of utilized antibiotics. The top-ranking antibiotics were amoxicillin, metronidazole, tetracycline, ciprofloxacin, and cefalexin. The DIDs and percentage contribution of these antibiotics were 53.78 (34.81%), 23.86 (15.44), 20.53 (13.29), 9.27 (6.0) and 6.94 (4.49), respectively. The time series model predicted a significant increase in utilization (p-value = 0.002). The model forecasted that by 2022, the total antibiotics consumed would be 89.6 DIDs, which is a 13-fold increase compared to 2010. Government intervention to curb inappropriate antibiotics utilization and mitigate the rising threat of antibiotic resistance should focus on implementing AMS programs in pharmacies and hospitals in Tanzania.

Abstract The anticipation of ethical issues that may arise with the clinical use of genomic technologies is crucial to envision their future implementation in a manner sensitive to local contexts. Yet, populations in low- and middle-income countries are underrepresented in studies that aim to explore stakeholders’ perspectives on the use of such technologies. Within the framework of a research project entitled “Personalized medicine in the treatment of epilepsy”, we sought to increase inclusiveness by widening the reach of our survey, inviting neurologists from around the world to share their views and practices regarding the use of whole-genome sequencing in clinical neurology and its associated ethics. We discuss herein the compelling scientific and ethical reasons that led us to attempt to recruit neurologists worldwide, despite the lack, in many low- or middle-income countries, of access to genomic technologies. Recruitment procedures and their results are presented and discussed, as well as the barriers we faced. We conclude that inclusive recruitment remains a challenging, albeit necessary and legitimate, endeavour.