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Background: Antenatal betamethasone is recommended before preterm delivery to accelerate fetal lung maturation. However, its optimal dose remains unknown. A 50% dose reduction was proposed to decrease the potential dose-related long-term neurodevelopmental side effects, including psychological development, sleep, and emotional disorders. Because noninferiority of the half dose in terms of the need for exogenous surfactant was not shown in the primary analysis, its impact on survival without major neonatal morbidity needs to be investigated., Objective: This study aimed to investigate the impact of antenatal betamethasone dose reduction on survival of very preterm infants without severe neonatal morbidity, a factor known to have a strong correlation with long-term outcomes., Study Design: We performed a post hoc secondary analysis of a randomized, multicenter, double-blind, placebo-controlled, noninferiority trial, testing half (11.4 mg once; n=1620) vs full (11.4 mg twice, 24 hours apart; n=1624) antenatal betamethasone doses in women at risk of preterm delivery. To measure survival without severe neonatal morbidity at hospital discharge among neonates born before 32 weeks of gestation, we used the definition of the French national prospective study on preterm children, EPIPAGE 2, comprising 1 of the following morbidities: grade 3 to 4 intraventricular hemorrhage, cystic periventricular leukomalacia, necrotizing enterocolitis stage ≥2, retinopathy of prematurity requiring anti-vascular endothelial growth factor therapy or laser, and moderate-to-severe bronchopulmonary dysplasia., Results: After exclusion of women who withdrew consent or had pregnancy termination and of participants lost to follow-up (8 in the half-dose and 10 in the full-dose group), the rate of survival without severe neonatal morbidity among neonates born before 32 weeks of gestation was 300 of 451 (66.5%) and 304 of 462 (65.8%) in the half-dose and full-dose group, respectively (risk difference, +0.7%; 95% confidence interval, -5.6 to +7.1). There were no significant between-group differences in the cumulative number of neonatal morbidities. Results were similar when using 2 other internationally recognized definitions of severe neonatal morbidity and when considering the overall population recruited in the trial., Conclusion: In the BETADOSE trial, severe morbidity at discharge of newborns delivered before 32 weeks of gestation was found to be similar among those exposed to 11.4-mg and 22.8-mg antenatal betamethasone. Additional studies are needed to confirm these findings., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

From both pharmaceutical and structural perspectives, the large family of prostaglandins represent a truly remarkable class of natural products. Prostaglandin A 2 is a tissue hormone naturally found in human seminal plasma and in the sea whip Plexaura homomalla with yet poorly understood biological or therapeutic effects. Herein, a novel strategy for the stereoselective construction of both naturally occurring prostaglandin A 2 epimers and first insights into their functional effects on the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) type A receptors (GABA A R) are provided. The synthesis of both epimers was achieved in only 11 steps starting from commercially available 2,5-dimethoxy-tetrahydrofuran employing an organocatalytic domino-aldol reaction, a Mizoroki-Heck reaction, a Wittig reaction as well as an oxidation-decarboxylation sequence. The (15R)-epimer significantly reduced GABA-induced currents through GABA A receptors while its (15S)-epimer did not show any significant effect. These data suggest that (15R)-PGA 2 might serve as a novel scaffold for the development of selective GABA A receptor modulators., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Pediatric acute myeloid leukemia (AML) is an aggressive blood cancer with a poor prognosis and high relapse rate. Current challenges in the identification of immunotherapy targets arise from patient-specific blast immunophenotypes and their change during disease progression. To overcome this, we present a new computational research tool to rapidly identify malignant cells. We generated single-cell flow cytometry profiles of 21 pediatric AML patients with matched samples at diagnosis, remission, and relapse. We coupled a classifier to an autoencoder for anomaly detection and classified malignant blasts with 90% accuracy. Moreover, our method assigns a developmental stage to blasts at the single-cell level, improving current classification approaches based on differentiation of the dominant phenotype. We observed major immunophenotype and developmental stage alterations between diagnosis and relapse. Patients with KMT2A rearrangement had more profound changes in their blast immunophenotypes at relapse compared to patients with other molecular features. Our method provides new insights into the immunophenotypic composition of AML blasts in an unbiased fashion and can help to define immunotherapy targets that might improve personalized AML treatment., (© 2024 Driessen et al.)

Hypereosinophilic syndromes (HES) represent a group of rare dis-immune conditions characterized by blood hyper-eosinophilia and eosinophilic related burden. Especially the idiopathic subtype (I-HES) is particularly difficult to diagnose because of its heterogeneous clinical presentation, the lack of specific findings on physical exam, lab tools, and imaging informative enough to unequivocally confirm the diagnosis and the overlap with other entities, including eosinophilic organ-diseases or systemic dis-immune conditions other than I-HES (from atopy to eosinophilic granulomatosis with polyangiitis [EGPA], the last often extremely difficult to distinguish from HES). Taken together, all the features mentioned above account for an extremely difficult early recognition HES and on-time referral to a specialized centre. The referral itself is challenging due to a not univocal specialist identification, because of the variability of physicians managing HES in different settings (including allergist/clinical immunologist, haematologist, internal medicine doctors, pulmonologist, rheumatologist). Furthermore, the approach in terms of personalized treatment identification and follow-up plan (timing, organ assessment), is poorly standardized. Further translational and clinical research is needed to address the mentioned unmet needs, but on practical grounds increasing the overall clinicians' awareness on HES and implementing healthcare pathways for HES patients represent a roadmap that every clinician might try to realize in his specific setting. The present review aims at providing an overview about the current challenges and unmet needs in the practical approach to HES and rare hypereosinophilic allergo-immunological diseases, including a proposal for an innovative multidisciplinary organizational model., Competing Interests: The authors declare that they have no competing interests in relation to the topic of the manuscript., (© 2024 The Author(s).)

Children deserve to be treated with appropriate medicines based on robust assessments. Despite the introduction of new regulations, the availability of medicines for children is suboptimal because of the frequent lack of relevant clinical trials due to the difficulty of conducting such trials. Thus, the Transparency Committee (TC) of the French National Authority for Health, who oversees the assessment of medicinal products in France, set up a pediatric working group with two aims: (1) The first aim was to review all opinions on medicines for pediatric use. Out of 536 opinions delivered between 2020 and 2022, 181 (34 %) concerned medicines for pediatric use. Whereas oncology largely dominated the medicines for adults, medicines for infectious diseases, endocrinology/metabolism, neurology, and hematology mostly prevailed for children. (2) The second aim was to clarify the evaluation criteria assessed by the TC, namely, the clinical benefit (CB), the clinical added value (CAV), and the public health impact (PHI) for pediatric medicinal products. An important CB was given to 113 out of 161 (71 %) opinions on medicines for pediatric use when it concerned pathologies with a severe prognosis. The quality of the demonstration (e.g., double-blind randomized trial vs. placebo or another active medicine) played a major role in the CB level. Clinical pediatric studies were also consistently associated with higher CAV levels: levels I (major) to III (moderate) in 26 out of 42 (62 %) opinions, level IV (minor) and level V (no therapeutic progress) in 43 out of 84 (51 %) and 30 out of 43 (70 %) opinions granting a sufficient CB, respectively. Conversely, 22 out of 30 (73 %) dossiers based only on literature reviews were given a level V. The main criteria leading to the qualification of a medicine for pediatric use as providing a PHI included a significant change in the morbidity and mortality of the disease and an improvement in the care pathway. Assessments were mostly aligned on the adults in the case of subsequent extensions of indications to children. Lastly, new measures were taken aimed at shortening median delays in the assessment process in order to reduce off-label use of medicines in France., Competing Interests: Declaration of competing interests None (See https://dpi-declaration.sante.gouv.fr)., (Copyright © 2024 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Purpose: Severe anterior maxillary atrophy offers few implant-supported rehabilitation solutions to Quad Zygoma characterized by a wide anterior cantilever. One of the possible alternatives to consider before the quad zygoma is the extra-long nasal/trans-nasal implant placement. This retrospective multicentric study shows the predictability of nasal/transnasal implant placement in patients affected by severe anterior maxilla atrophy, with residual anatomical features that indicate this surgery. This specific remote anchorage can often be safely involved in immediate loading with other remote anchorages, such as zygoma and pterygoid implants. In this rehabilitation, it's mandatory to reduce the instability of the frameworks and mechanical stress that could unfavorably affect the implant's prognosis due to the overloading derived from anterior bending., Materials and Methods: In this retrospective multicentric study, 52 nasal or trans-nasal implants were inserted in 31 atrophic anterior maxillas (Cawood and Howell's class V-VI). All implants were successful after the healing period; even if 27 nasal implants reached an insertional torque equal to or greater than 50 n/cm2, the threshold value estimated to be able to support an immediate load., Result: All 52 implants were successful, so the proportion of success was 100%, with a 97.5% one-sided confidence interval of 88.8-100%. The success rate is achieved only if at least two of the following criteria are met: 1) a greater torque than 50 Ncm as a minimum sufficient condition to plan immediate loading; 2) after a healing period of 16 weeks, the secondary stability is clinically and radiographically evaluated to exclude possible coronal bone resorption: this condition allows the successive prosthetic finalization; 3) the possibility of carrying out a full arch rehabilitation with minimal anterior spread. Insertion torque was <50 Newton centimeters (Ncm) in 14 patients (45%) and 50 Ncm in 17 (55%). Mechanical load was delayed in the former and immediate in the latter. The proportion of torque <50 Ncm was higher in men than in women (69% versus 28%, p&#61;0.033). Immediate torque was not significantly affected by age., Conclusion: Although the sample is not extremely numerically significant, it conveys a clear and significant clinical, surgical indication as never before in the literature; we can state that nasal/trans nasal implants have been very useful in reducing the anterior cantilever and overcoming the anatomical limitations affecting conventional Quad Zygoma.

Background : Petrous apex cholesterol granulomas (PACGs) are benign inflammatory cystic lesions of the temporal bone. Usually, asymptomatic patients may develop symptoms as the lesions expand. The diagnosis is based on both CT and MRI scans and the management relies on "wait and scan" or surgery. This paper aims at evaluating surgical outcomes and proposing a CT-based classification and a management algorithm. Methods : Patients with PACGs who were surgically treated between 2014 and 2024 were included. Symptoms, imaging, approach type and complications were considered. CT scans were classified as Type A (preserved apex cellularity), Type B (erosion of the apex cellularity), and Type C (involvement of the noble structures bone boundaries). The possible connection of the lesion with the infracochlear, perilabyrinthine and sphenoidal cellularity was assessed. Results : Nineteen patients with symptoms like diplopia, headache and sensorineural hearing loss were included. According to our classification, 1/19 patients was Type A, 4/19 were Type B and 14/19 were Type C. Five patients underwent a total resection, seven a subtotal and seven a surgical drainage. Only two complications were recorded, and 17/19 patients showed symptom regression and stability during follow-up. Conclusions : While the management of PACGs is still controversial, according to our classification and surgical outcomes, Type A, being mostly asymptomatic, should be managed with "wait and scan", Type B should undergo surgery when symptoms are present, while Type C should always undergo surgery because of their invasiveness and potential complications. When possible, a drainage should be attempted; otherwise, a surgical resection is chosen, and its completeness depends on the preoperative general and hearing status.

Mutations in the gene encoding MFN2 have been identified as associated with Charcot-Marie-Tooth disease type 2A (CMT2A), a neurological disorder characterized by a broad clinical phenotype involving the entire nervous system. MFN2, a dynamin-like GTPase protein located on the outer mitochondrial membrane, is well-known for its involvement in mitochondrial fusion. Numerous studies have demonstrated its participation in a network crucial for various other mitochondrial functions, including mitophagy, axonal transport, and its controversial role in endoplasmic reticulum (ER)-mitochondria contacts. Considerable progress has been made in the last three decades in elucidating the disease pathogenesis, aided by the generation of animal and cellular models that have been instrumental in studying disease physiology. A review of the literature reveals that, up to now, no definitive pharmacological treatment for any CMT2A variant has been established; nonetheless, recent years have witnessed substantial progress. Many treatment approaches, especially concerning molecular therapy, such as histone deacetylase inhibitors, peptide therapy to increase mitochondrial fusion, the new therapeutic strategies based on MF1/MF2 balance, and SARM1 inhibitors, are currently in preclinical testing. The literature on gene silencing and gene replacement therapies is still limited, except for a recent study by Rizzo et al.(Rizzo et al., 2023), which recently first achieved encouraging results in in vitro and in vivo models of the disease. The near-future goal for these promising therapies is to progress to the stage of clinical translation., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease that is associated with great suffering for those affected, as well as high socioeconomic costs. Early diagnosis and adequate medical care are essential for a mild course of the disease. However, there is a lack of current figures and data on the care situation of patients in the area., Methodology: A total of 1546 general practitioners, rheumatologists, neurologists, nephrologists and dermatologists in Rhineland-Palatinate and Saarland were interviewed by fax or mail using a questionnaire regarding epidemiology, symptoms, therapy and therapy success. In addition, there was the possibility of making suggestions for improvement., Results: Five out of six of the 635 reported SLE patients were female. The most common main symptoms were arthralgia, fatigue, myalgia, and skin changes. Of the patients, 68% received antimalarials (AMs), whereas 46% were treated with glucocorticoids (GCs) and 50% with an immunosuppressant (IS), mainly methotrexate. In terms of comorbidities, patients suffered mainly from cardiovascular disease, fibromyalgia syndrome and depression. Rheumatologists also frequently described anaemia, diabetes mellitus and osteoporosis., Discussion: Compared with guideline recommendations, the low rate of AMs in therapy was particularly striking in patients not treated by rheumatologists (35% on average compared with 81% for rheumatologists). Additionally, (sustained) high doses of GCs are not in line with literature recommendations. In the free text field, the main requests were for more rheumatologists in private practice and faster appointment scheduling, as well as better communication and networking. In addition, the desire for more training and education was frequently expressed.., (© 2024. The Author(s).)

Background: Early detection of pulmonary exacerbations (PEx) in patients with cystic fibrosis is important to quickly trigger treatment and reduce respiratory damage. An intervention was designed in the frame of the MucoExocet research study providing patients with cystic fibrosis with connected devices and educating them to detect and react to their early signs of PEx., Objective: This study aims to identify the contributions and conditions of home monitoring in relation to their care teams from the users' point of view to detect PEx early and treat it. This study focused on the patients' experiences as the first and main users of home monitoring., Methods: A qualitative study was conducted to explore patients' and professionals' experiences with the intervention. We interviewed patients who completed the 2-year study using semistructured guides and conducted focus groups with the care teams. All the interviews were recorded and transcribed verbatim. Their educational material was collected. A grounded analysis was conducted by 2 researchers., Results: A total of 20 patients completed the study. Three main categories emerged from the patients' verbatim transcripts and were also found in those of the professionals: (1) task technology fit, reflecting reliability, ease of use, accuracy of data, and support of the technology; (2) patient empowerment through technology, grouping patients' learnings, validation of their perception of exacerbation, assessment of treatment efficacy, awareness of healthy behaviors, and ability to react to PEx signs in relation to their care team; (3) use, reflecting a continuous or intermittent use, the perceived usefulness balanced with cumbersome measurements, routinization and personalization of the measurement process, and the way data are shared with the care team. Furthermore, 3 relationships were highlighted between the categories that reflect the necessary conditions for patient empowerment through the use of technology., Conclusions: We discuss a theorization of the process of patient empowerment through the use of connected devices and call for further research to verify or amend it in the context of other technologies, illnesses, and care organizations., Trial Registration: ClinicalTrials.gov NCT03304028; https://clinicaltrials.gov/ct2/show/results/NCT03304028., (©Maxime Morsa, Amélie Perrin, Valérie David, Gilles Rault, Enora Le Roux, Corinne Alberti, Rémi Gagnayre, Dominique Pougheon Bertrand. Originally published in JMIR Formative Research (https://formative.jmir.org), 23.01.2024.)

Competing Interests: Competing interests: DC reports an HIV grant from Janssen (2019-2020), personal fees from Gilead (2020) and Pfizer (2022) for lectures outside the submitted work. RT has been the coordinator of the IMI2 EBOVAC2 project in collaboration with Janssen (2014-2021). Other authors have no competing interests to disclose.