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IntroductionThe evolution of contraception has been crucial for public health and reproductive well-being. Over the past 60 years, combined oral contraceptives (COCs) have remained an important part of the contraceptive landscape worldwide; continued development has worked toward maintaining efficacy and improving safety.MethodsSeven global experts convened to discuss the clinical relevance of the oestrogen in COCs, focusing on the impact of the new oestrogen, oestetrol (E4). Participants then commented through an online forum on the summary content and other participants' feedback. We prepared this report to describe the experts' views, their follow-up from the open forum and the evidence supporting their views.ResultsEthinylestradiol (EE) and oestradiol (E2) affect receptors similarly whereas E4 has differential effects, especially in the liver and breast. Adequate oestrogen doses in COCs ensure regular bleeding and user acceptability. EE and E4 have longer half-lives than E2; accordingly, COCs with EE and E4 offer more predictable bleeding than those with E2. Oestrogen type and progestin influence VTE risk; E2 poses a lower risk than EE; although promising, E4/DRSP VTE risk is lacking population-based data. COCs alleviate menstrual symptoms, impact mental health, cognition, libido, skin, and bone health.ConclusionOestrogens play an important role in the contraceptive efficacy, bleeding patterns, and overall tolerability/safety of COCs. Recent studies exploring E4 combined with DRSP show promising results compared to traditional formulations, but more definitive conclusions await further research.

Abstract Malaria is preventable, but the burden of disease remains high with over 249 million cases and 608,000 deaths reported in 2022. Historically, the most important protective interventions have been vector control and chemopreventive medicines with over 50 million children receiving seasonal malaria chemoprevention in the year 2023. Two vaccines are approved and starting to be deployed, bringing additional protection for children up to 36 months. However, the impact of these currently available tools is somewhat limited on various fronts. Vaccines exhibit partial efficacy, are relatively costly, and not accessible in all settings. The challenges encountered with chemoprevention are barriers to acceptability and feasibility, including frequency of dosing, and the lack of options in the first trimester of pregnancy and for women living with HIV. Also, the emergence of resistance against chemopreventive medicines is concerning. To address these limitations, a target product profile (TPP) is proposed as a road map to guide innovation and to boost the quest for novel chemopreventive alternatives. This TPP describes the ideal product attributes, while acknowledging potential trade-offs that may be needed. Critically, it considers the target populations most at risk; primarily infants, children, and pregnant women. Malaria control and elimination requires appropriate chemoprevention, not only in areas of high endemicity and transmission, but also in lower transmission areas where immunity is declining, as well as for travellers from areas where malaria has been eliminated. New medicines should show acceptable safety and tolerability, with high and long protective efficacy. Formulations and costs need to support operational adherence, access, and effectiveness. Next generation long-acting oral and injectable drugs are likely to constitute the backbone of malaria prevention. Therefore, the perspectives of front-line experts in malaria prevention, researchers, and those involved in drug development are captured in the TPP. This inclusive approach aims at concentrating efforts and aligning responses across the community to develop new and transformative medicines.

Abstract A fundamental task for the brain is to generate predictions of future sensory inputs, and signal errors in these predictions. Many neurons have been shown to signal omitted stimuli during periodic stimulation, even in the retina. However, the mechanisms of this error signaling are unclear. Here we show that depressing inhibitory synapses shape the timing of the response to an omitted stimulus in the retina. While ganglion cells, the retinal output, responded to an omitted flash with a constant latency over many frequencies of the flash sequence, we found that this was not the case once inhibition was blocked. We built a simple circuit model and showed that depressing inhibitory synapses were a necessary component to reproduce our experimental findings. A new prediction of our model is that the accuracy of the constant latency requires a sufficient amount of flashes in the stimulus, which we could confirm experimentally. Depressing inhibitory synapses could thus be a key component to generate the predictive responses observed in the retina, and potentially in many brain areas.

The composition of the gut microbiota is a known factor in various diseases and has proven to be a strong basis for automatic classification of disease state. A need for a better understanding of microbiota data on the functional scale has since been voiced, as it would enhance these approaches' biological interpretability. In this paper, we have developed a computational pipeline for integrating the functional annotation of the gut microbiota into an automatic classification process and facilitating downstream interpretation of its results. The process takes as input taxonomic composition data, which can be built from 16S or whole genome sequencing, and links each component to its functional annotations through interrogation of the UniProt database. A functional profile of the gut microbiota is built from this basis. Both profiles, microbial and functional, are used to train Random Forest classifiers to discern unhealthy from control samples. SPARTA ensures full reproducibility and exploration of inherent variability by extending state-of-the-art methods in three dimensions: increased number of trained random forests, selection of important variables with an iterative process, repetition of full selection process from different seeds. This process shows that the translation of the microbiota into functional profiles gives non-significantly different performances when compared to microbial profiles on 5 of 6 datasets. This approach's main contribution however stems from its interpretability rather than its performance: through repetition, it also outputs a robust subset of discriminant variables. These selections were shown to be more consistent than those obtained by a state-of-the-art method, and their contents were validated through a manual bibliographic research. The interconnections between selected taxa and functional annotations were also analyzed and revealed that important annotations emerge from the cumulated influence of non-selected taxa.

Abstract Background Severe malaria is a life-threatening infection, particularly affecting children under the age of 5 years in Africa. Current treatment with parenteral artemisinin derivatives is highly efficacious. However, artemisinin partial resistance is widespread in Southeast Asia, resulting in delayed parasite clearance after therapy, and has emerged independently in South America, Oceania, and Africa. Hence, new treatments for severe malaria are needed, and it is prudent to define their characteristics now. This manuscript focuses on the target product profile (TPP) for new treatments for severe malaria. It also highlights preparedness when considering ways of protecting the utility of artemisinin-based therapies. Target product profile Severe malaria treatments must be highly potent, with rapid onset of antiparasitic activity to clear the infection as quickly as possible to prevent complications. They should also have a low potential for drug resistance selection, given the high parasite burden in patients with severe malaria. Combination therapies are needed to deter resistance selection and dissemination. Partner drugs which are approved for uncomplicated malaria treatment would provide the most rapid development pathway for combinations, though new candidate molecules should be considered. Artemisinin combination approaches to severe malaria would extend the lifespan of current therapy, but ideally, completely novel, non-artemisinin-based combination therapies for severe malaria should be developed. These should be advanced to at least phase 2 clinical trials, enabling rapid progression to patient use should current treatment fail clinically. New drug combinations for severe malaria should be available as injectable formulations for rapid and effective treatment, or as rectal formulations for pre-referral intervention in resource-limited settings. Conclusion Defining the TPP is a key step to align responses across the community to proactively address the potential for clinical failure of artesunate in severe malaria. In the shorter term, artemisinin-based combination therapies should be developed using approved or novel drugs. In the longer term, novel combination treatments should be pursued. Thus, this TPP aims to direct efforts to preserve the efficacy of existing treatments while improving care and outcomes for individuals affected by this life-threatening disease.

Background: Radiotherapy combined with fluorouracil (5FU) and cisplatin for locally advanced esophageal cancer is associated with a 20–25% pathologic complete response (pCR) rate. Cetuximab increases the efficacy of radiotherapy in patients with head and neck carcinomas. The aim of this phase I/II trial was to determine the optimal doses and the pCR rate with chemoradiotherapy (C-RT) plus cetuximab. Methods: A 45-Gy radiotherapy regimen was delivered over 5 weeks. The phase I study determined the dose-limiting toxicity and the maximum tolerated dose of 5FU-cisplatin plus cetuximab. The phase II trial aimed to exhibit a pCR rate > 20 % (25 % expected), requiring 33 patients (6 from phase I part plus 27 in phase II part). pCR was defined as ypT0Nx. Results: The phase I study established the following recommended doses: weekly cetuximab (400 mg/m2 one week before, and 250 mg/m2 during radiotherapy); 5FU (500 mg/m2/day, d1-d4) plus cisplatin (40 mg/m2, d1) during week 1 and 5. In the phase II part, 32 patients received C-RT before surgery, 31 patients underwent surgery, and resection was achieved in 27 patients. A pCR was achieved in five patients (18.5 %) out of 27. After a median follow-up of 19 months, the median progression-free survival was 13.7 months, and the median overall survival was not reached. Conclusions: Adding cetuximab to preoperative C-RT was toxic and did not achieve a pCR > 20 % as required. The recommended doses, determined during the phase I part, could explain these disappointing results due to a reduction in chemotherapy dose-intensity. Trial registration: This trial was registered with EudraCT number 2006-004770-27.

Objective: Tumor molecular genotyping plays a key role in improving the management of advanced thyroid cancers. Molecular tests are classically performed on formalin-fixed, paraffin-embedded (FFPE) carcinoma tissue. However alternative molecular testing strategies are needed when FFPE tumoral tissue is unavailable. The objective of our study was to retrospectively assess the performance of targeted DNA and RNA-based next-generation sequencing (NGS) on the fine needle aspirate from thyroid cancer cervical recurrences to determine if this strategy is efficient in clinical practice. Design/Methods: A retrospective study of 33 patients who had had DNA and/or RNA-based NGS on ultrasound (US)-guided fine needle aspirates of cervical thyroid cancer recurrences in our Department from July 2019 to September 2022. Results: In total, 34 DNA and 32 RNA-based NGS analyses were performed. Out of the 34 DNA-based NGS performed, 27 (79%) were conclusive allowing the identification of an oncogenic driver for 18 patients (53%). The most common mutation (n = 13) was BRAF c.1799T>A. Out of the 32 RNA-based NGS performed, 26 were interpretable (81%) and no gene fusion was found. The identification of a BRAFV600E mutation was decisive for one patient in our series, who was prescribed dabrafenib and trametinib. Conclusion: NGS performed on fine needle aspirates of neck lymph node metastases enabled the identification of an oncogenic driver alteration in 53% of the cases in our series of advanced thyroid cancer patients and could significantly alter patient management. Significance statement This paper shows that thyroid cancer genotyping on the fine needle aspirate (FNA) of a metastatic neck lymph node recurrence can be performed efficiently. This strategy of genotyping appears particularly effective and safe when FFPE tissue is unavailable and when the spread of the disease requires systemic treatment. To the best of our knowledge, our data regarding DNA and RNA next generation sequencing on FNA of metastatic neck recurrences are the first ever published.

Background and Objectives: Dry needling (DN) is a technique that involves inserting a thin filament needle through the skin to target myofascial trigger points for the treatment of musculoskeletal pain and dysfunction. Despite its efficacy in a broad plethora of musculoskeletal pain conditions, its safety remains a topic of debate among clinicians and researchers. The aim of this study was to provide an overview of the current practice of DN through a national survey, focusing on the frequency of its use and the incidence of adverse events (AEs), considering factors including physiotherapist experience, clinical workload, the extent of training received by practitioners, and the use of ultrasound guidance. Materials and Methods: An online cross-sectional survey was conducted. Respondents were licensed physical therapists (PTs) working in Spain. The survey covered demographics, professional data, frequency of adverse effects, and if they use ultrasound routinary for guiding interventions. Results: A total of 422 PTs participated in the study, mostly having 21–60 h of DN training (38.6%), less than 2 years of experience (36%), and not using ultrasound during the interventions (85.5%). Post-needling soreness and bent needles were the most common AEs, with most severe events rarely reported. Adverse event frequencies varied significantly based on training hours, experience, patient percentage treated with DN, and weekly clinical dedication. Clinicians with more hours of DN training or fewer years of experience reported higher incidences of certain complications. Conclusions: DN is a common intervention among PTs, with minor AEs frequently occurring and major AEs being less common but still significant. The accidental puncture of non-desired structures highlights the necessity for improve training on anatomical landmarks, needle insertion depth, cross-sectional anatomy education, and patient monitoring. To ensure safe practice, emphasize comprehensive training, adhere to safety protocols, exercise caution, and prioritize the use of ultrasound-guide is encouraged.

Summary: Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19. Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care). Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61–1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64–1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09–0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality. Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19. Funding: Hellenic Foundation for Research and Innovation.

Breast cancer is the most common female cancer in the world. Numerous studies have shown that the risk of metastatic disease increases with tumor volume. In this context, it is useful to assess whether the regular practice of formal breast self-examination (BSE) as opposed to breast awareness has an impact on the number of cancers diagnosed, their stage, the treatments used and mortality. Design: The Commission of Senology (CS) of the Collège National de Gynécologie et Obstétrique Français (CNGOF) respected and followed the Grading of Recommendations Assessment, Development and Evaluation method to assess the quality of the evidence on which the recommendations were based. Methods: The CS studied 16 questions individualizing four groups of women (general population, women aged over 75, high-risk women, and women previously treated for breast cancer). For each situation, it was determined whether the practice of BSE versus abstention from this examination led to detection of more breast cancers and/or recurrences and/or reduced treatment and/or increased survival. Results: BSE should not be recommended for women in the general population, who otherwise benefit from clinical breast examination by practitioners from the age of 25, and from organized screening from 50 to 74 (strong recommendation). In the absence of data on the benefits of BSE in patients aged over 75, for those at high risk and those previously treated for breast cancer, the CS was unable to issue recommendations. Thus, if women in these categories wish to undergo BSE, information on the benefits and risks observed in the general population must be given, notably that BSE is associated with a higher number of referrals, biopsies, and a reduced quality of life.

IntroductionThe evolution of contraception has been crucial for public health and reproductive well-being. Over the past 60 years, combined oral contraceptives (COCs) have remained an important part of the contraceptive landscape worldwide; continued development has worked toward maintaining efficacy and improving safety.MethodsSeven global experts convened to discuss the clinical relevance of the oestrogen in COCs, focusing on the impact of the new oestrogen, oestetrol (E4). Participants then commented through an online forum on the summary content and other participants' feedback. We prepared this report to describe the experts' views, their follow-up from the open forum and the evidence supporting their views.ResultsEthinylestradiol (EE) and oestradiol (E2) affect receptors similarly whereas E4 has differential effects, especially in the liver and breast. Adequate oestrogen doses in COCs ensure regular bleeding and user acceptability. EE and E4 have longer half-lives than E2; accordingly, COCs with EE and E4 offer more predictable bleeding than those with E2. Oestrogen type and progestin influence VTE risk; E2 poses a lower risk than EE; although promising, E4/DRSP VTE risk is lacking population-based data. COCs alleviate menstrual symptoms, impact mental health, cognition, libido, skin, and bone health.ConclusionOestrogens play an important role in the contraceptive efficacy, bleeding patterns, and overall tolerability/safety of COCs. Recent studies exploring E4 combined with DRSP show promising results compared to traditional formulations, but more definitive conclusions await further research.

Objectives: Positive direct antiglobulin tests (DATs) have been reported in cases of post-artesunate delayed hemolysis (PADH), but the causal role of auto-immune hemolysis remains unclear. We aimed to analyze a cohort of patients with PADH and DAT during severe malaria.Methods: We describe PADH and DAT results in a 7-year multi-center retrospective cohort of patients receiving artesunate for severe imported malaria.Results: Of 337 patients treated with artesunate, 46 (13.6%) had at least one DAT result within 30 days of treatment initiation, and 25/46 (54.3%) had at least one positive DAT. Among 40 patients with available data, 17 (42.5%) experienced PADH. Patient characteristics were similar for patients with a positive or negative DAT, and DAT positivity was not associated with PADH occurrence (P = 0.36). Among patients, 5/13 (38.5%) with a positive DAT after day 7 experienced PADH, compared to 10/13 (76.9%) of those with a negative DAT after day 7 (P = 0.11). Overall, 41% of patients required blood transfusions, and outcome was favorable without corticosteroids, even in cases of PADH.Conclusions: DAT does not appear to be a marker of PADH, but rather an indirect marker of an immune-mediated mechanism. DAT positivity should not lead to the administration of systemic corticosteroids during PADH.

Acute respiratory tract infections are one of the leading causes of morbidity and mortality worldwide. More data are needed on circulating respiratory microorganisms in different geographical areas and ecosystems. We analyzed nasopharyngeal swabs from 500 febrile patients living in the Niakhar area (Senegal), using FTDTM multiplex qPCR and simplex qPCR to target a panel of 25 microorganisms. We detected at least one microorganism for 366/500 patients (73.2%), at least one virus for 193/500 (38.6%), and at least one bacterium for 324/500 (64.8%). The most frequently detected microorganisms were Streptococcus pneumoniae (36.8%), Haemophilus influenzae (35.8%), adenovirus (11.8%), influenza viruses (6.4%), rhinovirus (5.0%), SARS-CoV-2 (4.0%), and RSV (4.0%). The main microorganisms significantly associated with respiratory symptoms, with a p-value ≤ 0.05, were influenza virus (11.9% in patients with respiratory symptoms versus 2.9% in patients without), RSV (6.5% versus 2.6%), metapneumovirus (5.4% versus 1.3%), HPIVs (7.6% versus 1.0%), S. pneumoniae (51.9% versus 28.0%), and H. influenzae (54.6% versus 24.5%). Co-infections were significantly associated with respiratory symptoms (65.4% versus 32.9%). All the epidemiological data show a high level of circulation of respiratory pathogens among febrile patients, including those preventable by vaccination such as S. pneumoniae, raising the question of the serotypes currently circulating. Furthermore, the availability of affordable real-time etiological diagnostic tools would enable management to be adapted as effectively as possible.

Discrete mathematics brings interesting problems for teaching and learning proof, with accessible objects such as integers (arithmetic), graphs (modeling, order) or polyominoes (geometry). Many problems that are still open can be explained to a large public. The objects can be manipulated by simple dynamic operations (removing, adding, 'gluing', contracting, splitting, decomposing, etc.). All these operations can be seen as tools for proving. In this paper we particularly explore the field of 'discrete optimization'. A theoretical background is defined by taking two main axes into account, namely, the epistemological analysis of discrete problems studied by contemporary researchers in discrete optimization and the design of adidactical situations for classrooms in the frame of the Theory of Didactical Situations. Two problems coming from ongoing research in discrete optimization (the Pentamino Exclusion and the Eight Queens problems) are developed and transposed for the classroom. They underscore the learning potentialities of discrete mathematics and epistemological obstacles concerning proving processes. They emphasize the understanding of a necessary condition and a sufficient condition and problematize the difference between optimal and optimum. They provide proofs involving partitioning strategies, greedy algorithms but also primal-dual methods leading to the concept of duality. The way such problems can be implemented in the classroom is described in a collaborative study by mathematicians and mathematics education researchers ("Maths à Modeler" Research Federation) through the Research Situations for the Classroom project.

Abstract Introduction The aim of this study was to describe the management of neovascular age-related macular degeneration (nAMD) in French patients between 2008 and 2018. Methods This was a retrospective longitudinal cohort study using exhaustive nationwide health records from the French National Health Information database. Enrollment criteria were adults aged ≥ 50 years, nAMD diagnosis, or reimbursement for nAMD treatments (anti-vascular epithelial growth factor [VEGF] injection or dynamic phototherapy with verteporfin). Exclusion criteria were high myopia, diagnosis of other retinal diseases, and treatments for other macular diseases (dexamethasone implant, laser). Main outcome measures were consumption of medical care and nAMD treatments per calendar year and number of years of follow-up. Results Between 2008 and 2018, we identified 342,961 patients who have been treated for nAMD. Median duration of ophthalmological follow-up exceeded 7 years (90 months). The median annual number of ophthalmology consultations decreased from nine visits in year 1 after treatment initiation to four visits from year 7 onwards. The median duration of nAMD treatment was 10.1 months for all patients, with 48.5% of patients undergoing treatment for < 1 year. Only 24.4% of patients had maintained treatment at year 11. Patients remaining under treatment had a median of four anti-VEGF treatments per year throughout the 10-year study period. Ranibizumab was the more common first-line treatment (67.5% of patients) compared to aflibercept (32.4%). About 20% of patients who initiated treatment switched treatment at least once. Conclusions LANDSCAPE provides exhaustive nationwide data on the real-world management of nAMD in France over a 10-year period. Further investigation into short treatment duration is required, especially in terms of understanding its relation to visual outcomes.

Abstract Background Plasmodium falciparum immature gametocytes accumulate in the bone marrow, but their exact location in this tissue remains unclear. Methods The stage and deposition pattern of gametocytes was analysed on histological sections of a bone marrow sample collected in a patient with subacute P. falciparum malaria. Results A majority (89%) of immature stages II to IV gametocytes and a minority (29%) of mature stage V gametocytes were observed in extravascular spaces. Discussion and conclusion These observations represent a valuable step towards understanding sequestration patterns of P. falciparum gametocytes and may ultimately lead to novel transmission-blocking interventions.

Abstract Plasmodium vivax threatens nearly half the world’s population and is a significant impediment to achievement of the millennium development goals. It is an important, but incompletely understood, cause of anaemia. This review synthesizes current evidence on the epidemiology, pathogenesis, treatment and consequences of vivax-associated anaemia. Young children are at high risk of clinically significant and potentially severe vivax-associated anaemia, particularly in countries where transmission is intense and relapses are frequent. Despite reaching lower densities than Plasmodium falciparum, Plasmodium vivax causes similar absolute reduction in red blood cell mass because it results in proportionately greater removal of uninfected red blood cells. Severe vivax anaemia is associated with substantial indirect mortality and morbidity through impaired resilience to co-morbidities, obstetric complications and requirement for blood transfusion. Anaemia can be averted by early and effective anti-malarial treatment.

Abstract At the 2010 Keystone Symposium on "Malaria: new approaches to understanding Host-Parasite interactions", an extra scientific session to discuss animal models in malaria research was convened at the request of participants. This was prompted by the concern of investigators that skepticism in the malaria community about the use and relevance of animal models, particularly rodent models of severe malaria, has impacted on funding decisions and publication of research using animal models. Several speakers took the opportunity to demonstrate the similarities between findings in rodent models and human severe disease, as well as points of difference. The variety of malaria presentations in the different experimental models parallels the wide diversity of human malaria disease and, therefore, might be viewed as a strength. Many of the key features of human malaria can be replicated in a variety of nonhuman primate models, which are very under-utilized. The importance of animal models in the discovery of new anti-malarial drugs was emphasized. The major conclusions of the session were that experimental and human studies should be more closely linked so that they inform each other, and that there should be wider access to relevant clinical material.

Authors propose their splenic mimetic filtration method, microsphiltration, and utilise this approach in a drug-screen, to identify compounds that induce a stiffening effect on Plasmodium falciparum-infected erythrocytes. They proceed to assess safety and tolerability of one identified compound in a phase I clinical trial.