Kernel-based testing for single-cell differential analysis.

Single-cell technologies offer insights into molecular feature distributions, but comparing them poses challenges. We propose a kernel-testing framework for non-linear cell-wise distribution comparison, analyzing gene expression and epigenomic modifications. Our method allows feature-wise and global transcriptome/epigenome comparisons, revealing cell population heterogeneities. Using a classifier based on embedding variability, we identify transitions in cell states, overcoming limitations of traditional single-cell analysis. Applied to single-cell ChIP-Seq data, our approach identifies untreated breast cancer cells with an epigenomic profile resembling persister cells. This demonstrates the effectiveness of kernel testing in uncovering subtle population variations that might be missed by other methods.

French national protocol for the management of congenital ichthyosis.

Congenital ichthyoses (CI) comprise a heterogeneous group of monogenic genetic skin diseases characterized by diffuse scaling, often associated with skin inflammation. Diagnosis of the individual form of ichthyosis is complex and is guided by clinical expertise. CI usually has a major impact on quality of life (QOL) and thus requires lifelong treatment. To date, there are no curative therapies, although various symptomatic treatment options exist. The present protocol for the management of CI has been drawn up in accordance with the recommendations published in 2012 by the French National Authority for Health, based on a literature review, with the help and validation of members of the French network for rare skin diseases (FIMARAD). It provides a summary of evidence and expert-based recommendations and is intended to help clinicians with the management of these rare and often complex diseases.

[Digital transformation of perioperative nurse-coordinated protocols in renal surgery for enhanced recovery and outpatient surgery using UroConnect® application]. / Digitalisation de la coordination infirmière des parcours périopératoires de chirurgie rénale en réhabilitation améliorée et ambulatoire par l'application UroConnect®.

Robot Assisted Partial Nephrectomy (RAPN) is a standard of care for localized renal tumors. It allows a good carcinological control while limiting complications. Despite numerous benefits, the economic sustainability of robotic assistance remains a challenge in the French health care system. The introduction in our institution of two perioperative nurse-coordinated protocols for patients undergoing RAPN (Enhanced Recovery After Surgery: NP-RAAC in 2015 and Outpatient: Ambu-Rein in 2016) is associated with a shortening of the average length of hospital stay, thus reducing the cost of robotic assisted procedures. With the aim of improving efficiency of nursing support within these protocols, we have introduced digitalized nursing coordination by developing a urological perioperative application: UroConnect®. This device is offered to patients by the coordinating nurses during a preoperative visit. It provides information on the pathology and its surgical management. Self-completed questionnaires sent at key moments collect data from the first month after surgery and detect patients presenting difficulties or complications, allowing the nurses to respond with appropriate care. The application allows a secure discharge, a personalised follow-up and an increase in the patient's autonomy and compliance with care.

Remote patient monitoring for chronic heart failure in France: When an innovative funding program (ETAPES) meets an innovative solution (Satelia® Cardio).

Introduction: Remote patient monitoring (RPM) is a telehealth activity to collect and analyze patient health or medical data. Its use has expanded in the past decade and has improved medical outcomes and care management of non-communicable chronic diseases. However, implementation of RPM into routine clinical activities has been limited. The objective of this study was to describe the French funding program for RPM (known as ETAPES) and one of the RPM solution providers (Satelia®) dedicated to chronic heart failure (CHF). Methods: A descriptive assessment of both the ETAPES funding program and Satelia® RPM solution was conducted. Data were collected from official legal documents and information that was publicly available online from the French Ministry of Health. Results and Discussion: ETAPES was formally created in 2016 based on previous legislation pertaining to the national health insurance funding strategy. However, it only started to operate in 2018. Patients with CHF were only eligible if they were at medium or high risk of re-hospitalization with a New York Heart Association (NYHA) score superior or equal to two and a BNP>100 pg/ml or NT pro BNP>1000 pg/ml. Medical monitoring was supported through the therapeutic education of a patient on the RPM model of care with a minimum of three training sessions during the first six months. The use of Satelia® Cardio is noteworthy since it relies only on symptomatic monitoring through which the patient manually reports their information by answering a simple questionnaire on a regular basis and does not rely on any connected devices. Conclusion: Innovative funding programs and solutions for RPM need real-world evaluation in the future.

Dermatologic manifestations in paediatric neurofibromatosis type 2: a cross sectional descriptive multicentric study.

BACKGROUND: Neurofibromatosis type 2 (NF2) is characterized by bilateral vestibular schwannoma (VS) more often in adults but a severe paediatric form with multiple neurological tumours is also described. In this population, a early diagnosis is important to prevent the onset of neurological complications but is difficult, particularly without a familial history. Cutaneous manifestations, which may precede VS or neurological tumours by several years, may contribute to an early diagnosis, but specific studies are lacking. The objective of this study was to characterize cutaneous manifestations of NF2 in a paediatric population. RESULTS: This observational, descriptive and multicentric study was conducted from April 2019 to April 2020 in seven academic French hospitals. We included patients ≤ 18 years old who fulfilled the Manchester diagnostic criteria or had a pathogenic mutation identified in the NF2 gene. All patients underwent a dermatological examination guided by a standardized questionnaire. 21 children were included, of whom 20 had at least one skin tumour (mean number 5 ± 4.6 [range 0-15]), which led to a diagnosis in four cases. In the other 17 cases, the diagnosis of NF2 was based on neurosensory complications (n = 10), family screening (n = 4) or ocular signs (n = 3). Before the NF2 diagnosis, 15 children had at least one "undiagnosed" cutaneous tumour that did not lead to a specific management. Patients' dermatological examination also revealed < 6 non specific café au lait macules (n = 15), hypopigmented macules (n = 12) with more than 3 lesions in 4 cases, and purple reticulated macules of the trunk (n = 4). CONCLUSION: Dermatological lesions are frequent and early in children with NF2 but rarely lead to the diagnosis. Cutaneous schwannomas are the most frequent but are often underdiagnosed. Café au lait macules are frequent, but atypical and mostly in small numbers. Multiple hypopigmented macules seem suggestive although inconsistent. The sensitivity of reticulated capillary malformation-like lesions remains to be assessed by further studies.

Safety and efficacy of low-dose PI3K inhibitor taselisib in adult patients with CLOVES and Klippel-Trenaunay syndrome (KTS): the TOTEM trial, a phase 1/2 multicenter, open-label, single-arm study.

PURPOSE: PIK3CA pathogenic variants in the PIK3CA-related overgrowth spectrum (PROS) activate phosphoinositide 3-kinase signaling, providing a rationale for targeted therapy, but no drug has proven efficacy and safety in this population. Our aim was to establish the six-month tolerability and efficacy of low-dose taselisib, a selective class I PI3K inhibitor, in PROS patients. METHODS: Patients over 16 years with PROS and PIK3CA pathogenic variants were included in a phase IB/IIA multicenter, open-label single-arm trial (six patients at 1 mg/day of taselisib, then 24 at 2 mg/day). The primary outcome was the occurrence of dose limiting toxicity (DLT). Efficacy outcomes were the relative changes after treatment of (1) tissue volume at affected and unaffected sites, both clinically and on imaging; (2) cutaneous vascular outcomes when relevant; (3) biologic parameters; (4) quality of life; and (5) patient-reported outcomes. RESULTS: Among 19 enrolled patients, 2 experienced a DLT (enteritis and pachymeningitis) leading to early trial termination (17 treated, 10 completed the study). No serious adverse reaction occurred in the 1 mg cohort (n = 6). No significant reduction in affected tissue volume was observed (mean -4.2%; p = 0.81; SD 14.01). Thirteen (76.4%) participants reported clinical improvement (pain reduction, chronic bleeding resolution, functional improvement). CONCLUSION: Despite functional improvement, the safety profile of low-dose taselisib precludes its long-term use.

Development and co-construction of a therapeutic patient education program for albinism.

BACKGROUND: Long-term and ongoing support in accordance with the changing needs of patients and their families is one of the main components of patient care, including therapeutic patient education (TPE). OBJECTIVE: To co-construct a TPE program for albinism with all those involved in the management of albinism patients. METHODS: Eight steps have been defined for the co-construction process: 1) identify all the relevant experts and invite them to participate in the construction of a TPE program to improve care for and support of patients with albinism, 2) review and analyse all publications regarding TPE for albinism, 3) conduct semi-structured interviews with the patients' parents, 4) conduct brainstorming meetings with the participating experts for an exchange of experience and expertise, 5) elaborate the program's concrete content with the experts, 6) draw up a TPE skills checklist, 7) create TPE educational tools to facilitate learning, 8) review and summarize each step of the co-construction protocol. RESULTS: Co-construction of a TPE program for children, adolescents, and young adults with albinism, and their parents. CONCLUSION: Strengths and advantages of the co-construction process include: i) highlighting of the experiential knowledge mentioned in the repository, ii) multiplicity of points of view and perspectives, iii) rapid improvement in TPE training both for the association and the patients, iv) awareness of the shift caregivers' position with regards to TPE and recognition of the polysemy of their discourse. The TPE program for albinism has been authorized since 2018.

Prediction of the intramuscular connective tissue components of fresh and freeze-dried samples by near infrared spectroscopy.

This study compared the performance of near-infrared spectroscopy (NIRS) models on fresh and freeze-dried beef muscle samples to predict intramuscular connective tissue (IMCT) components and to determine whether the accuracy of the models differed among different muscles from beef cattle. The hypothesis was that the water content of muscle samples would negatively influence the accuracy of the models, which would differ among muscles. Fresh and freeze-dried samples (n = 171) of four muscles were used to develop NIRS models to predict the contents IMCT. For the total collagen content, the standard error of cross validation (SECV) for model using freeze-dried samples (0.75 mg OH-prol/g DM) was lower than that for model using fresh samples (0.84 mg OH-prol/g DM). For cross-links and proteoglycans, the SECV for models using fresh sample spectra was lower than that for models using freeze-dried sample spectra. The accuracy of the prediction of the models also differed among predicted muscle types.

Management of albinism: French guidelines for diagnosis and care.

Albinism is a worldwide genetic disorder caused by mutations in at least 20 genes, identified to date, that affect melanin production or transport in the skin, hair and eyes. Patients present with variable degrees of diffuse muco-cutaneous and adnexal hypopigmentation, as well as ocular features including nystagmus, misrouting of optic nerves and foveal hypoplasia. Less often, albinism is associated with blood, immunological, pulmonary, digestive and/or neurological anomalies. Clinical and molecular characterizations are essential in preventing potential complications. Disease-causing mutations remain unknown for about 25% of patients with albinism. These guidelines have been developed for the diagnosis and management of syndromic and non-syndromic forms of albinism, based on a systematic review of the scientific literature. These guidelines comprise clinical and molecular characterization, diagnosis, therapeutic approach and management.

Incontinentia pigmenti in boys: Causes and consequences.

INTRODUCTION: Incontinentia pigmenti (IP) is an X-linked genodermatosis caused by mutation of the NEMO/IKBKG gene. While lethal in male foetuses, heterozygous females survive because of X-inactivation mosaicism. Herein we discuss 9 male patients with IP. MATERIALS AND METHODS: This is an observational, descriptive, retrospective, multicentre, French study carried out with the help of the SFDP research group. Statistical analysis was performed both on our own patients and on those reported in the literature. RESULTS: Nine boys with no family history of IP but with typical neonatal skin reactions were included. Genetic analysis of blood (n=8) and skin biopsy (n=3) confirmed the diagnosis of IP by identification of common deletion of the IKBKG/NEMO gene (exons 4 to 10) in the state of somatic mosaic in 6 and 2 cases respectively. Where analysed, the karyotype was normal (n=6). Over a median follow-up period of 48 months (3 months to 10 years), 3 patients had neurological abnormalities, 2 had severe ophthalmologic abnormalities, and 1 had dental abnormalities. Extensive skin involvement is a systemic risk factor, unlike cutaneous scarring. CONCLUSION: IP in boys is often due to a mosaic mutation that should be sought in blood and skin. Long-term neurological and ophthalmological monitoring is essential, especially in cases of extensive skin involvement.

Predictive criteria for acute heart failure in emergency department patients with acute dyspnoea: the PREDICA study.

OBJECTIVES: The early identification of patients with Acute Heart Failure Syndrome (AHFS) among patients admitted to the Emergency Department (ED) with dyspnoea can facilitate the introduction of appropriate treatments. The objectives are to identify the predictive factors for AHFS diagnosis in patients with acute dyspnoea (primary objective) and the clinical 'gestalt' (secondary objective) in ED. METHODS: PREDICA is an observational, prospective, multicentre study. The enrolment of patients admitted to the ED for nontraumatic acute dyspnoea and data collection on admission were recorded by the patient's emergency physician. The AHFS endpoints were assessed following a duplicate expert evaluation by pairs of cardiologists and emergency physicians. Step-by-step logistic regression was used to retain predictive criteria, and the area under the receiver operating characteristic (ROC) curve of the model was constructed to assess the ability of the selected factors to identify real cases. The probability of AHFS was estimated on a scale from 1 to 10 based on the emergency physician's perception and understanding (gestalt). RESULTS: Among 341 patients consecutively enrolled in three centres, 149 (44%) presented AHFS. Eight predictive factors of AHFS were detected with a performance test showing an area under the model ROC curve of 0.86. Gestalt greater than or equal to five showed sensitivity of 78% and specificity of 90% (AUC 0.91) and diagnosed 88% of AHF in our population. CONCLUSIONS: We identified several independant predictors of final AHFS diagnosis. They should contribute to the development of diagnostic strategies in ED. However, unstructured gestalts seem to perform very well alone.

The role of the dorsal anterior insula in ecstatic sensation revealed by direct electrical brain stimulation.

BACKGROUND: An ecstatic phenomenon is an altered state of consciousness with a sense of "hyper-reality", and a complete present-moment awareness with a feeling of union with the Universe. A better understanding of the network mechanisms underlying this fascinating subjective experience may help to unravel some mysteries of human consciousness. Insula has been recently proposed to be a key region to elicit these symptoms. OBJECTIVE/HYPOTHESIS: We studied functional connectivity changes in several brain areas during the induction of ecstatic auras by direct electrical stimulation of the dorsal anterior insular cortex in patients with refractory focal epilepsy implanted with intracerebral electrodes (stereotactic-EEG, SEEG) in the context of their pre-surgical evaluation. METHODS: Three patients were selected on the basis of the occurrence of ecstatic symptoms triggered by direct intracerebral electrical stimulation (ES) of the antero-dorsal part of the insula. ES was performed (50 Hz, 1.5-2.1 mA, in a bipolar fashion to each contact in the gray matter during a 3 s period) to map functional cortices and trigger habitual seizures. One stimulation inducing ecstatic changes in each patient was analyzed. Functional connectivity analysis was performed by measuring interdependencies (nonlinear regression analysis based on the h2 coefficient) between SEEG signals before and after stimulations. RESULTS: In all patients, only the stimulation of dorsal anterior insula was able to reproduce an ecstatic aura. We observed a significant increase of functional connectivity values between several brain regions in the immediate period following stimulations. The most commonly implicated region was the dorsal anterior insula. Out-degrees (a measure intended to identify leading structures in a network) identified the dorsal anterior insula as the most common leading region in the induced networks. CONCLUSION(S): Our findings bring additional support in favor of a major role played by the dorsal anterior insula in ecstatic experiences.

[Genetics and dermatology]. / Génétique en dermatologie.

Many types of genodermatosis exist, with numerous modes of transmission. The development of molecular genetic methods, in particular the most recent sequencing techniques, can be used to identify an increasing number of genes involved in these forms of genodermatosis while providing confirmation or more details regarding clinical diagnosis. Thanks to this approach, it is possible to determine risk of recurrence and to formulate an antenatal strategy. These technologies have led to improved molecular definition and to a better understanding of the physiopathological mechanisms involved in different genodermatoses such as bullous epidermolysis, keratinisation disorders, pigmentation disorders, potentially tumoral conditions, and epidermal and pilar dysplasia. The large amount of information provided by high-throughput sequencing makes it possible to study modifying genes as well as genotype-phenotype correlations. However, this genetic information in its turn poses problems of interpretation and of control of the resulting data. The use of genetics in dermatology for the purposes of diagnosis or research requires a consultation to provide patients with information regarding the genetic tests involved and the potential consequences thereof for them and their families. Furthermore, with pangenomic approaches there is a higher probability of fortuitous discovery of abnormalities such as variants associated with risks predisposing to cancer or neurodegenerative disease. Collaboration between dermatologists and geneticists enables optimisation of patient management in terms of diagnosis and genetic counselling in the event of such rare diseases. Therapeutic applications are beginning to be developed. The scope of therapeutic application includes gene therapy, replacement therapy (enzyme therapy) and targeted therapy.

[Peculiarities of botulinum toxin injections for the aesthetic treatment of men's face. A review of the literature]. / Particularités des injections de toxine botulique pour le traitement esthétique du visage chez l'homme. Une mise au point de la littérature.

INTRODUCTION: Botulinum toxin injections in aesthetic medicine are the most widely used products, ahead of hyaluronic acid, and aesthetic medicine is constantly increasing, including in the male population. The objective of this development was to show the specificities described in the literature concerning botulinum toxin injections in men. MATERIAL AND METHOD: A systematic literature search was carried out using the Pubmed search engine. Data were then collected to determine the specificities of botulinum toxin injections in men according to the morphology of the male face and the wishes of these patients. RESULTS: The studies conducted show that it is necessary to inject higher doses in men than in women to obtain a satisfactory result, due to a higher muscle mass. This adjustment gives the number of points to be performed per injection site, as well as the number of points to be performed, compared to the female population. CONCLUSION: Botulinum toxin injections for aesthetic purposes in men are different from those in women. Taking these particularities into account is essential to patient satisfaction.