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.

[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.

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.

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.

[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.

Dermatological manifestations in cardiofaciocutaneous syndrome: a prospective multicentric study of 45 mutation-positive patients.

BACKGROUND: Data on dermatological manifestations of cardiofaciocutaneous syndrome (CFCS) remain heterogeneous and almost without expert dermatological classification. OBJECTIVES: To describe the dermatological manifestations of CFCS; to compare them with the literature findings; to assess those discriminating CFCS from other RASopathies, including Noonan syndrome (NS) and Costello syndrome (CS); and to test for dermatological phenotype-genotype correlations. METHODS: We performed a 4-year, large, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Forty-five patients were enrolled. Hair abnormalities were ubiquitous, including scarcity or absence of eyebrows and wavy or curly hair in 73% and 69% of patients, respectively. Keratosis pilaris (KP), ulerythema ophryogenes (UO), palmoplantar hyperkeratosis (PPHK) and multiple melanocytic naevi (MMN; over 50 naevi) were noted in 82%, 44%, 27% and 29% of patients, respectively. Scarcity or absence of eyebrows, association of UO and PPHK, diffuse KP and MMN best differentiated CFCS from NS and CS. Oral acitretin may be highly beneficial for therapeutic management of PPHK, whereas treatment of UO by topical sirolimus 1% failed. No significant dermatological phenotype-genotype correlation was determined. CONCLUSIONS: A thorough knowledge of CFCS skin manifestations would help in making a positive diagnosis and differentiating CFCS from CS and NS.

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation.

BACKGROUND: Data on dermatological manifestations of Noonan syndrome (NS) remain heterogeneous and are based on limited dermatological expertise. OBJECTIVES: To describe the dermatological manifestations of NS, compare them with the literature findings, and test for dermatological phenotype-genotype correlations with or without the presence of PTPN11 mutations. METHODS: We performed a large 4-year, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Overall, 129 patients with NS were enrolled, including 65 patients with PTPN11-NS, 34 patients with PTPN11-NS with multiple lentigines (NSML), and 30 patients with NS who had a mutation other than PTPN11. Easy bruising was the most frequent dermatological finding in PTPN11-NS, present in 53·8% of patients. Multiple lentigines and café-au-lait macules (n ≥ 3) were present in 94% and 80% of cases of NSML linked to specific mutations of PTPN11, respectively. Atypical forms of NSML could be associated with NS with RAF1 or NRAS mutations. In univariate analysis, patients without a PTPN11 mutation showed (i) a significantly higher frequency of keratinization disorders (P = 0·001), including keratosis pilaris (P = 0·005), ulerythema ophryogenes (P = 0·0001) and palmar and/or plantar hyperkeratosis (P = 0·06, trend association), and (ii) a significantly higher frequency of scarce scalp hair (P = 0·035) and scarce or absent eyelashes (P = 0·06, trend association) than those with PTPN11 mutations. CONCLUSIONS: The cutaneous phenotype of NS with a PTPN11 mutation is generally mild and nonspecific, whereas the absence of a PTPN11 mutation is associated with a high frequency of keratinization disorders and hair abnormalities.

Intraoperative instillation of ropivacaine during the placement of sub-muscular cosmetic breast implants: Is there a clinical benefit?

INTRODUCTION: The sub-muscular placement of cosmetic breast implants leads to substantial pain due to the muscular distention. The aim of this study was to assess the efficiency of intraoperative ropivacaine instillation to reduce postoperative pain the day after surgery. MATERIAL AND METHODS: We conducted a prospective, controlled, single-blinded study comparing the intraoperative instillation of 7.5mg of ropivacaine through Redon drains with the standard procedure in 72 patients undergoing sub-muscular cosmetic breast augmentation for the first time. RESULTS: Pain at the awakening on postoperative day 1 was 4.8 on a simple numeric pain scale in the treatment group and 5.1 in the control group (P>0.05). On postoperative day 3, pain at awakening was 3.7 in both groups (P>0.05), and on postoperative day 5, pain was 2.8 in the treatment group and 2.7 in the control group (P>0.05). CONCLUSION: Local instillation of ropivacaine in the implant pocket during surgery did not decrease postoperative pain on day 1, day 3 and day 5. From now on, we are able to tell to patients that the postoperative pain after sub-muscular cosmetic breast implants surgery is about 5/10 on postoperative day 1, 4/10 at day 3 and 3/10 at day 5. LEVEL OF EVIDENCE: Level II.

Injections of platelet-rich plasma for androgenic alopecia: A systematic review.

The aim of this literature review was to evaluate the effects of PRP injections into the scalp of patients with androgenic alopecia. A literature review was conducted using the Pubmed and Google Scholar databases with the search terms "platelet-rich plasma" or "platelet-rich fibrin" and "hair" or "alopecia" or "androgenic alopecia". The publications included had to clinically assess the efficacy of PRP injections in patients with androgenic alopecia. Out of the 32 publications retrieved, 14 publications were included, of which 3 randomized, 4 prospective controlled, 4 prospective uncontrolled and 3 retrospective studies. Seven out of 9 studies reported a significant increase of hair density ranging between 12.3 and 45.9 hairs/cm2, (i.e. 19-31% hairs/cm2). Four studies assessed hair loss with the traction test and found a negative result after treatment in more than 95% of patients. Regarding hair thickness, 1 study reported an increase in hair diameter of 46.4% and 1 reported an increase of 106.4% of the "Hair mass index". Overall, the use of PRP injections in patients with androgenic alopecia seems effective with respect to promoting lost hair regrowth, decreasing hair loss and increasing hair thickness. The effects appear to be progressive from the first injection session, to peak after 3 to 5 sessions and to be attenuated in the absence of further injections. No major adverse effect was reported in the 14 clinical studies.

Platelet-rich plasma-enriched autologous fat graft in regenerative and aesthetic facial surgery: Technical note.

The goal of adding platelet-rich plasma (PRP) to autologous fat graft is to increase the survival rate of the graft. After their activation, platelets release some important growth factors. As a result, PRP may increase the proliferation and differentiation of Adipose-derived stem cells (ASCs) into adipocytes, improve fat graft vascularisation, and may block the apoptosis of grafted adipocytes. The other benefit expected from the addition of PRP to fat graft is the improvement of cutaneous trophicity above the grafted areas. An exhaustive review of the literature retrieved 11 clinical studies on humans and 7 on animals. A statistically significant increase of the survival rate of fat grafts has been found in 9 comparative studies. Our synthesis allowed us to set up the following protocol: addition of 20% of PRP activated with calcium hydrochloride to fat grafts. It may enhance the results of autologous facial fat graft in regenerative and aesthetic facial surgery.

[Mitral valve repair with the MitraClip following surgical mitral annuloplasty failure]. / Réparation mitrale à l'aide du MitraClip après échec précoce d'une réparation chirurgicale.

Mitral repair using the MitraClip device is on ongoing expansion and has been evaluated in different patterns of mitral regurgitation. Nevertheless, surgical approaches to mitral regurgitation remain the standard of care, at least in absence of contraindication. We report the first Canadian experience of mitral valve repair with the MitraClip following surgical mitral annuloplasty failure. Therapeutic considerations and potential challenges are discussed.