Autoimmune cytopenia and Kabuki syndrome in paediatrics: Insights in 11 patients.

Kabuki syndrome (KS) is now listed in the Human Inborn Errors of Immunity (IEI) Classification. It is a rare disease caused by KMT2D and KDM6A variants, dominated by intellectual disability and characteristic facial features. Recurrently, pathogenic variants are identified in those genes in patients examined for autoimmune cytopenia (AIC), but interpretation remains challenging. This study aims to describe the genetic diagnosis and the clinical management of patients with paediatric-onset AIC and KS. Among 11 patients with AIC and KS, all had chronic immune thrombocytopenic purpura, and seven had Evans syndrome. All had other associated immunopathological manifestations, mainly symptomatic hypogammaglobinaemia. They had a median of 8 (5-10) KS-associated manifestations. Pathogenic variants were detected in KMT2D gene without clustering, during the immunological work-up of AIC in three cases, and the clinical strategy to validate them is emphasized. Eight patients received second-line treatments, mainly rituximab and mycophenolate mofetil. With a median follow-up of 17 (2-31) years, 8/10 alive patients still needed treatment for AIC. First-line paediatricians should be able to recognize and confirm KS in children with ITP or multiple AIC, to provide early appropriate clinical management and specific long-term follow-up. The epigenetic immune dysregulation in KS opens exciting new perspectives.

Social Networks in French Balneotherapy: A Focus on Spa Doctors.

Spa therapy is a medical treatment based on the use of natural mineral water. In France, spa therapy is delivered in spa care facilities (SCF) involving the intervention of several actors (stakeholders). Spa doctors are key stakeholders as they prescribe the treatments, follow spa patients and assess spa therapy with scientific studies. This study aimed to analyze the spa doctors' relationships in order to highlight their role in transferring information to other stakeholders, particularly to spa managers. For that purpose, we used the social network analysis (SNA) method by means of snowball data collection. We sent a questionnaire to all the spa therapy categories of actors. In total, 80 persons answered and declared 397 relationships. Our results, based on the categorization of respondents and of their relationships and on quantitative indicators (density, response rate), show that spa doctors demonstrate a very acceptable density of relations with spa managers and elected local authorities. However, they appear to be poorly involved in relations concerning the strategy and management of SCF, although they are essential actors in ensuring the medical relevance and sustainability of spa therapy. This research is of interest to patients' care as it recommends deeper involvement of spa doctors in the management of SCF in order to optimize access to informational resources, specifically regarding the evolution of treatments in accordance with scientific progress. Our data are of international scope because the organizational model of balneotherapy, based on the cooperation between spa doctors and SCF, is universal.

Fast Track Management of Primary Thyroid Lymphoma in the Very Elderly Patient.

A rapid growing cervical mass mobile while swallowing is the most common clinical presentation of severe thyroid malignancy. A 91-year-old female patient with a history of Hashimoto thyroiditis presented with clinical compressive neck symptoms. The patient had gastric Maltoma diagnosed that was surgically resected thirty years ago. A straightforward process was needed to reach full histological diagnosis and initiate prompt therapy. Ultrasound (US) showed a 67 mm hypoechoic left thyroid mass with reticulated pattern without signs of locoregional invasion. Percutaneous trans isthmic US-guided 18G core needle biopsy (CNB) disclosed diffuse large B cell lymphoma of the thyroid gland. FDG PET revealed two distinct thyroid and gastric foci (both SUVmax 39.1). Therapy was initiated rapidly to decrease clinical symptoms in this aggressive stage III primitive malignant thyroid lymphoma. The prognostic nomogram was calculated by using a seven-item scale, which disclosed a one-year overall survival rate of 52%. The patient underwent three R-CVP chemotherapy courses, then refused further treatment and died within five months. Real-time US-guided CNB approach led to rapid patient's management that was tailored to patient's characteristics. Transformation of Maltoma into diffuse large B cell lymphoma (DLBCL) into two body areas is deemed to be extremely rare.

A focus on dominant negative variants in a series of 170 heterozygous FXI-deficient patients.

INTRODUCTION: Dominant-negative effects have been described for 10 F11 variants in the literature. AIM: The current study aimed at identifying putative dominant-negative F11 variants. MATERIAL AND METHODS: This research consisted in a retrospective analysis of routine laboratory data. RESULTS: In a series of 170 patients with moderate/mild factor XI (FXI) deficiencies, we identified heterozygous carriers of previously reported dominant-negative variants (p.Ser243Phe, p.Cys416Tyr, and p.Gly418Val) with FXI activities inconsistent with a dominant-negative effect. Our findings also do not support a dominant-negative effect of p.Gly418Ala. We also identified a set of patients carrying heterozygous variants, among which five out of 11 are novel, with FXI activities suggesting a dominant-negative effect (p.His53Tyr, p.Cys110Gly, p.Cys140Tyr, p.Glu245Lys, p.Trp246Cys, p.Glu315Lys, p.Ile421Thr, p.Trp425Cys, p.Glu565Lys, p.Thr593Met, and p.Trp617Ter). However, for all but two of these variants, individuals with close to half normal FXI coagulant activity (FXI:C) were identified, indicating an inconstant dominant effect. CONCLUSION: Our data show that for some F11 variants recognized has having dominant-negative effects, such effects actually do not occur in many individuals. The present data suggest that for these patients, the intracellular quality control mechanisms eliminate the variant monomeric polypeptide before homodimer assembly, thereby allowing only the wild-type homodimer to assemble and resulting in half normal activities. In contrast, in patients with markedly decreased activities, some mutant polypeptides might escape this first quality control. In turn, assembly of heterodimeric molecules as well as mutant homodimers would result in activities closer to 1:4 of FXI:C normal range.

Assessment of barium diffusion from therapeutic mud wrapped in micro-perforated polyethylene bags towards the human organism.

Barium is present within the clay-derived therapeutic mud packs deposed on the patient's skin for treating some rheumatologic conditions. We studied in twenty-four young healthy volunteers the diffusion of Ba from mud wrapped in micro-perforated polyethylene bags and soaked in mineral water. No significant systematic increase in plasma or urine Ba levels was evidenced when comparing pre- and post-treatment samples using inductively-coupled plasma mass spectrometry. These levels were markedly inferior to the recommended thresholds in nearly all the participants. Noticeably variability in blood and especially urine Ba concentrations was large and mainly explained by environmental exposure (alimentation). Interestingly, we evidenced an intense Ba accumulation within the therapeutic mud at the end of the regimen. Because we chose a clay with one of the highest Ba content available in France for medical therapy and participants with an optimal transcutaneous diffusion capacity (young individuals with low-fat mass), we conclude unambiguously that there is no risk of Ba overexposure in patients receiving pelotherapy according to the procedure used in French medical spas.

Transfusional iron overload in heavily transfused patients: Real-life data from a 10-year retrospective study of 611 cases managed in a French general hospital.

OBJECTIVES: Epidemiological studies on transfusional iron overload (TIO) in the general population of heavily transfused patients are scarce. The aim of this work was to provide a picture on the distribution and management of this complication within the context of unselected individuals attending a general hospital. METHODS: We retrospectively assessed the characteristics of 611 patients from a single institution having received at least 20 red blood cell (RBC) units over a 10-year period. RESULTS: About two-thirds of these individuals were males and their median age at the 20th RBC was 72years (range: 10-98). Myelodysplastic syndromes (MDS) and acute myeloid leukemia represented the most frequent underlying conditions (53%) but lymphoid malignancies and solid malignancies accounted for 13.6 and 7.3% respectively. In the vast majority of cases various comorbidities (range: 1-6 per patient) were registered including especially cardiovascular disorders. The highest cumulative RBC numbers were observed in MDS patients. Serum ferritin was assessed in 451 patients (73.8%) and ≥1000µg/L in 250 cases, ≥2000µg/L in 100 cases and ≥2500µg/L in 71 cases. Only 97 patients (15.9%) received a treatment for TIO using either a chelator (n=93) or phlebotomy (n=4). CONCLUSION: TIO is not limited to MDS or hemoglobin disorders. Its assessment and management are suboptimal in clinical practice. The ratio of patients receiving iron chelation is markedly lower than theoretically expected mainly because of comorbidities or drug intolerance.

Mortality in the Western Pyrenees during the 18th century. Data from the parish register of the village of Arudy (1741-1800), Bearn, France.

OBJECTIVES: We aimed to determine the public health status of an 18th century mountain locality. METHODS: We collected data registered in parish death certificates from Arudy, a small village in the French Pyrenees during the period 1741-1800. RESULTS: Two thousand and six hundred and sixty-three cases were studied. About 50% of deaths occurred during the first 10 years of life. There were some particularities in deaths pattern with regards to age categories between males and females and seasonality. A fraction of individuals died at advanced ages (24.1% ≥60 years and of note three cases ≥100 years). The cause of death was reported in only 2.2% of cases (nearly always sudden fatalities). Maternal mortality could not be precisely determined. Throughout this period we identified a series of mortality crises which targeted mostly children and were probably in relation with undocumented epidemics. CONCLUSIONS: These data offer some clues about the sanitary situation of an European mountain community during the 18th century.

Relevance of treatment-free remission recommendations in chronic phase chronic leukemia patients treated with frontline tyrosine kinase inhibitors.

BACKGROUND: Tyrosine kinase inhibitors (TKI) can be safely discontinued in chronic phase chronic myeloid leukemia (CP-CML) patients who had achieved a sustained deep molecular response. Based on the results of discontinuation trials, recommendations regarding patient selection for a treatment-free remission (TFR) attempt had been proposed. The aims of this study were to evaluate the rate of patients eligible for TKI discontinuation and molecular recurrence-free survival (MRFS) after stop according to recommendations. METHODS: Over a 10-year period, newly diagnosed CP-CML patients and treated with first-line TKI in the nine French participating centers were included. Eligibility to treatment discontinuation and MRFS were analyzed and compared according to selection criteria defined by recommendations and first-line treatments. RESULTS: From January 2006 to December 2015, 398 patients were considered. Among them, 73% and 27% of patients received imatinib or either second or third generation tyrosine kinase inhibitors as frontline treatment, respectively. Considering the selection criteria defined by recommendations, up to 55% of the patients were selected as optimal candidates for treatment discontinuation. Overall 95/398 (24%) discontinued treatment. MRFS was 51.8% [95% CI 41.41-62.19] at 2 years and 43.8% [31.45-56.15] at 5 years. Patients receiving frontline second-generation TKI and fulfilling the eligibility criteria suggested by recommendations had the lowest probability of molecular relapse after TKI stop when compare to others. CONCLUSION: One third of CP-CML patients treated with TKI frontline fulfilled the selection criteria suggested by European LeukemiaNet TFR recommendations. Meeting selection criteria and second-generation TKI frontline were associated with the highest MRFS.

Genetic origins, singularity, and heterogeneity of Basques.

Basques have historically lived along the Western Pyrenees, in the Franco-Cantabrian region, straddling the current Spanish and French territories. Over the last decades, they have been the focus of intense research due to their singular cultural and biological traits that, with high controversy, placed them as a heterogeneous, isolated, and unique population. Their non-Indo-European language, Euskara, is thought to be a major factor shaping the genetic landscape of the Basques. Yet there is still a lively debate about their history and assumed singularity due to the limitations of previous studies. Here, we analyze genome-wide data of Basque and surrounding groups that do not speak Euskara at a micro-geographical level. A total of ∼629,000 genome-wide variants were analyzed in 1,970 modern and ancient samples, including 190 new individuals from 18 sampling locations in the Basque area. For the first time, local- and wide-scale analyses from genome-wide data have been performed covering the whole Franco-Cantabrian region, combining allele frequency and haplotype-based methods. Our results show a clear differentiation of Basques from the surrounding populations, with the non-Euskara-speaking Franco-Cantabrians located in an intermediate position. Moreover, a sharp genetic heterogeneity within Basques is observed with significant correlation with geography. Finally, the detected Basque differentiation cannot be attributed to an external origin compared to other Iberian and surrounding populations. Instead, we show that such differentiation results from genetic continuity since the Iron Age, characterized by periods of isolation and lack of recent gene flow that might have been reinforced by the language barrier.

Incidences of Deep Molecular Responses and Treatment-Free Remission in de Novo CP-CML Patients.

Background: Tyrosine Kinase Inhibitors (TKIs) discontinuation in patients who had achieved a deep molecular response (DMR) offer now the opportunity of prolonged treatment-free remission (TFR). Patients and Methods: Aims of this study were to evaluate the proportion of de novo chronic-phase chronic myeloid leukemia (CP-CML) patients who achieved a sustained DMR and to identify predictive factors of DMR and molecular recurrence-free survival (MRFS) after TKI discontinuation. Results: Over a period of 10 years, 398 CP-CML patients treated with first-line TKIs were included. Median age at diagnosis was 61 years, 291 (73%) and 107 (27%) patients were treated with frontline imatinib (IMA) or second- or third-generation TKIs (2-3G TKI), respectively. With a median follow-up of seven years (range, 0.6 to 13.8 years), 182 (46%) patients achieved a sustained DMR at least 24 months. Gender, BCR-ABL1 transcript type, and Sokal and ELTS risk scores were significantly associated with a higher probability of sustained DMR while TKI first-line (IMA vs. 2-3G TKI) was not. We estimate that 28% of CML-CP would have been an optimal candidate for TKI discontinuation according to recent recommendations. Finally, 95 (24%) patients have entered in a TFR program. MRFS rates at 12 and 48 months were 55.1% (95% CI, 44.3% to 65.9%) and 46.9% (95% CI, 34.9% to 58.9%), respectively. In multivariate analyses, first-line 2-3G TKIs compared to IMA and TKI duration were the most significant factors of MRFS. Conclusions: Our results suggest that frontline TKIs have a significant impact on TFR in patients who fulfill the selection criteria for TKI discontinuation.

Influence of hydrotherapy pool water recirculation regime on Staphylococcus species concentration at subsurface: Preliminary experimental data from a pilot.

Pools are prone to contamination from microbial pathogens from human external microbiota, including mainly Staphylococcus species. These bacteria originate mainly from the skin and rhinopharynx and tend to concentrate at the surface/subsurface. Being protected by films derived from mucus and sebum, they are markedly resistant to biocides. Our study aimed to evaluate the respective impact of mixed and reverse hydraulicity techniques on the concentration of Staphylococcus species at the subsurface following bathing by four individuals in an experimental pool. Disinfection, filtration and water renewal of the pool were stopped in order to study only the influence of the water recirculation regime. We found a significant reduction of 31.7% (Test 1), 50.9% (Test 2) and 41.9% (Test 3) in total Staphylococcus species counts at the subsurface when using reverse versus mixed hydraulicity. However, this reduction is not a pollution cut but a pollution shift, resulting from an increase in the outlet water flow rate by overflow channel from 49.3 to 100%. This experimental model was far removed from real life conditions and associated with a series of limitations. However, it seems that the type of water recirculation regime is a critical factor in the bacterial quality of pool water. These preliminary findings need to be confirmed in additional studies using more realistic conditions.

The use of octagam and gammanorm in immunodeficiency associated with hematological malignancies: a prospective study from 21 French hematology departments.

OBJECTIVE: Immunoglobulin replacement therapy (IgRT) is increasingly used in secondary immunodeficiency (SID) related to hematological malignancies (HM) to prevent infections. Study's objective was to document prospectively the efficacy and safety of IgRT in patients with HM-associated SID. METHODS: Non-interventional, prospective French longitudinal study. RESULTS: One-hundred and sixty patients starting IgRT for HM-associated SID (myeloma: 54 cases, chronic lymphoid leukemia: 54, aggressive non-Hodgkin B-cell lymphoma: 19, indolent non-Hodgkin B-cell lymphoma: 29, and Hodgkin disease: 4. entered an observational, prospective, longitudinal study and were followed-up for 8.7 ± 4.0 months. Seventeen patients died (five within the context of sepsis). Compared to baseline, IgRT increased serum immunoglobulin levels by 3.4 ± 2.4 g/L and decreased frequency and severity of infections. Treatment was discontinued in 9% of patients, stopped for futility in 31%, temporally interrupted in 8%, suspended during summertime in 14% and pursued without interruption in 38% of patients. CONCLUSION: Our data confirm the efficacy of IgRT in reducing the risk of infections in HM-associated SID therefore fulfilling physicians' main expectations. They also illustrate the heterogeneity of management policies within the community setting.

Red cell groups and Basque population(s): From anthropology to public health.

The particular distribution of blood groups in Basques was initially described during the first half of the 20th century especially regarding the ABO and Rhesus systems. We report herein the largest synthesis published so far on the distribution of blood groups in this population using serological or molecular methods. These characteristics are to be discussed in the light of evolutive forces acting in population genetics i.e. drift, peopling history and natural selection. The Basque population is of very ancient descent, has remained relatively unmixed through the ages and demonstrates some degree of heterogeneity. The possible impact of this hemotypology profile for public health is also discussed here.

[Prescription of physical activity by general practitioners: The Biarritz Côte Basque Sport Santé experience]. / La prescription d'activité physique par le médecin traitant : l'expérience de Biarritz Côte Basque Sport Santé.

INTRODUCTION: Physical inactivity represents a public health challenge because it is associated with an increased risk of chronic disease and premature death. The prescription of physical activity (PA) by general practitioners in the context of sports clubs was used to fight against physical inactivity. METHODS: Since May 2015, the Biarritz Côte Basque Sport Santé (BSS) association has proposed a primary prevention scheme based on physical activity prescribed by a panel of voluntary general practitioners designed for inactive persons with no significant chronic diseases. Participants are referred either directly to a sports club in which they are managed by a trained sports instructor or initially to a BSS sport health educator, who proposes an interview and physical evaluation in order to choose the most appropriate sporting activity. PA (comprising a total of 15 activities) is prescribed for twelve weeks and each participant is evaluated at the end of this period. We report our experience with this programme after the inclusion of 200 individuals. RESULTS: Eighty-six physicians from seventeen sites of the Basque coast area participated in this study. Two hundred persons received a PA prescription (men: 27%, mean age: 54 years, range: 18-80); 20% of them were referred directly to participating sports clubs and 80% were first evaluated by our BSS educator. Aquatic gymnastics was the PA most frequently chosen (23%). The number of affiliated sport clubs increased from seven at the beginning of our project to twenty five at the time of analysis. Twenty-eight sport instructors have now been trained and accredited to manage participants. One hundred and thirty eight subjects have completed the planned twelve-week schedule and have been evaluated: 90% of them continue their sport in the sports club. DISCUSSION: Our experience suggests than general practitioner-based PA referral to well-trained sports club educators is a feasible strategy for managing physically inactive individuals. This protocol comprises an intermediary structure, the BSS unit, which allows evaluation and referral to adapted PA for each participant plus compliance monitoring. However, the long-term efficacy of this programme has yet to be evaluated.

Mutations in the SRP54 gene cause severe congenital neutropenia as well as Shwachman-Diamond-like syndrome.

Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome sequencing, we identified a heterozygous mutation in the SRP54 gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the SRP54 gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germ line SRP54 mutations including a recurrent in-frame deletion (Thr117del) in 14 cases. In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest, occurring within the first months of life, and required long-term granulocyte colony-stimulating factor therapy with a poor response. Neutropenia was sometimes associated with a severe neurodevelopmental delay (n = 5) and/or an exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). We showed that SRP54 was specifically upregulated during the in vitro granulocytic differentiation, and that SRP54 mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent apoptosis. Bone marrow examination of SRP54-mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and autophagy that were confirmed using SRP54-mutated primary cells and SRP54 knockdown cells. In conclusion, we characterized a pathological pathway, which represents the second most common cause of CN with maturation arrest in the French CN registry.