[Updated indications and contraindications in 2022 for lung transplantation in France]. / Transplantation pulmonaire en France : actualisation des indications et contre-indications en 2022.

Lung transplantation (LTx) is the last-resort treatment for end-stage respiratory insufficiency, whatever its origin, and represents a steadily expanding field of endeavor. Major developments have been impelled over the years by painstaking efforts at LTx centers to improve donor and recipient selection, and multifaceted attempts have been made to meet the challenges raised by surgical management, perioperative care, and long-term medical complications. The number of procedures has increased, leading to improved post-LTx prognosis. One consequence of these multiple developments has been a pruning away of contraindications over time, which has, in some ways, complicated the patient selection process. With these considerations in mind, the Francophone Pulmonology Society (Société de Pneumology de Langue Française [SPLF]) has set up a task force to produce up-to-date working guidelines designed to assist pulmonologists in managing end-stage respiratory insufficiency, determining which patients may be eligible for LTx, and appropriately timing LTx-center referral. The task force has examined the most recent literature and evaluated the risk factors that continue to limit patient survival after LTx. Ideally, the objectives of LTx are to prolong life while improving quality of life. The guidelines developed by the task force apply to a limited resource and are consistent with the ethical principles described below.

Factors influencing quality of life in children with low-flow vascular malformations: a qualitative study using focus groups.

BACKGROUND: Very few studies have evaluated the quality of life (QoL) of children suffering from low-flow vascular malformations. This is the first study investigating the influencing factors. OBJECTIVES: To identify the factors influencing QoL in children with low-flow vascular malformations. METHODS: We conducted a qualitative study employing focus group interviews (Clinical Trials Number: NCT03440827). The study was a prospective, interventional, non-comparative, multicentre study performed in four expert centres for vascular anomalies. Qualitative data about personal experiences, feelings, difficulties, needs and various factors influencing behaviours were collected. Theme-based content analysis (manual and specialist textural software guided) were used to analyse the verbatim transcripts of all focus group sessions. Manual qualitative discourse analysis was performed to identify the different themes and categories. Informatics' analyses were subsequently performed for each individual category. RESULTS: Ten focus groups (26 individuals including 10 children aged 11 to 15 years) were conducted until saturation. Influencing factors were related to 4 categories: medical care, self-image, social impact on daily activities and challenging social relationships. These factors were responsible for intrafamily upheavals and may lead to future identity-building problems. CONCLUSIONS: This study provides an essential framework from which physicians can develop strategies to improve patient care and quality of life. These data may also be useful to develop specific age-sensitive QoL questionnaires.

[Pneumocystis jirovecii and quantitative PCR: Pneumonia or colonization?] / Pneumocytis jirovecii et PCR quantitative : pneumonie ou colonisation à Pneumocystis jirovecii ?

BACKGROUND: Quantitative PCR to detect Pneumocystis jirovecii (Pj) is a new tool for the diagnosis of Pneumocystis jirovecii pneumonia (PJP). The yield of this technique, in cases of low fungal burden, when the standard technique using immunofluorescence (IF) is negative, needs to be evaluated. METHODS: We retrospectively reviewed the charts of all patients with a positive PCR but negative IF test (PCR+/IF-) in bronchoalveolar lavage (BAL) fluid performed over one year. We used an algorithm based on underlying immunosuppression, clinical picture, thoracic CT scan appearances, existence of an alternative diagnosis and the patient's outcome on treatment. Using this, each case was classified as probable PJP, possible PJP or colonization. RESULTS: Among the 416 BAL performed, 48 (12%) were PCR+/IF- and 43 patients were analyzed. Patients were mostly male (56%) with a median age of 60 years. Thirty-five (84%) were immunocompromised: 4 (9%) HIV-infected patients, 26 (60%) with hematologic or solid organ cancer, 3 (7%) were renal transplant recipients. Seven (16%) were classified as probable PPJ and 9 (21%) as possible PJP. Patients with a probable or possible PJP were more frequently admitted to the ICU (P<0.02) and had higher risk of death (P<0.01) when compared to those with colonization. Median PCR levels were very low and were not different between PJP or colonized patients (P=0.23). CONCLUSIONS: Among patients with a positive Pj PCR in BAL but with negative IF, only 37% had probable or possible PJP and PCR could not discriminate PJP from colonization.

[The role of new antibiotics in the treatment of acute adult community acquired pneumonia]. / Place des nouveaux antibiotiques dans le traitement de la pneumonie aiguë communautaire de l'adulte.

INTRODUCTION: Several new antibiotics (ceftaroline, ceftobiprole, omadacycline, solithromycine and delafloxacin) have recently been developed. Their place in the management of community acute pneumonia (CAP) needs to be clarified. STATE OF THE ART: Because multiresistant bacteria are infrequently involved in CAP, usual regimens using third generation cephalosporins, fluoroquinolones or macrolides, alone or in combination, are effective in the overwhelming majority of cases. Several studies have highlighted the non-inferiority of the new molecules regarding their clinical efficacy compared to usual regimens. The use of these new antibiotics could reduce the treatment duration of CAP and in some cases avoid combined therapy. These antibiotics do not offer real benefits in terms of spectrum of activity compared to the current recommended treatment. The anti-toxin effect of ceftaroline and the anti-inflammatory properties of solithromycin could potentially justify their prescription over molecules currently used. CONCLUSION: Results are still pending regarding the efficacy and any possible advantages of these new molecules, and also the emergence of drug resistant bacteria. Although these drugs share some advantages, they should not be selected over antibiotics usually prescribed for the treatment of CAP.

Bacillus Calmette-Guerin infection following intravesical instillation: Does the strain matter?

PURPOSE: Intravesical BCG is the standard treatment of non-muscle invasive bladder cancer. No difference has yet been reported in the safety profiles of the various BCG strains. METHODS: A nationwide multidisciplinary retrospective survey was conducted between January 2013 and December 2016 to identify cases of BCG infection and differentiate them based on the type of BCG strain used. RESULTS: Forty patients were identified (BCG RIVM 28; other strains 8; unknown 4). Patients treated with BCG RIVM were less severely ill, with fewer occurrences of septic shock (3.6% vs. 50%, P=0.003) and ICU admission (7.1% vs. 62.5%, P=0.003). A higher frequency of pulmonary miliaries (71.4% vs. 12.5%, P=0.005) but lower transaminase levels (mean AST 65 vs. 264 U/L, P=0.001) were observed in these patients. No difference in terms of recovery was reported. CONCLUSION: The type of BCG strain could correlate with the frequency and severity of subsequent BCG infections.

[BCG infection following intravesicular immunotherapy for bladder cancer]. / BCGites après immunothérapie pour cancer de vessie, une pathologie hétérogène: physiopathologie, description clinique, prise en charge diagnostique et thérapeutique.

BACKGROUND: Bacille of Calmette et Guérin (BCG) immunotherapy is the most effective treatment for non-muscle-invasive bladder cancer. Yet, potentially severe localized or systemic mycobacterial infections can happen. STATE OF KNOWLEDGE: In a patient who underwent BCG instillation for bladder cancer, the diagnosis of BCG infection is usually suggested by more than 3 days of high-grade fever and systemic and/or local symptoms with no other plausible alternative diagnosis. BCG infection can be localized (usually to the genitourinary tract, the bones or blood vessels) or systemic (mainly with pulmonary and hepatic involvements). The presence of granuloma in tissue biopsies (other than from the genitourinary tract) supports the diagnosis. The advent of polymerase chain reaction has recently improved the sensitivity of microbiological investigations. The management of BCG infection is not well established but relies on broad-spectrum antimycobacterial therapy (with the exclusion of pyrazinamide), glucocorticoids (in the context of general symptoms refractory to antimicrobial therapy alone) and occasionally surgery. CONCLUSION: BCG infection is a rare but not exceptional complication of BCG immunotherapy with heterogeneous clinical presentation. Prospective studies are warranted in order to improve treatment outcomes.

[Respiratory infections caused by slow-growing bacteria: Nocardia, Actinomyces, Rhodococcus]. / Infections respiratoires à bactéries à croissance lente : Nocardia, Actinomyces, Rhodococcus.

INTRODUCTION: Pneumonia caused by slow-growing bacteria is rare but sometimes severe. STATE OF THE ART: These infections share many similarities such as several differential diagnoses, difficulties to identify the pathogen, the importance of involving the microbiologist in the diagnostic investigation and the need for prolonged antibiotic treatment. However, major differences distinguish them: Nocardia and Rhodococcus infect mainly immunocompromised patients while actinomycosis also concerns immunocompetent patients; the severity of nocardioses is related to their hematogenous spread while locoregional extension by contiguity makes the gravity of actinomycosis. PROSPECTIVE: For these diseases, molecular diagnostic tools are essential, either to obtain a species identification and guide treatment in the case of nocardiosis or to confirm the diagnosis from a biological sample. Treatment of these infections is complex due to: (1) the limited data in the literature; (2) the need for prolonged treatment of several months; (3) the management of toxicities and drug interactions for the treatment of Nocardia and Rhodococcus. CONCLUSION: Close cooperation between pneumonologists, infectious disease specialists and microbiologists is essential for the management of these patients.

[Allergic bronchopulmonary aspergillosis: Evaluation of a maintenance therapy with nebulized Ambisome®]. / Aspergillose bronchopulmonaire allergique : évaluation d'un traitement d'entretien par Ambisome® nébulisé.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) affects 3-13% of patients with asthma. Its natural history includes possibly life-threatening exacerbations and evolution towards fixed obstructive ventilatory disorders or even irreversible lung fibrosis lesions. ABPA prognosis is directly associated with exacerbation control and the main objective of the treatment is to decrease their frequency and duration. Recommendations regarding dosage and duration of treatment are not very precise. The currently used combination of itraconazole and corticosteroid therapy has many limitations. The interests of a therapeutic strategy using nebulized liposomal amphotericin B (LAmB) are to heighten antifungal lung tissue concentration, to circumvent drug interactions and decrease the potential toxicity of systemic antifungal treatments. Finally, this association leads to improved eradication of Aspergillus, thereby limiting the risk of side effects and the emergence of treatment-resistant Aspergillus strains. METHODS: This is a phase II, multicentre, randomized, single blind, controlled therapeutic study, with the objective of comparing the potential benefit on exacerbation control of a maintenance therapy by LAmB nebulization. The main objective of the study is to compare the incidence of severe clinical exacerbations in ABPA treatment, between a maintenance treatment strategy with nebulized LAmB and a conventional strategy without antifungal maintenance therapy. EXPECTED RESULTS: The results will guide practitioners in the management of ABPA treatments and help to define the place of aerosols of LAmB on "evidence base medicine" criteria.

Papaverine-sensitive phosphodiesterase activity is measured in bovine spermatozoa.

Cyclic adenosine monophosphate (cAMP) plays a crucial role as a signaling molecule for capacitation, motility, and acrosome reaction in mammalian spermatozoa. It is well-known that cAMP degradation by phosphodiesterase (PDE) enzyme has a major impact on sperm functions. This study was undertaken to characterize cAMP-PDE activity in bovine spermatozoa. Total cAMP-PDE activity in cauda epididymal and ejaculated spermatozoa was 543.2 ± 49.5 and 1252.6 ± 86.5 fmoles/min/106 spermatozoa, respectively. Using different family-specific PDE inhibitors, we showed that in cauda epididymal and ejaculated spermatozoa, the major cAMP-PDE activity was papaverine-sensitive (44.5% and 57.5%, respectively, at 400 nm, papaverine is a specific inhibitor of the PDE10 family). These data are supporting the functional presence of PDE10 in bovine spermatozoa and were further confirmed by western blot to be PDE10A. Using immunocytochemistry, we showed immunoreactive signal for PDE10A present on the post-acrosomal region of the head and on the flagella of ejaculated spermatozoa. Using papaverine, we showed that it promotes tyrosine phosphorylation of sperm proteins, phosphorylation of Erk1 and Erk2, and Ca2+ release from Ca2+ store. These results suggest that PDE10 is functionally present in bovine spermatozoa and is affecting different molecular events involved in capacitation, most probably by cAMP local regulation.

Modeling human MLL-AF9 translocated acute myeloid leukemia from single donors reveals RET as a potential therapeutic target.

Acute myeloid leukemias (AMLs) result from a series of genetic events occurring in a stem or progenitor hematopoietic cell that gives rise to their clonal expansion and an impaired capacity to differentiate. To circumvent the genetic heterogeneity of AML patient cohorts, we have developed a model system, driven by the MLL-AF9 (MA9) oncogene, to generate multiple human leukemias using progenitor cells from a single healthy donor. Through stepwise RNA-sequencing data generated using this model and AML patients, we have identified consistent changes associated with MA9-driven leukemogenesis and demonstrate that no recurrent secondary mutations are required. We identify 39 biomarkers whose high expression level is specific to this genetic subtype of AML and validate that many of these have diagnostic utility. We further examined one biomarker, the receptor tyrosine kinase (RTK) RET, and show through shRNA knockdowns that its expression is essential for in vivo and in vitro growth of MA9-AML. These results highlight the value of novel human models of AML derived from single donors using specific oncogenic fusions to understand their biology and to uncover potential therapeutic targets.

Adverse neuropsychological effects associated with cumulative doses of corticosteroids to treat childhood acute lymphoblastic leukemia: A literature review.

Corticosteroids (CS) are an essential component of childhood acute lymphoblastic leukemia treatments (cALL). Although there is evidence that daily doses of CS can have neuropsychological effects, few studies have investigated the role of cumulative doses of CS in short- and long-term neuropsychological effects in cALL. The aims of this review were to identify the measures used for documenting adverse neuropsychological effects (ANEs) of CS treatment and to study the association between cumulative doses of CS and the presence of ANEs. Twenty-two articles met the inclusion criteria. A variety of measures were used to evaluate outcomes in the domains of emotion, behaviour, neurocognition, and fatigue/sleep. The results suggest that we cannot conclude in favour of an association between the cumulative dosage of CS and ANEs. Yet, several factors including the heterogeneity of measures used to evaluate outcomes and reporting biases may limit the scope of the results. We offer several recommendations that could help improve the future published evidence on ANEs in relation to CS treatment in cALL.

Characterization of cAMP-phosphodiesterase activity in bovine seminal plasma.

The second messenger cyclic adenosine monophosphate (cAMP) has a central role in sperm physiology. Extracellular cAMP can be sequentially degraded into 5'AMP and adenosine by ecto-phosphodiesterases (ecto-PDE) and ecto-nucleotidases, a phenomenon called extracellular cAMP-adenosine pathway. As cAMP-adenosine pathway is involved in sperm capacitation, we hypothesize that extracellular PDEs are functionally present in seminal plasma. Exclusively measuring cAMP-PDE activity, total activity in bovine seminal plasma was 10.1 ± 1.5 fmoles/min/µg. Using different family-specific PDE inhibitors, we showed that in seminal plasma, the major cAMP-PDE activity was papaverine sensitive (47.5%). These data support the presence of PDE10 in bovine seminal plasma and was further confirmed by western blot. In epididymal fluid, total cAMP-PDE activity was 48.2 ± 14.8 fmoles/min/µg and we showed that the major cAMP-PDE activity was 3-isobutyl-methylxanthine insensitive and thus ascribed to PDE8 family. PDE10A mRNAs were found in the testis, epididymis, and seminal vesicles. cAMP-PDE activity is present in bovine seminal plasma and epididymal fluid. The results suggest a role for ecto-PDEs present in those fluids in the signaling pathways involved in sperm functions.

[Small airway diseases and immune deficiency]. / Atteinte des voies aériennes distales et immunodépression.

INTRODUCTION: Innate or acquired immune deficiency may show respiratory manifestations, often characterized by small airway involvement. The purpose of this article is to provide an overview of small airway disease across the major causes of immune deficiency. BACKGROUND: In patients with common variable immune deficiency, recurrent lower airway infections may lead to bronchiolitis and bronchiectasis. Follicular and/or granulomatous bronchiolitis of unknown origin may also occur. Bronchiolitis obliterans is the leading cause of death after the first year in patients with lung transplantation. Bronchiolitis obliterans also occurs in patients with allogeneic haematopoietic stem cell transplantation, especially in the context of systemic graft-versus-host disease. VIEWPOINT AND CONCLUSION: Small airway diseases have different clinical expression and pathophysiology across various causes of immune deficiency. A better understanding of small airways disease pathogenesis in these settings may lead to the development of novel targeted therapies.

[Lung disease in adult common variable immunodeficiency]. / Atteintes respiratoires au cours du déficit immunitaire commun variable de l'adulte.

INTRODUCTION: Common variable immunodeficiency (CVID) is characterized by a defect in antibody production and may be complicated by infectious or non-infectious respiratory disease. BACKGROUND: In addition to recurrent infectious complications, mainly due to encapsulated bacteria, CVID may be complicated by diffuse infiltrative, non-infectious lung disease. The latter may be related to granulomatosis, lymphoid interstitial pneumonia, follicular bronchiolitis, follicular nodular hyperplasia, organizing pneumonia or lymphoma. Different lymphoid histological lesions can co-exist and form a new entity called GLILD (granulomatous lymphocytic interstitial lung disease), which is associated with a poor prognosis. Replacement of immunoglobulins significantly decreases the frequency and severity of infections but has no impact on the non-infectious complications. OUTLOOK: Studies are needed to determine the modalities of follow-up and better understand the long-term progress of GLILD. These studies should improve the management of GLILD in the context of immunosuppressive treatments, which increase the risk of infection in CVID. CONCLUSION: The identification of GLILD, which reflects a variable histological spectrum, rather than a well-defined entity, necessitates revising the approach to diffuse infiltrative lung diseases in CVID.

Phonon Engineering in Isotopically Disordered Silicon Nanowires.

The introduction of stable isotopes in the fabrication of semiconductor nanowires provides an additional degree of freedom to manipulate their basic properties, design an entirely new class of devices, and highlight subtle but important nanoscale and quantum phenomena. With this perspective, we report on phonon engineering in metal-catalyzed silicon nanowires with tailor-made isotopic compositions grown using isotopically enriched silane precursors (28)SiH4, (29)SiH4, and (30)SiH4 with purity better than 99.9%. More specifically, isotopically mixed nanowires (28)Si(x)(30)Si(1-x) with a composition close to the highest mass disorder (x ∼ 0.5) were investigated. The effect of mass disorder on the phonon behavior was elucidated and compared to that in isotopically pure (29)Si nanowires having a similar reduced mass. We found that the disorder-induced enhancement in phonon scattering in isotopically mixed nanowires is unexpectedly much more significant than in bulk crystals of close isotopic compositions. This effect is explained by a nonuniform distribution of (28)Si and (30)Si isotopes in the grown isotopically mixed nanowires with local compositions ranging from x = ∼0.25 to 0.70. Moreover, we also observed that upon heating, phonons in (28)Si(x)(30)Si(1-x) nanowires behave remarkably differently from those in (29)Si nanowires suggesting a reduced thermal conductivity induced by mass disorder. Using Raman nanothermometry, we found that the thermal conductivity of isotopically mixed (28)Si(x)(30)Si(1-x) nanowires is ∼30% lower than that of isotopically pure (29)Si nanowires in agreement with theoretical predictions.