Nebulised liposomal amphotericin-B as maintenance therapy in allergic bronchopulmonary aspergillosis: a randomised, multicentre trial.

BACKGROUND: In allergic bronchopulmonary aspergillosis (ABPA), prolonged nebulised antifungal treatment may be a strategy for maintaining remission. METHODS: We performed a randomised, single-blind, clinical trial in 30 centres. Patients with controlled ABPA after 4-month attack treatment (corticosteroids and itraconazole) were randomly assigned to nebulised liposomal amphotericin-B or placebo for 6 months. The primary outcome was occurrence of a first severe clinical exacerbation within 24 months following randomisation. Secondary outcomes included the median time to first severe clinical exacerbation, number of severe clinical exacerbations per patient, ABPA-related biological parameters. RESULTS: Among 174 enrolled patients with ABPA from March 2015 through July 2017, 139 were controlled after 4-month attack treatment and were randomised. The primary outcome occurred in 33 (50.8%) out of 65 patients in the nebulised liposomal amphotericin-B group and 38 (51.3%) out of 74 in the placebo group (absolute difference -0.6%, 95% CI -16.8- +15.6%; OR 0.98, 95% CI 0.50-1.90; p=0.95). The median (interquartile range) time to first severe clinical exacerbation was longer in the liposomal amphotericin-B group: 337 days (168-476 days) versus 177 days (64-288 days). At the end of maintenance therapy, total immunoglobulin-E and Aspergillus precipitins were significantly decreased in the nebulised liposomal amphotericin-B group. CONCLUSIONS: In ABPA, maintenance therapy using nebulised liposomal amphotericin-B did not reduce the risk of severe clinical exacerbation. The presence of some positive secondary outcomes creates clinical equipoise for further research.

Ptchd1 deficiency induces excitatory synaptic and cognitive dysfunctions in mouse.

Synapse development and neuronal activity represent fundamental processes for the establishment of cognitive function. Structural organization as well as signalling pathways from receptor stimulation to gene expression regulation are mediated by synaptic activity and misregulated in neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID). Deleterious mutations in the PTCHD1 (Patched domain containing 1) gene have been described in male patients with X-linked ID and/or ASD. The structure of PTCHD1 protein is similar to the Patched (PTCH1) receptor; however, the cellular mechanisms and pathways associated with PTCHD1 in the developing brain are poorly determined. Here we show that PTCHD1 displays a C-terminal PDZ-binding motif that binds to the postsynaptic proteins PSD95 and SAP102. We also report that PTCHD1 is unable to rescue the canonical sonic hedgehog (SHH) pathway in cells depleted of PTCH1, suggesting that both proteins are involved in distinct cellular signalling pathways. We find that Ptchd1 deficiency in male mice (Ptchd1-/y) induces global changes in synaptic gene expression, affects the expression of the immediate-early expression genes Egr1 and Npas4 and finally impairs excitatory synaptic structure and neuronal excitatory activity in the hippocampus, leading to cognitive dysfunction, motor disabilities and hyperactivity. Thus our results support that PTCHD1 deficiency induces a neurodevelopmental disorder causing excitatory synaptic dysfunction.

[Nagashima-type palmoplantar keratoderma: A little-known palmoplantar keratoderma in Europe]. / Kératodermie palmo-plantaire de Nagashima : une kératodermie palmo-plantaire méconnue en Europe.

BACKGROUND: Herein we present a case of palmoplantar keratoderma (PPK) in a young adopted girl of Chinese origin living in France. OBSERVATION: The patient, aged six years, had presented transgressive PPK since birth, as well as erythema progressing in congestive inflammatory episodes, palmoplantar hyperhidrosis and progressive characteristics (moderate hyperkeratosis in areas of rubbing other than the palms and soles, namely the elbows and knees). Histopathological examination of a skin biopsy revealed a thick epidermis with lengthening and thickening of crests. The epithelium displayed a thick granular layer. Electron microscopy showed hyperorthokeratosis with hypergranulosis and loss of lamellar structure of the keratinosomes, as well as cleavage between corneocytes. Molecular studies showed the presence of two composite heterozygous mutations of the SERPINB7 gene, enabling a diagnosis of Nagashima-type PPK (NPPK) to be made. DISCUSSION: NPPK is an autosomal recessive disease caused by a mutation in the SERPINB7, a member of the superfamily of serine protease inhibitors. It was described by Nagashima in 1977 with molecular characterisation by Kubo following in 2013. It is the most widespread form of PPK in Asia (with a prevalence of 1.2/10,000 in Japan and 3.1/10,000 in China). It is distinguished from the other PPKs in terms of transgressive soft hyperkeratosis, inflammatory episodes and hyperhidrosis, as well as by its non-progressive nature. In the present case, while the clinical presentation was characteristic, diagnosis was only made thanks to sequencing of a panel of over 50 genes responsible for PPK. The disease is effectively little-known in Europe. This study highlights the increasing importance of diagnostic investigation methods involving the use of gene panels.

High endemism and stem density distinguish New Caledonian from other high-diversity rainforests in the Southwest Pacific.

Background and Aims: The biodiversity hotspot of New Caledonia is globally renowned for the diversity and endemism of its flora. New Caledonia's tropical rainforests have been reported to have higher stem densities, higher concentrations of relictual lineages and higher endemism than other rainforests. This study investigates whether these aspects differ in New Caledonian rainforests compared to other high-diversity rainforests in the Southwest Pacific. Methods: Plants (with a diameter at breast height ≥10 cm) were surveyed in nine 1-ha rainforest plots across the main island of New Caledonia and compared with 14 1-ha plots in high-diversity rainforests of the Southwest Pacific (in Australia, Fiji, Papua New Guinea and the Solomon Islands). This facilitated a comparison of stem densities, taxonomic composition and diversity, and species turnover among plots and countries. Key Results: The study inventoried 11 280 stems belonging to 335 species (93 species ha-1 on average) in New Caledonia. In comparison with other rainforests in the Southwest Pacific, New Caledonian rainforests exhibited higher stem density (1253 stems ha-1 on average) including abundant palms and tree ferns, with the high abundance of the latter being unparalleled outside New Caledonia. In all plots, the density of relictual species was ≥10 % for both stems and species, with no discernible differences among countries. Species endemism, reaching 89 % on average, was significantly higher in New Caledonia. Overall, species turnover increased with geographical distance, but not among New Caledonian plots. Conclusions: High stem density, high endemism and a high abundance of tree ferns with stem diameters ≥10 cm are therefore unique characteristics of New Caledonian rainforests. High endemism and high spatial species turnover imply that the current system consisting of a few protected areas is inadequate, and that the spatial distribution of plant species needs to be considered to adequately protect the exceptional flora of New Caledonian rainforests.

Azacitidine-induced pyoderma gangrenosum at injection sites in a patient with myelodysplastic syndrome.

Pyoderma gangrenosum (pg) is a rare neutrophilic dermatosis characterized by painful necrotic ulceration affecting preferentially the lower extremities. Diagnosis is challenging, and a thorough workup (including biopsy) is required. In this case report, we describe a 67-year-old patient with a diagnosis of myelodysplastic syndrome (mds) who developed fever and pg two days after the first cycle of subcutaneous azacitidine (Vidaza; Celgene Corporation, Summit, NJ, USA). On physical examination, the patient had four erythematous plaques at sites of subcutaneous injections of azacitidine on the arms, as well as three other plaques in proximity. A skin biopsy demonstrated a dense neutrophilic interstitial infiltrate in the dermis. After the diagnosis of pg, prednisone 1 mg/kg was started and the fever subsided rapidly. This was followed by the resolution of the cutaneous lesions. Changing the route of administration of azacitidine from subcutaneous to intravenous and adding a daily dose of prednisone during the treatment allowed the patient to receive a total of 10 cycles of azacitidine. This is the second case reported in the literature. Because azacitidine is frequently used in mds and acute myeloid leukemia, clinicians should be aware of this rare cutaneous adverse event. Our approach can be used to avoid the recurrence of pg when continuing azacitidine treatment.

Procarbazine, lomustine and vincristine toxicity in low-grade gliomas.

BACKGROUND: Procarbazine, lomustine, and vincristine (pcv) significantly improve survival outcomes in lgg (low-grade gliomas). Administration of pcv to lgg patients increased tremendously over the past years as it went from 2 patients per year between 2005 and 2012 to 23 patients in 2015 only in our centre. However, serious hematological and non-hematological adverse events may occur. The purpose of this study was to evaluate the toxicity of pcv and its clinical relevance in our practice. METHODS: We retrospectively reviewed the charts of 57 patients with lgg who received pcv at the Centre hospitalier de l'Université de Montréal between 1 January 2005 and 27 July 2016. RESULTS: Procarbazine, lomustine, and vincristine were associated with severe hematological toxicity as clinically significant grade 3 anemia, neutropenia, and thrombocytopenia occurred in 7%, 10%, and 28% of patients, respectively. Other frequent adverse events such as the increase of liver enzymes, cutaneous rash, neurotoxicity, and vomiting occurred in 65%, 26%, 60%, and 40% of patients, respectively. Patients with prophylactic trimethoprim/sulfamethoxazole had more grade 3 hematological toxicity with pcv, especially anemia (p = 0.040) and thrombocytopenia (p = 0.003) but we found no increase in pcv toxicity in patients on concurrent anticonvulsants. Patients with grade 3 neutropenia had a significantly lower survival (median survival 44.0 months vs. 114.0 months, p = 0.001). Patients who were given pcv at diagnosis had more grade 3 anemia than those who received it at subsequent lines of treatment (p = 0.042). CONCLUSION: Procarbazine, lomustine, and vincristine increase survival in lgg but were also associated with major hematologic, hepatic, neurologic, and cutaneous toxicity. Anti-Pneumocystis jiroveci pneumonia (pjp) prophylaxis, but not anticonvulsants, enhances hematologic toxicity.

[Circumscribed palmar hypokeratosis (CPM): The diagnostic value of dermoscopy]. / Hypokératose acrale circonscrite (HAC) : utilité diagnostique de la dermoscopie.

BACKGROUND: Circumscribed palmar hypokeratosis (CPH) is a rare skin disease, first described in 2002, associated with sudden localized reduction of the corneal layer. In most cases, it presents as an isolated rounded erythematous palmar lesion on the thenar eminence. We describe the dermoscopic semiology of CPH in 3 cases. PATIENTS AND METHODS: Three patients between the ages of 59 and 72 presented very limited erythematous lesions suggestive of CPH. Dermoscopic examination of these lesions provided similar findings. Biopsy, which was performed in one patient, confirmed the diagnosis of CPH. RESULTS: Two dermoscopic elements of CPH are characteristic: (1) the sides of the lesion have a "stair step" or "geological strata" type of configuration, and the thickness of the different strata varies; (2) the centre of the lesion showed a homogeneous erythematous area with a vascular pattern composed of dotted vessels of the superficial dermis and sometime vascular loops. DISCUSSION: These dermoscopic aspects are characteristic and enable CPH to be differentiated from Bowen's disease or porokeratosis of Mibelli. In Bowen's disease, there is no stair step like aspect to the sides of lesions; further, the centre of the lesion shows glomerular vessels (coiled vessels) and/or globular vessels (small red clods). In porokeratosis, peripheral keratotic "white track" structures comprise a single pigmented channel or a double white line. There is no "stair step" or central vascular pattern. CONCLUSION: The dermoscopic semiology of CPH is highly characteristic and enables differentiation from Bowen's disease and porokeratosis.

Not so sweet: autoimmune diabetes mellitus on triple therapy for chronic hepatitis C infection.

BACKGROUND: Triple therapy with pegylated interferon, ribavirin and a protease inhibitor has proven efficacy in hepatitis C infection and is currently the standard of care. Interferon-based therapies have been, rarely, associated with the development of Type 1 diabetes mellitus, but few cases have yet been reported in triple therapy for hepatitis C. CASE REPORT: We describe a case of autoimmune Type 1 diabetes developing in a 23-year-old woman after initiation of triple therapy for chronic hepatitis C virus infection. The patient had the IL-28B gene polymorphism rs12979860 CT genotype, which is associated not only with antiviral therapy response but also with diabetes risk after liver transplantation for hepatitis C. CONCLUSION: Further studies are required to determine which individual characteristics may identify patients who are at risk of developing Type 1 diabetes when treated with interferon-based regimens for hepatitis C infection.

Health Care-Associated Infections Among Hospitalized Patients With COVID-19, March 2020-March 2022.

Importance: The reported incidence of many health care-associated infections (HAIs) increased during the COVID-19 pandemic; however, it is unclear whether this is due to increased patient risk or to increased pressure on the health care system. Objective: To assess HAI occurrence among patients admitted to hospitals with and without COVID-19. Design, Setting, and Participants: A cross-sectional retrospective analysis of inpatients discharged both with and without laboratory-confirmed COVID-19 infection was conducted. Data were obtained between January 1, 2019, and March 31, 2022, from community hospitals affiliated with a large health care system in the US. Exposure: COVID-19 infection. Main Outcomes and Measures: Occurrence of central line-associated bloodstream infection (CLABSI), catheter-associated urinary tract infection (CAUTI), methicillin-resistant Staphylococcus aureus (MRSA) bacteremia, and Clostridioides difficile infection as reported to the National Healthcare Safety Network. Results: Among nearly 5 million hospitalizations in 182 hospitals between 2020 and 2022, the occurrence of health care-associated infections (HAIs) was high among the 313 200 COVID-19 inpatients (median [SD] age, 57 [27.3] years; 56.0% women). Incidence per 100 000 patient-days showed higher HAIs among those with COVID-19 compared with those without. For CLABSI, the incidence for the full 9 quarters of the study was nearly 4-fold higher among the COVID-19 population than the non-COVID-19 population (25.4 vs 6.9). For CAUTI, the incidence in the COVID-19 population was 2.7-fold higher in the COVID-19 population (16.5 vs 6.1), and for MRSA, 3.0-fold higher (11.2 vs 3.7). Quarterly trends were compared with the same quarter in 2019. The greatest increase in the incidence of HAI in comparison with the same quarter in 2019 for the entire population occurred in quarter 3 of 2020 for CLABSI (11.0 vs 7.3), quarter 4 of 2021 for CAUTI (7.8 vs 6.8), and quarter 3 of 2021 for MRSA (5.2 vs 3.9). When limited to the non-COVID-19 population, the increase in CLABSI incidence vs the 2019 incidence was eliminated, and the quarterly rates of MRSA and CAUTI were lower vs the prepandemic 2019 comparator quarter. Conclusions and Relevance: In this cross-sectional study of hospitals during the pandemic, HAI occurrence among inpatients without COVID-19 was similar to that during 2019 despite additional pressures for infection control and health care professionals. The findings suggest that patients with COVID-19 may be more susceptible to HAIs and may require additional prevention measures.

[French practical guidelines for the diagnosis and management of IPF - 2021 update, full version]. / Recommandations pratiques pour le diagnostic et la prise en charge de la fibrose pulmonaire idiopathique ­ Actualisation 2021. Version intégrale.

BACKGROUND: Since the previous French guidelines were published in 2017, substantial additional knowledge about idiopathic pulmonary fibrosis has accumulated. METHODS: Under the auspices of the French-speaking Learned Society of Pulmonology and at the initiative of the coordinating reference center, practical guidelines for treatment of rare pulmonary diseases have been established. They were elaborated by groups of writers, reviewers and coordinators with the help of the OrphaLung network, as well as pulmonologists with varying practice modalities, radiologists, pathologists, a general practitioner, a head nurse, and a patients' association. The method was developed according to rules entitled "Good clinical practice" in the overall framework of the "Guidelines for clinical practice" of the official French health authority (HAS), taking into account the results of an online vote using a Likert scale. RESULTS: After analysis of the literature, 54 recommendations were formulated, improved, and validated by the working groups. The recommendations covered a wide-ranging aspects of the disease and its treatment: epidemiology, diagnostic modalities, quality criteria and interpretation of chest CT, indication and modalities of lung biopsy, etiologic workup, approach to familial disease entailing indications and modalities of genetic testing, evaluation of possible functional impairments and prognosis, indications for and use of antifibrotic therapy, lung transplantation, symptom management, comorbidities and complications, treatment of chronic respiratory failure, diagnosis and management of acute exacerbations of fibrosis. CONCLUSION: These evidence-based guidelines are aimed at guiding the diagnosis and the management in clinical practice of idiopathic pulmonary fibrosis.

[French practical guidelines for the diagnosis and management of IPF - 2021 update, short version]. / Recommandations pratiques pour le diagnostic et la prise en charge de la fibrose pulmonaire idiopathique ­ Actualisation 2021. Version courte.

BACKGROUND: Since the previous French guidelines were published in 2017, substantial additional knowledge about idiopathic pulmonary fibrosis has accumulated. METHODS: Under the auspices of the French-speaking Learned Society of Pulmonology and at the initiative of the coordinating reference center, practical guidelines for treatment of rare pulmonary diseases have been established. They were elaborated by groups of writers, reviewers and coordinators with the help of the OrphaLung network, as well as pulmonologists with varying practice modalities, radiologists, pathologists, a general practitioner, a head nurse, and a patients' association. The method was developed according to rules entitled "Good clinical practice" in the overall framework of the "Guidelines for clinical practice" of the official French health authority (HAS), taking into account the results of an online vote using a Likert scale. RESULTS: After analysis of the literature, 54 recommendations were formulated, improved, and validated by the working groups. The recommendations covered a wide-ranging aspects of the disease and its treatment: epidemiology, diagnostic modalities, quality criteria and interpretation of chest CT, indication and modalities of lung biopsy, etiologic workup, approach to familial disease entailing indications and modalities of genetic testing, evaluation of possible functional impairments and prognosis, indications for and use of antifibrotic therapy, lung transplantation, symptom management, comorbidities and complications, treatment of chronic respiratory failure, diagnosis and management of acute exacerbations of fibrosis. CONCLUSION: These evidence-based guidelines are aimed at guiding the diagnosis and the management in clinical practice of idiopathic pulmonary fibrosis.

TRAF6-IRF5 kinetics, TRIF, and biophysical factors drive synergistic innate responses to particle-mediated MPLA-CpG co-presentation.

Innate immune responses to pathogens are driven by co-presentation of multiple pathogen-associated molecular patterns (PAMPs). Combinations of PAMPs can trigger synergistic immune responses, but the underlying molecular mechanisms of synergy are poorly understood. Here, we used synthetic particulate carriers co-loaded with monophosphoryl lipid A (MPLA) and CpG as pathogen-like particles (PLPs) to dissect the signaling pathways responsible for dual adjuvant immune responses. PLP-based co-delivery of MPLA and CpG to GM-CSF-driven mouse bone marrow-derived antigen-presenting cells (BM-APCs) elicited synergistic interferon-ß (IFN-ß) and interleukin-12p70 (IL-12p70) responses, which were strongly influenced by the biophysical properties of PLPs. Mechanistically, we found that MyD88 and interferon regulatory factor 5 (IRF5) were necessary for IFN-ß and IL-12p70 production, while TRIF signaling was required for the synergistic response. Both the kinetics and magnitude of downstream TRAF6 and IRF5 signaling drove the synergy. These results identify the key mechanisms of synergistic Toll-like receptor 4 (TLR4)-TLR9 co-signaling in mouse BM-APCs and underscore the critical role of signaling kinetics and biophysical properties on the integrated response to combination adjuvants.

[Iatrogenic cutaneous emphysema]. / Emphysème cutané iatrogène.

BACKGROUND: Tracheal perforation following orotracheal intubation is a rare but classic complication of general anaesthesia, and marked cutaneous emphysema can occur. We report a rare case of facial cutaneous emphysema revealed by swelling with pseudovesicles on the eyelids. CASE REPORT: A 99-year-old woman developed extensive facial swelling with pseudo-vesicles on the upper and lower eyelids following right hip replacement surgery. Swelling of the upper members and thoracic area was also seen. Chest X-rays showed marked cutaneous emphysema of the thoracic wall. Bronchial endoscopy revealed perforation of the posterior aspect of the trachea. The patient was presenting cutaneous emphysema as a result of post-intubation tracheal perforation. DISCUSSION: We report a rare case of cutaneous emphysema in a 99-year-old woman after tracheal perforation following orotracheal intubation. The significant feature of our case report is the actual manifestation of the condition. Our patient developed swelling of the eyelid with pseudovesicles. When confronted with sudden onset of pseudovesicles of the eyelids after surgery, dermatologists must not misdiagnose cutaneous emphysema and must examine their patient carefully for other clinical signs. Bronchial endoscopy should be undertaken immediately to investigate for tracheal perforation.

[Infiltrative basal cell carcinoma presenting as chronic leg ulcer]. / Carcinome basocellulaire infiltrant se présentant comme un ulcère de jambe chronique.

BACKGROUND: Basal cell carcinoma is the most common carcinoma of the skin and is usually found on the head and neck. We report an unusual case of basal cell carcinoma presenting as a chronic leg ulcer, with underlying bone involvement. CASE REPORT: A 70-year-old woman presented with a 15-year history of leg ulcer refractory to treatment. Because of the exuberant granulation tissue on the base and the indurated edges of this circumferential leg ulcer, several biopsies were taken from the edge and the base of the ulcer. Histological examination revealed infiltrative basal cell carcinoma. Treatment consisted of surgical excision of 80% of the primary lesion and coverage with a split-thickness skin graft. Examination of the surgical piece revealed invasion of bone by the carcinoma. The remainder of the lesion not accessible to surgery was irradiated. DISCUSSION: There is a need for awareness among all doctors of the clinical signs evocative of malignant transformation of a leg ulcer so that a skin biopsy may be performed for suspicious ulcers. Our case is distinguished by the underlying invasion of bone by basal cell carcinoma, as attested by imaging and histology.

[Invasive pulmonary aspergillosis]. / Aspergillose pulmonaire invasive.

INTRODUCTION: Invasive pulmonary aspergillosis (IPA) is an important cause of morbidity and mortality in a wide range of patients. Early recognition and diagnosis have become a major focus in improving the management and outcomes of this life-threatening disease. BACKGROUND: IPA typically occurs during a period of severe and prolonged neutropenia. However, solid organ transplant recipients, patients under immunosuppressive therapy or hospitalized in intensive care units are also at risk. The diagnosis is suspected in the presence of a combination of clinical, biological and CT scan evidence. The microbiological diagnostic strategy should be adapted to the patient's profile. Conventional methods with culture and species identification remain the standard but early diagnosis has been improved by the use of biomarkers such as galactomannan antigen in serum or in bronchoalveolar lavage. OUTLOOK: The epidemiology of IPA should change with the increased use of antifungal prophylactic regimens and the arrival of targeted therapies. Other microbiological tools, such as PCR and other biomarkers, are currently being assessed. CONCLUSIONS: IPA must be considered in a wide range of patients. Its prognosis remains poor despite progress in the microbiological diagnosis and therapeutic management.

Evaluation of superficially and fully porous particles for HILIC separation of lanthanide-polyaminocarboxylic species and simultaneous coupling to ESIMS and ICPMS.

In this work, amide-bonded columns packed with fully porous particles (FPP) and superficially porous particles (SPP) were evaluated to separate lanthanide-polyaminocarboxylic species by hydrophilic interaction liquid chromatography (HILIC), using two model samples of interest in nuclear and other industrial applications. We assessed the gains achieved by reducing the dimensions of the columns along with the size of the FPPs to sub-2 µm and by using sub-3 µm SPP-packed columns. The FPP-packed Acquity column (100 × 2.1 mm; 1.7 µm) performed better than the SPP-packed Accucore column (150 × 2.1 mm; 2.6 µm), with a separation that was two times more efficient and three times shorter, while generating around 30% less in effluent volumes. This column was also coupled simultaneously to electrospray ionisation mass spectrometry (ESIMS) and inductively coupled plasma mass spectrometry (ICPMS). The instrumental set-up was performed in a conventional laboratory, by taking into account the geometrical constraints existing in the laboratory dedicated to radioelement analysis. Furthermore, separation of the series of lanthanide (Ln) species was demonstrated for the first time thanks to the separation mode of hydrophilic interaction liquid chromatography.