Highly Conserved gsc1 Gene of Pneumocystis jirovecii in Patients with or without Prior Exposure to Echinocandins.

Echinocandins are noncompetitive inhibitors of the GSC1 subunit of the enzymatic complex involved in synthesis of 1,3-beta-d-glucan, a cell wall component of most fungi, including Pneumocystis spp. Echinocandins are widely used for treating systemic candidiasis and rarely used for treating Pneumocystis pneumonia. Consequently, data on P. jirovecii gsc1 gene diversity are still scarce compared to that for the homologous fks1 gene of Candida spp. In this study, we analyzed P. jirovecii gsc1 gene diversity and the putative selection pressure of echinocandins on P. jirovecii. gsc1 gene sequences of P. jirovecii specimens from two patient groups were compared. One group of 27 patients had prior exposure to echinocandins, whereas the second group of 24 patients did not, at the time of P. jirovecii infection diagnoses. Two portions of the P. jirovecii gsc1 gene, HS1 and HS2, homologous to hot spots described in Candida spp., were sequenced. Three single-nucleotide polymorphisms (SNPs) at positions 2204, 2243, and 2303 close to the HS1 region and another SNP at position 4540 more distant from the HS2 region were identified. These SNPs represent synonymous mutations. Three gsc1 HS1 alleles, A, B, and C, and two gsc1 HS2 alleles, a and b, and four haplotypes, Ca, Cb, Aa, and Ba, were defined, without significant difference in haplotype distribution in both patient groups (P = 0.57). Considering the identical diversity of P. jirovecii gsc1 gene and the detection of synonymous mutations in both patient groups, no selection pressure of echinocandins among P. jirovecii microorganisms can be pointed out so far.

Mucoactive drugs and multiple applications in pulmonary disease therapy.

Mucus is a complex polymeric hydrogel that serves as a critical defense in several organs. In the lungs, it provides a formidable barrier against inhaled particles such as microorganisms. In addition, mucus is essential for normal lung physiology, as it promotes immune tolerance and facilitates a normal commensal pulmonary microbiome. Hypersecretion of airway mucus is a characteristic of numerous respiratory diseases, such as Chronic Obstructive Pulmonary Disease (COPD) and Cystic Fibrosis (CF), and creates pulmonary obstruction, limiting the effectiveness of inhaled therapies. Due to those alterations, therapeutic strategies must be optimal to limit airway obstruction and restore pulmonary function. Mucoactive drugs are common therapeutic options and are classified into different groups depending on their modes of action, i.e., expectorants, mucokinetics, mucoregulators and mucolytics. This review focuses on mucoactive drugs and their modes of action. A special focus will be made on two challenging pulmonary pathologies: COPD and CF, and on their clinical studies conducted with mucoactive drugs.

Enoxaparin versus Placebo to Prevent Symptomatic Venous Thromboembolism in Hospitalized Older Adult Medical Patients.

BACKGROUND: Admission to the hospital is a major risk factor for the development of venous thromboembolism (VTE). Whether thromboprophylaxis with low-molecular-weight heparin prevents symptomatic VTE in medically ill, hospitalized older adults remains debated. METHODS: In a prospective, randomized, placebo-controlled, double-blind, multicenter trial, older adults (>70 years of age) hospitalized for acute medical conditions were randomly assigned to receive 40 mg a day of low-molecular-weight heparin (enoxaparin) or placebo for 6 to 14 days. The primary efficacy outcome was the cumulative incidence of symptomatic VTE (distal or proximal deep vein thrombosis, fatal or nonfatal pulmonary embolism) at 30 days. The primary safety outcome was major bleeding. Secondary outcomes included efficacy and safety outcomes at 90 days. RESULTS: The trial was prematurely discontinued in September 2020, 5 years after enrollment began, because of drug supply issues. By the time of trial discontinuation, 2559 patients had been randomly assigned at 47 centers. Median age was 82 years and 60% of patients were female. In the intention-to-treat population, the primary efficacy outcome occurred in 22 out of 1278 (cumulative incidence, 1.8%) patients in the enoxaparin group and in 27 out of 1263 (cumulative incidence, 2.2%) patients in the placebo group (cumulative incidence difference, −0.4 percentage points; 95% confidence interval, −1.5 to 0.7), with no significant difference in time to VTE (P=0.46). The incidence of major bleeding was 0.9% in the enoxaparin group and 1.0% in the placebo group. At 90 days there were 14 symptomatic pulmonary emboli in the enoxaparin group and 25 in the placebo group; all 39 pulmonary embolism events resulted in hospital readmission and/or death, with 5 deaths from pulmonary embolism in the enoxaparin group and 11 deaths in the placebo group. CONCLUSIONS: This trial of thromboprophylaxis in medically ill, hospitalized older adults did not demonstrate that enoxaparin reduced the risk of symptomatic VTE after 1 month. Because the trial was prematurely discontinued, larger trials are needed to definitively address this question. (Funded by the French Ministry of Health Programme Hospitalier de Recherche Clinique, grant number PHRC-N-13-0283; ClinicalTrials.gov number, NCT02379806.)

Effect of Local Anesthesia on Pain During Arterial Puncture: The GAEL Randomized Placebo-Controlled Trial.

BACKGROUND: Arterial puncture is often painful for patients. The aim of this study was to compare use of local anesthesia as a eutectic mixture of 2 local anesthetics, lidocaine and prilocaine, versus placebo. METHODS: We conducted a double-blind, randomized controlled trial. Subjects were eligible if arterial puncture was indicated. The primary outcome was an experienced pain > 2 on a numerical pain rating scale. As having had a previous experience of arterial puncture was expected to be predictive of the current response, we planned 3 comparisons between use of local anesthesia and placebo: in the whole sample, among subjects with a painful previous experience, and among subjects with a painless previous experience. Multiple testing was analyzed using the Bonferroni correction for the primary outcome. The secondary outcome was the numerical pain rating scale score itself. All analyses were performed on an intention-to-treat basis. RESULTS: A total of 136 subjects were included in this study. The primary outcome occurred in 20.9% in the active arm versus 37.7% in the placebo arm in the whole sample (relative risk 0.55; 95% CI when adjusting for multiple testing ranged was 0.28-1.09, P = .10; 95% CI without adjustment was 0.32-0.97, P = .038). No significant heterogeneity in the study treatment effect was found when considering previous painful or painless arterial puncture (P = .70). The numerical pain rating scale score was 1.55 ± 2.03 in active group versus 2.09 ± 2.15 in the placebo group (P = .13). CONCLUSIONS: We found that application of a eutectic mixture reduced the number of painful arterial punctures by 50% compared with placebo. However, this result was not statistically significant. (ClinicalTrials.gov registration NCT01964248.).

68Ga-Labelled Carbon Nanoparticles for Ventilation PET/CT Imaging: Physical Properties Study and Comparison with Technegas®.

PURPOSE: The use of 68Ga-labelled carbon nanoparticles has been proposed for lung ventilation PET/CT imaging. However, no study has assessed the physical properties of 68Ga-labelled carbon nanoparticles. The aim of this study therefore was to evaluate the shape and size of 68Ga-labelled carbon nanoparticles, and to determine the composition of the aerosol, as opposed to 99mTc-labelled carbon nanoparticles aerosol. PROCEDURES: 99mTc- and 68Ga-labelled carbon nanoparticles, stable gallium carbon nanoparticles, 0.9 % NaCl and 0.1 N HCl-based carbon nanoparticles were produced using an unmodified Technegas® generator, following the usual technique used for clinical Technegas® production. The shape and size of particles were studied by transmission electron microscopy (TEM) after decay of the radioactive samples. The composition of the 68Zn- and 99Tc-labelled carbon nanoparticles aerosols was assessed using scanning electron microscopy (SEM) coupled with energy dispersive X-ray (EDX) analysis after decay of the 68Ga- and 99mTc-labelled carbon nanoparticles, respectively. RESULTS: On TEM, all samples showed similar shape with hexagonally structured primary particles, agglomerated in clusters. The mean diameters of primary stable gallium carbon nanoparticles, 99Tc- and 68Zn-labelled carbon nanoparticles were 22.4 ± 10 nm, 20.9 ± 7.2 nm and 19.8 ± 11.7 nm, respectively. CONCLUSION: Using Technegas® generator in the usual clinical way, 99mTc- and 68Ga-labelled carbon nanoparticles demonstrated similar shape and diameters in the same size range size. These results support the use of 68Ga-labelled carbon nanoparticles for the assessment of regional lung ventilation function with PET imaging.

[Drugs administration by subcutaneous injection within palliative care]. / Administration des médicaments par voie sous-cutanée en soins palliatifs.

Drugs delivery by subcutaneous injection is often the last resort/appeal for a doctor anxious to limit the aggressive and invasive treatments, particularly within palliative care. A review was made to list the drugs which can be administered by this route. Concerned antibiotics are teicoplanin, netilmicin and gentamicin with a risk of skin necrosis for aminoglycosids. Midazolam is useful in various indications and can be associated with morphine in case of dyspnoea. Data about subcutaneous injection of dexamethasone, clonazepam, haloperidol and levomepromazine are published; it is the same for fentanyl, nefopam, ondansetron and metoclopramide. The subcutaneous injection of these quoted drugs is possible, but requires further studies.

Hydroxychloroquine for prevention of recurrent miscarriage: study protocol for a multicentre randomised placebo-controlled trial BBQ study.

INTRODUCTION: Recurrent miscarriage (RM), defined by three or more consecutive losses during the first trimester of pregnancy, affects 1%-2% of fertile couples. Standard investigations fail to reveal any apparent cause in ~50% of couples. However, on the basis of animal models and clinical studies, several hypotheses have been put forward concerning underlying mechanisms of RM: altered ovarian reserve, progesterone defect, thrombotic and/or endothelial dysfunction and immunological disturbances. Nonetheless, no study has yet reached conclusive beneficial clinical evidence for a potential treatment in unexplained RM. Hydroxychloroquine (HCQ) is a molecule with extensive safety data during pregnancy. The pharmacological properties of HCQ (eg, antithrombotic, vascular protective, immunomodulatory, improved glucose tolerance, lipidlowering and anti-infectious) could be effective against some mechanisms of unexplained RM. Furthermore, eventhough clinical benefit of HCQ is suggested in prevention of thrombotic and late obstetric events in antiphospholipid (APL) syndrome, there are no data suggesting the benefit of HCQ in RM in the presence of APL antibodies. METHODS AND ANALYSIS: Taken all together and given the low cost of HCQ, the aim of this multicentre, randomised, placebo-controlled, double-blind study is to investigate whether HCQ would improve the live birth rate in women with RM, irrespective of maternal thrombophilic status: (1) no known thrombophilia, (2) inherited thrombophilia or (3) APL antibodies. The primary end point is a live and viable birth. After confirming eligibility and obtaining consent, 300 non-pregnant women will be randomised into two parallel groups for a daily oral treatment (HCQ 400 mg or placebo), initiated before conception and stopped at 10 weeks' gestation. If pregnancy does not occur after 1 year, the treatment will be stopped. ETHICS AND DISSEMINATION: Agreement from the French National Public Health and Drug Security Agency (160765A-22) and ethical approval from the Committee for the Protection of Persons of NORD-OUEST I (2016-001330-97) have been obtained. TRIAL REGISTRATION NUMBERS: NCT0316513; Pre-results.

Early discontinuation of empirical antibacterial therapy in febrile neutropenia: the ANTIBIOSTOP study.

INTRODUCTION: Immediate empirical antibiotic therapy is mandatory in febrile chemotherapy-induced neutropenia, but its optimal duration is unclear, especially in patients with fever of unknown origin (FUO). OBJECTIVES: The primary objective of this 20-month prospective observational study was to evaluate the feasibility and safety of short-term antibiotic treatment in afebrile or febrile patients exhibiting FUO, irrespective of their neutrophil count. The secondary objective was to describe the epidemiology of all episodes of febrile neutropenia. METHODS: In the first phase of the study, empirical antibiotic therapy in FUO patients was stopped after 48 h of apyrexia, in accordance with European Conference on Infections in Leukaemia guidelines (n = 45). In the second phase of the study, antibiotics were stopped no later than day 5 for all FUO patients, regardless of body temperature or leukocyte count (n = 37). RESULTS: Two hundred and thirty-eight cases of febrile neutropenia in 123 patients were included. Neither the composite endpoint (p = .11), nor each component (in-hospital mortality (p = .80), intensive care unit admission (p = 0.48), relapse of infection ≤48 h after discontinuation of antibiotics (p = .82)) differed between the two FUO groups. Violation of protocol occurred in 17/82 episodes of FUO without any major impact on statistical results. Twenty-six (57.3%) and 22 (59.5%) FUO episodes did not relapse during hospital-stay (p = 1), and nine (20%) and five (13.5%) presented another FUO, respectively. One hundred and fifty-six episodes of febrile neutropenia (65.5%) were clinically or microbiologically documented, including 85 bacteremia. CONCLUSIONS: These results suggest that early discontinuation of empirical antibiotics in FUO is safe for afebrile neutropenic patients.