Utilization of intravenous or subcutaneous immunoglobulins in secondary immune deficiency (ULTIMATE): A retrospective multicenter study.

INTRODUCTION: We conducted a retrospective multicenter cohort study of patients receiving Immunoglobulin replacement therapy (IgRT) for secondary immune deficiency (SID) during 2012. METHODS: Data were retrospectively collected from the first dose of Ig administered in 2012 to 1 year afterward in terms of the indication for IgRT, as well as efficacy and safety. RESULTS: In total, 16 hospitals participated in the study, and 368 patients were included. Indications for IgRT were non-Hodgkin lymphoma (82 [22.3%] patients), multiple myeloma (76 [20.7%]), chronic lymphocytic leukemia (64 [17.4%]) and other (79 [21.5%]). Only 89 (24.2%) patients received IgRT according to 2011 European Medical Agency (EMA) recommendations; 196 (53.3%) received prophylactic antibiotics and 262 (76.2%) had an IgG level < 4 g/L before IgRT initiation. CONCLUSION: In this study, whatever the criteria, only 24.2% of patients with SID who received IgRT met EMA recommendations, which suggests a misuse of IgRT in SID.

The discovery of Candidatus Nanopusillus phoceensis sheds light on the diversity of the microbiota nanoarchaea.

To further assess the spectrum of nanoarchaea in human microbiota, we prospectively searched for nanoarchaea in 110 leftover stool specimens, using the complementary approaches of PCR-sequencing screening, fluorescent in situ hybridization, scanning electron microscopy and metagenomics. These investigations yielded a nanoarchaea, Candidatus Nanopusillus phoceensis sp. nov., detected in stool samples by specific PCR-based assays. Microscopic observations indicated its close contact with the archaea Methanobrevibacter smithii. Genomic sequencing revealed 607,775-bp contig with 24.5% G + C content encoding 30 tRNAs, 3 rRNA genes, and 1,403 coding DNA sequences, of which 719 were assigned to clusters of orthologous groups. Ca. Nanopusillus phoceensis is only the second nanoarchaea to be detected in humans, expanding our knowledge of the repertoire of nanoarchaea associated with the human microbiota and encouraging further research to explore the repertoire of this emerging group of nanomicrobes in clinical samples.

Candidatus Methanosphaera massiliense sp. nov., a methanogenic archaeal species found in a human fecal sample and prevalent in pigs and red kangaroos.

Methanosphaera stadtmanae was the sole Methanosphaera representative to be cultured and detected by molecular methods in the human gut microbiota, further associated with digestive and respiratory diseases, leaving unknown the actual diversity of human-associated Methanosphaera species. Here, a novel Methanosphaera species, Candidatus Methanosphaera massiliense (Ca. M. massiliense) sp. nov. was isolated by culture using a hydrogen- and carbon dioxide-free medium from one human feces sample. Ca. M. massiliense is a non-motile, 850 nm Gram-positive coccus autofluorescent at 420 nm. Whole-genome sequencing yielded a 29.7% GC content, gapless 1,785,773 bp genome sequence with an 84.5% coding ratio, encoding for alcohol and aldehyde dehydrogenases promoting the growth of Ca. M. massiliense without hydrogen. Screening additional mammal and human feces using a specific genome sequence-derived DNA-polymerase RT-PCR system yielded a prevalence of 22% in pigs, 12% in red kangaroos, and no detection in 149 other human samples. This study, extending the diversity of Methanosphaera in human microbiota, questions the zoonotic sources of Ca. M. massiliense and possible transfer between hosts.IMPORTANCEMethanogens are constant inhabitants in the human gut microbiota in which Methanosphaera stadtmanae was the only cultivated Methanosphaera representative. We grew Candidatus Methanosphaera massiliense sp. nov. from one human feces sample in a novel culture medium under a nitrogen atmosphere. Systematic research for methanogens in human and animal fecal samples detected Ca. M. massiliense in pig and red kangaroo feces, raising the possibility of its zoonotic acquisition. Host specificity, source of acquisition, and adaptation of methanogens should be further investigated.

Current knowledge and clinical perspectives for a unique new phylum: Nanaorchaeota.

Nanoarchaea measuring less than 500 nm and encasing an average 600-kb compact genome have been studied for twenty years, after an estimated 4193-million-year evolution. Comprising only four co-cultured representatives, these symbiotic organisms initially detected in deep-sea hydrothermal vents and geothermal springs, have been further distributed in various environmental ecosystems worldwide. Recent isolation by co-culture of Nanopusillus massiliensis from the unique ecosystem of the human oral cavity, prompted us to review the evolutionary diversity of nanaorchaea resulting in a rapidly evolving taxonomiy. Regardless of their ecological niche, all nanoarchaea share limited metabolic capacities correlating with an obligate ectosymbiotic or parasitic lifestyle; focusing on the dynamics of nanoarchaea-bacteria nanoarchaea-archaea interactions at the morphological and metabolic levels; highlighting proteins involved in nanoarchaea attachment to the hosts, as well metabolic exchanges between both organisms; and highlighting clinical nanoarchaeology, an emerging field of research in the frame of the recent discovery of Candidate Phyla radiation (CPR) in human microbiota. Future studies in clinical nanobiology will expand knowledge of the nanaorchaea repertoire associated with human microbiota and diseases, to improve our understanding of the diversity of these nanoorganims and their intreactions with microbiota and host tissues.

A multicenter prospective observational study of the conformity of temozolomide prescriptions in France.

CONTEXT: Temozolomide (TMZ) is approved for the treatment of high-grade gliomas such as glioblastoma (GBM) multiforme and refractory anaplastic astrocytoma, but it is also used in indications not mentioned in the summary of product characteristics (SPC). The main objective of this study was to evaluate the conformity of TMZ prescriptions to the French SPC and prescription guidebook. METHODS: We conducted a prospective observational study of all consecutive patients treated with TMZ in 21 French hospitals between September 2006 and February 2007, accounting for 39% of total TMZ consumption in France. The conformity of TMZ prescriptions was evaluated in terms of the indication, dosage, treatment duration, and combination with other treatments, with respect to the SPC and prescription guidebook. RESULTS: We enrolled 831 patients (median age, 56 years) who received a total of 5982 TMZ treatment cycles. TMZ was mainly prescribed to patients with newly diagnosed GBM (384 patients), GBM in progression/relapse (28 patients), or anaplastic astrocytoma in progression/relapse (19 patients). Prescriptions conformed to the SPC in 51.9% of cases and to the prescription guidebook in 91.5% of cases. Global conformity with the SPC, in terms of the dosage, treatment duration, and combination with other treatments, was 62% for newly diagnosed GBM treated with radiotherapy plus TMZ, 72% for TMZ maintenance monotherapy, and 66% for GBM and anaplastic astrocytoma in progression/relapse. CONCLUSION/DISCUSSION: In France, routine TMZ prescriptions conform to the SPC and practice guidebook. This is one of the largest studies of drug use in neuro-oncology in terms of the number of patients and cycles analyzed.

Detection of Methanobrevobacter smithii and Methanobrevibacter oralis in Lower Respiratory Tract Microbiota.

Methanogens, the sole microbes producing methane, are archaea commonly found in human anaerobic microbiota. Methanogens are emerging as opportunistic pathogens associated with dysbiosis and are also detected and cultured in anaerobic abscesses. Their presence in the respiratory tract is yet unknown. As a preliminary answer, prospective investigation of 908 respiratory tract samples using polyphasic approach combining PCR-sequencing, real-time PCR, fluorescent in situ hybridization (FISH), and methanogens culture was carried out. Methanobrevibacter smithii and Methanobrevibacter oralis DNA sequences, were detected in 21/527 (3.9%) sputum samples, 2/188 (1.06%) bronchoalveolar lavages, and none of 193 tracheo-bronchial aspirations. Further, fluorescence in situ hybridization detected methanogens in three sputum investigated specimens with stick morphology suggesting M. oralis and in another one bronchoalveolar lavage sample investigated, diplococal morphology suggesting M. smithii. These observations extend the known territory of methanogens to the respiratory tract and lay the foundations for further interpretation of their detection as pathogens in any future cases of isolation from bronchoalveolar lavages and the lungs.

Factors associated with hearing impairment in patients with congenital hypothyroidism treated since the neonatal period: a national population-based study.

CONTEXT: Untreated hypothyroidism is known to impair hearing, but little is known about the long-term hearing of patients treated for congenital hypothyroidism (CH) since the neonatal period. OBJECTIVE: The purpose of this study was to assess hearing and its determinants in a population-based registry of young adult patients with CH. DESIGN, SETTING, AND PARTICIPANTS: Self-declared hearing loss was evaluated in 1202 of the 1748 eligible patients with CH who completed a questionnaire on health status at a median age of 23.4 years. Audiograms were obtained for one third of the patients declaring hearing loss (37 of 107). MAIN OUTCOME MEASURES: Self-declared hearing loss and audiogram characteristics for patients reporting hearing impairment were measured. RESULTS: These patients had a risk of self-declared hearing loss more than 3 times higher than that for the reference population (relative risk [RR] = 3.7; 95% confidence interval [CI], 2.9-4.7). Hearing impairment was diagnosed at a median age of 7.0 (25th-75th percentiles, 3.4-19.0) years, and 17% of affected patients required hearing support in early adulthood. Hearing loss was associated with the type of CH (patients with athyreosis and gland in situ were more frequently affected than those with an ectopic gland [RR = 2.61; 95% CI, 1.77-3.88]), with disease severity, as assessed by bone maturation delay at the time of diagnosis, with at least one knee epiphyseal ossification center absent in the most severe form (RR = 2.29; 95% CI, 1.39-3.79), and with other associated chronic diseases (RR = 3.64; 95% CI, 2.35-5.62). A trend for association with serum free T4 concentration at diagnosis was also observed (RR = 1.47; 95% CI, 0.96-2.23). Hearing loss was mostly bilateral (90%), mild to moderate (96%), of the sensorineural type (76%), and concerned high or very high frequencies. CONCLUSION: Despite major improvements in prognosis, hearing loss remains a significant problem, particularly in patients with severe CH. Parents and primary care providers should be aware of this risk, because early diagnosis and intervention could improve the long-term prognosis in these patients.

Fecundity in young adults treated early for congenital hypothyroidism is related to the initial severity of the disease: a longitudinal population-based cohort study.

CONTEXT: Untreated hypothyroidism is known to impair fecundity. Patients treated early for congenital hypothyroidism (CH) have yet to be evaluated in adulthood, because screening programs have been running for only the last 30 years in most industrialized countries. OBJECTIVE: Our objective was to assess the fecundity of young adults treated early for CH and its determinants. DESIGN, SETTING, AND PARTICIPANTS: Of the 1748 subjects diagnosed with CH in the first 10 yr after the introduction of neonatal screening in France, 1158 completed a questionnaire on fecundity at a mean age of 25.3 yr. This self-administered questionnaire focused on first attempts to have a child and time to pregnancy. The control group was that used in an analogous study on subjects born between 1971 and 1985. MAIN OUTCOME MEASURES: Fecundability hazard ratios (HR) were estimated with Cox regression models and adjusted for known fecundity confounders (age, smoking, and reproductive history). RESULTS: Fecundability was similar for the CH and control groups: HR = 1.14 (0.89-1.47) for women, and HR = 0.98 (0.58-1.66) for men. In women, the most severe initial forms of the disease, athyreosis, absence of bone maturation at the knee epiphyseal ossification centers, and a low serum free T(4) concentration at diagnosis (<5 pmol/liter), were associated with lower fecundity: HR = 0.68 (0.50-0.98) (P = 0.02); HR = 0.65 (0.45-0.94) (p = 0.02) and HR = 0.70 (0.50-0.97) (P = 0.03), respectively. However, fecundability was not associated with age at the start of treatment, initial levothyroxine dose, or the adequacy of hypothyroidism control. CONCLUSION: There is no evidence that fecundity is generally lower in young adults treated early than in the general population. However, fecundity was lower in women suffering from the most severe form of the disease.

[Monitoring and evaluation tools for irinotecan and bevacizumab in glioblastoma: from prescription to patient's information]. / Outils de suivi et d'autoévaluation de l'irinotécan et du bévacizumab dans les glioblastomes : de la prescription à l'information du patient.

In 2007, the use of a new therapeutic association that included two expensive drugs (bevacizumab and irinotecan), used in second line treatment for progressive glioblastoma, led to the increase of the monitoring and self-evaluation of the medical prescriptions. Methodological tools have been designed by neuro-oncologists together with pharmacists of the Pitié-Salpêtrière Hospital in order to be consistent with the "good use economic contract". Those drugs have not been approved by European authorities in this indication and, moreover, this combination presents adverse effects and contraindications that need to be known by the professionals, the patient and his family. Some documents have been created in order to facilitate prescriptions for neuro-oncologists and others provide monitoring tools for the physicians and nurses. A letter of information targets the patient and his family, another one targets the general practitioner. This is useful for a better coordination between these ones and the hospital. The patient receives a document and a monitoring book in order to inform him about his treatment and help him to prevent and react in time in case of side effects occurrence. Those measures have been designed to put a frame around the prescriptions and to decrease iatrogenic events as well as the economic costs.