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Cryptococcosis is a life-threatening opportunistic fungal infection in both HIV-positive and -negative patients. Information on clinical presentation and therapeutic guidelines, derived mostly from clinical trials performed before introduction of highly active antiretroviral therapy in patients with cryptococcal meningoencephalitis, is missing data on extrameningeal involvement and infections by serotype D as opposed to serotype A of Cryptococcus neoformans. The prospective multicenter study CryptoA/D was designed in France (1997-2001) to analyse the factors influencing clinical presentation and outcome without the bias of inclusion into therapeutic trials. Of the 230 patients enrolled, 177 (77%) were HIV-positive, 50 (22%) were female, and 161 (72.5%) were infected with serotype A. Based on culture results at baseline, cryptococcosis was more severe in men, in HIV-positive patients, and in patients infected with serotype A. Factors independently associated with mycological failure at week 2 independent of HIV status were initial dissemination (OR, 2.4 [95% confidence interval (CI), 1.2-4.9]), high (>1:512) serum antigen titre (OR, 2.6 [1.3-5.4]), and lack of flucytosine during induction therapy (OR, 3.8 [1.9-7.8]). The three-month survival was shorter in patients with abnormal neurology or brain imaging at baseline, and in those with haematological malignancy. Thus sex, HIV status, and infecting serotype are major determinants of presentation and outcome during cryptococcosis. We propose a modification of current guidelines for the initial management of cryptococcosis based on systematic fungal burden evaluation.

Cryptococcus neoformans is a human opportunistic fungal pathogen causing severe disseminated meningoencephalitis, mostly in patients with cellular immune defects. This species is divided into three serotypes: A, D, and the AD hybrid. Our objectives were to compare population structures of serotype A and D clinical isolates and to assess whether infections with AD hybrids differ from infections with the other serotypes. For this purpose, we analyzed 483 isolates and the corresponding clinical data from 234 patients enrolled during the CryptoA/D study or the nationwide survey on cryptococcosis in France. Isolates were characterized in terms of ploidy, serotype, mating type, and genotype, utilizing flow cytometry, serotype- and mating type-specific PCR amplifications, and multilocus sequence typing (MLST) methods. Our results suggest that C. neoformans serotypes A and D have different routes of multiplication (primarily clonal expansion versus recombination events for serotype A and serotype D, respectively) and important genomic differences. Cryptococcosis includes a high proportion of proven or probable infections (21.5%) due to a mixture of genotypes, serotypes, and/or ploidies. Multivariate analysis showed that parameters independently associated with failure to achieve cerebrospinal fluid (CSF) sterilization by week 2 were a high serum antigen titer, the lack of flucytosine during induction therapy, and the occurrence of mixed infection, while infections caused by AD hybrids were more likely to be associated with CSF sterilization. Our study provides additional evidence for the possible speciation of C. neoformans var. neoformans and grubii and highlights the importance of careful characterization of causative isolates. IMPORTANCE Cryptococcus neoformans is an environmental fungus causing severe disease, estimated to be responsible for 600,000 deaths per year worldwide. This species is divided into serotypes A and D and an AD hybrid, and these could be considered two different species and an interspecies hybrid. The objectives of our study were to compare population structures of serotype A and serotype D and to assess whether infections with AD hybrids differ from infections with serotype A or D isolates in terms of clinical presentation and outcome. For this purpose, we used clinical data and strains from patients diagnosed with cryptococcosis in France. Our results suggest that, according to the serotype, isolates have different routes of multiplication and high genomic differences, confirming the possible speciation of serotypes A and D. Furthermore, we observed a better prognosis for infections caused by AD hybrid than those caused by serotype A or D, at least for those diagnosed in France. Cryptococcus neoformans is an environmental fungus causing severe disease, estimated to be responsible for 600,000 deaths per year worldwide. This species is divided into serotypes A and D and an AD hybrid, and these could be considered two different species and an interspecies hybrid. The objectives of our study were to compare population structures of serotype A and serotype D and to assess whether infections with AD hybrids differ from infections with serotype A or D isolates in terms of clinical presentation and outcome. For this purpose, we used clinical data and strains from patients diagnosed with cryptococcosis in France. Our results suggest that, according to the serotype, isolates have different routes of multiplication and high genomic differences, confirming the possible speciation of serotypes A and D. Furthermore, we observed a better prognosis for infections caused by AD hybrid than those caused by serotype A or D, at least for those diagnosed in France.

The benefits provided by disease-modifying treatments in multiple sclerosis have been demonstrated in clinical trials, but the extent to which they can be extrapolated to everyday care is less clear, as are the long-term benefits of treatment. The objective of this prospective observational cohort study performed in France was to evaluate the effectiveness and safety of glatiramer acetate in patients with relapsing–remitting multiple sclerosis over a 5-year period. All neurologists in France were invited to participate and enroll adult patients starting a first treatment with brand glatiramer acetate 20 mg. Given the observational nature of the study, no fixed study visits were imposed; consultations took place according to the investigator’s normal practice. Occurrence of disease exacerbations and adverse events was documented and neurological disability evaluated with the EDSS at each consultation. Overall, 852 patients were analysable and 269 took glatiramer acetate continuously for 5 years. Median treatment duration was 3.4 years. Principal reasons for discontinuation were inadequate efficacy (38.9%), local tolerability (22.6%) and personal convenience (21.3%). Age, employment status, baseline EDSS score and number of previous exacerbations were variables associated with treatment persistence. The annualised exacerbation rate (5 years) was 0.41 [95% CI 0.39–0.44]; 316 patients (37.2%) remained exacerbation-free throughout. The risk of confirmed disability worsening (5 years) was 43.8% [95% CI 39.9–47.9%]. The most frequent adverse drug reactions were local injection site reactions (584 patients; 68.5%) and systemic immediate post-injection reactions (168 patients; 19.7%). Overall, these findings are consistent with those of previous clinical trials.

To optimize the molecular diagnosis of hereditary breast and ovarian cancer (HBOC), we developed a next-generation sequencing (NGS)-based screening based on the capture of a panel of genes involved, or suspected to be involved in HBOC, on pooling of indexed DNA and on paired-end sequencing in an Illumina GAIIx platform, followed by confirmation by Sanger sequencing or MLPA/QMPSF. The bioinformatic pipeline included CASAVA, NextGENe, CNVseq and Alamut-HT. We validated this procedure by the analysis of 59 patients' DNAs harbouring SNVs, indels or large genomic rearrangements of BRCA1 or BRCA2. We also conducted a blind study in 168 patients comparing NGS versus Sanger sequencing or MLPA analyses of BRCA1 and BRCA2. All mutations detected by conventional procedures were detected by NGS. We then screened, using three different versions of the capture set, a large series of 708 consecutive patients. We detected in these patients 69 germline deleterious alterations within BRCA1 and BRCA2, and 4 TP53 mutations in 468 patients also tested for this gene. We also found 36 variations inducing either a premature codon stop or a splicing defect among other genes: 5/708 in CHEK2, 3/708 in RAD51C, 1/708 in RAD50, 7/708 in PALB2, 3/708 in MRE11A, 5/708 in ATM, 3/708 in NBS1, 1/708 in CDH1, 3/468 in MSH2, 2/468 in PMS2, 1/708 in BARD1, 1/468 in PMS1 and 1/468 in MLH3. These results demonstrate the efficiency of NGS in performing molecular diagnosis of HBOC. Detection of mutations within other genes than BRCA1 and BRCA2 highlights the genetic heterogeneity of HBOC.

Background PTEN hamartoma tumour syndrome (PHTS) encompasses several clinical syndromes with germline mutations in the PTEN tumour suppressor gene, including Cowden syndrome which is characterised by an increased risk of breast and thyroid cancers. Because PHTS is rare, data regarding cancer risks and genotype–phenotype correlations are limited. The objective of this study was to better define cancer risks in this syndrome with respect to the type and location of PTEN mutations. Methods 154 PHTS individuals with a deleterious germline PTEN mutation were recruited from the activity of the Institut Bergonié genetic laboratory. Detailed phenotypic information was obtained for 146 of them. Age and sex adjusted standardised incidence ratio (SIR) calculations, cumulative cancer risk estimations, and genotype–phenotype analyses were performed. Results Elevated SIRs were found mainly for female breast cancer (39.1, 95% CI 24.8 to 58.6), thyroid cancer in women (43.2, 95% CI 19.7 to 82.1) and in men (199.5, 95% CI 106.39 to 342.03), melanoma in women (28.3, 95% CI 7.6 to 35.4) and in men (39.4, 95% CI 10.6 to 100.9), and endometrial cancer (48.7, 95% CI 9.8 to 142.3). Cumulative cancer risks at age 70 were 85% (95% CI 70% to 95%) for any cancer, 77% (95% CI 59% to 91%) for female breast cancer, and 38% (95% CI 25% to 56%) for thyroid cancer. The risk of cancer was two times greater in women with PHTS than in men with PHTS (p<0.05). Conclusions This study shows a considerably high cumulative risk of cancer for patients with PHTS, mainly in women without clear genotype–phenotype correlation for this cancer risk. New recommendations for the management of PHTS patients are proposed.

This paper deals with a study of H−/D− negative ion surface production on diamond in low pressure H2/D2 plasmas. A sample placed in the plasma is negatively biased with respect to plasma potential. Upon positive ion impacts on the sample, some negative ions are formed and detected according to their mass and energy by a mass spectrometer placed in front of the sample. The experimental methods developed to study negative ion surface production and obtain negative ion energy and angle distribution functions are first presented. Different diamond materials ranging from nanocrystalline to single crystal layers, either doped with boron or intrinsic, are then investigated and compared with graphite. The negative ion yields obtained are presented as a function of different experimental parameters such as the exposure time, the sample bias which determines the positive ion impact energy and the sample surface temperature. It is concluded from these experiments that the electronic properties of diamond materials, among them the negative electron affinity, seem to be favourable for negative-ion surface production. However, the negative ion yield decreases with the plasma induced defect density.

It has been known that the work function of plasma electrode (PE) surfaces such as Cs-covered Mo and C12A7-electride can be decreased when the surfaces are immersed in hydrogen (or deuterium) plasma. We discovered that the work function of the C12A7-electride changed right after the termination of plasma exposure with the time constant of a few minutes. This phenomenon was not observed on the surface of clean metals (Mo or Ta). By extrapolating the dependence of work function against time to determine the value at the plasma termination, the work function during plasma exposure was estimated to be 2.4 – 2.5 eV, which can be compared with the value of the electride exhibiting metallic conductivity.

Background Women with HIV have a higher risk of getting cervical cancer due to induced immunosuppression. Though this burden could be avoided through early identification and appropriate management, there is a paucity of information about the utilization of cervical cancer screening (CCS) services in Lira City, Uganda. This study investigated the level and factors associated with the utilization of cervical cancer screening services among HIV-positive women aged 18 to 49 years at Lira Regional Referral Hospital, Lira City, Uganda. Methods We conducted a facility-based cross-sectional study employing quantitative techniques. We used consecutive sampling to recruit 297 HIV-positive women at the ART clinic of Lira Regional Referral Hospital. A structured researcher-administered questionnaire was used to collect data. Descriptive statistics were performed to summarize the data. A modified Poisson regression using robust standard errors was performed to ascertain the factors associated with the utilization of cervical cancer screening. Prevalence ratios at 95% confidence intervals were reported. Results Out of 297 respondents, 175(58.9%) utilized cervical cancer screening in this study. The factors found to be associated with CCS were; having ever heard of CCS (Adjusted Prevalence Ratio [PR] 1.80, 95% CI 1.31–2.49, p  < 0.001), knowing where CCS is done (Adjusted PR 1.99, 95% CI 1.42–2.81, p  < 0.001), fear of CCS outcomes (Adjusted PR 0.67, 95% CI 0.54–0.84, p  < 0.001), not knowing whether CCS is beneficial or not (Adjusted PR 0.39, 95% CI 0.20–0.75, p  = 0.005) and having friends/relatives who screened for cervical cancer (Adjusted PR 1.31, 95% CI 1.09–1.59, p  = 0.005). Conclusion The level of utilization of cervical cancer screening services among HIV-positive women was suboptimal. Implementation of structured interventions aimed at improving cervical cancer screening awareness among HIV-positive women is crucial. Additionally, to increase opportunities for screening and knowledge on cervical cancer prevention, screening programs can target HIV-positive women during their routine clinic visits.

ObjectiveThe aim of our study was to evaluate screw placement accuracy, safety, complications, and clinical outcomes including functional and pain score, in 32 patients treated with CT-guided pelvic ring fixation after high-energy trauma.Materials and methodsConsecutive patients who were treated by CT-guided fixation of sacral or acetabular fractures after high-energy trauma were included. All procedures were performed under general anesthesia, with dual CT and fluoroscopic guidance, by interventional radiologists. Fractures were minimally displaced or reduced unstable posterior pelvic ring disruptions, with or without sacroiliac disjunction (Tile B or C) and minimally displaced acetabular fractures. The primary outcome evaluated was screw accuracy. Secondary outcomes included patient radiation exposure, duration of the procedure, complications, clinical functional score (Majeed score), and pain scale (VAS, visual analog scale) evaluation during a follow-up period from 4 to 30 months postoperatively.ResultsThirty-two patients were included (mean age 46) and 62 screws were inserted. Screw placement was correct in 90.3% of patients (95% of screws). Mean procedure duration was 67 min and mean patient radiation exposure was 965 mGy cm. Mean follow-up was 13 months and no complications were observed. The mean Majeed score at final follow-up was 84/100 and the mean VAS was 1.6/10.ConclusionThis technique is an effective and safe procedure in specific cases of pelvic ring and acetabulum fractures. It allows accurate screw placement in a minimally invasive manner, leading to effective management of poly-traumatized patients.Key Points• CT-guided pelvic ring fixation, including sacroiliac and acetabular fractures, is an effective and safe procedure.• It allows accurate and minimally invasive screw placement, leading to effective management of poly-traumatized patients.• Multidisciplinary cooperation is essential to ensure efficiency and safety.

Background Segmental progeroid syndromes are a heterogeneous group of rare and often severe genetic disorders that have been studied since the twentieth century. These progeroid syndromes are defined as segmental because only some of the features observed during natural aging are accelerated. Methods Since 2015, the Molecular Genetics Laboratory in Marseille La Timone Hospital proposes molecular diagnosis of premature aging syndromes including laminopathies and related disorders upon NGS sequencing of a panel of 82 genes involved in these syndromes. We analyzed the results obtained in 4 years on 66 patients issued from France and abroad. Results Globally, pathogenic or likely pathogenic variants (ACMG class 5 or 4) were identified in about 1/4 of the cases; among these, 9 pathogenic variants were novel. On the other hand, the diagnostic yield of our panel was over 60% when the patients were addressed upon a nosologically specific clinical suspicion, excepted for connective tissue disorders, for which clinical diagnosis may be more challenging. Prenatal testing was proposed to 3 families. We additionally detected 16 variants of uncertain significance and reclassified 3 of them as benign upon segregation analysis in first degree relatives. Conclusions High throughput sequencing using the Laminopathies/ Premature Aging disorders panel allowed molecular diagnosis of rare disorders associated with premature aging features and genetic counseling for families, representing an interesting first-level analysis before whole genome sequencing may be proposed, as a future second step, by the National high throughput sequencing platforms (“Medicine France Genomics 2025” Plan), in families without molecular diagnosis.