Impact of oxygen tension according to embryo stage of development: a prospective randomized study.

Human embryo culture under 2-8% O2 is recommended by ESHRE revised guidelines for good practices in IVF labs. Nevertheless, notably due to the higher costs of embryo culture under hypoxia, some laboratories perform embryo culture under atmospheric O2 tension (around 20%). Furthermore, recent meta-analyses concluded with low evidence to a superiority of hypoxia on IVF/ICSI outcomes. Interestingly, a study on mice embryos suggested that oxidative stress (OS) might only have an adverse impact on embryos at cleavage stage. Hence, we aimed to demonstrate for the first time in human embryos that OS has a negative impact only at cleavage stage and that sequential culture conditions (5% O2 from Day 0 to Day 2/3, then «conventional¼ conditions at 20% O2 until blastocyst stage) might be a valuable option for human embryo culture. 773 IVF/ICSI cycles were included in this randomized clinical trial from January 2016 to April 2018. At Day 0 (D0), patients were randomized using a 1:2 allocation ratio between group A (20% O2; n = 265) and group B (5% O2; n = 508). Extended culture (EC) was performed when ≥ 5 Day 2-good-quality-embryos were available (n = 88 in group A (20% O2)). In subgroup B, 195 EC cycles were randomized again at Day 2 (using 1:1 ratio) into groups B' (5% O2 until Day 6 (n = 101)) or C (switch to 20% O2 from Day 2 to Day 6 (n = 94). Fertilization rate, cleavage-stage quality Day 2-top-quality-embryo (D2-TQE), blastocyst quality (Day 5-top-quality-blastocyst (D5-TQB) and implantation rate (IR) were compared between groups A and B (= cleavage-stage analysis), or A(20% O2), B'(5% O2) and C(5%-to-20% O2). Overall, characteristics were similar between groups A and B. Significantly higher rates of early-cleaved embryos, top-quality and good-quality embryos on Day 2 were obtained in group B compared to group A (P < 0.05). This association between oxygen tension and embryo quality at D2 was confirmed using an adjusted model (P < 0.05). Regarding blastocyst quality, culture under 20% O2 from Day 0 to Day 6 (group A) resulted in significantly lower Day 5-TQB number and rates (P < 0.05) compared to both groups B' and C. Furthermore, blastocyst quality was statistically equivalent between groups B' and C (P = 0.45). At Day 6, TQB numbers and rates were also significantly higher in groups B' and C compared to group A (P < 0.05). These results were confirmed analyzing adjusted mean differences for number of Day 5 and Day 6 top quality embryos obtained in group A when compared to those respectively in groups B' and C (P < 0.05). No difference in clinical outcomes following blastocyst transfers was observed. These results would encourage to systematically culture embryos under hypoxia at least during early development stages, since OS might be detrimental exclusively before embryonic genome activation.

Appraisal of cancer drugs: a comparison of the French health technology assessment with value frameworks of two oncology societies.

OBJECTIVES: Our primary objective was to compare the grading of the value of cancer drugs ('Amélioration du Service Médical Rendu' [ASMR] level) by the French health technology assessment authority ('Haute Autorité de santé' [HAS]) with that by the American Society of Clinical Oncology Value Framework (ASCO-VF) and the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Our secondary objective was to study the drivers of the French grading system. METHODS: We included new drugs for solid tumors assessed by the HAS between 2010 and 2016 and compared their ASMR level to scores calculated by the 2016-updated ASCO-VF and 2015 ESMO-MCBS. RESULTS: We investigated 27 new cancer drugs assessed by the French HAS between 2010 and 2016. Among the 17 drugs eligible for comparison, the correlation between ASMR levels and ASCO and ESMO scores was weak (r = 0.34 and r = 0.27, respectively). The agreement between the HAS and ESMO regarding the level of meaningful additional benefit was moderate (kappa = 0.43). We found no significant association between 12 potential variables and ASMR level of additional benefit of drugs. CONCLUSION: Our findings show inconsistencies in cancer drug appraisals among the three appraisers.

Clinical benefit, price and approval characteristics of FDA-approved new drugs for treating advanced solid cancer, 2000-2015.

Background: Prices of anti-cancer drugs are skyrocking. We aimed to assess the clinical benefit of new drugs for treating advanced solid tumors at the time of their approval by the US Food and Drug Administration (FDA) and to search for a relation between price and clinical benefit of drugs. Materials and methods: We included all new molecular entities and new biologics for treating advanced solid cancer that were approved by the FDA between 2000 and 2015. The clinical benefit of drugs was graded based on FDA medical review of pivotal clinical trials using the 2016-updated of the American Society of Clinical Oncology Value Framework (ASCO-VF) and the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Characteristics of drugs and approvals were obtained from publicly available FDA documents and price was evaluated according to US Medicare, US Veterans Health Administration and United Kingdom market systems. Results: The FDA approved 51 new drugs for advanced solid cancer from 2000 to 2015; we could evaluate the value of 37 drugs (73%). By the ESMO-MCBS, five drugs (14%) were grade one (the lowest), nine (24%) grade two, 10 (27%) grade three, 11 (30%) grade four and two (5%) grade five (the highest). Thus, 13 drugs (35%) showed a meaningful clinical benefit (scale levels 4 and 5). By the ASCO-VF which had a range of 3.4-67, the median drug value was 37 (interquartile range 20-52). We found no relationship between clinical benefit and drug price (P = 0.9). No characteristic of drugs and of approval was significantly associated with clinical benefit. Conclusion: Many recently FDA-approved new cancer drugs did not have high clinical benefit as measured by current scales. We found no relation between the price of drugs and benefit to society and patients.

Association of Alzheimer's related genotypes with cognitive decline in multiple domains: results from the Three-City Dijon study.

Several genetic polymorphisms have been associated with Late Onset Alzheimer's Disease (LOAD), but there has been limited evidence on whether these polymorphisms predict intermediary stage outcomes such as cognitive changes in prospective community-based studies. Our aim was to evaluate whether polymorphisms previously established as predictors of LOAD also predict worse cognitive function and accelerated decline across multiple cognitive domains. We analyzed data from the 3C-Dijon study, in which 4931 respondents aged 65+ were examined up to 5 times over 10 years with a neuropsychological assessment. We evaluated the associations of polymorphisms in APOE, CR1, BIN1, CLU, PICALM, ABCA7, MS4A6A, CD33, MS4A4E and CD2AP with level and change in 5 neuropsychological tests, assuming a dominant effect model. To optimize measurement, we used a mixed regression model with a latent process for each cognitive domain: global cognition (Mini Mental State Examination); verbal fluency (Isaac's Set Test); visual memory (Benton Visual Retention Test); information processing (Trail Making Test B) and literacy (National Adult Reading Test). APOE was associated with accelerated decline in global cognition and verbal fluency. Only two non-APOE genetic polymorphisms were associated with cognitive decline: CR1 was associated with rate of change in verbal fluency and BIN1 was associated with rate of change in global cognition. In a large prospective population-based study of dementia-free individuals, only a few cognitive domains were associated with established LOAD risk alleles. The most consistent associations were for global cognition and verbal fluency.

Magnetisation transfer parameters and stroke outcome.

Our aim was to evaluate the association between magnetisation transfer imaging (MTI) parameters measured 30 to 45 days after a cerebrovascular insult and post-stroke functional outcome at the same time. MTI offers the opportunity to depict subtle microstructural changes in infarcted areas. The clinical significance of the heterogeneity of brain damage within ischaemic stroke lesions is unknown. We prospectively included 58 patients with acute middle cerebral artery stroke. Diffusion-weighted imaging was performed within 12 hours after onset and the final infarct was documented by MRI with fluid-attenuated inversion recovery (FLAIR) and MTI at 30 to 45 days follow-up. We evaluated the association between MTI histogram parameters and the clinical outcome assessed by dichotomised (threshold >2) modified rankin scale (mRS) using multivariable logistic regression models adjusted on baseline characteristics. In multivariable analyses, stroke outcome was mostly driven by initial National Institutes of Health Stroke Scale (odds ratio [OR]=1.23; 95% confidence interval [CI]=1.07-1.41; p<0.01) while after adjustment of initial stroke severity magnetisation transfer ratio peak position was the only MRI parameter associated with functional status at 30 to 45 days post-stroke (OR=0.86; 95% CI=0.75-0.98; p=0.02); lower peak position values associated with higher mRS. Conversely, stroke volume measured on FLAIR sequence was not associated with stroke prognosis (p=0.87). The intensity of microstructural changes within the infarct core measured at 30 to 45 days follow-up is independently associated with the functional status evaluated at the same time. MTI and related parameters could be used as surrogate markers of treatment response in stroke clinical trials.

[Fetal heart rate patterns of breech presentations during expulsion. A comparative study with cephalic presentations]. / L'analyse du rythme cardiaque fœtal au cours de l'expulsion des présentations podaliques. Analyse comparative dans une maternité de niveau III.

INTRODUCTION: Expulsion upon vaginal delivery is a period at risk for the foetus, especially in case of breech presentation. In fact, monitoring the fetal well-being is complex in this phase. The correct interpretation of fetal heart rate (FHR) during expulsion, using Melchior's classification, is important because it helps screen for fetal acidosis. The aim of this study was to determine if it was possible to tolerate an abnormal FHR during expulsion of breech presentations. MATERIAL AND METHODS: A retrospective study was conducted to compare FHR during expulsion and neonatal results between breech and cephalic presentations at Besançon's university hospital. RESULTS: We collected data from 118 breech presentations and 236 cephalic presentations. Melchior's FHR classification types were significantly different between breech and cephalic presentations with a majority of type 1. Neonatal results were significantly less favorable for breech presentations, but without any increase in mortality and in severe morbidity. DISCUSSION AND CONCLUSION: Melchior's expulsion FHR classification seems to be applicable for breech presentations with a different distribution of FHR types compared to cephalic presentations. Following the results of this study, it seems to be possible to tolerate an abnormal FHR during expulsion of breech presentation, so far as is reasonable.

Skin autofluorescence is associated with past glycaemic control and complications in type 1 diabetes mellitus.

As skin autofluorescence (AF) can assess subcutaneous accumulation of fluorescent advanced glycation end-products (AGEs), this study aimed to investigate whether it was linked to glycaemic control and complications in patients with type 1 diabetes mellitus (T1DM). Using the AGE Reader™, AF was measured in T1DM patients referred to Haut-Levêque Hospital (Bordeaux, France); data on their HbA1c levels measured every 6months as far back as the last 5years were also collected. The association of AF with the patients' past glucose control, based on their latest HbA1c values, and the means of the last five and 10 HbA1c values, and with diabetic complications was also examined by linear regression analysis. The sample included 300 patients: 58% were male; the mean age was 49 (SD 17) years and the mean diabetes duration was 21 (SD 13) years. The median skin AF measurement was 2.0 [25th-75th percentiles: 1.7-2.4] arbitrary units (AU), and this was associated with age (ß=0.15 per 10years, P<0.001) and diabetes duration (ß=0.17 per 10years, P<0.001). After adjusting for age and estimated glomerular filtration rate (eGFR), the skin AF measurement was also related to the means of the last five and 10 HbA1c values (ß=0.10 per 1% of HbA1c, P=0.005, and ß=0.13 per 1% of HbA1c, P=0.001, respectively). In addition, the skin AF was associated with retinopathy (P<0.001), albuminuria (P<0.001) and decreased eGFR (P<0.001). In conclusion, the skin AF is related to the long-term glucose control and diabetic complications.

Ruptura del bronquio fuente en los traumatismos cerrados del torax. / Bronchial rupture in thoracic traumatisms

Se presentan 4 pacientes con ruptura traumatica en bronquios fuentes. Uno fallecio dentro de las 36 hs de producida luego de una incompleta correccion quirurgica. Los 3 restantes sobrevivieron el episodio agudo sin que se efectuara el diagnostico; se operaron al mes y medio, 2 y 10 meses en forma exitosa. Se discute el mecanismo de produccion: de acuerdo a datos de laboratorio y clinicos, se acepta que el tironeamiento lateral y la hipertension en la via aerea simultanea, son las causas de la efraccion bronquial. Esta situacion es mas factible en pacientes lucidos y con torax elastico. En cuanto a la evolucion se destaca la diferencia neta entre la que sufre la lesion parcial, seguida de estenosis e infeccion y la total, seguida habitualmente de cierre de ambos cabos. Esto evita la infeccion y permite la restauracion mediante una plastica, con recuperacion del parenquima atelectasiado

Ruptura del bronquio fuente en los traumatismos cerrados del torax. / Bronchial rupture in thoracic traumatisms

Se presentan 4 pacientes con ruptura traumatica en bronquios fuentes. Uno fallecio dentro de las 36 hs de producida luego de una incompleta correccion quirurgica. Los 3 restantes sobrevivieron el episodio agudo sin que se efectuara el diagnostico; se operaron al mes y medio, 2 y 10 meses en forma exitosa. Se discute el mecanismo de produccion: de acuerdo a datos de laboratorio y clinicos, se acepta que el tironeamiento lateral y la hipertension en la via aerea simultanea, son las causas de la efraccion bronquial. Esta situacion es mas factible en pacientes lucidos y con torax elastico. En cuanto a la evolucion se destaca la diferencia neta entre la que sufre la lesion parcial, seguida de estenosis e infeccion y la total, seguida habitualmente de cierre de ambos cabos. Esto evita la infeccion y permite la restauracion mediante una plastica, con recuperacion del parenquima atelectasiado