The free plasma amyloid Aß1-42/Aß1-40 ratio predicts conversion to dementia for subjects with mild cognitive impairment with performance equivalent to that of the total plasma Aß1-42/Aß1-40 ratio. The BALTAZAR study.

BACKGROUND AND PURPOSE: Blood-based biomarkers are a non-invasive solution to predict the risk of conversion of mild cognitive impairment (MCI) to dementia. The utility of free plasma amyloid peptides (not bound to plasma proteins and/or cells) as an early indicator of conversion to dementia is still debated, as the results of studies have been contradictory. In this context, we investigated whether plasma levels of the free amyloid peptides Aß1-42 and Aß1-40 and the free plasma Aß1-42/Aß1-40 ratio are associated with the conversion of MCI to dementia, in particular AD, over three years of follow-up in a subgroup of the BALTAZAR cohort. We also compared their predictive value to that of total plasma Aß1-42 and Aß1-40 levels and the total plasma Aß1-42/Aß1-40 ratio. METHODS: The plasma Aß1-42 and Aß1-40 peptide assay was performed using the INNO-BIA kit (Fujirebio Europe). Free amyloid levels (defined by the amyloid fraction directly accessible to antibodies of the assay) were obtained with the undiluted plasma, whereas total amyloid levels were obtained after the dilution of plasma (1/3) with a denaturing buffer. Free and total Aß1-42 and Aß1-40 levels were measured at inclusion for a subgroup of participants (N = 106) with mild cognitive impairment (MCI) from the BALTAZAR study (a large-scale longitudinal multicenter cohort with a three-year follow-up). Associations between conversion and the free/total plasma Aß1-42 and Aß1-40 levels and Aß1-42/Aß1-40 ratio were analyzed using logistic and Cox Proportional Hazards models. Demographic, clinical, cognitive (MMSE, ADL and IADL), APOE, and MRI characteristics (relative hippocampal volume) were compared using non-parametric (Mann-Whitney) or parametric (Student) tests for quantitative variables and Chi-square or Fisher exact tests for qualitative variables. RESULTS: The risk of conversion to dementia was lower for patients in the highest quartile of free plasma Aß1-42/Aß1-40 (≥ 25.8%) than those in the three lower quartiles: hazard ratio = 0.36 (95% confidence interval [0.15-0.87]), after adjustment for age, sex, education, and APOE ε4 (p-value = 0.022). This was comparable to the risk of conversion in the highest quartile of total plasma Aß1-42/Aß1-40: hazard ratio = 0.37 (95% confidence interval [0.16-0.89], p-value = 0.027). However, while patients in the highest quartile of total plasma Aß1-42/Aß1-40 showed higher MMSE scores and a higher hippocampal volume than patients in the three lowest quartiles of total plasma Aß1-42/Aß1-40, as well as normal CSF biomarker levels, the patients in the highest quartile of free plasma Aß1-42/Aß1-40 did not show any significant differences in MMSE scores, hippocampal volume, or CSF biomarker levels relative to the three lowest quartiles of free plasma Aß1-42/Aß1-40. CONCLUSION: The free plasma Aß1-42/Aß1-40 ratio is associated with a risk of conversion from MCI to dementia within three years, with performance comparable to that of the total plasma Aß1-42/Aß1-40 ratio. Threshold levels of the free and total plasma Aß1-42/Aß1-40 ratio could be determined, with a 60% lower risk of conversion for patients above the threshold than those below.

Does the guidance method affect the doses of botulinum toxin in writer's cramp?

PURPOSE: Botulinum neurotoxin (BoNT) injections are the main medical treatment of writer's cramp. When the outcome is favourable, patients usually receive injections several times per year in the long-term. However, we know little about the course of BoNT doses and nothing about the impact of the guidance method on the clinical outcome or injection strategy. METHODS: We studied, in the long-term, the doses of BoNT and the target muscles in a group of patients with writer's cramp, according to the guidance method (electrical stimulation or ultrasound). Patients received at least three injection cycles guided by electrical stimulation, followed by at least three injection cycles guided by ultrasound. RESULTS: Twenty-four patients were included. More target muscles were injected after switching to ultrasound guidance, especially the flexor carpi ulnaris and the flexor carpi radialis. The mean dose by muscle was lower when ultrasound guidance was used. When using electrical stimulation guidance, the dose in the flexors of the fingers decreased in the long-term, but increased in the flexors of the wrist. The course of the BoNT doses and of the number of target muscles per cycle were not the same during the first period (electrical stimulation) and the second period (ultrasound). CONCLUSIONS: Switching to ultrasound guidance, the BoNT dose decreased, mainly in the flexors of the wrist. Based on the results of our study, we suggest a starting dose in several muscles (flexor carpi ulnaris, flexor carpi radialis, flexor digitorum profundus and flexor pollicis longus).

Long-term outcomes of primary cystocele repair by transvaginal mesh surgery versus laparoscopic mesh sacropexy: extended follow up of the PROSPERE multicentre randomised trial.

OBJECTIVE: To compare the effectiveness and safety of laparoscopic sacropexy (LS) and transvaginal mesh (TVM) at 4 years. DESIGN: Extended follow up of a randomised trial. SETTING: Eleven centres. POPULATION: Women with cystocele stage ≥2 (pelvic organ prolapse quantification [POP-Q], aged 45-75 years without previous prolapse surgery. METHODS: Synthetic non-absorbable mesh placed in the vesicovaginal space and sutured to the promontory (LS) or maintained by arms through pelvic ligaments and/or muscles (TVM). MAIN OUTCOME MEASURES: Functional outcomes (pelvic floor distress inventory [PFDI-20] as primary outcome); anatomical assessment (POP-Q), composite outcome of success; re-interventions for complications. RESULTS: A total of 220 out of 262 randomised patients have been followed at 4 years. PFDI-20 significantly improved in both groups and was better (but below the minimal clinically important difference) after LS (mean difference -7.2 points; 95% CI -14.0 to -0.05; P = 0.029). The improvement in quality of life and the success rate (LS 70%, 61-81% versus TVM 71%, 62-81%; hazard ratio 0.92, 95% CI 0.55-1.54; P = 0.75) were similar. POP-Q measurements did not differ, except for point C (LS -57 mm versus TVM -48 mm, P = 0.0093). The grade III or higher complication rate was lower after LS (2%, 0-4.7%) than after TVM (8.7%, 3.4-13.7%; hazard ratio 4.6, 95% CI 1.007-21.0, P = 0.049)). CONCLUSIONS: Both techniques provided improvement and similar success rates. LS had a better benefit-harm balance with fewer re-interventions due to complications. TVM remains an option when LS is not feasible. TWEETABLE ABSTRACT: At 4 years, Laparoscopic Sacropexy (LS) had a better benefit-harm balance with fewer re-interventions due to complications than Trans-Vaginal Mesh (TVM).

Does ultrasound-guidance improve the outcome of botulinum toxin injections in cervical dystonia?

PURPOSE: Ultrasound-guided injections of botulinum neurotoxin in cervical dystonia have a number of theoretical advantages. However, their action has never been compared to that of non-guided injections. The objectives of the study were to compare the outcome of botulinum neurotoxin type A treatment in patients with idiopathic, focal cervical dystonia, according to two methods: inspection and palpation of anatomical landmarks (non-guided group) or ultrasound guidance (ultrasound-guided group). METHODS: We included consecutive patients in this single-center, prospective, real-life, non-randomized study. The outcomes were evaluated one month after the injections: Cervical Dystonia Impact Profile 58 (main outcome), Toronto Western Spasmodic Torticollis Rating Scale-2 (pain and disability subscores), Toronto Western Spasmodic Torticollis Rating Scale-PSYCH, patient-rated Clinical Global Impression - Improvement and adverse events. We used propensity score methods for statistical analysis; ten predefined confounding factors were used to build the propensity score. RESULTS: Sixty-three patients were included in the non-guided group, and 60 other patients in the ultrasound-guided group. We found no difference in main and secondary outcomes between the two study groups. CONCLUSION: This is the first direct comparison between ultrasound-guided and non-guided botulinum neurotoxin type A injections in patients with cervical dystonia. We hypothesize that ultrasound guidance made it possible to obtain the same results in the most severe (or the most demanding) patients as in the best responders. Further studies are still needed to assess the impact of botulinum neurotoxin injections into deep cervical muscles.

A re-assessment of the oldest therapsid Raranimus confirms its status as a basal member of the clade and fills Olson's gap.

The non-mammalian therapsids comprise a paraphyletic assemblage of Permian-Jurassic synapsids closely related to mammals that includes six major clades of largely unresolved phylogenetic affinity. Understanding the early evolutionary radiation of therapsids is complicated by a gap in the fossil record during the Roadian (middle Permian) known as Olson's gap. Because of its early stratigraphic occurrence and its primitive features, Raranimus dashankouensis, from the Dashankou fauna (Rodian), Qingtoushan Formation (China), is currently considered the best candidate to fill this gap. However, it is known from only a single specimen, an isolated snout, which limits the amount of usable phylogenetic characters to reconstruct its affinities. In addition, understanding of the stratigraphy of the Qingtoushan Formation is poor. Here, we used CT scanning techniques to digitally reconstruct the bones and trigeminal canals of the snout of Raranimus in 3D. We confirm that Raranimus shares a high number of synapomorphies with more derived therapsids and is the only therapsid known so far to display a "pelycosaur"-like maxillary canal bearing a long caudal alveolar canal that gives off branches at regular intervals. This plesiomorphic feature supports the idea that Raranimus is basal to other therapsids.

Validation in French of the Montreal Cognitive Assessment 5-Minute, a brief cognitive screening test for phone administration.

BACKGROUND: The prevalence of cognitive impairment and dementia is high and steadily increasing. Early detection of cognitive decline is crucial since some interventions can reduce the risk of progression to dementia. However, there is a lack of manageable scales for assessing cognitive functions outside specialized consultations. Recently, the MoCA-5min, a short version of the Montreal Cognitive assessment (MoCA), phone-administered, was validated for screening for vascular cognitive impairment. The aim of the present study was to validate the MoCA-5min in French in diverse clinical populations. METHODS: The Cantonese version of the MoCA-5min was adapted for French language. Healthy volunteers and patients with possible or established cognitive impairment (Alzheimer's disease or related disorders, Parkinson's disease, Huntington's disease, type-2 diabetes) participated in the study. The original MoCA and the MoCA-5min were administered, by phone, with a 30-day interval. Alternate forms were used to reduce learning effects. RESULTS: The scores of the original MoCA and MoCA-5min correlated significantly (Spearman rho=0.751, P<0.0001, 95% confidence interval 0.657 to 0.819). Internal consistency was good (Cronbach alpha=0.795). The area under the ROC curve was 0.870 and the optimal cut-off value for separating patients with and without cognitive impairment with the MoCA-5min was≤27 with 87.32% sensitivity and 76.09% specificity. Interrater and test-retest reliability were adequate. CONCLUSION: This study demonstrates that the French version of the MoCA-5min is a valid and reliable scale for detecting cognitive impairment in different clinical populations. It is administrable by phone and thus suitable for remote assessment as well as for large-scale screening and epidemiological studies.

The conventional protocol vs. a protocol including illumination with a fabric-based biophotonic device (the Phosistos protocol) in photodynamic therapy for actinic keratosis: a randomized, controlled, noninferiority clinical study.

BACKGROUND: Topical photodynamic therapy (PDT) using methyl aminolaevulinate is a noninvasive treatment option suitable to treat clinical and subclinical actinic keratosis (AK) over a large area (field cancerization). The most widely used, conventional protocol in Europe includes illumination with a red-light lamp. This illumination commonly causes pain, and patients often cannot complete the treatment. OBJECTIVES: The aims of this paper are twofold. The first aim is to introduce a novel protocol, the Phosistos protocol (P-PDT), which includes illumination with a fabric-based biophotonic device. The second and major aim is to assess the noninferiority, in terms of efficacy for PDT of AK, of P-PDT compared with the conventional protocol (C-PDT). METHODS: A randomized, controlled, multicentre, intraindividual clinical study was conducted. Forty-six patients with grade I-II AK of the forehead and scalp were treated with P-PDT on one area (280 AK lesions) and with C-PDT on the contralateral area (280 AK lesions). The primary end point was the lesion complete response (CR) rate at 3 months, with an absolute noninferiority margin of -10%. Secondary end points included pain scores, incidence of adverse effects and cosmetic outcome. RESULTS: Three months following treatment, the lesion CR rate of P-PDT was noninferior to that of C-PDT (79·3% vs. 80·7%, respectively; absolute difference -1·6%; one-sided 95% confidence interval -4·5% to infinity). The noninferiority of P-PDT to C-PDT in terms of the lesion CR rate remained at the 6-month follow-up (94·2% vs. 94·9%, respectively; absolute difference -0·6%; one-sided 95% confidence interval -2·7% to infinity). Moreover, the pain score at the end of illumination was significantly lower for P-PDT than for C-PDT (mean ± SD 0·3 ± 0·6 vs. 7·4 ± 2·3; P < 0·001). CONCLUSIONS: P-PDT is noninferior to C-PDT in terms of efficacy for treating AK of the forehead and scalp and resulted in much lower pain scores and fewer adverse effects. What's already known about this topic? Topical photodynamic therapy using methyl aminolaevulinate is effective for treating actinic keratosis. In Europe, the conventional protocol involves illumination with a red-light lamp. Unfortunately, pain is often experienced by patients undergoing this protocol. An alternative protocol that uses daylight illumination has recently been shown to be as effective as the conventional protocol while being nearly painless. However, this alternative protocol can be conducted only in suitable weather conditions. What does this study add? The Phosistos protocol is demonstrated to be as effective as the conventional protocol, nearly as painless as the daylight protocols and suitable year round for treatment of actinic keratosis.

Photodynamic therapy for actinic keratosis of the forehead and scalp: a randomized, controlled, phase II clinical study evaluating the noninferiority of a new protocol involving irradiation with a light-emitting, fabric-based device (the Flexitheralight protocol) compared with the conventional protocol involving irradiation with the Aktilite CL 128 lamp.

BACKGROUND: Photodynamic therapy (PDT) is an effective treatment for actinic keratosis (AK), particularly for patients with large areas of field cancerization. Among the approved protocols in Europe, the most widely used requires irradiation with the Aktilite CL 128 lamp. However, pain during irradiation and the suboptimal adaptability of the lamp relative to the treatment area are two limiting factors of this protocol. To overcome these limits, a new protocol (referred to as the Flexitheralight protocol) involving irradiation with a light-emitting, fabric-based device was developed. OBJECTIVES: This paper aims to assess the noninferiority, in terms of PDT efficacy for treating AK, of the Flexitheralight protocol compared with the conventional protocol, which requires irradiation with the Aktilite CL 128 lamp. METHODS: A monocentric, randomized, controlled, phase II clinical study was performed. Twenty-five patients with grade I-II AKs of the forehead and scalp were treated with methyl aminolaevulinate PDT in two symmetrical areas. One area was treated with the conventional protocol (n = 154 AKs), whereas the other area was treated with the Flexitheralight protocol (n = 156 AKs). The primary end-point was the lesion complete response (CR) rate at 3 months (an absolute noninferiority margin of -10% was used). The secondary end-points included patient-reported pain at the end of the irradiation. RESULTS: At 3 months, the lesion CR rate with the Flexitheralight protocol was noninferior to that obtained with the conventional protocol (66·0% vs. 59·1%, respectively; absolute difference, 6·9%; 95% confidence interval -0·6% to 14·5%). Patient-reported pain was significantly lower with the Flexitheralight protocol than with the conventional protocol (mean ± SD: 0·4 ± 0·6 vs. 5·0 ± 2·6; P < 0·0001). CONCLUSIONS: The Flexitheralight protocol is noninferior in terms of efficacy and superior in terms of tolerability to the conventional protocol for treating AKs of the forehead and scalp.

[Elaboration and psychometric properties of a well-being scale at work. The Serenat study among employees in occupational medicine unit]. / Élaboration et qualités psychométriques d'une échelle de bien-être au travail. Étude SERENAT auprès de salariés vus en médecine du travail.

BACKGROUND: Well-being at work is nowadays a major public health challenge. It includes, among others, absence of psychological (anxio-depressive) symptoms, perceived positive work conditions (environment and organization), happiness and good quality of life at work. Many studies have shown that social support and control at work protect mental health while high job demands and effort-reward imbalance are risk factors for anxiety and depression. There is currently no global indicator to measure both the state of mental health and social working conditions. The main objective of this work is to construct and explore the psychometric properties of scale of well-being at work called "Serenat" in order to validate it. METHODS: The Serenat Scale is a self-report questionnaire composed of 20 items. All items are scored on a four-point Likert scale ranging from 0 (strongly disagree) to 3 (strongly agree) resulting in a range of 0 to 60. It was constructed from data collected from the literature and from consultations in an Occupational Health Unit. From January 2014 to May 2017 193 subjects who have consulted an occupational doctor are included in this cross sectional survey. Validation included item quality and data structure diagnosis, internal consistency, intraobserver reliability evaluation and external consistency. RESULTS: The Serenat scale showed very good item quality, with a maximal non-response rate of 0.01 % per item, and no floor effect. Factor analysis concluded that the scale can be considered unidimensional. Cronbach's alpha of internal consistency was 0.89. The intraclass correlation coefficient for intraobserver reliability was 0.89. Serenat scale was correlated with HADS (r=-0.54; P<0.001), STAI-Y (r=-0.78; P<0.001) and BDI-13 (r=-0.57; P<0.001). CONCLUSION: Serenat's well-being at work scale shows good psychometric properties for final validation. It could be useful to occupational physicians for individual and collective screening. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02905071.

Anticoagulation withdrawal in antiphospholipid syndrome: a retrospective matched-control study.

Background/Purpose Long-term anticoagulation is the standard treatment for thrombotic antiphospholipid syndrome (APS). However, in daily practice, the question of withdrawing anticoagulation may arise, without any evidence-based recommendations. This study aimed to assess outcomes in APS patients after anticoagulation withdrawal. Methods Thrombotic APS patients followed in our centre, whose anticoagulation was withdrawn after APS diagnosis, were retrospectively selected, and were match-controlled with patients under anticoagulation, based on sex, age, APS clinical phenotype and disease duration. Results Thirty cases with anticoagulation withdrawal were included. Median follow-up was 51 months (12-124). The risk of thrombotic relapse was higher in cases compared to controls (7.3% versus 1.5% patient-year ( p = 0.01); hazard ratio 4.8; 95% confidence interval (1.4-16.7)). Male gender, anti-ß2GP1 and triple positivity at inclusion were predictive factors for thrombotic relapse. Conversely, aspirin prescription was a protective factor against relapses. Persistence of LA, anti-ß2GP1 and triple positivity over time were associated with a higher risk of thrombosis and aPL disappearance with a lower risk. Conclusion In our study, anticoagulation withdrawal was associated with an increased risk of thrombotic relapse. Our findings emphasize the influence of anti-ß2GP1 and triple positivity persistence over time on the risk of relapse and the benefit of aspirin prescription when anticoagulation has been withdrawn.

[Preferences of general practitioners in metropolitan France with regard to the delegation of medico-administrative tasks to secretaries assisting medico-social workers: Study in conjoint analysis]. / Préférences des médecins généralistes libéraux en France métropolitaine quant à la délégation des tâches médico-administratives aux secrétaires assistant(e)s médico-social(e)s : étude en analyse conjointe.

BACKGROUND: A general practitioner's office is an economic unit where task delegation is an essential component in improving the quality and performance of work. AIM: To classify the preferences of general practitioners regarding the delegation of medical-administrative tasks to assistant medical-social secretaries. METHOD: Conjoint analysis was applied to a random sample of 175 general practitioners working in metropolitan France. Ten scenarios were constructed based on seven attributes: training for medical secretaries, logistical support during the consultation, delegation of management planning, medical records, accounting, maintenance, and taking initiative on the telephone. A factorial design was used to reduce the number of scenarios. Physicians' socio-demographic variables were collected. RESULTS: One hundred and three physicians responded and the analysis included 90 respondents respecting the transitivity of preferences hypothesis. Perceived difficulty was scored 2.8 out of 5. The high rates of respondents (59%; 95% CI [51.7-66.3]) and transitivity (87.5%; 95% CI [81.1-93.9]) showed physicians' interest in this topic. Delegation of tasks concerning management planning (OR=2.91; 95% CI [2.40-13.52]) and medical records (OR=1.88; 95% CI [1.56-2.27]) were the two most important attributes for physicians. The only variable for which the choice of a secretary was not taken into account was logistical support. CONCLUSION: This is a first study examining the choices of general practitioners concerning the delegation of tasks to assistants. These findings are helpful to better understand the determinants of practitioners' choices in delegating certain tasks or not. They reveal doctors' desire to limit their ancillary tasks in order to favor better use of time for "medical" tasks. They also expose interest for training medical secretaries and widening their field of competence, suggesting the emergence of a new professional occupation that could be called "medical assistant".

Polycystic ovarian morphology and the diagnosis of polycystic ovary syndrome: redefining threshold levels for follicle count and serum anti-Müllerian hormone using cluster analysis.

STUDY QUESTION: Can cluster analysis be used to differentiate between normo-ovulatory women with normal ovaries and normo-ovulatory women with polycystic ovarian morphology (PCOM) in a non-subjective manner? SUMMARY ANSWER: Cluster analysis can be used to accurately and non-subjectively differentiate between normo-ovulatory women with normal ovaries and normo-ovulatory women with PCOM. WHAT IS KNOWN ALREADY: Currently, PCOM is diagnosed using a fixed threshold level, i.e. 12 or more follicles per ovary, and is one of the diagnostic criteria of polycystic ovary syndrome (PCOS). However, PCOM is also encountered in normo-ovulatory women, suggesting that it could just represent a normal variant. On the other hand, recent studies have shown subtle endocrine abnormalities in women with isolated PCOM that resemble those found in women with PCOS. Because of the strong correlation between anti-Müllerian hormone (AMH) and follicle number, a high serum AMH level has been proposed as a surrogate marker for PCOM and could, therefore, be integrated in the diagnostic classifications for PCOS. STUDY DESIGN, SIZE, DURATION: This was a retrospective observational cohort study. Original cohorts had been recruited for previous studies between 1998 and 2010. Two hundred ninety-seven regularly cycling women and 700 women with PCOS were eligible for inclusion. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cluster analysis was performed in 297 regularly cycling women. After exclusion of 'PCOM' clusters, each 'non-PCOM' cluster (young, n = 118 and old, n = 100) was included in the construction of a receiver operating characteristics curve to test the diagnostic performance of follicle number per ovary (FNPO) and serum AMH in discriminating similarly aged full-blown PCOS patients (n = 411 and 237, respectively) from normal regularly cycling non-PCOM women. MAIN RESULTS AND ROLE OF CHANCE: The optimal number of clusters was four; age was the most important classifying variable, followed by the FNPO and serum AMH. Two distinct clusters of normo-ovulatory women with PCOM were isolated and differed solely by age, i.e. 'young' and 'old'. Both 'PCOM' clusters had their similarly aged counterpart of 'non-PCOM' clusters. Likewise, two clusters comprised women younger than 30 years, with (n = 28, 'PCOM regularly cycling women') or without (n = 118, 'normal regularly cycling women') features of PCOM (increased FNPO and/or serum AMH). The two other clusters in older women could be labelled 'normal regularly cycling women' or 'PCOM regularly cycling women' (n = 100 and 51, respectively). The prevalence of PCOM was significantly greater in old than in young regularly cycling women controls. In the young population, after exclusion of the 'PCOM regularly cycling women', the diagnostic performance of AMH, expressed by area under the curve (AUC) (AUC = 0.903; CI (0.876-0.930)) to differentiate PCOS women from normal regularly cycling women was similar to that using the FNPO (AUC = 0.915, CI (0.891-0.940)) (P = 0.25), confirming results from earlier studies. In the old population, the diagnostic performance of AMH was greater than that of FNPO (AUCs = 0.948 (0.927-0.970) vs 0.874 (0.836-0.912), respectively, P = 0.00035). Cut-off levels of AMH and antral follicle count distinguishing regularly cycling non-PCOM women from PCOS women were higher in young women than in older women. LIMITATIONS, REASONS FOR CAUTION: Data of normal women were obtained from earlier studies, aiming to measure normal endocrine values. Apparently, the strong effect of age in cluster analysis revealed a dichotomy in the age distribution among the cohort of regularly cycling women included. This was involuntary since in none of the original studies, eligibility was limited by age and there was considerable overlap in age ranges of the cohorts. Transvaginal ultrasound was performed using a 6.5-8 mHz probe and our data confirm that this threshold level for FNPO is still valid if using such probe frequencies, although the use of devices with a maximum frequency lower than 8 mHz has become obsolete. Obviously, newer ultrasound scanner using higher transducer frequency will facilitate the detection of more follicles. WIDER IMPLICATIONS OF THE FINDINGS: Our data support the use of AMH as a surrogate for ultrasound to define PCOM, which is one of the three items of the Rotterdam classification. They also show that age should be taken into account to define the optimal threshold. The fact that the prevalence of PCOM was increased in the older regularly cycling women, may be due to 'attenuated' PCOS, a phenomenon that has been described in ageing women with PCOS. These women might have had anovulatory cycles in the past and have become ovulatory with increasing age, and were, therefore, eligible for this study. However, since most women included at older age have had spontaneous pregnancies in the past, PCOM at older age may be associated with a subclinical form of PCOS, which may also be present in young regularly cycling women. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for this study. J.S.E.L. has received grants and support from Ferring, MSD, Organon, Merck-Serono, Schering Plough and Serono during recruitment and analysis of data for this study. S.L.F., A.D. and D.D. do not have any conflict of interest.

Persistent triple antiphospholipid antibody positivity as a strong risk factor of first thrombosis, in a long-term follow-up study of patients without history of thrombosis or obstetrical morbidity.

Introduction The long-term risk of first thrombosis and benefit of prophylaxis in antiphospholipid antibody (aPL) carriers without history of thrombosis or obstetrical morbidity is poorly known. This study aimed to evaluate the long-term rate and risk factors associated with a first thrombosis in those patients. Patients and methods After a prior study ended in December 2005 and was already published, we extended the follow-up period of our cohort of aPL carriers. Results Ninety-eight of the 103 patients of the previous study were included. The annual first thrombosis rate was 2.3% per patient-year during a median of 13 years (6-17). None of the baseline characteristics was predictive of risk of first thrombosis, but persistent aPL over time were associated with an increased risk. The stronger association was found in triple aPL-positive carriers: OR 3.38 (95% CI: 1.24-9.22). Of note, conversely to our previous findings, no benefit of aspirin prophylaxis was observed. Conclusion The risk of first thrombosis in aPL carriers without history of thrombosis or obstetrical morbidity was significant, persisted linearly over time and was associated with persistent aPL. This risk was especially increased in triple aPL-positive carriers, in whom a close follow-up seems to be necessary. Nevertheless, the benefit of aspirin prophylaxis remained unclear.

Factors influencing plasma transfusion practices in paediatric intensive care units around the world.

BACKGROUND AND OBJECTIVES: Plasma transfusions are a frequent treatment worldwide, but many studies have reported a wide variation in the indications to transfuse. Recently, an international paediatric study also showed wide variation in frequency in the use of plasma transfusions: 25% of the centres transfused plasma to >5% of their patients, whereas another 25% transfused plasma to <1% of their patients. The objective of this study was to explore the factors associated with different plasma transfusion practices in these centres. MATERIALS AND METHODS: Online survey sent to the local investigators of the 101 participating centres, in February 2016. Four areas were explored: beliefs regarding plasma transfusion, patients' case-mix in each unit, unit's characteristics, and local blood product transfusion policies and processes. RESULTS: The response rate was 82% (83/101). 43% of the respondents believed that plasma transfusions can arrest bleeding, whereas 27% believe that plasma transfusion can prevent bleeding. Centres with the highest plasma transfusion rate were more likely to think that hypovolaemia and mildly abnormal coagulation tests are appropriate indications for plasma transfusions (P = 0·02 and P = 0·04, respectively). Case-mix, centre characteristics or local transfusion services were not identified as significant relevant factors. CONCLUSION: Factors influencing plasma transfusion practices reflect beliefs about indications and the efficacy of transfusion in the prevention and management of bleeding as well as effects on coagulation tests. Educational and other initiatives to target these beliefs should be the focus of research.

Counter-intuitive plasma vitamin D and zinc status in HIV-1-infected adults with persistent low-level viraemia after treatment initiation: a pilot case-control study.

Determinants of persistent low-level viraemia [PLLV, a viral load (VL) of between 50 and 500 copies/mL] have not been elucidated. In a case-control study, we evaluated the influence of micronutrients on PLLV in a population of 454 HIV-1 adults having initiated antiretroviral therapy (ART) between January 2007 and December 2011. Plasma levels of retinol (vitamin A), 25-OH vitamin D2 + D3, vitamin E and zinc were measured at ART initiation in cases (PLLV after 6 months of ART) and in controls (VL <50 copies/mL after 6 months). Cases and controls were matched for the CD4 cell count (±50/mm3) and ethnic origin. Intergroup differences in demographic, biological and treatment parameters and sunshine intensity at ART initiation were adjusted using a propensity score. A receiver operating characteristic (ROC) curve was used to assess intergroup differences in plasma micronutrient levels. Thirty-three of the 454 patients (7.3%) displayed PLLV (median VL: 92 copies/mL). Patients were predominantly male (89%), Caucasian (64%) and CDC stage C (25%). The median age was 38 years, the median initial VL was 5.2 log10 copies/mL and the median CD4 count was 74/mm3. The 22 cases and matched controls were balanced in these respects, and had similar vitamin A/E levels. Two cases (9%) and 9 controls (41%) had a vitamin D level <10.3 ng/mL (p = 0.0015), and 2 cases (9%) and 10 controls (48%) had a zinc level <74.6 µg/dL (p = 0.04). Our results support in vitro studies suggesting that vitamin D favours HIV-1 replication and that HIV-1 is zinc-dependent. Wide-scale, prospective studies are required.

Statistical controversies in clinical research: should schedules of tumor size assessments be changed?

BACKGROUND: Time to progression (TTP) is often used as a primary end point in phase II clinical trials. Since the actual date of nadir and progression is never known, most calculated TTP are overestimated. This study evaluates the imprecision on the estimate of TTP under two hypothetical tumor kinetic settings and various assessment schedules. DESIGN: A two-component tumor growth model was used to account for treatment effect assuming exponential decay for tumor shrinkage and linear growth for progression. Evolution of tumor burden (TB) was modelized according to two scenarios using either a cytotoxic or a cytostatic agent and several assessment schedules. TB, nadir, progression and TTP were simulated for each visit schedule. RESULTS: For cytotoxic agents, our model predicted response at 1.5 weeks, a TB at nadir of 40.2 mm (starting from 100 mm) occurring at 6.7 weeks and true progression at 11.2 weeks with a TB of 48.2 mm. For cytostatic agents, our model predicted no response, a TB at nadir of 77 mm occurring at 9.2 weeks and true progression at 19.4 weeks with a TB of 92 mm. Depending on the assessment schedule, estimated TTP was increased from 0.8 to 36.8 weeks and from 0.6 to 28.6 weeks when compared with the true TTP and varied from 5.2% to 298% and from 1.66 to 109.58% when compared with the true TB at progression for cytotoxic and cytostatic agents, respectively. Our model further shows that for cytotoxic agents, evaluation of TB every 6 weeks is optimal to capture the true nadir, the time to nadir, the true progression and the true TTP, whereas for cytostatic agents, this evaluation is optimal every 10 weeks. CONCLUSIONS: Our results emphasize the importance to estimate the effects of tested drugs on tumor shrinkage before design any phase II clinical trials to choose optimal TB evaluation's timing.

How obesity relates to socio-economic status: identification of eating behavior mediators.

BACKGROUND: Socio-economic status (SES) is a strong determinant of eating behavior and the obesity risk. OBJECTIVE: To determine which eating and lifestyle behaviors mediate the association between SES and obesity. METHODS: We performed a case-control study of 318 obese people and 371 non-obese people in northern France. Ten eating behavior traits were assessed using the Three-Factor Eating Questionnaire Revised 21-Item and an eating attitude questionnaire (on plate size, the number of servings, reasons for stopping eating and the frequency of eating standing up, eating in front of the television set (TV) and eating at night). The SES score (in three categories) was based on occupation, education and income categories. Mediation analysis was performed using the test of joint significance and the difference of coefficients test. RESULTS: The age- and gender-adjusted obesity risk was higher for individuals in the low-SES groups (odds ratio (OR) (95% confidence interval (CI)=1.82 (1.48-2.24), P<0.0001). Additional servings were associated with a higher obesity risk (OR=3.43, P<0.0001). Cognitive restraint (P<0.0001) and emotional eating (P<0.0001) scores were higher in obese participants than in non-obese participants but did not depend on SES. Of the 10 potential factors tested, eating off a large plate (P=0.01), eating at night (P=0.04) and uncontrolled eating (P=0.03) significantly mediated the relationship between SES and obesity. CONCLUSION: Our results highlighted a number of obesogenic behaviors among socially disadvantaged participants: large plate size, uncontrolled eating and eating at night were significant mediators of the relationship between SES and the obesity risk.

Multicentre study of neoadjuvant chemotherapy for stage I and II oesophageal cancer.

BACKGROUND: The benefit of neoadjuvant chemotherapy (NCT) for early-stage oesophageal cancer is unknown. The aim of this study was to assess whether NCT improves the outcome of patients with stage I or II disease. METHODS: Data were collected from 30 European centres from 2000 to 2010. Patients who received NCT for stage I or II oesophageal cancer were compared with patients who underwent primary surgery with regard to postoperative morbidity, mortality, and overall and disease-free survival. Propensity score matching was used to adjust for differences in baseline characteristics. RESULTS: Of 1173 patients recruited (181 NCT, 992 primary surgery), 651 (55·5 per cent) had clinical stage I disease and 522 (44·5 per cent) had stage II disease. Comparisons of the NCT and primary surgery groups in the matched population (181 patients in each group) revealed in-hospital mortality rates of 4·4 and 5·5 per cent respectively (P = 0·660), R0 resection rates of 91·7 and 86·7 per cent (P = 0·338), 5-year overall survival rates of 47·7 and 38·6 per cent (hazard ratio (HR) 0·68, 95 per cent c.i. 0·49 to 0·93; P = 0·016), and 5-year disease-free survival rates of 44·9 and 36·1 per cent (HR 0·68, 0·50 to 0·93; P = 0·017). CONCLUSION: NCT was associated with better overall and disease-free survival in patients with stage I or II oesophageal cancer, without increasing postoperative morbidity.

Length of optic nerve double inversion recovery hypersignal is associated with retinal axonal loss.

OBJECTIVES: To assess the association between optic nerve double inversion recovery (DIR) hypersignal length and retinal axonal loss in neuroinflammatory diseases affecting optic nerves. METHODS: We recruited patients previously affected (> 6 months) by a clinical episode of optic neuritis (ON). We had 25 multiple sclerosis (MS) patients, eight neuromyelitis optica spectrum disorder (NMOSD) patients and two patients suffering from idiopathic caused ON undergo brain magnetic resonance imaging (MRI); including a 3-dimensional (3D) DIR sequence, optical coherence tomography (OCT) examination and visual disability evaluation. Evaluation criteria were retinal thickness/volume, optic nerve DIR hypersignal length and high/low contrast vision acuity. RESULTS: In the whole cohort, we found good associations (< 0.0001) between optic nerve DIR hypersignal length, peripapillary retinal nerve fiber layer thickness, inner macular layers volumes, and visual disability. We found subclinical radiological optic nerve involvement in 38.5% of non-ON MS eyes. CONCLUSIONS: Optic nerve DIR hypersignal length may be a biomarker for retinal axonal loss, easily applicable in routine and research on new anti-inflammatory or neuroprotective drug evaluation. Detection of subclinical ON with 3D-DIR in a non-negligible proportion of MS patients argues in favor of optic nerve imaging in future OCT MS studies, in order to achieve a better understanding of retinal axonal loss in non-ON eyes.

Postpartum haemorrhage related early increase in D-dimers is inhibited by tranexamic acid: haemostasis parameters of a randomized controlled open labelled trial.

BACKGROUND: Beneficial effects of tranexamic acid (TA) have been established in surgery and trauma. In ongoing postpartum haemorrhage (PPH), a moderate reduction of blood loss was observed in a previously published randomized controlled trial. Analysis of haemostasis parameters obtained from samples collected as part of this study are presented. METHODS: Women with PPH >800 ml after vaginal delivery were assigned to receive either TA (4 g over 1 h, then 1 g per h over six h) (TA) or not (H). A non-haemorrhagic group (NH), <800 ml blood loss, was included as postpartum reference. At four time-points (enrolment, +30 min, +2 h, +6 h), haemostasis was assessed. Haemostasis assays were performed blinded to group allocation. Data were expressed as median [interquartiles] and compared with non-parametric tests. RESULTS: In H compared with NH group, D-dimers increase (3730 ng ml(-1) [2468-8493] vs 2649 [2667-4375]; P=0.0001) and fibrinogen and factor II decrease were observed at enrolment and became maximal 2 h later. When comparing TA to H patients, the increase in Plasmin-Antiplasmin-complexes at +30 min (486 ng ml(-1) [340-1116] vs 674 [548-1640]; P=0.03) and D-dimers at +2 h (3888 ng ml(-1) [2688-6172] vs 7495 [4400-15772]; P=0.0001) was blunted. TA had no effect on fibrinogen decrease. CONCLUSIONS: This study provides biological evidence of an early increase in D-dimers and plasmin-antiplasmin complexes associated with active post-partum haemorrhage and its attenuation by the early use of a clinically effective high dose of TA, opening the perspective of dose ranging studies to determinate the optimal dose and timing in this setting. CLINICAL TRIAL REGISTRATION: ISRCTN09968140.