A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences.

Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency=0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P=1.2 × 10(-4)). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7-2.3 for lung cancer (LC; P=4.0 × 10(-4)), chronic obstructive pulmonary disease (COPD; P=9.3 × 10(-4)), peripheral artery disease (PAD; P=0.090) and abdominal aortic aneurysms (AAAs; P=0.12), and the variant associates strongly with the early-onset forms of LC (OR=4.49, P=2.2 × 10(-4)), COPD (OR=3.22, P=2.9 × 10(-4)), PAD (OR=3.47, P=9.2 × 10(-3)) and AAA (OR=6.44, P=6.3 × 10(-3)). Joint analysis of the four smoking-related diseases reveals significant association (P=6.8 × 10(-5)), particularly for early-onset cases (P=2.1 × 10(-7)). Our results are in agreement with functional studies showing that the human α4ß2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.

SmartPilot® view-guided anaesthesia improves postoperative outcomes in hip fracture surgery: a randomized blinded controlled study.

BACKGROUND: Both under-dosage and over-dosage of general anaesthetics can harm frail patients. We hypothesised that computer-assisted anaesthesia using pharmacokinetic/pharmacodynamic models guided by SmartPilot® View (SPV) software could optimise depth of anaesthesia and improve outcomes in patients undergoing hip fracture surgery. METHODS: This prospective, randomized, single-centre, blinded trial included patients undergoing hip fracture surgery under general anaesthesia. In the intervention group, anaesthesia was guided using SPV with predefined targets. In the control group, anaesthesia was delivered by usual practice using the same agents (propofol, sufentanil and desflurane). The primary endpoint was the time spent in the "appropriate anaesthesia zone" defined as bispectral index (BIS) (blinded to the anaesthetist during surgery) of 45-60 and systolic arterial pressure of 80-140 mm Hg. Postoperative complications were recorded for one month in a blinded manner. RESULTS: Of 100 subjects randomised, 97 were analysed (n=47 in SPV and 50 in control group). Anaesthetic drug consumption was reduced in the SPV group (for propofol and desflurane). Intraoperative duration of low BIS (<45) was similar, but cumulative time of low systolic arterial pressure (<80 mm Hg) was significantly shorter in the SPV group (median (Q1-Q3); 3 (0-40) vs 5 (0-116) min, P=0.013). SPV subjects experienced fewer moderate or major postoperative complications at 30-days (8 (17)% vs 18 (36)%, P=0.035) and shorter length of hospitalisation (8 (2-20) vs 8 (2-60) days, P=0.017). CONCLUSIONS: SmartPilot® View-guided anaesthesia reduces intraoperative hypotension duration, occurrence of postoperative complications and length of stay in hip fracture surgery patients. CLINICAL TRIAL REGISTRATION: NCT 02556658.

Seasonal gonadal development and age-related maturity patterns of introduced pumpkinseed (Lepomis gibbosus Linnaeus, 1758) in a heated thermal reservoir and an adjacent river reach.

Testis and ovarian maturation status, maturity profile and gonado-somatic index (GSI) were assessed in pumpkinseed (Lepomis gibbosus) collected from Mirgenbach, a cooling-water reservoir associated with a nuclear power plant, and from the River Moselle 7km downstream of the reservoir's thermal outflow. Histological investigation indicated that in both sexes, gonadal development of pumpkinseed in the heated reservoir was more advanced than in the cooler Moselle River throughout the breeding season. The histological maturity profile of reservoir males ranked by the advancement of sperm cells was highly correlated with its GSI (rs=0.73, P<0.001). GSI of females in the reservoir increased with the stage at maturity, but GSI was not significantly correlated with total length, age or growth rate of the individual. All sampled individuals of both sexes were mature at age 1 in the heated reservoir, whereas 48% of age 1 males and 57% of age 1 females were not mature in the river. GSI patterns suggest that males in the reservoir adopted one of two reproductive strategies (nesters or cuckolders), whereas no small males with large enough testes to be considered cuckolders were apparent in the river. The warm thermal regime of Mirgenbach Reservoir led to precocial maturity, early season reproduction, and the greater prevalence of apparent cuckolder males than would normally occur in this climatic zone.

'It's something you have to put up with'--service users' experiences of in utero transfer: a qualitative study.

OBJECTIVE: The purpose of this study was to gain in-depth insight and enhance understanding of service users' experiences of the in utero transfer (IUT) process, in order to inform policy and improve the current service provision of maternal care. DESIGN: Qualitative descriptive study using semi-structured interviews. SETTING: Participant's home or hospital in the Midlands, UK. POPULATION: Fifteen women transferred in utero to a tertiary level maternity hospital; five male partners and two grandmothers. METHODS: Audio-recorded individual or paired semi-structured interviews transcribed verbatum and analysed thematically using nvivo 9. MAIN OUTCOME MEASURES: Facilitators and barriers of the IUT experience. RESULTS: Findings suggest that IUT is an emotional experience that financially disadvantages patients and their families. Male partners were perceived to be most negatively affected by the experience. The quality of the IUT experience was influenced by a range of factors, including the lack of proximity to home and the lack of information. Patients had little knowledge or awareness of IUT, and most felt unprepared for displacement. Despite this, there was resigned acceptance that IUT was a necessary rather than adverse experience. CONCLUSIONS: The experience of IUT for service users could be enhanced by ensuring that they are better informed about the process and the circumstances that necessitate displacement, that they are better informed about the hospital to which they are being transferred, and that they are transferred as close to home as possible. Efforts to minimise the emotional and socio-economic impact of IUT on women and their families also need to be considered.

Impact of the cestode Triaenophorus nodulosus on the exotic Lepomis gibbosus and the autochthonous Perca fluviatilis.

The effects of plerocercoids of the cestode Triaenophorus nodulosus infecting the livers of native Eurasian perch Perca fluviatilis and non-native pumpkinseed Lepomis gibbosus was investigated in 17 sites along the Moselle watershed. With a single exception, infected individuals were not observed in the main channel whether or not northern pike Esox lucius, a final host, was present. In ponds where the pike was present, the prevalence of T. nodulosus averaged 86% in Eurasian perch and 15% in pumpkinseed. The parasite was not present at all in ponds when pike were absent. Parasite load, hepatosomatic index (HSI), gonadosomatic index (GSI) and body condition index (CI) were compared between hosts in one site where parasite prevalence and fish abundance was highest. HSI in infected perch was significantly higher than in uninfected perch, whereas no differences in HSI were detected between infected and uninfected pumpkinseed. While perch were more frequently infected and had a greater average parasite load than pumpkinseed, there were no significant differences in either indicator between the two species. Furthermore, no significant differences in GSI or CI were observed between infected and uninfected fish in either species, by either gender or maturity stage. We hypothesize that pumpkinseed is more resistant to the parasite or less likely to feed upon infected copepods than perch.

Bifurcation study of a neural field competition model with an application to perceptual switching in motion integration.

Perceptual multistability is a phenomenon in which alternate interpretations of a fixed stimulus are perceived intermittently. Although correlates between activity in specific cortical areas and perception have been found, the complex patterns of activity and the underlying mechanisms that gate multistable perception are little understood. Here, we present a neural field competition model in which competing states are represented in a continuous feature space. Bifurcation analysis is used to describe the different types of complex spatio-temporal dynamics produced by the model in terms of several parameters and for different inputs. The dynamics of the model was then compared to human perception investigated psychophysically during long presentations of an ambiguous, multistable motion pattern known as the barberpole illusion. In order to do this, the model is operated in a parameter range where known physiological response properties are reproduced whilst also working close to bifurcation. The model accounts for characteristic behaviour from the psychophysical experiments in terms of the type of switching observed and changes in the rate of switching with respect to contrast. In this way, the modelling study sheds light on the underlying mechanisms that drive perceptual switching in different contrast regimes. The general approach presented is applicable to a broad range of perceptual competition problems in which spatial interactions play a role.

Factors associated with survival after early at-home NIV initiation in ALS patients.

BACKGROUND: The initiation of early non-invasive ventilation (NIV) often involves a careful balance between tolerance and effectiveness. In amyotrophic lateral sclerosis (ALS) patients, the establishment of a strategy, including the decision to focus on adhering to a cut-off, setting specific targets, or correcting all events, is crucial. OBJECTIVE: To identify factors at 1 month after early at-home NIV initiation that are associated with improved survival in ALS patients. We explored the impacts of adherence (ADH), quality of treatment, and NIV parameters at 1 month after early at-home NIV initiation on patient survival. METHODS: We conducted a retrospective study of 184 ALS patients at the Bordeaux ALS Centre for whom NIV was initiated between September 2017 and June 2021, and we collected data for a minimum period of 2 years after the last patient included. The primary outcome was the risk of death according to baseline characteristics of our population and the NIV parameters and monitoring during the early NIV initiation period. The secondary outcomes were association with NIV ADH during the early NIV initiation period on prognosis, and NIV ADH cut-off for good versus poor prognosis. RESULTS: Among the 178 ALS patients analysed, we found that quality of NIV treatment and device settings did not significantly influence prognosis. However, low ADH was significantly associated with a higher risk of death. The use of NIV for > 5 h/day during the early NIV initiation period was linked to a decreased risk of death [hazard ratio = 0.4; 95% confidence interval: 0.27-0.9]. CONCLUSION: The use of NIV for > 5 h/day during the early NIV initiation period was associated with increased survival.

Host switch and infestation by Ligula intestinalis L. in a silver bream (Blicca bjoerkna L.) population.

Sampling of the fish community was carried out for 20 years in the Mirgenbach reservoir, in North-Eastern France. The prevalence and the mean intensity of Ligula intestinalis (Cestoda) were analysed in roach (Rutilus rutilus) and silver bream (Blicca bjoerkna) populations, the main two infected species. The aim of this study was to investigate the host switch from roach to silver bream and the consequences of L. intestinalis infestation in silver bream, which is an unusual host for this parasite as Ligula parasitism in silver bream appears to be rare. We analysed in detail the relationships between parasitism index (PI), gonadosomatic index (GSI), perivisceral fat abundance (PFA) and condition index (CI) in the silver bream population. In 1998, prevalence of L. intestinalis highlighted a clear host switch from roach to silver bream. In the silver bream population, young fish were the most severely infected and the impact of plerocercoids appeared to be different depending on the host sex. In male silver bream, plerocercoids drew energy from fat reserves even if GSI was also slightly impacted. On the contrary, in females energy was diverted from gonad maturation rather than from perivisceral fat reserves. No significant difference was observed in terms of CI in either sex.

Increased cardiovascular reactivity to agiotensin caused by renin.

After a short period of tachyphylaxis, there is a marked and sustained enhancement of pressor re sponses to renin and angiotensin during chronic administration of renin.

CDKN2A mutations and melanoma risk in the Icelandic population.

BACKGROUND: Germline CDKN2A mutations have been observed in 20-40% of high risk, melanoma prone families; however, little is known about their prevalence in population based series of melanoma cases and controls. METHODS: We resequenced the CDKN2A gene, including the p14ARF variant and promoter regions, in approximately 703 registry ascertained melanoma cases and 691 population based controls from Iceland, a country in which the incidence of melanoma has increased rapidly. RESULTS: We identified a novel germline variant, G89D, that was strongly associated with increased melanoma risk and appeared to be an Icelandic founder mutation. The G89D variant was present in about 2% of Icelandic invasive cutaneous malignant melanoma cases. Relatives of affected G89D carriers were at significantly increased risk of melanoma, head and neck cancers, and pancreatic carcinoma compared to relatives of other melanoma patients. Nineteen other germline variants were identified, but none conferred an unequivocal risk of melanoma. CONCLUSIONS: This population based study of Icelandic melanoma cases and controls showed a frequency of disease related CDKN2A mutant alleles ranging from 0.7% to 1.0%, thus expanding our knowledge about the frequency of CDKN2A mutations in different populations. In contrast to North America and Australia where a broad spectrum of mutations was observed at a similar frequency, in Iceland, functional CDKN2A mutations consist of only one or two different variants. Additional genetic and/or environmental factors are likely critical for explaining the high incidence rates for melanoma in Iceland. This study adds to the geographic regions for which population based estimates of CDKN2A mutation frequencies are available.

Causes of death amongst French patients with amyotrophic lateral sclerosis: a prospective study.

BACKGROUND AND PURPOSE: To prospectively investigate causes of death and the circumstances surrounding death in 302 patients with amyotrophic lateral sclerosis (ALS). The functional status of patients immediately before death was also determined. METHODS: Information was obtained from neurologists at ALS centres, patients' files, and, when deaths occurred outside a medical facility, attending physicians. RESULTS: Most patients (63%) died in a medical facility. The most frequently reported cause of death was respiratory failure (77%), including terminal respiratory insufficiency (58%), pneumonia (14%), asphyxia due to a foreign body (3%) and pulmonary embolism (2%). Ten per cent of patients died from other causes: post-surgical or traumatic conditions (5%), cardiac causes (3.4%), suicide (1.3%) and sudden death of unknown origin (0.7%). The cause of death could not be determined in 13% of cases (6% inside a medical facility and 25% outside). At the time of death, only 55% of patients were receiving riluzole, 33% were undergoing non-invasive ventilation, 3% had a tracheotomy and 37% a gastrostomy. CONCLUSION: The information provided by this study helps to improve our understanding of the natural history of the disease and may help optimize the quality of care we can offer patients at the end of life.

Assessment of sediment concentration and nutrient loads in effluents drained from extensively managed fishponds in France.

Expansion of aquaculture has increased concern over its environmental impact. The composition of effluents from intensive aquaculture is well documented, but few data on extensive aquaculture are available. During 12 draining operations, 523 water samples were collected downstream from six extensively-managed fishponds in northeastern France. Study ponds had surface areas of 2-620 ha and were managed for production of Cyprinids and Percids. Concentrations of total suspended solids, total phosphorus, and Kjeldahl nitrogen in effluents from the ponds were greatest during the final stage of draining. Loads of phosphorus were higher than those reported for effluents of more intensive aquaculture ponds in the USA, but the source of the potential pollutants was catchments and sediment rather than feeds and fertilizer. It will be necessary to reduce the water drawdown rate during the fishing stage and possibly implement other best management practices to prevent the TSS concentration from exceeding 1 g/L.

Motion perception during saccadic eye movements.

During rapid eye movements, motion of the stationary world is generally not perceived despite displacement of the whole image on the retina. Here we report that during saccades, human observers sensed visual motion of patterns with low spatial frequency. The effect was greatest when the stimulus was spatiotemporally optimal for motion detection by the magnocellular pathway. Adaptation experiments demonstrated dependence of this intrasaccadic motion percept on activation of direction-selective mechanisms. Even two-dimensional complex motion percepts requiring spatial integration of early motion signals were observed during saccades. These results indicate that the magnocellular pathway functions during saccades, and that only spatiotemporal limitations of visual motion perception are important in suppressing awareness of intrasaccadic motion signals.

Metabolic Reprogramming in Amyotrophic Lateral Sclerosis.

Mitochondrial dysfunction in the spinal cord is a hallmark of amyotrophic lateral sclerosis (ALS), but the neurometabolic alterations during early stages of the disease remain unknown. Here, we investigated the bioenergetic and proteomic changes in ALS mouse motor neurons and patients' skin fibroblasts. We first observed that SODG93A mice presymptomatic motor neurons display alterations in the coupling efficiency of oxidative phosphorylation, along with fragmentation of the mitochondrial network. The proteome of presymptomatic ALS mice motor neurons also revealed a peculiar metabolic signature with upregulation of most energy-transducing enzymes, including the fatty acid oxidation (FAO) and the ketogenic components HADHA and ACAT2, respectively. Accordingly, FAO inhibition altered cell viability specifically in ALS mice motor neurons, while uncoupling protein 2 (UCP2) inhibition recovered cellular ATP levels and mitochondrial network morphology. These findings suggest a novel hypothesis of ALS bioenergetics linking FAO and UCP2. Lastly, we provide a unique set of data comparing the molecular alterations found in human ALS patients' skin fibroblasts and SODG93A mouse motor neurons, revealing conserved changes in protein translation, folding and assembly, tRNA aminoacylation and cell adhesion processes.

Input-output transformation in the visuo-oculomotor loop: comparison of real-time optical imaging recordings in V1 to ocular following responses upon center-surround stimulation.

In psychophysics and physiology, it is well established that lateral interactions are crucial mechanisms to constrain response normalization and contextual modulations. To study the cortical mechanisms involved in the contextual modulation of the behavioral contrast response function, we compared in behaving monkeys the Ocular Following Response (OFR) to V1 population activity measured using Optical Imaging of Voltage-Sensitive Dyes (VSD). If contrast response functions (CRF) to a simple local stimulus are similar in V1 and in the OFR, lateral interaction leads however to quite different modulation at those two levels. At the behavioural level, contrast response function is strongly suppressed by lateral interactions, and this suppression is stronger for higher contrasts. In V1, we showed a slow dynamic of facilitation for low contrasts integration and a fast suppression operating on high contrasts. These modulatory interactions influence differently the contrast response functions, interrupting the dynamic increase of contrast sensitivity in OFR, but not in V1 response. The temporal properties of those effects lead us to hypothesize that horizontal and feedback connectivity have differential effect on low and high contrasts integration in V1. V1 provides then an input to MT whose contextual dependency is not totally determined and must be refined before affecting the behavioural OFR.

[Episiotomy and prevention of perineal and pelvic floor injuries]. / Episiotomie et prévention des lésions pelvi-périnéales.

OBJECTIVES: The objective of this review was to assess the efficacy of episiotomy to prevent severe perineal tears, urinary incontinence, faecal incontinence and genital prolapse. MATERIAL AND METHODS: A systematic review on Medline database was performed between 1980 and 2005. One hundred seventy seven articles were selected. Trial quality was assessed on the following parameters: design (prospective, randomized, meta-analysis), sample size (>50) and relevant results. Finally, 43 articles were analysed. RESULTS: The routine use of episiotomy did not prevent severe perineal tears. It decreased the risk of moderate anterior perineal lacerations. The risk of severe perineal tears during episiotomy increased in the following circumstances: primiparity, Asian women, perineal length

Contribution of limb momentum to power transfer in athletic wheelchair pushing.

Pushing capacity is a key parameter in athletic racing wheelchair performance. This study estimated the potential contribution of upper limb momentum to pushing. The question is relevant since it may affect the training strategy adopted by an athlete. A muscle-free Lagrangian dynamic model of the upper limb segments was developed and theoretical predictions of power transfer to the wheelchair were computed during the push phase. Results show that limb momentum capacity for pushing can be in the order of 40J per push cycle at 10m/s, but it varies with the specific pushing range chosen by the athlete. Although use of momentum could certainly help an athlete improve performance, quantifying the actual contribution of limb momentum to pushing is not trivial. A preliminary experimental investigation on an ergometer, along with a simplified model of the upper limb, suggests that momentum is not the sole contributor to power transfer to a wheelchair. Muscles substantially contribute to pushing, even at high speeds. Moreover, an optimal pushing range is challenging to find since it most likely differs if an athlete chooses a limb momentum pushing strategy versus a muscular exertion pushing strategy, or both at the same time. The study emphasizes the importance of controlling pushing range, although one should optimize it while also taking the dynamics of the recovery period into account.

Perinatal care regionalization and acceptability by professionals in France.

BACKGROUND: For twenty years, most of industrial countries developed recommendations on regionalization of perinatal care. Perinatal regionalization is particularly aimed at improving morbidity and mortality outcomes of low birth weight newborns by transferring pregnant women to the maternity units having a medical or neonatal environment suited to the risks incurred by mothers or babies. Perinatal regionalization cannot be effective without being well accepted by the majority of professionals. The objectives of this study were then to identify professionals'expectations and objections to perinatal regionalisation and to compare them from a professional group to another one. METHODS: Professionals of 3 French perinatal networks were under consideration: the Rhône, the Auvergne and the Gard-Lozère networks. The study included two stages: 1) a psychosociological qualitative study, based on professionals'interviews, aimed at identifying main concerns of professionals and developing a questionnaire; then 2) an epidemiological quantitative study, using this questionnaire within French networks. In the questionnaire, 8 dimensions explored the professionals'views: constraints related to regulation aspects and to the setting up of maternity units care levels, risk of loss of professionals' competence and prestige, consequences on medical practices, on inter-professional relationship, on work organization and financial aspects, and related to the new role of 'private practice'professionals, legal consequences. RESULTS: The response rate of the epidemiological study was 80%. The results permitted to construct 8 dimension scores describing the reasons of poor acceptability of regionalization. After taking into account the age, the sex, the network and the juridical status of the institution, the study revealed a significant poorer acceptability of regionalization by most of medical specialty groups (anesthetists, obstetricians, midwives and "private practice" professionals) compared with neonatologists, or by "private" professionals (professionals working in private clinics and "private practice" professionals) compared with professionals working in university or community hospitals. The study described also network setting up conditions related to its functioning. CONCLUSION: By identifying clearly professionals 'objections and expectations, this study should facilitate improvement in the organization of studied perinatal networks.

[Neonatal consequences of maternal smoking during pregnancy]. / Conséquences du tabagisme in utero pour le nouveau-né.

In utero tobacco consumption is a serious public health problem in France; it is very frequent and the long term consequences are not only numerous but also misinterpreted by our population. 25 to 29% of women arrive at the end of their pregnancy without stopping smoking and 50% of non smoking mothers live in an environment polluted by tobacco during pregnancy. The authors would like to stress the gravity of this situation. At the maternity hospital in Nîmes, 358 women who gave birth at term and after a normal pregnancy were enrolled in a survey and monitored with thiocyanate for their tobacco consumption. Birth weight, height, and cranial perimeter of the infants were noted at birth. Results confirmed earlier work on this subject: the three variables studied were consistently weakened by the mother's addiction to tobacco. The authors recall previous medical literature on the pathophysiology and other consequences on the brain: such as I.Q. behavior, sudden infant death syndrome, vascular alterations with possible long-term complications, as well as pulmonary alterations on which there has recently been much research. The question is raised as to why this problem is so neglected in our society and what could be done to change this state of affairs.

Peripheral myelin modification in CMT1B correlates with MPZ gene mutations.

Morphological modifications were investigated in the peripheral nerve of three unrelated patients with CMT1B. In two patients, molecular genetic analysis showed an Arg98His mutation in the extracellular domain of MPZ, associated with irregularly uncompacted lamellae. This observation confirms previous studies of a well-defined correlation between mutations and morphological phenotypes. In the third patient, a de novo Asp109Asn mutation was associated with abnormally thick myelin sheaths. This adds to the known list of MPZ gene mutations associated with this morphological phenotype.