Ultrafast electron dynamics in excited states of conjugated thiophene-fluorene organic polymer (pF8T2) thin films.

The electronic states of poly(9,9-dioctylfluorenyl-alt-bithiophene) pF8T2 on H/Si(100) substrates, prototypical for organic photovoltaics, were investigated by ultrafast photoelectron spectroscopy and by time-resolved fluorescence studies. Occupied and unoccupied electronic states were analysed by ultraviolet photoelectron spectroscopy (UPS), static and dynamic femtosecond two-photon photoemission (2PPE), and time-correlated single photon counting (TCSPC). Time-resolved measurements allow assessment of population lifetimes of intermediate states. The combination of time-resolved photoelectron spectroscopy and fluorescence excitation allows following the electronic dynamics in excited states from the femtosecond to the nanosecond time scale. For this prototypical material the electron kinetic energy resolved lifetimes range from about a few tens of femtoseconds up to hundreds of picoseconds. After annealing these types of organic thin films the efficiency of organic solar cells usually increases. We show that annealing does not influence the initial ultrafast charge generation processes, but the long-lived states. However, the nanosecond scale fluorescence lifetimes measured by TCSPC are prolonged after annealing, which therefore is identified as the cause of a greater exciton diffusion range and thus is beneficial for charge carrier extraction.

Tailored positioning and number of hand rub dispensers: the fundamentals for optimized hand hygiene compliance.

BACKGROUND: Availability of alcohol-based hand rub (ABHR) dispensers at positions adapted to the work flow of healthcare workers (HCWs) is decisive in order to carry out indication-based hand rubbing. Although requirements and guidelines regarding the positioning of ABHR dispensers are in place, scientific evidence is often lacking. METHODS: In order to analyse the impact of the location and number of ABHR dispensers on hand hygiene performance, additional dispensers were systematically placed in patient rooms in a surgical 38-bed ward at Marburg University Hospital, Germany to complement the existing dispenser locations. ABHR use was monitored continuously before and after complementation using the NosoEx hand hygiene monitoring system. The ward had 53 dispensers before the intervention and 82 dispensers after the intervention. RESULTS: The addition of dispensers increased ABHR consumption across the entire ward. Before the intervention, mean consumption was 20.6 mL/patient-day, whereas mean consumption after the intervention was 25.3 mL/patient-day. Depending on the combination of dispenser locations, consumption increased through targeted supplementation in patient rooms. The presence of two or three dispensers per patient room resulted in significantly greater ABHR consumption compared with one dispenser per patient room. The preferred location combinations were entrance-front bed-back bed and entrance-foot end. CONCLUSION: ABHR consumption can be increased significantly by optimizing the position and number of dispensers. The outstanding factors are visibility and integrability of dispenser use into the work flow; in particular, a dispenser should be positioned in the entrance area. Recommendations should be optimized with regard to the required number and location of dispensers in patient rooms.

SAMCEP Society consensus on the treatment of upper facial lines with botulinum neurotoxin type A: A tailored approach.

BACKGROUND: The safety and efficacy of botulinum neurotoxin type A (BoNTA) treatments are well established, but injection techniques, target muscles, and toxin doses continue to evolve, with each refinement producing improvements in treatment outcomes. The recommendations in this consensus move away from standard templates and illustrate how to tailor treatments to individual patterns and strengths of muscle activity, and patient preferences. METHODS: Seventeen experts in the fields of plastic surgery, dermatology, ophthalmology, otorhinolaryngology, and neurology convened in 2022 to develop consensus-based recommendations for the use of botulinum toxin A for the treatment of horizontal forehead lines, glabellar frown lines, and crow's feet lines that reflect current clinical practice. The focus was on how to tailor injections to individual patients to optimize treatment outcomes. RESULTS: For each upper face indication, consensus members describe how to perform a dynamic assessment to optimize the dose and injection technique for each patient. A tailored treatment protocol is presented for commonly observed patterns of dynamic lines. Units of Inco are defined and the precise location of injection points, illustrated with the use of anatomical images. CONCLUSION: This consensus provides up-to-date recommendations on the tailored treatment of upper facial lines based on the latest research and collective clinical experience of the expert injectors. Optimal outcomes require thorough patient evaluation, both at rest and during animation, using both visual and tactile cues; detailed understanding of facial muscular anatomy and how opposing muscles interact; and use of a BoNTA with high precision to target identified zones of excess muscle activity.

Intramuscular oxytocin versus Syntometrine® versus carbetocin for prevention of primary postpartum haemorrhage after vaginal birth: a randomised double-blinded clinical trial of effectiveness, side effects and quality of life.

OBJECTIVE: To compare intramuscular oxytocin, Syntometrine® and carbetocin for prevention of postpartum haemorrhage after vaginal birth. DESIGN: Randomised double-blinded clinical trial. SETTING: Six hospitals in England. POPULATION: A total of 5929 normotensive women having a singleton vaginal birth. METHODS: Randomisation when birth was imminent. MAIN OUTCOME MEASURES: Primary: use of additional uterotonic agents. Secondary: weighed blood loss, transfusion, manual removal of placenta, adverse effects, quality of life. RESULTS: Participants receiving additional uterotonics: 368 (19.5%) oxytocin, 298 (15.6%) Syntometrine and 364 (19.1%) carbetocin. When pairwise comparisons were made: women receiving carbetocin were significantly more likely to receive additional uterotonics than those receiving Syntometrine (odds ratio [OR] 1.28, 95% CI 1.08-1.51, P = 0.004); the difference between carbetocin and oxytocin was non-significant (P = 0.78); Participants receiving Syntometrine were significantly less likely to receive additional uterotonics than those receiving oxytocin (OR 0.75, 95% CI 0.65-0.91, P = 0.002). Non-inferiority between carbetocin and Syntometrine was not shown. Use of Syntometrine reduced non-drug PPH treatments compared with oxytocin (OR 0.64, 95% CI 0.42-0.97) but not carbetocin (P = 0.64). Rates of PPH and blood transfusion were not different. Syntometrine was associated with an increase in maternal adverse effects and reduced ability of the mother to bond with her baby. CONCLUSIONS: Non-inferiority of carbetocin to Syntometrine was not shown. Carbetocin is not significantly different to oxytocin for use of additional uterotonics. Use of Syntometrine reduced use of additional uterotonics and need for non-drug PPH treatments compared with oxytocin. Increased maternal adverse effects are a disadvantage of Syntometrine. TWEETABLE ABSTRACT: IM carbetocin does not reduce additional uterotonic use compared with IM Syntometrine or oxytocin.

(p)ppGpp and CodY Promote Enterococcus faecalis Virulence in a Murine Model of Catheter-Associated Urinary Tract Infection.

In Firmicutes, the nutrient-sensing regulators (p)ppGpp, the effector molecule of the stringent response, and CodY work in tandem to maintain bacterial fitness during infection. Here, we tested (p)ppGpp and codY mutant strains of Enterococcus faecalis in a catheter-associated urinary tract infection (CAUTI) mouse model and used global transcriptional analysis to investigate the relationship of (p)ppGpp and CodY. The absence of (p)ppGpp or single inactivation of codY led to lower bacterial loads in catheterized bladders and diminished biofilm formation on fibrinogen-coated surfaces under in vitro and in vivo conditions. Single inactivation of the bifunctional (p)ppGpp synthetase/hydrolase rel did not affect virulence, supporting previous evidence that the association of (p)ppGpp with enterococcal virulence is not dependent on the activation of the stringent response. Inactivation of codY in the (p)ppGpp0 strain restored E. faecalis virulence in the CAUTI model as well as the ability to form biofilms in vitro Transcriptome analysis revealed that inactivation of codY restores, for the most part, the dysregulated metabolism of (p)ppGpp0 cells. While a clear linkage between (p)ppGpp and CodY with expression of virulence factors could not be established, targeted transcriptional analysis indicates that a possible association between (p)ppGpp and c-di-AMP signaling pathways in response to the conditions found in the bladder may play a role in enterococcal CAUTI. Collectively, data from this study identify the (p)ppGpp-CodY network as an important contributor to enterococcal virulence in catheterized mouse bladder and support that basal (p)ppGpp pools and CodY promote virulence through maintenance of a balanced metabolism under adverse conditions.IMPORTANCE Catheter-associated urinary tract infections (CAUTIs) are one of the most frequent types of infection found in the hospital setting that can develop into serious and potentially fatal bloodstream infections. One of the infectious agents that frequently causes complicated CAUTI is the bacterium Enterococcus faecalis, a leading cause of hospital-acquired infections that are often difficult to treat due to the exceptional multidrug resistance of some isolates. Understanding the mechanisms by which E. faecalis causes CAUTI will aid in the discovery of new druggable targets to treat these infections. In this study, we report the importance of two nutrient-sensing bacterial regulators, named (p)ppGpp and CodY, for the ability of E. faecalis to infect the catheterized bladder of mice.

Natural disease history of the dy2J mouse model of laminin α2 (merosin)-deficient congenital muscular dystrophy.

Merosin deficient congenital muscular dystrophy 1A (MDC1A) is a very rare autosomal recessive disorder caused by mutations in the LAMA2 gene leading to severe and progressive muscle weakness and atrophy. Although over 350 causative mutations have been identified for MDC1A, no treatment is yet available. There are many therapeutic approaches in development, but the lack of natural history data of the mouse model and standardized outcome measures makes it difficult to transit these pre-clinical findings to clinical trials. Therefore, in the present study, we collected natural history data and assessed pre-clinical outcome measures for the dy2J/dy2J mouse model using standardized operating procedures available from the TREAT-NMD Alliance. Wild type and dy2J/dy2J mice were subjected to five different functional tests from the age of four to 32 weeks. Non-tested control groups were taken along to assess whether the functional test regime interfered with muscle pathology. Respiratory function, body weights and creatine kinase levels were recorded. Lastly, skeletal muscles were collected for further histopathological and gene expression analyses. Muscle function of dy2J/dy2J mice was severely impaired at four weeks of age and all mice lost the ability to use their hind limbs. Moreover, respiratory function was altered in dy2J/dy2J mice. Interestingly, the respiration rate was decreased and declined with age, whereas the respiration amplitude was increased in dy2J/dy2J mice when compared to wild type mice. Creatine kinase levels were comparable to wild type mice. Muscle histopathology and gene expression analysis revealed that there was a specific regional distribution pattern of muscle damage in dy2J/dy2J mice. Gastrocnemius appeared to be the most severely affected muscle with a high proportion of atrophic fibers, increased fibrosis and inflammation. By contrast, triceps was affected moderately and diaphragm only mildly. Our study presents a complete natural history dataset which can be used in setting up standardized studies in dy2J/dy2J mice.

Early neuromodulation prevents the development of brain and behavioral abnormalities in a rodent model of schizophrenia.

The notion that schizophrenia is a neurodevelopmental disorder in which neuropathologies evolve gradually over the developmental course indicates a potential therapeutic window during which pathophysiological processes may be modified to halt disease progression or reduce its severity. Here we used a neurodevelopmental maternal immune stimulation (MIS) rat model of schizophrenia to test whether early targeted modulatory intervention would affect schizophrenia's neurodevelopmental course. We applied deep brain stimulation (DBS) or sham stimulation to the medial prefrontal cortex (mPFC) of adolescent MIS rats and respective controls, and investigated its behavioral, biochemical, brain-structural and -metabolic effects in adulthood. We found that mPFC-DBS successfully prevented the emergence of deficits in sensorimotor gating, attentional selectivity and executive function in adulthood, as well as the enlargement of lateral ventricle volumes and mal-development of dopaminergic and serotonergic transmission. These data suggest that the mPFC may be a valuable target for effective preventive treatments. This may have significant translational value, suggesting that targeting the mPFC before the onset of psychosis via less invasive neuromodulation approaches may be a viable preventive strategy.

Body composition and blood pressure in 6-year-old singletons born after pre-implantation genetic testing for monogenic and structural chromosomal aberrations: a matched cohort study.

STUDY QUESTION: Does Day 3 embryo biopsy for pre-implantation genetic testing for monogenic (PGT-M) and structural chromosomal aberrations (PGT-SR) affect body composition and blood pressure readings of 6-year-old singletons? SUMMARY ANSWER: This study of 87 PGT-M and PGT-SR conceived singletons showed no differences in anthropometric measurements and blood pressure readings in comparison with a matched cohort of peers born after ICSI without embryo biopsy. WHAT IS KNOWN ALREADY: While neonatal outcomes after PGT conception have been found comparable to those after ICSI without embryo biopsy, only a few studies have reported outcomes after PGT at older ages. Moreover, embryo biopsy is also applied in couples who opt for PGT-M and PGT-SR and hence are not necessarily infertile. Health parameters and in particular body composition data in this group of children are lacking. STUDY DESIGN SIZE DURATION: This single-centre matched-pair cohort study evaluated body composition of 6-year-old children born after fresh blastocyst embryo transfer with or without embryo biopsy performed at Day 3 for the purpose of PGT-M and PGT-SR. For each child born after embryo biopsy, a singleton born after transfer of a fresh ICSI embryo at the blastocyst stage and reaching the age of 6 years between May 2011 and June 2017 was matched as closely as possible for gender, age, maternal educational level and birth order. PARTICIPANTS/MATERIALS SETTING METHODS: Anthropometry (weight, height, BMI, skinfold thickness, waist and mid-upper arm circumference) and blood pressure readings in a longitudinally followed cohort of 87 singletons conceived by PGT-M and PGT-SR and a pairwise matched sample of 87 children conceived by ICSI are described. Results are adjusted for current, neonatal and parental characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: From the 124 eligible PGT-M and PGT-SR families, 110 could be reached of whom 23 refused and 87 (87/110 = 79%) participated. All anthropometric measurements, including z-scores of BMI, waist and mid-upper arm circumference, were comparable between the PGT-M and PGT-SR (-0.23; 0.27; 0.17, respectively) and ICSI (-0.29; 0.11; 0.11, respectively) groups (all P > 0.05). Furthermore, indices of peripheral (triceps) and central (subscapular) adiposity derived from skinfold thickness were comparable (PGT-M and PGT-SR: 14.7 mm; 11.6 mm and ICSI: 15.5 mm; 11.5 mm) as well as the percentage total body fat mass derived from these (PGT-M and PGT-SR: 13.7% and ICSI: 13.9%) (all P > 0.05). Z-scores for blood pressure were also comparable between the PGT and ICSI groups (all P > 0.05). Results did not change when adjusted for neonatal (birthweight, birth order), current (age) and parental (smoking during pregnancy, parental BMI) characteristics. Hospitalization rate and surgical intervention rate were not different for PGT-M and PGT-SR children compared to matched peers born after ICSI. LIMITATIONS REASONS FOR CAUTION: Although our study describes the largest cohort of singletons born after embryo biopsy worldwide, we were only able to detect moderate differences in anthropometrics and blood pressure with our sample size. WIDER IMPLICATIONS OF THE FINDINGS: Although Day 3 embryo biopsy followed by blastocyst transfer is not associated with adverse outcomes regarding anthropometry and blood pressure, future studies should focus on outcomes in children born after trophectoderm biopsy and/or transfer of warmed embryos after vitrification. STUDY FUNDING/COMPETING INTERESTS: This study was supported by Methusalem grants and by grants from Wetenschappelijk Fonds Willy Gepts; all issued by the Vrije Universiteit Brussel (VUB). All co-authors, except M.B. declared no conflict of interest. M.B. has received consultancy fees from MSD, Serono Symposia and Merck. The Universitair Ziekenhuis Brussel (UZ Brussel) and the Centre for Medical Genetics have received several educational grants from IBSA, Ferring, Organon, Shering-Plough, Merck for establishing the database for follow-up research and organizing the data collection.

Fetal head position and perineal distension associated with the use of the BD Odon Device™ in operative vaginal birth: a simulation study.

OBJECTIVE: To investigate (1) the placement of the BD Odon Device on the model fetal head and (2) perineal distention during simulated operative vaginal births conducted with the BD Odon Device. DESIGN: Observational simulation study. SETTING: North Bristol NHS Trust, UK. POPULATION OR SAMPLE: Four hundred and forty simulated operative vaginal births. METHODS: Three bespoke fetal mannequins were developed to represent (1) bi-parietal diameter of the 50th centile at term, (2) bi-parietal diameter at the 5th centile at term, and (3) 50th centile head with 2 cm of caput. Siting of the BD Odon Device on model heads was determined before and after 400 simulated operative vaginal births. Variables were analysed to determine their effect on device siting and movement during birth. The fetal mannequins were placed inside a maternal mannequin and the BD Odon Device was placed around the fetal head as per the instructions for use. The location of the air cuff was determined before and after the head was delivered. Perineal distension was determined by recording maximum perineal distention during a simulated operative vaginal birth using the same procedure, as well as scenarios employing an inappropriately non-deflated air cuff (for the BD Odon Device), the Kiwi ventouse and non-rotational forceps. MAIN OUTCOME MEASURES: Site and displacement during birth of the BD Odon Device on a model head. Maximal perineal distension during birth. RESULTS: The BD Odon Device was reliably sited in a standard over the fetal head position (approximately 40 mm above the fetal chin) for all stations, head sizes and positions with no significant displacement. In occipito-posterior births, compared with occipito-anterior or transverse, the BD Odon Device routinely sited further down the fetal head (toward the chin). The BD Odon Device was not associated with more perineal distension compared with forceps or Kiwi ventouse (respectively 21, 26 and 21 mm at posterior fourchette). CONCLUSIONS: The BD Odon Device reliably sited over a safe area of the fetal head in 400 simulated births representative of clinical practice. The BD Odon Device generates similar levels of perineal distension compared with Kiwi ventouse when used correctly. TWEETABLE ABSTRACT: Location of the BD Odon Device on a fetal head in simulation.

Design and development of the BD Odon DeviceTM : a human factors evaluation process.

OBJECTIVE: To (1) determine how intended users interact with and use the BD Odon Device in simulation, (2) use these findings to alter progressively the design of the BD Odon Device and (3) validate that these changes have improved the ability of practitioners to use the BD Odon Device. DESIGN: Human factors evaluation study. SETTING: Simulation suite designed to mimic delivery room. POPULATION OR SAMPLE: Three hundred and ninety simulated operative births, performed by 100 practising clinicians. METHODS: Simulated operative vaginal births performed using the BD Odon Device and the device Instructions for use were subjected to three formative human factors evaluations and one human factors validation test. Following each evaluation, findings were reviewed and the design of the BD Odon Device and Instructions for use were modified. MAIN OUTCOME MEASURES: Successful performance of an operative vaginal birth using the BD Odon Device in accordance with provided training and Instructions for use. RESULTS: Using version two of the BD Odon Device, and following exposure to face-to-face training and written instructions, 25% of accouchers were able successfully to perform a simulated operative vaginal birth. In the final evaluation, following device design and training material alterations, all accouchers were able successfully to perform a simulated operative vaginal birth using version four of the BD Odon Device. CONCLUSIONS: Human factors evaluations have enabled a multi-professional device and training materials design team to alter the design of the BD Odon Device and the Instructions for use in an evidence-based fashion. This process has resulted in a device which has a predictable and likely safe pattern of use. TWEETABLE ABSTRACT: Human Factors evaluations help make the BD Odon Device safe and usable for clinical practice.

Pressure and traction on a model fetal head and neck associated with the use of forceps, Kiwi™ ventouse and the BD Odon Device™ in operative vaginal birth: a simulation study.

OBJECTIVE: To determine the pressure and traction forces exerted on a model fetal head by the BD Odon Device, forceps and Kiwi ventouse during simulated births. DESIGN: Simulation study. SETTING: Simulated operative vaginal birth. POPULATION OR SAMPLE: Eighty-four simulated operative vaginal births. METHODS: A bespoke fetal mannequin with pressure sensors around the head and strain gauge across the neck was used to investigate pressure applied over the head, and traction across the neck during 84 simulated births using the BD Odon Device, non-rotational forceps and Kiwi ventouse. MAIN OUTCOME MEASURES: Peak pressure on the fetal face and lateral aspects of the head during correct use of the BD Odon Device and forceps. Peak pressure on orbits and neck during misplacement of the BD Odon Device and forceps. Peak traction force generated until instrument failure using the BD Odon Device, forceps and Kiwi ventouse. RESULTS: When correctly sited and using 80 kPa inflation pressure on the cuff, the BD Odon Device generated a lower peak pressure on the fetal head than forceps (83 versus 146 kPa). When instruments were purposefully misplaced over the orbits, the BD Odon Device generated a lower peak pressure on the orbits compared with forceps (70 versus 123 kPa). When purposefully misplaced over the neck, the BD Odon Device, compared with forceps, generated a greater peak pressure on the anterio-lateral aspect of the neck (56 versus 17 kPa) and a lower peak pressure on the posterior aspect of the neck (76 versus 93 kPa) than forceps. In cases of true cephalic disproportion, the BD Odon Device 'popped-off' at a lower traction force than did forceps (208 versus 270 N). CONCLUSIONS: In simulated assisted vaginal birth with correctly placed instruments, the peak pressure exerted on the fetal head by a BD Odon Device is lower than the pressure exerted by non-rotational forceps. In cases in which delivery of the fetal head is not possible due to cephalo-pelvic disproportion, lower traction forces could be applied using the BD Odon Device than with forceps before the procedure was abandoned due to device failure. TWEETABLE ABSTRACT: BD Odon Device exerts less pressure on a model fetal head than forceps, but more than Kiwi ventouse.

Natural disease history of mouse models for limb girdle muscular dystrophy types 2D and 2F.

Limb-girdle muscular dystrophy types 2D and 2F (LGMD 2D and 2F) are autosomal recessive disorders caused by mutations in the alpha- and delta sarcoglycan genes, respectively, leading to severe muscle weakness and degeneration. The cause of the disease has been well characterized and a number of animal models are available for pre-clinical studies to test potential therapeutic interventions. To facilitate transition from drug discovery to clinical trials, standardized procedures and natural disease history data were collected for these mouse models. Implementing the TREAD-NMD standardized operating procedures, we here subjected LGMD2D (SGCA-null), LGMD2F (SGCD-null) and wild type (C57BL/6J) mice to five functional tests from the age of 4 to 32 weeks. To assess whether the functional test regime interfered with disease pathology, sedentary groups were taken along. Muscle physiology testing of tibialis anterior muscle was performed at the age of 34 weeks. Muscle histopathology and gene expression was analysed in skeletal muscles and heart. Muscle histopathology and gene expression was analysed in skeletal muscles and heart. Mice successfully accomplished the functional tests, which did not interfere with disease pathology. Muscle function of SGCA- and SGCD-null mice was impaired and declined over time. Interestingly, female SGCD-null mice outperformed males in the two and four limb hanging tests, which proved the most suitable non-invasive tests to assess muscle function. Muscle physiology testing of tibialis anterior muscle revealed lower specific force and higher susceptibility to eccentric-induced damage in LGMD mice. Analyzing muscle histopathology and gene expression, we identified the diaphragm as the most affected muscle in LGMD strains. Cardiac fibrosis was found in SGCD-null mice, being more severe in males than in females. Our study offers a comprehensive natural history dataset which will be useful to design standardized tests and future pre-clinical studies in LGMD2D and 2F mice.

Association of Metal Homeostasis and (p)ppGpp Regulation in the Pathophysiology of Enterococcus faecalis.

In Enterococcus faecalis, the regulatory nucleotides pppGpp and ppGpp, collectively, (p)ppGpp, are required for growth in blood, survival within macrophages, and virulence. However, a clear understanding of how (p)ppGpp promotes virulence in E. faecalis and other bacterial pathogens is still lacking. In the host, the essential transition metals iron (Fe) and manganese (Mn) are not readily available to invading pathogens because of a host-driven process called nutritional immunity. Considering its central role in adaptation to nutritional stresses, we hypothesized that (p)ppGpp mediates E. faecalis virulence through regulation of metal homeostasis. Indeed, supplementation of serum with either Fe or Mn restored growth and survival of the Δrel ΔrelQ [(p)ppGpp0] strain to wild-type levels. Using a chemically defined medium, we found that (p)ppGpp accumulates in response to either Fe depletion or Mn depletion and that the (p)ppGpp0 strain has a strong growth requirement for Mn that is alleviated by Fe supplementation. Although inactivation of the nutrient-sensing regulator codY restored some phenotypes of the (p)ppGpp0 strain, transcriptional analysis showed that the (p)ppGpp/CodY network does not promote transcription of known metal transporters. Interestingly, physiologic and enzymatic investigations suggest that the (p)ppGpp0 strain requires higher levels of Mn in order to cope with high levels of endogenously produced reactive oxygen species (ROS). Because (p)ppGpp mediates antibiotic persistence and virulence in several bacteria, our findings have broad implications and provide new leads for the development of novel therapeutic and preventive strategies against E. faecalis and beyond.

Paradoxical augmented relapse in alcohol-dependent rats during deep-brain stimulation in the nucleus accumbens.

Case reports indicate that deep-brain stimulation in the nucleus accumbens may be beneficial to alcohol-dependent patients. The lack of clinical trials and our limited knowledge of deep-brain stimulation call for translational experiments to validate these reports. To mimic the human situation, we used a chronic-continuous brain-stimulation paradigm targeting the nucleus accumbens and other brain sites in alcohol-dependent rats. To determine the network effects of deep-brain stimulation in alcohol-dependent rats, we combined electrical stimulation of the nucleus accumbens with functional magnetic resonance imaging (fMRI), and studied neurotransmitter levels in nucleus accumbens-stimulated versus sham-stimulated rats. Surprisingly, we report here that electrical stimulation of the nucleus accumbens led to augmented relapse behavior in alcohol-dependent rats. Our associated fMRI data revealed some activated areas, including the medial prefrontal cortex and caudate putamen. However, when we applied stimulation to these areas, relapse behavior was not affected, confirming that the nucleus accumbens is critical for generating this paradoxical effect. Neurochemical analysis of the major activated brain sites of the network revealed that the effect of stimulation may depend on accumbal dopamine levels. This was supported by the finding that brain-stimulation-treated rats exhibited augmented alcohol-induced dopamine release compared with sham-stimulated animals. Our data suggest that deep-brain stimulation in the nucleus accumbens enhances alcohol-liking probably via augmented dopamine release and can thereby promote relapse.

Targeted sequencing of BRCA1 and BRCA2 across a large unselected breast cancer cohort suggests that one-third of mutations are somatic.

BACKGROUND: A mutation found in the BRCA1 or BRCA2 gene of a breast tumor could be either germline or somatically acquired. The prevalence of somatic BRCA1/2 mutations and the ratio between somatic and germline BRCA1/2 mutations in unselected breast cancer patients are currently unclear. PATIENTS AND METHODS: Paired normal and tumor DNA was analyzed for BRCA1/2 mutations by massively parallel sequencing in an unselected cohort of 273 breast cancer patients from south Sweden. RESULTS: Deleterious germline mutations in BRCA1 (n = 10) or BRCA2 (n = 10) were detected in 20 patients (7%). Deleterious somatic mutations in BRCA1 (n = 4) or BRCA2 (n = 5) were detected in 9 patients (3%). Accordingly, about 1 in 9 breast carcinomas (11%) in our cohort harbor a BRCA1/2 mutation. For each gene, the tumor phenotypes were very similar regardless of the mutation being germline or somatically acquired, whereas the tumor phenotypes differed significantly between wild-type and mutated cases. For age at diagnosis, the patients with somatic BRCA1/2 mutations resembled the wild-type patients (median age at diagnosis, germline BRCA1: 41.5 years; germline BRCA2: 49.5 years; somatic BRCA1/2: 65 years; wild-type BRCA1/2: 62.5 years). CONCLUSIONS: In a population without strong germline founder mutations, the likelihood of a BRCA1/2 mutation found in a breast carcinoma being somatic was ∼1/3 and germline 2/3. This may have implications for treatment and genetic counseling.

Depression, pregnancy-related anxiety and parental-antenatal attachment in couples using preimplantation genetic diagnosis.

STUDY QUESTION: Do preimplantation genetic diagnosis (PGD) couples experience higher levels of stress during pregnancy and the perinatal period compared with couples who conceive spontaneously (SC) or with ICSI? SUMMARY ANSWER: PGD couples did not experience more psychological stress during pregnancy and beyond than ICSI or SC couples. WHAT IS ALREADY KNOWN: Previous studies have shown that assisted reproduction technology (ART) couples are more prone to pregnancy-related anxieties than SC couples, but display depressed feelings to an equal or lesser extent. However, only one study has focused on a female PGD sample, which may be a more vulnerable group than other ART groups, due to the potentially complex hereditary background, adverse childhood experiences and losses. In that study, PGD women experienced a reduction in state anxiety, and maternal-antenatal attachment did not differ from normative data. Unfortunately, no data exist on pregnancy-related anxiety, depression and parental-antenatal attachment. Valuable information from both parents (e.g.: couples) is also lacking. STUDY DESIGN, SIZE, DURATION: For this longitudinal prospective study questionnaire, data from 185 women and 157 men (157 couples) were collected between February 2012 until April 2014. Data were analysed using multilevel analysis. The couples conceiving after PGD, ICSI or SC were followed from the first trimester of the pregnancy until the third month post-partum. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 60 PGD, 58 ICSI and 69 SC couples were initially recruited by various departments of Universitair Ziekenhuis Brussel (UZ Brussel). At each trimester (T1: 12-14 weeks, T2: 20-22 weeks, T3: 30-32 weeks) of pregnancy, depression (EPDS), pregnancy-related anxieties (PRAQ) and parental-antenatal attachment (M/PAAS) were recorded. At T4 (3 months post-partum), depression (EPDS) was assessed again. In the first trimester (T1) broad socio-demographic data and at T4 perinatal health data of both mother and child were recorded. Differences between conception groups over time were analysed using multilevel analyses, taking into account covariation between measurements and within couples. Several perinatal covariates as well as social desirability, coping and adult attachment style were controlled for. MAIN RESULTS AND THE ROLE OF CHANCE: All three conception groups had similar scores for depression during pregnancy and beyond. Also, pregnancy-related anxiety scales did not differ among the three groups. All groups also followed a similar trajectory in time regarding their scores for anxiety, depression and parental-antenatal attachment. ART groups did not give more socially desirable answers than SC controls. The subsequent moderators: coping and adult attachment style did not add any relevant information. No interaction effects occurred between gender and conception groups. LIMITATIONS, REASONS FOR CAUTION: The participants were Caucasian, Dutch-speaking couples, with medium to high socio-economic status, from a single centre. Our data should be replicated by multicultural and multicentre studies. Furthermore, the inclusion of an additional control group of couples who did not opt for PGD but for prenatal diagnosis may point to the most beneficial strategy for the couple. WIDER IMPLICATIONS OF THE FINDINGS: PGD parents invest a similar amount of time and emotion in their future children compared with controls. This implies that successful PGD treatment makes an important psychological contribution towards the well-being of couples given their complex hereditary and family backgrounds. STUDY FUNDING/COMPETING INTERESTS: This research project was funded by grants from the internal research council of the Vrije Universiteit Brussel (OZR), the Flemish Fonds Wetenschappelijk Onderzoek (FWO) and the Wetenschappelijk Fonds Willy Gepts (WGFG). UZ Brussel and the Centre for Medical Genetics have received several educational grants for organizing the data collection, from IBSA, Ferring, Organon, Shering-Plough, Merck and Merck Belgium. M.B. has received consultancy and speaker's fees from Organon, Serono Symposia and Merck.

Re-exposure to the hypobaric hypoxic brain injury of high altitude: plasma S100B levels and the possible effect of acclimatisation on blood-brain barrier dysfunction.

Hypobaric hypoxic brain injury results in elevated peripheral S100B levels which may relate to blood-brain barrier (BBB) dysfunction. A period of acclimatisation or dexamethasone prevents altitude-related illnesses and this may involve attenuation of BBB compromise. We hypothesised that both treatments would diminish the S100B response (a measure of BBB dysfunction) on re-ascent to the hypobaric hypoxia of high altitude, in comparison to an identical ascent completed 48 h earlier by the same group. Twelve healthy volunteers, six of which were prescribed dexamethasone, ascended Mt Fuji (summit 3700 m) and serial plasma S100B levels measured. The S100B values reduced from a baseline 0.183 µg/l (95 % CI 0.083-0.283) to 0.145 µg/l (95 % CI 0.088-0.202) at high altitude for the dexamethasone group (n = 6) and from 0.147 µg/l (95 % CI 0.022-0.272) to 0.133 µg/l (95 % CI 0.085-0.182) for the non-treated group (n = 6) [not statistically significant (p = 0.43 and p = 0.82) for the treated and non-treated groups respectively]. [These results contrasted with the statistically significant increase during the first ascent, S100B increasing from 0.108 µg/l (95 % CI 0.092-0.125) to 0.216 µg/l (95 % CI 0.165-0.267) at high altitude]. In conclusion, an increase in plasma S100B was not observed in the second ascent and this may relate to the effect of acclimatisation (or hypoxic pre-conditioning) on the BBB. An exercise stimulated elevation of plasma S100B levels was also not observed during the second ascent. The small sample size and wide confidence intervals, however, precludes any statistically significant conclusions and a larger study would be required to confirm these findings.

A 3-year follow-up study on cardiovascular disease and mortality in older people with intellectual disabilities.

BACKGROUND: With increasing longevity and a similar or increased prevalence of cardiovascular disease risk factors (as compared to the general population), people with intellectual disabilities (IDs) are at risk of developing cardiovascular disease. However, prospective studies on incidence and influencing factors of cardiovascular disease and mortality are lacking. METHODS: A three year follow-up study was undertaken to study the incidence and symptoms at presentation of myocardial accident, stroke and heart failure in older people with ID. Furthermore, the predictive value of cardiovascular disease risk factors on myocardial accident, stroke and heart failure and on all-cause mortality were studied. The baseline group consisted of the 1050 participants, aged 50 years and over, in the Dutch Healthy Ageing and Intellectual Disability (HA-ID) study. Baseline measurements were conducted between November 2008 and July 2010. Three years after baseline, medical files of 790 participants were studied. RESULTS: Cardiovascular disease (myocardial infarction, stroke and heart failure) occurred in 5.9% of the population during 3 year follow-up, and 32% of them died due to the condition. Incidence of myocardial infarction is 2.8 per 1000 personyears, for stroke 3.2 per 1000 personyears and for heart failure 12.5 per 1000 personyears. Incidence of these conditions is probably underestimated, due to atypical symptom presentation. The use of atypical antipsychotics and a history of heart failure were predictive for myocardial infarction. Heart failure was predicted by abdominal obesity, chronic kidney disease and a history of heart failure. A total of cardiovascular disease (myocardial infarction, stroke or heart failure) was predicted by abdominal obesity, a history of stroke and a history of heart failure. A low body-mass index, peripheral arterial disease, chronic kidney disease and inflammation were predictive for 3-year all-cause mortality. CONCLUSION: Incidence of cardiovascular disease in older people with ID is similar to that in the general population. A pro-active assessment and treatment of the presented cardiovascular disease risk factors may reduce cardiovascular disease and mortality in older people with ID.

On the formation of current ripples.

For grain sizes finer than coarse sand, the first flow-transverse bedforms to develop are current ripples. Although numerous studies have analysed different aspects of bedform morphodynamics, to date no comprehensive physical explanation for the formation of ripples has been given. We offer such an explanation based on a virtual boundary layer concept, and present a model predicting ripple height on the basis of grain size, current velocity and water depth. The model contradicts the conventional view of current ripples as bedforms not scaling with flow depth. Furthermore, it confirms the dependence of ripple dimensions on grain size, and their relative insensitivity to flow strength.

Ebola response missions: to go or not to go? Cross-sectional study on the motivation of European public health experts, December 2014.

We surveyed European infectious disease epidemiologists and microbiologists about their decisions to apply for Ebola response missions. Of 368 respondents, 49 (15%) had applied. Applicants did not differ from non-applicants in terms of age, sex or profession but had more training in field epidemiology and more international experience. Common concerns included lack of support from families and employers. Clearer terms of reference and support from employers could motivate application and support outbreak response in West Africa.