Chronic Low-Calorie Sweetener Use and Risk of Abdominal Obesity among Older Adults: A Cohort Study.
Low-calorie sweetener use for weight control has come under increasing scrutiny as obesity, especially abdominal obesity, remain entrenched despite substantial low-calorie sweetener use. We evaluated whether chronic low-calorie sweetener use is a risk factor for abdominal obesity. We used 8268 anthropometric measurements and 3096 food diary records with detailed information on low-calorie sweetener consumption in all food products, from 1454 participants (741 men, 713 women) in the Baltimore Longitudinal Study of Aging collected from 1984 to 2012 with median follow-up of 10 years (range: 0-28 years). At baseline, 785 were low-calorie sweetener non-users (51.7% men) and 669 participants were low-calorie sweetener users (50.1% men). Time-varying low-calorie sweetener use was operationalized as the proportion of visits since baseline at which low-calorie sweetener use was reported. We used marginal structural models to determine the association between baseline and time-varying low-calorie sweetener use with longitudinal outcomes-body mass index, waist circumference, obesity and abdominal obesity-with outcome status assessed at the visit following low-calorie sweetener ascertainment to minimize the potential for reverse causality. All models were adjusted for year of visit, age, sex, age by sex interaction, race, current smoking status, dietary intake (caffeine, fructose, protein, carbohydrate, and fat), physical activity, diabetes status, and Dietary Approaches to Stop Hypertension score as confounders. With median follow-up of 10 years, low-calorie sweetener users had 0.80 kg/m2 higher body mass index (95% confidence interval [CI], 0.17-1.44), 2.6 cm larger waist circumference (95% CI, 0.71-4.39), 36.7% higher prevalence (prevalence ratio = 1.37; 95% CI, 1.10-1.69) and 53% higher incidence (hazard ratio = 1.53; 95% CI 1.10-2.12) of abdominal obesity than low-calorie sweetener non-users. Low-calorie sweetener use is independently associated with heavier relative weight, a larger waist, and a higher prevalence and incidence of abdominal obesity suggesting that low-calorie sweetener use may not be an effective means of weight control.


Human prostatic tissue constituents respond differently to thermal injury induced by Nd-YAG laser ITT fiber applied ex-situ.
The human prostate is a glandular organ that has intervening fibromuscular elements. The objective of this study was to evaluate the thermocoagulative effect on the different components of the organ exposed to Nd-YAG laser irradiation using a new ITT optic fiber design (Interstitial Thermal Therapy). Twelve fresh transvesical prostatectomy specimens were irradiated ex-situ at 4 to 6 sites using an ITT fiber with laser energies ranging from 900 to 4500 joules (J) applied at times ranging from 60 to 300 seconds corresponding to 10 to 15 watts. The specimens were serially sectioned to include the proximal, mid and distal regions of the centrally coagulated channel. An ocular grid was utilized to measure the radius (r) of thermal injury from the margin of the centrally coagulated channel to the furthermost detectable area of thermally induced changes. The maximal extent of thermal injury was seen at the mid-length of the irradiated channel at energy of 2700 J (15w/180 sec). The fibromuscular compartment of the prostate was more affected (r = 855 microm) and showed more interstitial vacuolization and charring than the adenomatous one (r = 495 microm). Utilization of higher energy doses did not significantly alter the depth of injury but did reduce the extent of interstitial vacuolization of both components. The study indicates that the extent of laser induced coagulative necrosis depends on the histologic architecture of the prostate and also varies in extent along the length of the channel surrounding the fiber.


Altered interoceptive processing in smokers: Evidence from the heartbeat tracking task.
Neuroimaging evidence suggests that interoceptive processing might be altered in nicotine addiction, however this has not yet been confirmed with behavioural measures. Therefore, we investigated the perception of internal bodily states in smokers (n = 49) and people who had never smoked (n = 51), by measuring interoceptive accuracy (IAcc) and interoceptive sensibility (IS). IAcc was measured with a heartbeat tracking task and a heartbeat discrimination task. Performance on the heartbeat tracking task may be influenced by one's ability to estimate an elapsed time interval so this was controlled by also administering a time-estimation (TE) task. IS was measured using two sub-scales from the Multidimensional Assessment of Interoceptive Awareness (MAIA). All smokers completed the Revised Fagerström Test for Nicotine Dependence (FTND-R) to measure addiction severity. Non-smokers performed significantly better than smokers on the heartbeat tracking task. There were no significant group differences observed for the remaining variables. Furthermore, none of the variables predicted addiction severity. This is the first demonstration of behavioural differences in interoception between smokers and non-smokers.


Characterization of a set of novel meiotically-active promoters in Arabidopsis.
Homologous recombination, together with selection, laid the foundation for traditional plant breeding. The recombination process that takes place during meiotic cell division is crucial for the creation of novel variations of highly desired traits by breeders. Gaining control over this process is important for molecular breeding to achieve more precise, large-scale and quicker plant improvement. As conventional ubiquitous promoters are neither tissue-specific nor efficient in driving gene expression in meiocytes, promoters with high meiotic activities are potential candidates for manipulating the recombination process. So far, only a few meiotically-active promoters have been reported. Recently developed techniques to profile the transcriptome landscape of isolated meiocytes provided the means to discover promoters from genes that are actively expressed in meiosis. In a screen for meiotically-active promoters, we examined ten promoter sequences that are associated with novel meiotic candidate genes. Each promoter was tested by expressing a GFP reporter gene in Arabidopsis. Characterization of regulatory regions revealed that these meiotically-active promoters possessed conserved motifs and motif arrangement. Some of the promoters unite optimal properties which are invaluable for meiosis-directed studies such as delivering specific gene expression in early meiosis I and/or meiosis II. Furthermore, the examination of homologs of the corresponding genes within green plants points to a great potential of applying the information from Arabidopsis to other species, especially crop plants. We identified ten novel meiotically-active promoters; which, along with their homologs, are prime candidates to specifically drive gene expression during meiosis in plants and can thus provide important tools for meiosis study and crop breeding.


HIV Infection, Antiretroviral Therapy and Cardiovascular Risk.
In the last 15 years, highly active antiretroviral therapy (HAART) has determined a dramatic reduction of both morbidity and mortality in human immunodeficiency virus (HIV)-infected subjects, transforming this infection in a chronic and manageable disease. Patients surviving with HIV in the developed world, in larger number men, are becoming aged. As it would be expected for a population of comparable age, many HIV-infected individuals report a family history of cardiovascular disease, a small proportion have already experienced a cardiovascular event and an increasing proportion has diabetes mellitus. Smoking rate is very high while an increasing proportion of HIV-infected individuals have dyslipidaemia. Studies suggest that these traditional risk factors could play an important role in the development of cardiovascular disease in these patients as they do in the general population. Thus, whilst the predicted 10-year cardiovascular disease risk remains relatively low at present, it will likely increase in relation to the progressive aging of this patient population. Thus, the long-term follow-up of HIV infected patients has to include co-morbidity management such as cardiovascular disease prevention and treatment. Two intriguing aspects related to the cardiovascular risk in patients with HIV infection are the matter of current investigation: 1) while these subjects share many cardiovascular risk factors with the general population, HIV infection itself increases cardiovascular risk; 2) some HAART regimens too influence atherosclerotic profile, partly due to lipid changes. Although the mechanisms involved in the development of cardiovascular complications in HIV-infected patients remain to be fully elucidated, treatment guidelines recommending interventions to prevent cardiovascular disease in these individuals are already available; however, their application is still limited.


Patterning of the R7 and R8 photoreceptor cells of Drosophila: evidence for induced and default cell-fate specification.
Opsin gene expression in the R7 and R8 photoreceptor cells of the Drosophila compound eye is highly coordinated. We have found that the R8 cell specific Rh5 and Rh6 opsins are expressed in non-overlapping sets of R8 cells, in a precise pairwise fashion with Rh3 and Rh4 in the R7 cells of individual ommatidia. Removal of the R7 cells in sevenless, boss or sina mutants, disrupts Rh5 expression and dramatically increases the number of Rh6-expressing R8 cells. This suggests that the expression of Rh5 may be induced by an Rh3-expressing R7 cell, whereas Rh6 expression is most likely a default state of the R8 cell. We found that the paired expression of opsin genes in the R7 and R8 cells occurs in a sevenless and boss independent manner. Furthermore, we found that the generation of both Rh3- and Rh4-expressing R7 cells can occur in the absence of an R8 cell. These results suggest that the specification of opsin expression in the R7 cells may occur autonomously, whereas the R7 photoreceptor cell may be responsible for regulating a binary developmental switch between induced and default cell-fates in the R8 cell.


A large-insert (130 kbp) bacterial artificial chromosome library of the rice blast fungus Magnaporthe grisea: genome analysis, contig assembly, and gene cloning.
Magnaporthe grisea (Hebert) Barr causes rice blast, one of the most devastating diseases of rice (Oryza sativa) worldwide. This fungus is an ideal organism for studying a number of aspects of plant-pathogen interactions, including infection-related morphogenesis, avirulence, and pathogen evolution. To facilitate M. grisea genome analysis, physical mapping, and positional cloning, we have constructed a bacterial artificial chromosome (BAC) library from the rice infecting strain 70-15. A new method was developed for separation of partially digested large-molecular-weight DNA fragments that facilitated library construction with large inserts. The library contains 9216 clones, with an average insert size of 130 kbp (> 25 genome equivalents) stored in 384-well microtiter plates that can be double spotted robotically on to a single nylon membrane. Several unlinked single-copy DNA probes were used to screen 4608 clones in the library and an average of 13 (minimum of 6) overlapping BAC clones was found in each case. Hybridization of total genomic DNA to the library and analysis of individual clones indicated that approximately 26% of the clones contain single-copy DNA. Approximately 35% of BAC clones contained the retrotransposon MAGGY. The library was used to identify BAC clones containing a adenylate cyclase gene (mac1). In addition, a 550-kbp contig composed of 6 BAC clones was constructed that encompassed two adjacent RFLP markers on chromosome 2. These data show that the BAC library is suitable for genome analysis of M. grisea. Copies of colony hybridization membranes are available upon request.


The prevalence and volumetry of pituitary cysts in children with growth hormone deficiency and idiopathic short stature.
Background Pituitary cysts have been speculated to cause endocrinopathies. We sought to describe the prevalence and volumetry of pituitary cysts in patients with growth hormone deficiency (GHD) and idiopathic short stature (ISS). Methods Six hundred and eighteen children evaluated for growth failure at the Division of Pediatric Endocrinology at New York Medical College between the years 2002 and 2012, who underwent GH stimulation testing and had a brain magnetic resonance imaging (MRI) prior to initiating GH treatment were randomly selected to be a part of this study. High resolution MRI was used to evaluate the pituitary gland for size and the presence of a cyst. Cyst prevalence, cyst volume and percentage of the gland occupied by the cyst (POGO) were documented. Results Fifty-six patients had a cyst, giving an overall prevalence of 9.1%. The prevalence of cysts in GHD patients compared to ISS patients was not significant (13.5% vs. 5.7%, p=0.46). Mean cyst volume was greater in GHD patients than ISS patients (62.0 mm3 vs. 29.4 mm3, p=0.01). POGO for GHD patients was significantly greater (p=0.003) than for ISS patients (15.3%±12.8 vs. 7.1%±8.0). Observers were blinded to patient groups. Conclusions GHD patients had a significantly greater volume and POGO compared to ISS patients. This raises the question of whether cysts are implicated in the pathology of growth failure.


A Colombian survey found intensive care mortality ratios were better in private vs. public hospitals.
Our main outcome was to identify organizational characteristics that help to evaluate the differences between the intensive care mortality ratios adjusted by APACHE II. We incorporated the variation associated with the ranking of institutions simulating its random effects under a binomial distribution. A nationwide survey on structure, technology, and staffing resources available in Colombian intensive care units during 1997-1998 was conducted. We collected data on admissions from 20 randomly selected adult medical and surgical intensive care units. The mortality ratio from the 20 intensive care units ranged from 0.59 to 2.36; 80% of the intensive care units had a mortality ratio greater than 1. All four intensive care units with the lowest mortality ratio belonged to private institutions, while four of five institutions with the highest mortality belonged to the public sector. Intensive care units in private institutions also had fewer number of beds, lower median length of stay, lower occupancy rates, higher education training for specialists and nurses and fewer emergency nonelective surgical procedures. We successfully accounted for intensive care mortality baseline differences and random effects variations. There were substantial differences between intensive care units in institution type, bed availability, technology, staffing resources, and degree of training, which may have been associated with patient outcome. These results are of crucial importance to track, detect and assess future changes.


Association of chest radiographic abnormalities with tuberculosis disease in asymptomatic HIV-infected adults.
Francistown and Gaborone, Botswana. Chest radiography is used to screen for tuberculosis (TB) in asymptomatic persons living with the human immunodeficiency virus (PLWH) seeking isoniazid preventive therapy (IPT). We describe radiographic features in PLWH in a TB-endemic setting and identify features associated with TB disease. Asymptomatic PLWH seeking IPT under program conditions for a clinical trial between 2004 and 2006 received chest radiographs (CXRs) that were read using the standardized Chest Radiograph Reading and Recording System (CRRS). Clinical characteristics, including TB disease, were compared with the radiographic findings. From 2732 screening CXRs, 183 had one or more abnormalities and were scored using CRRS, with 42% having infiltrates (36% upper lobes), 35% parenchymal fibrosis and 32% adenopathy. TB disease status was determined in 129 (70%) PLWH, of whom 22 (17%) had TB disease. TB disease was associated with upper lobe infiltrates (relative risk [RR] 3.0, 95%CI 1.5-6.2) and mediastinal adenopathy (RR 3.9, 95%CI 1.8-8.4). The sensitivity and specificity of either upper lobe infiltrates or mediastinal lymphadenopathy for TB disease were respectively 64% and 82%. A combination of CXR features was useful for predicting TB disease in asymptomatic PLWH. CRRS should be used more frequently in similar studies.


Adiposity and cardiovascular outcomes in three-year-old children of participants in UPBEAT, an RCT of a complex intervention in pregnant women with obesity.
Maternal obesity is associated with offspring cardiometabolic risk. UPBEAT was a randomised controlled trial of an antenatal diet and physical activity intervention in 1555 women with obesity. The intervention was associated with lower gestational weight gain, healthier diet and metabolic profile in pregnancy, and reduced infant adiposity at six months. We have investigated whether the UPBEAT intervention influenced childhood cardiometabolic outcomes or was associated with sustained improvements in maternal lifestyle 3-years after delivery. In UPBEAT mother-child dyads at the 3-year follow-up, we assessed childhood blood pressure, resting pulse rate, and adiposity (body mass index, skinfold thicknesses, body fat, waist and arm circumferences) and maternal diet, physical activity, and anthropometry. 514 three-year-old children attended the appointment (49% intervention, 51% standard care). There was no difference in the main outcome of interest, subscapular skinfold thickness, between the trial arms (-0.30 mm, 95% confidence interval: -0.92, 0.31). However, the intervention was associated with a lower resting pulse rate (-5 bpm [-8.41, -1.07]). There was also a non-significant lower odds of overweight/obesity (OR 0.73; 0.50, 1.08). Maternal dietary improvements observed in the UPBEAT trial, including glycaemic load and saturated fat were maintained 3-years postpartum. This study has demonstrated that an antenatal dietary and physical activity intervention in women with obesity is associated with lower offspring pulse rate and sustained improvement in maternal diet. Whilst larger than previous cohorts, there remains potential for bias from attrition and these findings require validation in future cohorts.


Air lead, blood lead and travel by car.
Evidence on the relevance of lead in petrol to lead in blood has come from two main sources. Cross sectional studies of blood lead levels in population samples and in the air to which they are exposed suggest that petrol makes only a very small contribution. However longitudinal studies in the USA in which changes in lead levels in petrol and changes in blood lead have been studied suggest that petrol makes a substantial contribution to blood lead. The possibility that this discrepancy might be explained by the exposure of subjects to very high levels of lead when travelling in motor vehicles is examined, and rejected.


Sicca Symptoms and their Association with Chronic Rhinosinusitis in a Community Sample.
To determine associations between sicca symptoms, chronic rhinosinusitis (CRS) symptoms and asthma in a community survey. Data was obtained from the Spring 2009 South Australian Health Omnibus Survey which sampled, via interviewer administered questionnaire, 3007 individuals aged 15 years and over whose socio-demographic distribution corresponded to South Australian population estimates. Respondents were asked a range of questions relating to the presence of persistent dry eyes or dry mouth, CRS and medically diagnosed nasal polyps and asthma. Relationships between symptoms were explored using maximum likelihood dependency tree analysis. THE RESPECTIVE POPULATION PREVALENCES WERE: dry mouth (5.9%), dry eyes (8.6%), nasal polyps (3.8%), CRS (13.2%) and asthma (12.0%). The overall prevalence of sicca symptoms (dry eyes or dry mouth) was 12.4%. Dependency tree analysis revealed the expected symptom clustering between (1) sicca symptoms and their association with female gender and increasing age and (2) CRS, nasal polyps and asthma (one airway hypothesis). However there was also an association between dry eyes and CRS (OR 2.5, 95% CI 1.9, 3.4), which was in fact stronger than the association between CRS and asthma (OR 1.9, 95% CI 1.4, 2.5). Sicca symptoms are common in the community. Our novel finding of a strong association between dry eyes and CRS suggests that further research into the relationship between airway inflammation and sicca symptoms is required. These findings may have particular relevance to Sjögren's syndrome (SS) in both its primary and secondary forms.


Advances in surgery.
In the last decade, technological advances, new staging tools, better understanding the role of surgery within multimodal treatment concepts in advanced stages and progress in the functional assessment of surgical candidates improved the quality of surgery in the management of patients with lung cancer. Lung resection with video-assisted thoracoscopic access gained wide acceptance, the indication for lobectomy or sublobar resection in early stages was applied based on new data and selection for multimodal treatment in stage III is better understood based on the data. a major impact on the outcome of patients with lung cancer has the treatment in specialized high-volume centers.


Augmented reality assisted surgery: a urologic training tool.
Augmented reality is widely used in aeronautics and is a developing concept within surgery. In this pilot study, we developed an application for use on Google Glass ® optical head-mounted display to train urology residents in how to place an inflatable penile prosthesis. We use the phrase Augmented Reality Assisted Surgery to describe this novel application of augmented reality in the setting of surgery. The application demonstrates the steps of the surgical procedure of inflatable penile prosthesis placement. It also contains software that allows for detection of interest points using a camera feed from the optical head-mounted display to enable faculty to interact with residents during placement of the penile prosthesis. Urology trainees and faculty who volunteered to take part in the study were given time to experience the technology in the operative or perioperative setting and asked to complete a feedback survey. From 30 total participants using a 10-point scale, educational usefulness was rated 8.6, ease of navigation was rated 7.6, likelihood to use was rated 7.4, and distraction in operating room was rated 4.9. When stratified between trainees and faculty, trainees found the technology more educationally useful, and less distracting. Overall, 81% of the participants want this technology in their residency program, and 93% see this technology in the operating room in the future. Further development of this technology is warranted before full release, and further studies are necessary to better characterize the effectiveness of Augmented Reality Assisted Surgery in urologic surgical training.


Effect of Ambrotose AO® on resting and exercise-induced antioxidant capacity and oxidative stress in healthy adults.
The purpose of this investigation was to determine the effects of a dietary supplement (Ambrotose AO®) on resting and exercise-induced blood antioxidant capacity and oxidative stress in exercise-trained and untrained men and women. 25 individuals (7 trained and 5 untrained men; 7 trained and 6 untrained women) received Ambrotose AO® (4 capsules per day = 2 grams per day) or a placebo for 3 weeks in a random order, double blind cross-over design (with a 3 week washout period). Blood samples were collected at rest, and at 0 and 30 minutes following a graded exercise treadmill test (GXT) performed to exhaustion, both before and after each 3 week supplementation period. Samples were analyzed for Trolox Equivalent Antioxidant Capacity (TEAC), Oxygen Radical Absorbance Capacity (ORAC), malondialdehyde (MDA), hydrogen peroxide (H2O2), and nitrate/nitrite (NOx). Quality of life was assessed using the SF-12 form and exercise time to exhaustion was recorded. Resting blood samples were analyzed for complete blood count (CBC), metabolic panel, and lipid panel before and after each 3 week supplementation period. Dietary intake during the week before each exercise test was recorded. No condition effects were noted for SF-12 data, for GXT time to exhaustion, or for any variable within the CBC, metabolic panel, or lipid panel (p > 0.05). Treatment with Ambrotose AO® resulted in an increase in resting levels of TEAC (p = 0.02) and ORAC (p < 0.0001). No significant change was noted in resting levels of MDA, H2O2, or NOx (p > 0.05). Exercise resulted in an acute increase in TEAC, MDA, and H2O2 (p < 0.05), all which were higher at 0 minutes post exercise compared to pre exercise (p < 0.05). No condition effects were noted for exercise related data (p > 0.05), with the exception of ORAC (p = 0.0005) which was greater at 30 minutes post exercise for Ambrotose AO® compared to placebo. Ambrotose AO® at a daily dosage of 4 capsules per day increases resting blood antioxidant capacity and may enhance post exercise antioxidant capacity. However, no statistically detected difference is observed in resting or exercise-induced oxidative stress biomarkers, in quality of life, or in GXT time to exhaustion.


Relationship of periodontitis and edentulism to angiographically diagnosed coronary artery disease: A cross-sectional study.
The objective of the study is to examine the connection between oral status and the extent of coronary artery disease (CAD), which is diagnosed by angiography. Periodontitis and tooth loss have been linked to atherosclerosis and CAD in previous studies. However, no distinct connection was revealed due to the diversity of the results and the variety of diagnostic methods. To provide a more consistent data pool and stronger evidence, there is a need for studies with standard measurements and diagnostic criteria. 309 patients, who consulted to Ankara University, Faculty of Medicine, Department of Cardiology and had coronary angiography, were enrolled to this study. Individuals were grouped based on their coronary angiography results, as CAD (+) (n = 233) and CAD (-) (n = 76). Studied parameters included cardiovascular risk factors, plaque index (PI), remaining teeth count, bleeding on probing (BOP), and probing pocket depth (PPD). Periapical radiographs were taken from teeth with ≥4 mm PPD. Oral status was categorized as periodontally healthy subjects/patients with gingivitis (Group 1), patients with periodontitis (Group 2), and edentulous subjects (Group 3). PI (P < 0.001), PPD (P = 0.001), BOP (P = 0.004), the number of patients with less than 10 teeth (P = 0.014), and edentulism (P = 0.009) were significantly higher in CAD (+) patients, who were mostly older (P < 0.001) and male (P < 0.001). Multivariate logistic regression analysis revealed that Group 2 (odds ratio = 2.48, 95% confidence interval = 1.24-4.95, P = 0.010) and Group 3 (odds ratio = 2.01, 95% confidence interval = 1.14-5.17, P = 0.040) were highly associated with CAD. Two and three stenosed vessels were significantly higher in Groups 2 and 3 compared to Group 1 (P = 0.003). It was found that both edentulism and periodontitis were related to CAD.


Biochemical magnetic resonance imaging of knee articular cartilage: T1rho and T2 mapping as cartilage degeneration biomarkers.
Osteoarthritis (OA) is a disease whose hallmark is the degeneration of articular cartilage. There is a worsening epidemic of OA in the United States today, with considerable economic costs. In order to develop more effective treatments for OA, noninvasive biomarkers that permit early diagnosis and treatment monitoring are necessary. T1rho and T2 mapping are two magnetic resonance imaging techniques that have shown great promise as noninvasive biomarkers of cartilage degeneration. Each of the two techniques is endowed with advantages and disadvantages: T1rho can discern earlier biochemical changes of OA than T2 mapping, while T2 mapping is more widely available and can be incorporated into existing imaging protocols in a more time-efficient manner than T1rho. Both techniques have been applied in numerous instances to study how cartilage is affected by OA risk factors, such as age and exercise. Additionally, both techniques have been repeatedly applied to the study of posttraumatic OA in patients with torn anterior cruciate ligaments.


Perceptions of a Home Hospice Crisis: An Exploratory Study of Family Caregivers.
Background: Crises that occur in home hospice care affect family caregivers' satisfaction with care and increase risk of disenrollment. Because hospice care focuses on achieving a peaceful death, understanding the prevalence and nature of crises that occur in this setting could help to improve end-of-life outcomes. Objective: To ascertain the prevalence and nature of, as well as factors associated with crises in the home hospice setting as reported by family caregivers. Design: A multiple-method approach was used. Content analysis was employed to evaluate semistructured interview responses collected from caregivers. Potential associations between crisis occurrence and caregiver and patient factors were examined. Setting/Subjects: Family caregivers whose care recipients were discharged (dead or alive) from a nonprofit hospice organization. Measurements: Participants were asked to identify any crisis-defined as a time of intense distress due to a physical, psychological, and/or spiritual cause-they or the patient experienced, while receiving home hospice care. Results: Of the 183 participants, 76 (42%) experienced a perceived crisis, while receiving hospice care. Three types of crises emerged: patient signs and symptoms (n = 51, 67%), patient and/or caregiver emotional distress (n = 22, 29%), and caregiver burden (n = 10, 13%). Women were more likely than men (46% vs. 26%, p = 0.03) to report a crisis. Conclusions: A large minority of caregivers report perceiving a crisis while their loved one was receiving home hospice care. Physical (symptoms), psychological (emotional distress) function, and caregiver burden constituted the crises reported. Further studies are needed to better understand and address these gaps in care.


Microtechnology applied to stem cells research and development.
Microfabrication and microfluidics contribute to the research of cellular functions of cells and their interaction with their environment. Previously, it has been shown that microfluidics can contribute to the isolation, selection, characterization and migration of cells. This review aims to provide stem cell researchers with a toolkit of microtechnology (mT) instruments for elucidating complex stem cells functions which are challenging to decipher with traditional assays and animal models. These microdevices are able to investigate about the differentiation and niche interaction, stem cells transcriptomics, therapeutic functions and the capture of their secreted microvesicles. In conclusion, microtechnology will allow a more realistic assessment of stem cells properties, driving and accelerating the translation of regenerative medicine approaches to the clinic.


Development of a group A meningococcal conjugate vaccine, MenAfriVac(TM).
Group A meningococcal disease has been an important public health problem in sub-Saharan Africa for over a century. Outbreaks occur there annually, and large epidemics occur at intervals ranging between 8 and 12 y. The Meningitis Vaccine Project was established in 2001 with funding from the Gates Foundation with the goal of developing, testing, licensing, and introducing an affordable group A meningococcal conjugate vaccine into Africa. From 2003 to 2009 a monovalent group A conjugate vaccine, MenAfriVac(TM) , was developed at the Serum Institute of India, Ltd through an innovative public/private partnership. Preclinical studies of the new conjugate vaccine were completed in 2004 and a Phase 1 study began in India in 2005. Phase 2/3 studies in African 1-29 y olds were completed in 2009 showing the new meningococcal A conjugate vaccine to be as safe as currently licensed meningococcal polysaccharide vaccines, but much more immunogenic. After Indian market authorization (December 2009) and WHO prequalification (June 2010), MenAfriVac(TM) was introduced at public health scale using a single 10 µg dose in individuals 1-29 y of age in Burkina Faso, Mali, and Niger in December 2010. We summarize the laboratory and clinical studies leading to prequalification of MenAfriVac(TM). The 2011 epidemic season ended with no reported case of group A meningitis in vaccinated individuals.


Identification of a novel cell type in peripheral lymphoid organs of mice. IV. Identification and distribution in mouse spleen.
White pulp nodules of mouse spleen contain a minor population of cells with morphologic features that are identical to those of dendritic cells, a cell type recently described in vitro. They have characteristic large, irregularly shaped nuclei with distinctive chromatin patterns and small nucleoli. The cytoplasm is extended in processes that contain relatively few organelles. These presumptive dendritic cells can be distinguished from other cell types that are known to exist in spleen including those that have irregular or branching cell shapes. In particular, dendritic cells do not contain the large number of lysosomes seen in phagocytes, and do not actively interiorize intravenously administered colloidal thorium dioxide particles. They also lack the well developed secretory apparatus (rough endoplasmic reticulum and Golgi zone) and microfilament bundles that are noted in connective tissue cells. These morphologic observations, combined with previous in vitro work, substantiate the existence of a novel class of cells in mouse lymphoid organs.


Progress toward a general species concept.
New insights in the speciation process and the nature of "species" that accumulated in the past decade demand adjustments of the species concept. The standing of some of the most broadly accepted or most innovative species concepts in the light of the growing evidence that reproductive barriers are semipermeable to gene flow, that species can differentiate despite ongoing interbreeding, that a single species can originate polyphyletically by parallel evolution, and that uniparental organisms are organised in units that resemble species of biparental organisms is discussed. As a synthesis of ideas in existing concepts and the new insights, a generalization of the genic concept is proposed that defines species as groups of individuals that are reciprocally characterized by features that would have negative fitness effects in other groups and that cannot be regularly exchanged between groups upon contact. The benefits of this differential fitness species concept are that it classifies groups that keep differentiated and keep on differentiating despite interbreeding as species, that it is not restricted to specific mutations or mechanisms causing speciation, and that it can be applied to the whole spectrum of organisms from uni- to biparentals.


Biphasic regulation of polymorphonuclear leukocyte spreading by polyphenolic compounds with pyrogallol moieties.
Green tea polyphenols have been reported to have anti-inflammatory activities, although the molecular mechanisms responsible for this effect remain unclear. In the present study, we examined the effect of green tea extract and a variety of polyphenolic compounds on spreading of peripheral blood polymorphonuclear leukocytes (PMNs) over fibrinogen-coated surfaces. Green tea extract exerted a biphasic effect on PMN spreading; it induced or suppressed spreading at low and high concentrations, respectively. We also found that pyrogallol-bearing compounds have spreading induction activity. Among the compounds tested, tannic acid (TA) had the strongest activity; the concentrations required for induction of maximal spreading were 2 microM for TA, 200 microM for (-)-epigallocatechin gallate, and 2000 microM for the other active compounds. Furthermore, TA was the only compound showing a biphasic effect similar to that of green tea extract; TA at 20 or 200 microM suppressed spreading. The spreading-stimulatory signal was still latent during PMN exposure to TA at concentrations that inhibited spreading, because the pre-exposed PMNs underwent spreading when plated after removal of free TA by centrifugation. The spreading-inhibitory effect of TA at high concentrations overcame the induction of spreading by other stimuli, including phorbol 12-myristate 13-acetate, hydrogen peroxide, denatured fibrinogen surfaces, and naked plastic surfaces. These results suggest that TA as well as green tea extract is bi-functional, having pro-inflammatory and anti-inflammatory effects at low and high concentrations, respectively. Pharmacological use of TA may thus provide new strategies aimed at regulation of PMN spreading for control of inflammation.


Fiber-free white flour with fructose offers a better model of metabolic syndrome.
The metabolic syndrome (MS) is a combination of metabolic abnormalities that lead to an increased risk of cardiovascular diseases. Due to its rising incidence and demanding life-long use of multiple drugs, there is a growing interest in testing and developing new allopathic, complementary and alternative therapies for controlling or curing disorders of MS. The discovery of new therapeutic modalities requires animal models of disease and currently available models have limitations. Developing an appropriate animal model for MS to achieve various therapeutic targets remains a challenge and this study aims to develop a rat model which closely depicts MS in humans. Rat model of MS was developed by replacing 60% of diet with fructose. Four groups of Sprague-Dawley rats were either given whole wheat or refined flour with and without fructose for 8 weeks. Data were analyzed on SPSS and Graphpad Prism using ANOVA with Tukey's and Bonferonni tests for multiple group comparison. A p-value of less than 0.05 was considered significant for differences between groups. Replacing whole wheat with refined wheat flour in rat chow in 60% fructose-fed Sprague-Dawley rats resulted in hypertension (p 0.01), hyper-insulinemia (p < 0.001), hyperglycemia (p 0.03) and a reduction in HDL levels (p 0.002) at 4 weeks while hyper-triglyceridemia (p 0.001) with endothelial dysfunction was observed at 8 weeks. It is concluded that the refined wheat flour with 60% fructose in diet hastens the development of metabolic syndrome in 4 weeks and replacing whole wheat flour with refined flour in diet induces a more effective abnormality including a low HDL. Further studies may be directed to assess the associated pathological changes, which can be used to study the effect of different therapeutic modalities on an animal model of MS with low HDL.


Power and sample size calculations for stochastic cost-effectiveness analysis.
As the data for economic analyses are increasingly collected prospectively alongside clinical trials, many commentators have highlighted that the sample sizes in such trials should be based on the requirements for the economic analysis as well as those for the clinical evaluation. However, issues associated with sample size calculations for economic analysis have yet to receive the rigorous attention given to sample size calculation for clinical evaluation. In particular, no sample size formula for cost-effectiveness analysis is available for analysts hoping either to calculate the required sample size at the design stage of a study or to calculate the power a given size of clinical trial will generate for cost-effectiveness analysis. Building on the recent literature for calculating confidence intervals for cost-effectiveness ratios, the authors explore possible techniques for deriving a sample size formula for cost-effectiveness analysis based on simple combination of the confidence limits on costs and effects.


Multiplex PCR assay to aid in the identification of the highly transmissible Mycobacterium tuberculosis strain CDC1551.
Mycobacterium tuberculosis strain CDC1551 outbreak area in Tennessee and Kentucky and selected locations in the USA. Develop a PCR assay to distinguish the highly transmissible CDC1551 from strains which have similar 4-band IS6110 fingerprints. Compare the IS6110 insertion sites in CDC1551 with those in 10 isolates which have similar 4-band IS6110 fingerprints. Utilize unique characteristics of insertion sites in CDC1551 to design a multiplex PCR to identify this strain. A multiplex PCR was developed which targets an IS6110 insertion conserved in most IS6110 low copy number strains and a deletion within the direct repeat region adjacent to an IS6110 insertion. Of 139 isolates with similar 4-band fingerprints, the CDC1551 PCR pattern was generated by only the 14 outbreak associated isolates. Of 154 isolates with different fingerprints, only four generated the CDC1551 pattern and these could be distinguished from CDC1551 by their IS6110 fingerprint. The multiplex PCR used in conjunction with the IS6110 fingerprint should be a useful tool to aid in the continued surveillance of the outbreak area and follow the spread of this highly transmissible strain of M. tuberculosis.


Autofluorescence flow sorting of breast cancer cell metabolism.
Clinical cancer treatment aims to target all cell subpopulations within a tumor. Autofluorescence microscopy of the metabolic cofactors NAD(P)H and FAD has shown sensitivity to anti-cancer treatment response. Alternatively, flow cytometry is attractive for high throughput analysis and flow sorting. This study measures cellular autofluorescence in three flow cytometry channels and applies cellular autofluorescence to sort a heterogeneous mixture of breast cancer cells into subpopulations enriched for each phenotype. Sorted cells were grown in culture and sorting was validated by morphology, autofluorescence microscopy, and receptor expression. Ultimately, this method could be applied to improve drug development and personalized treatment planning.


Impact of the 2017 American Academy of Pediatrics Guideline on Hypertension Prevalence Compared With the Fourth Report in an International Cohort.
In 2017, the American Academy of Pediatrics (AAP) updated the clinical practice guideline for high blood pressure (BP) in the pediatric population. In this study, we compared the difference in prevalence of elevated and hypertensive BP values defined by the 2017 AAP guideline and the 2004 Fourth Report and estimated the cardiovascular risk associated with the reclassification of BP status defined by the AAP guideline. A total of 47 200 children and adolescents aged 6 to 17 years from 6 countries (China, India, Iran, Korea, Poland, and Tunisia) were included in this study. Elevated BP and hypertension were defined according to 2 guidelines. In addition, 1606 children from China, Iran, and Korea who were reclassified upward by the AAP guideline compared with the Fourth Report and for whom laboratory data were available were 1:1 matched with children from the same countries who were normotensive by both guidelines. Compared with the Fourth Report, the prevalence of elevated BP defined by the AAP guideline was lower (14.9% versus 8.6%), whereas the prevalence of stages 1 and 2 hypertension was higher (stage 1, 6.6% versus 14.5%; stage 2, 0.4% versus 1.7%). Additionally, comparison of laboratory data in the case-control study showed that children who were reclassified upward were more likely to have adverse lipid profiles and high fasting blood glucose compared with normotensive children. In conclusion, the prevalence of elevated BP and hypertension varied significantly between both guidelines. Applying the new AAP guideline could identify more children with hypertension who are at increased cardiovascular risk.


Circadian rhythms in crassulacean acid metabolism: phase relationships between gas exchange, leaf water relations and malate metabolism in Kalanchoë daigremontiana.
Gas exchange, leaf water relations, malate content and phosphoenolpyruvate (PEP) carboxylase activity in crude extracts were examined for circadian rhythmicity in the crassulacean acid metabolism plant Kalanchoë daigremontiana. At low irradiance (20 W m(-2)) the rhythm in CO2 uptake continued for several days with a period length of approx. 22 h, whereas the transpiration rhythm was no longer apparent after 24 h. This shows that the CO2 rhythm in continuous light (LL) is not under stomatal control. Circadian oscillations in malate content were detectable for up to 72 h in LL but were of much reduced amplitude. This was reflected in the changes in leaf water relations, which quickly damped after transfer to LL. The activity of PEP carboxylase assayed immediately after extraction showed a rhythmicity for at least 18 h, but after 36 h, values from different plants were scattered. We suggest that the CO2-uptake rhythm is primarily the result of endogenous changes in the activity of PEP carboxylase, which competes to varying degrees with ribulose-1,5-bisphosphate carboxylase for CO2.


Convergence and divergence of bitterness biosynthesis and regulation in Cucurbitaceae.
Differentiation of secondary metabolite profiles in closely related plant species provides clues for unravelling biosynthetic pathways and regulatory circuits, an area that is still underinvestigated. Cucurbitacins, a group of bitter and highly oxygenated tetracyclic triterpenes, are mainly produced by the plant family Cucurbitaceae. These compounds have similar structures, but differ in their antitumour activities and ecophysiological roles. By comparative analyses of the genomes of cucumber, melon and watermelon, we uncovered conserved syntenic loci encoding metabolic genes for distinct cucurbitacins. Characterization of the cytochrome P450s (CYPs) identified from these loci enabled us to unveil a novel multi-oxidation CYP for the tailoring of the cucurbitacin core skeleton as well as two other CYPs responsible for the key structural variations among cucurbitacins C, B and E. We also discovered a syntenic gene cluster of transcription factors that regulates the tissue-specific biosynthesis of cucurbitacins and may confer the loss of bitterness phenotypes associated with convergent domestication of wild cucurbits. This study illustrates the potential to exploit comparative genomics to identify enzymes and transcription factors that control the biosynthesis of structurally related yet unique natural products.


Gene name errors are widespread in the scientific literature.
The spreadsheet software Microsoft Excel, when used with default settings, is known to convert gene names to dates and floating-point numbers. A programmatic scan of leading genomics journals reveals that approximately one-fifth of papers with supplementary Excel gene lists contain erroneous gene name conversions.


[An analysis of the Ministry of Health of Brazil investments in research and development between 2000-2002: a base line towards future valuations beginning with the implementation of the National Health Research Priority Agenda].
The aim of this paper is to examine the Ministry of Health of Brazil investments in research and development in health (R&D/H) between the years of 2000-2002, trying to contrast them with the items of the National Health Research Priority Agenda, in order to attempt a base line that makes capable future evaluations on the inductor role. The data was collected by a research carried out with the main goal of measure resources invested in R&D/H in the country on the period, considering only the Ministry of Health investments. The researches were independently categorized by 2 researchers based on 24 subdivisions which compose the Agenda. The amount of the resources invested by the Ministry of Health on the period was of R$ 199.3 millions. Most of the expense was related to researches in transmittable diseases (31.5%), followed by systems and policies in health (16.3%) and communication and information in health (8.6%). Conditions that represent a substantial disease burden (non transmittable diseases, mental health, violence, accidents and traumas, elderly person health) received relative small amount of resource. The work establishes a starting point from which managers of scientific and technological policy may assess the progressive influence of the Agenda and the reduction of the identified imbalances.


Brain-derived neurotrophic factor--a major player in stimulation-induced homeostatic metaplasticity of human motor cortex?
Repetitive transcranial magnetic stimulation (rTMS) of the human motor hand area (M1HAND) can induce lasting changes in corticospinal excitability as indexed by a change in amplitude of the motor-evoked potential. The plasticity-inducing effects of rTMS in M1HAND show substantial inter-individual variability which has been partially attributed to the val(66)met polymorphism in the brain-derived neurotrophic factor (BDNF) gene. Here we used theta burst stimulation (TBS) to examine whether the BDNF val(66)met genotype can be used to predict the expression of TBS-induced homeostatic metaplasticity in human M1HAND. TBS is a patterned rTMS protocol with intermittent TBS (iTBS) usually inducing a lasting increase and continuous TBS (cTBS) a lasting decrease in corticospinal excitability. In three separate sessions, healthy val(66)met (n = 12) and val(66)val (n = 17) carriers received neuronavigated cTBS followed by cTBS (n = 27), cTBS followed by iTBS (n = 29), and iTBS followed by iTBS (n = 28). Participants and examiner were blinded to the genotype at the time of examination. As expected, the first TBS intervention induced a decrease (cTBS) and increase (iTBS) in corticospinal excitability, respectively, at the same time priming the after effects caused by the second TBS intervention in a homeostatic fashion. Critically, val(66)met carriers and val(66)val carriers showed very similar response patterns to cTBS and iTBS regardless of the order of TBS interventions. Since none of the observed TBS effects was modulated by the BDNF val(66)met polymorphism, our results do not support the notion that the BDNF val(66)met genotype is a major player with regard to TBS-induced plasticity and metaplasticity in the human M1HAND.


Modeling a variable-focus liquid-filled optical lens.
Research has been conducted on a variable-focus liquid-filled optical lens built from a polymer elastic-film window and a rigid plastic window with a transparent refractive liquid between these windows. The pressure inside the lens deforms the elastic film, which takes the form of a paraboloid. The absolute value of the tension in the film was calculated, allowing theoretical evaluation of the focal length of the lens and its aberrations. The developed mathematical model of the liquid-filled flexible lens agrees well with experimental results.


The chemistry of benzodisilacyclobutenes and benzobis(disilacyclobutene)s: new development of transition-metal-catalyzed reactions, stereochemistry and theoretical studies.
The synthesis and reactions of 3,4-benzo-1,2-disilacyclobut-3-enes and benzo[1,2:4,5]bis(1,2-disilacyclobut-3-ene)s developed by our group are reported in this review. The palladium-, platinum- and nickel-catalyzed reactions of benzodisilacyclobutenes and benzobis(disilacyclobutene)s with unsaturated compounds afford various types of products. The structures of the products are dependent upon the nature of the transition metal used as a catalyst. The reactions of cis- and trans-benzodisilacyclobutenes with alkenes and alkynes in the presence of a transition-metal catalyst proceed with high stereospecificity to give the respective adducts. The thermal reactions of cis- and trans-benzodisilacyclobutenes with various substrates also proceed stereospecifically to give adducts. The results of theoretical calculations for the platinum-catalyzed reaction of disilacyclobutene with acetylene, the nickel-catalyzed reaction of benzodisilacyclobutene and the thermal reaction of benzobis(disilacyclobutene) are discussed in this review.


Should we feed back research results in the midst of a study?
This report is an introduction to a series of three research papers that describe the evolution of the approaches taken by the Translating Research in Elder Care (TREC) research team during its first four years to feed back the research findings to study participants. TREC is an observational multi-method health services research project underway in 36 nursing homes in the prairie provinces of Canada. TREC has actively involved decision makers from the sector in all stages from initial planning, through data collection to dissemination activities. However, it was not planned as a fully integrated knowledge translation project. These three papers describe our progress towards fully integrated knowledge translation--with respect to timely and requested feedback processes. The first paper reports on the process and outcomes of creating and evaluating the feedback of research findings to healthcare aides (unregulated health professionals). These aides provide over 80% of the direct care in our sample and actively requested the feedback as a condition of their continued cooperation in the data acquisition process. The second paper describes feedback from nursing home administrators on preliminary research findings (a facility annual report) and evaluation of the reports' utility. The third paper discusses an approach to providing a more in-depth form of feedback (expanded feedback report) at one of the TREC nursing homes. Survey and interview feedback from healthcare aides is presented in the first paper. Overall, healthcare aides' opinions about presentation of the feedback report and the understand ability, usability, and usefulness of the content were positive. The second paper describes the use of telephone interviews with facility administrators and indicates that the majority of contextual areas (e.g., staff job satisfaction) addressed in facility annual report to be useful, meaningful, and understandable. More than one-half of the administrators would have liked to have received information on additional areas. The third paper explores how a case study that examined how involvement with the TREC study influenced management and staff at one of the TREC nursing homes. The importance of understanding organizational routines and the impact of corporate restructuring were key themes emerging from the case study. In addition, the Director of Care suggested changes to the structure and format of the feedback report that would have improved its usefulness. We believe that these findings will inform others undertaking integrated knowledge translation activities and will encourage others to become more engaged in feedback processes.


Public views on food addiction and obesity: implications for policy and treatment.
According to their advocates, neurobiological explanations of overeating, or "food addiction", have the potential to impact public understanding and treatment of obesity. In this study, we examine the public's acceptance of the concept of food addiction as an explanation of overeating and assess its effects upon their attitudes toward obese persons and the treatment of obesity. We conducted an online survey of 479 adults from the US (n = 215) and Australia (n = 264). There was substantial support for the idea of food addiction, particularly among obese participants. Over half favoured treating obesity as a type of addiction. Psychotherapy was believed to be the most effective treatment and educational and support programs were the preferred policies to address food addiction. There was very little support for increasing taxes on obesogenic foods. Despite the strong support for seeing obesity as a form of addiction, respondents still saw obesity as primarily the result of personal choices and emphasized the need for individuals to take responsibility for their eating. Our sample of the general public strongly supported the idea of obesity as a form of food addiction; but this did not translate into support of clinical and public health policies that experts believe are most likely to reduce the prevalence of obesity. The reasons for the apparent disjunction between support for food addiction and a strong emphasis on personal choice for weight warrant further examination.


Prediction of twin pregnancy preeclampsia based on clinical risk factors, early pregnancy serum markers, and uterine artery pulsatility index.
To investigate whether a combination of clinical risk factors, early pregnancy serum markers, and uterine artery pulsatility index (UTPI) can be used to predict twin preeclampsia (PE). This case control study included women with twin pregnancies who had undergone obstetrics treatments and gave birth at the Huzhou Maternity and Child Health Care Hospital from October 2018 to November 2020. Patients with PE comprised study group, and patients without PE comprised control group based on selection criteria and a 1:1 ratio. Statistical analysis was performed using clinical risk factors, early pregnancy serum markers, and UTPIs, and the area under the receiver operating curve (AUC. Sensitivity, and the specificity of different combinations of these variables were calculated to predict PE in women with twin pregnancy. Logistic regression analysis revealed four independent predictors for the onset of PE during twin pregnancies: first delivery (OR, 7.51; P=0.045), conception method (OR, 7.11; P=0.036), β-HCG level (per SD OR, 2.73; P=0.026), and UTPI (OR, 0.17; P=0.043). First-delivery and IVF pregnancy methods both lead to a 7-fold increase in the PE risk during twin pregnancies. Every one sigma (standard deviation) increase in the β-HCG level led to a 2.73-fold increase in the PE risk. Every UTPI increment by 1.0 reduces the risk of PE by 83%. The prediction efficiencies were based on an AUC of 0.837, a sensitivity of 69%, and a specificity of 92% for the clinical risk factors; an AUC of 0.800, a sensitivity of 81%, and specificity of 78% for the β-HCG level, and an AUC of 0.814, a sensitivity of 88%, and a specificity of 65% for the UTPI. AUC was 0.928, sensitivity 85%, and a specificity 88% after applying the three types of indicators together for prediction. By combining early pregnancy serum markers (β-HCG), and UTPI, the predictive value for PE during twin pregnancy is improved together with its sensitivity and specificity.


Ocean Acidification Affects the Phyto-Zoo Plankton Trophic Transfer Efficiency.
The critical role played by copepods in ocean ecology and biogeochemistry warrants an understanding of how these animals may respond to ocean acidification (OA). Whilst an appreciation of the potential direct effects of OA, due to elevated pCO2, on copepods is improving, little is known about the indirect impacts acting via bottom-up (food quality) effects. We assessed, for the first time, the chronic effects of direct and/or indirect exposures to elevated pCO2 on the behaviour, vital rates, chemical and biochemical stoichiometry of the calanoid copepod Acartia tonsa. Bottom-up effects of elevated pCO2 caused species-specific biochemical changes to the phytoplanktonic feed, which adversely affected copepod population structure and decreased recruitment by 30%. The direct impact of elevated pCO2 caused gender-specific respiratory responses in A.tonsa adults, stimulating an enhanced respiration rate in males (> 2-fold), and a suppressed respiratory response in females when coupled with indirect elevated pCO2 exposures. Under the combined indirect+direct exposure, carbon trophic transfer efficiency from phytoplankton-to-zooplankton declined to < 50% of control populations, with a commensurate decrease in recruitment. For the first time an explicit role was demonstrated for biochemical stoichiometry in shaping copepod trophic dynamics. The altered biochemical composition of the CO2-exposed prey affected the biochemical stoichiometry of the copepods, which could have ramifications for production of higher tropic levels, notably fisheries. Our work indicates that the control of phytoplankton and the support of higher trophic levels involving copepods have clear potential to be adversely affected under future OA scenarios.


Novel formulations and modes of delivery of levodopa.
Ever since its early clinical use in the 1960s, levodopa has remained the gold standard of symptomatic efficacy in the drug treatment of Parkinson's disease (PD). Motor response fluctuations and drug-induced dyskinesias seriously compromise the unparalleled symptomatic efficacy of l-dopa during long-term treatment. Discontinuous drug delivery resulting from the short half-life of l-dopa and erratic gastrointestinal absorption plays a major role in the pathophysiology of these motor complications. Several approaches to improve the pharmacokinetics and ways of administration of l-dopa are in different stages of clinical development and include novel formulations as well as nonoral routes of drug delivery. IPX066 is a novel extended-release l-dopa capsule that has successfully completed phase III clinical trials while the l-dopa prodrug XP21279 and a gastric retention formulation ("accordion pill") are in earlier phases of clinical development. Novel enzyme inhibitors enhancing l-dopa efficacy and half-life are also still being developed, including a novel catechol-O-methyltransferase inhibitor with once-daily pharmacokinetics, and there are studies testing the effects of increasing the dose of amino acid decarboxylase inhibitors given concomitantly with l-dopa. Intrajejunal infusion of a gel formulation of l-dopa/carbidopa is in clinical use in Europe, and its efficacy to smooth out motor fluctuations has recently been shown in a randomized, controlled trial. Subcutaneous and intrapulmonal delivery routes of l-dopa have reached phase III of clinical development. After more than 50 years of clinical use, l-dopa not only remains the gold standard of symptomatic efficacy, but it also remains a drug in active clinical development.


Theoretical treatment of particle-size measurements by applying attenuated-total-reflection technique and its comparisons with experimental results.
Theoretical equations for a particle size-determination method by applying an attenuated-total-reflection (ATR) technique were obtained. Based on these equations, the ATR-spectral intensities were calculated as functions of the sample amount and on the particle size for various choices of the experimental parameters. A mono layer region was more adequate for size measurements than a multiple-layers region. A prism and the incidence angle should be adequately selected according to the aims of the measurements. Experimental results of the sample amount dependences of the spectral intensities were almost consistent with calculations. The experimental results of size dependences showed the same tendency as those by calculations for SiO2 and SiC; especially for SiC, they were in just accord with those by calculations in the case of a KBr prism. Each component of a mixed plural-kind-particles sample almost agreed in its spectral intensity with that of a corresponding single-kind-particles sample. The particle size-determination method, based on the ATR technique, was theoretically supported, and its characteristics were revealed.


An epidemiological assessment of lens opacifications that impaired vision in patients injected with radium-224.
The incidence of lens opacifications that impaired vision (cataract) was analyzed among 831 patients who were injected with known dosages of 224Ra in Germany shortly after World War II. The dependence of the incidence on dosage, i.e., injected activity per unit body weight, and on time after treatment was determined. The observations are equally consistent with proportionality of the incidence of cataract to the square of dosage or with a linear dependence beyond a threshold of 0.5 MBq/kg. The possibility of a linear dependence without threshold was strongly rejected (P less than 0.001). The analysis of temporal dependences yielded a component that was correlated with the injected amount of 224Ra and a component that was uncorrelated. The former was inferred by a maximum likelihood analysis to increase approximately as the square of the time after treatment. The component unrelated to the treatment was found to increase steeply with age and to become dominant within the collective of patients between age 50 and 60. The relative magnitudes of the two components were such that a fraction of 55 to 60% of the total of 58 cataracts had to be ascribed to the dose-related incidence. Impaired vision due to cataract was diagnosed before age 54 in 25 cases. In terms of injected activity per unit body weight no dependence of the sensitivity on age was found; specifically there was no indication of a faster occurrence of the treatment-related cataracts in patients treated at older ages.


Calcium plays a key role in the effects induced by a snake venom Lys49 phospholipase A2 homologue on a lymphoblastoid cell line.
A catalytically-inactive Lys49 phospholipase A2 homologue from the venom of the snake Bothrops asper induces diverse effects (necrosis, apoptosis and proliferation) in a lymphoblastoid cell line, depending on the toxin concentration. The increments in cytosolic Ca2+ levels induced by this toxin in this cell line were assessed. At high toxin concentration (100 microg/mL) the toxin induces drastic disruption of the plasma membrane, associated with a prominent Ca2+ influx and necrosis. Previous incubation of the cells with the chelating agent EGTA or with ruthenium red, an inhibitor of the uniporter mitochondrial Ca2+ transport, greatly reduced necrosis. At a toxin concentration of 12.5 microg/mL, apoptosis is the predominant response, being associated with lower increments in cytosolic Ca2+. This effect was inhibited by preincubation with ruthenium red and the cytosolic Ca2+ chelator BAPTA-AM. The proliferative response, which occurs at a low toxin concentration (0.5 microg/mL), is associated with a small and oscillatory increment in cytosolic Ca2+. It was inhibited by EGTA, ruthenium red and BAPTA-AM, by inhibitors of the endoplasmic reticulum Ca2+ -ATPase (SERCA) and by blockade of the ryanodine receptor. It is concluded that necrosis and apoptosis induced by this toxin are associated with increments in cytosolic Ca2+ levels following plasma membrane perturbation, together with the involvement of mitochondria. The cellular proliferative response depends on a limited Ca2+ influx through the plasma membrane, being associated with a concerted functional unit constituted by SERCA, the ryanodine receptor and mitochondria, which regulate the observed oscillations in cytosolic Ca2+ concentration.


Umbilical reconstruction: different techniques, a single aim.
The umbilicus is a unique physiologic scar of human life resulting from the healing process of the cut umbilical cord at birth. Its absence leads to an unnatural abdominal appearance, and an abnormally shaped or misplaced umbilicus may draw undue attention to the central abdomen. Loss of the umbilicus can be an embarrassing deformity; this occurs when older techniques of umbilical hernia or incisional hernia repair are employed and after abdominoplasty, urachal cyst repair, omphalocele repair, gastroschisis repair, some tumor excisions, and mobilization of bipedicled or bilateral TRAM/DIEP flaps for breast reconstruction. Umbilicoplasty, in which the umbilicus remains anchored to the deep abdominal fascia but is transposed through a newly-formed aperture in the upper abdominal skin flap, is performed in abdominoplasty either for abdominal flap harvest or purely for aesthetics. On the other hand, umbiliconeoplasty describes the de novo creation of an umbilicus that is absent for either congenital or acquired reasons. The optimal umbilical reconstruction should be reliable, reproducible, aesthetically appropriate, and associated with low morbidity. Ideally, it is also single-staged, except in the case of an infected wound, in which case a delayed primary approach may be prudent. (www.actabiomedica.it).


Molecular dynamics simulations of polycarbonate doped with Lemke chromophores.
In the search for optimal electro-optical modulating materials we report in this work molecular dynamics simulations of polycarbonate doped with Lemke chromophores which is a promising candidate system for materials with such functionality. The simulations cover the electric field poling effects on the chromophore order at a temperature above the glass transition temperature (Tg) of the material, the cooling procedure from liquid state to the glass state in the presence of the poling field, and the back relaxation of the system after removal of the field. Our study shows that electric field poling results in a higher chromophore order and that the order is also maintained during the cooling procedure with the poling field applied. In the liquid state, the applied poling field has little effect on the structure of the material. However, after the cooling procedure, the structure changes significantly because the polymer matrix tends to become closely packed. Our study thus indicates that for the bulk material, the structure of the host matrix is very important in determining the performance of the material.


Increased production of IL-4 by gut T-cell lines from patients with dermatitis herpetiformis compared to patients with isolated gluten-sensitive enteropathy.
Dermatitis herpetiformis (DH) and isolated gluten-sensitive enteropathy (GSE) are gluten-sensitive diseases in which ingestion of dietary gluten results in the development of clinical disease. Patients with DH develop cutaneous IgA deposits and a severe skin disease, but rarely develop gastrointestinal symptoms. Patients with isolated GSE develop clinically significant gastrointestinal symptoms, but not skin disease or cutaneous IgA deposits. The aim of this study was to investigate the mechanism by which a mucosal immune response to the same dietary antigen can result in two distinct clinical phenotypes. T-cell lines were derived from activated T-cells in the small bowel mucosa of five patients with DH and 14 patients with isolated GSE and analyzed for T-cell markers and cytokine production in vitro. T-cell lines from DH and isolated GSE patients produced IFN-gamma after stimulation (mean: DH = 2,619 pg/ml; isolated GSE = 1,993 pg/ml; NS). T-cell lines from patients with DH, however, produced significantly more IL-4 than the T-cell lines from patients with isolated GSE (IL-4: DH = 2,010 pg/ml; isolated GSE = 235 pg/ml; P < 0.05). Analysis of intracytoplasmic cytokine production by the T-cell lines showed that T-cell lines from patients with DH were CD4+ predominant, with a greater proportion of CD4+/IL4+ cells than CD4+/IFN-gamma+ cells. In contrast, isolated GSE T-cell lines were predominantly CD8+, with an equal proportion of IL-4- and IFN-gamma-positive cells. These studies demonstrate that T cell lines from patients with DH produce significantly more IL-4 than T-cell lines from patients with isolated GSE, while producing similar amounts of IFN-gamma. This difference in cytokine pattern may play an important role in the different clinical manifestations of these two forms of gluten sensitivity.


Visibility in three-dimensional cluttered scenes.
Three-dimensional (3D) cluttered scenes consist of a large number of small surfaces distributed randomly in a 3D view volume. The canonical example is the foliage of a tree or bush. 3D cluttered scenes are challenging for vision tasks such as object recognition and depth perception because most surfaces or objects are only partly visible. This paper examines the probabilities of surface visibility in 3D cluttered scenes. We model how the probabilities of visible gaps, depth discontinuities, and binocular and half-occluded points depend on scene parameters such as the size and density of the surfaces that make up the clutter, as well as on depth and inverse depth. Inverse depth is of particular interest since both binocular disparity and motion parallax depend directly on it. The probability models are verified using data from synthetic 3D cluttered scenes, which are generated using computer graphics.


Ventral Intermediate Nucleus Versus Zona Incerta Region Deep Brain Stimulation in Essential Tremor.
The ventral intermediate nucleus (VIM) is the target of choice for Essential Tremor (ET) deep brain stimulation (DBS). Renewed interest in caudal zona incerta (cZI) stimulation for tremor control has recently emerged and some groups believe this approach may address long-term reduction of benefit seen with VIM-DBS. To compare clinical outcomes and DBS programming in the long-term between VIM and cZI neurostimulation in ET-DBS patients. A retrospective review of 53 DBS leads from 47 patients was performed. Patients were classified into VIM or cZI groups according to the location of the activated DBS contact. Demographics, DBS settings, and Tremor Rating Scale scores were compared between groups at baseline and yearly follow-up to 4 years after DBS. Student t-tests and analysis of variance (ANOVA) were used to compare variables between groups. Relative to baseline, an improvement in ON-DBS tremor scores was observed in both groups from 6 months to 4 years post-DBS (p < 0.05). Although improvement was still significant at 4 years, scores from month 6 to 2 years were comparable between groups but at 3 and 4 years post-DBS the outcome was better in the VIM group (p < 0.01). Stimulation settings were similar across groups, although we found a lower voltage in the VIM group at 3 years post-DBS. More ventral DBS contacts in the cZI region do improve tremor, however, VIM-DBS provided better long-term outcomes. Randomized controlled trials comparing cZI vs VIM targets should confirm these results.


Acute Achilles Tendon Ruptures: An Update on Treatment.
Acute rupture of the Achilles tendon is common and seen most frequently in people who participate in recreational athletics into their thirties and forties. Although goals of treatment have not changed in the past 15 years, recent studies of nonsurgical management, specifically functional bracing with early range of motion, demonstrate rerupture rates similar to those of tendon repair and result in fewer wound and soft-tissue complications. Satisfactory outcomes may be obtained with nonsurgical or surgical treatment. Newer surgical techniques, including limited open and percutaneous repair, show rerupture rates similar to those of open repair but lower overall complication rates. Early research demonstrates no improvement in functional outcomes or tendon properties with the use of platelet-rich plasma, but promising results with the use of bone marrow-derived stem cells have been seen in animal models. Further investigation is necessary to warrant routine use of biologic adjuncts in the management of acute Achilles tendon ruptures.


The Effect of Untraditional Lipid Parameters in the Development of Coronary Artery Disease: Atherogenic Index of Plasma, Atherogenic Coefficient and Lipoprotein Combined Index.
In this study, we investigated the usability of atherogenic indices of patients who underwent coronary artery bypass surgery (CABG) due to coronary artery disease and patients without CAD as risk factors and markers for cardiovascular disease (CVD). The data of 150 patients who underwent CABG, and 155 patients who underwent coronary angiography and was not diagnosed with CAD were analysed retrospectively. Demographic data and plasma lipid values were collected. The relationship between these ratios and CVD was investigated via univariate logistic regression analysis performed by creating atherogenic indices. The data of 125 patients who underwent CABG between May 2018 and May 2020 (90 males, 35 females; mean age 64,94 ± 9,61), and 155 patients who had coronary angiography between the same dates and found to have no CAD (64 males, 91 females; mean age 60,12 ± 11,6) were analysed retrospectively. The atherogenic index of plasma (AIP), atherogenic coefficient (AC) and lipoprotein combined index (LCI) ratios were found to be significantly higher in the CABG group compared to the control group (p < 0.001). CABG applied patients were divided into three groups according to their SYNTAX Score-I values. There was no statistical difference in the AIP (p = 0.434), AC (p = 0.715) and LCI (p = 0.891) ratios between the groups. In the ROC analysis of the CABG group, it was found that the AC value was the highest in terms of sensitivity with a value of 74.4% (AUC = 0.669, p < 0.001), and the LCI was the highest in terms of specificity with a value of 65.8% (AUC = 0.634, p < 0.001). In the univariate logistic regression analysis created, it was seen that all three indices had a significant effect in the CABG group (AIP; OR 0.493 p = 0,002, AC; OR 0.298 p < 0,001, LCI; OR 0.358 p = 0,001). The use of atherogenic indices in daily practice can be recommended in the process of monitoring the risk of CVD in CAD patients, along with determining those patients' lipid profiles.


Relation between serum albumin and carotid atherosclerosis: the NHLBI Family Heart Study.
Lower concentrations of albumin have been positively related to coronary disease. The aim of this project was to assess the association between serum albumin and carotid atherosclerosis. B-mode ultrasound was used to assess carotid plaques and intima-media thickness (IMT) among white subjects from 592 randomly ascertained families in the National Heart, Lung, and Blood Institute Family Heart Study. Logistic regression was used to estimate prevalence odds ratios of any carotid plaques. Of the 2072 persons studied, 47% were men. Higher serum albumin was associated with younger age, lower body mass index, and lower prevalence of hypertension and coronary disease. Lower serum albumin levels were not associated with an increased odds of carotid plaques. From the lowest to the highest quartile of albumin, multivariate adjusted odds ratios for the prevalence of any carotid plaques were 1.05 (95% CI, 0.59 to 1.86), 1.34 (95% CI, 0.78 to 2.32), 1.03 (95% CI, 0.52 to 1.86), and 1.0 (reference), respectively, in men and 0.71 (95% CI, 0.40 to 1.26), 0.76 (95% CI, 0.42 to 1.36), 0.79 (95% CI, 0.46 to 1.36), and 1.0, respectively, in women. Similarly, in a linear regression model adjusted for demographic, lifestyle, and metabolic factors, serum albumin was not associated with carotid IMT. When the first 3 were compared with the highest quartile of serum albumin, regression coefficients for internal carotid IMT were 0.06458 (SE, 0.06408), 0.07205 (SE, 0.05469), and 0.000773 (SE, 0.05687), respectively, for men and -0.01795 (SE, 0.05085), -0.08501 (SE, 0.04800), and 0.009528 (SE, 0.04622), respectively, for women. Our data suggest that lower serum albumin levels are not associated with an increased odds of prevalent carotid atherosclerosis in either men or women.


[Reduction of the need for blood derivatives in liver transplantation using aprotinin].
To evaluate the efficacy of aprotinin in reducing the need for blood products in orthotopic liver transplantation. Blood product needs and coagulation test results were studied in 42 adults with cirrhosis of the liver who received orthotopic liver transplants. The first 16 liver transplants carried out without aprotinin (control group) were compared with the next 26 consecutive transplant patients who received aprotinin. Each of the first 9 received a loading dose of 2 million units that was followed by the infusion of half a million units per hour until the end of surgery. The next 17 received the same infusion dose at the same rate but no loading dose. Patients who received aprotinin required fewer transfusions of blood products (5.3 units of packed red blood cells as opposed to 13 units; 9 units of fresh frozen plasma versus 14.6 units; 1.7 units of platelets versus 4.2 units; and 3.8 units of cryoprecipitates versus 8.8 units). We observed a marked reduction of fibrinolysis (less increase in D dimers after removal of the liver when aprotinin was used. Prophylactic use of aprotinin during surgery has a beneficial effect on hemostatic mechanisms, reducing the need for blood products. A reduction in fibrinolysis seems to contribute to this effect.


Using Shakespeare's Sotto Voce to Determine True Identity From Text.
Little is known of the private life of William Shakespeare, but he is famous for his collection of plays and poems, even though many of the works attributed to him were published anonymously. Determining the identity of Shakespeare has fascinated scholars for 400 years, and four significant figures in English literary history have been suggested as likely alternatives to Shakespeare for some disputed works: Bacon, de Vere, Stanley, and Marlowe. A myriad of computational and statistical tools and techniques have been used to determine the true authorship of his works. Many of these techniques rely on basic statistical correlations, word counts, collocated word groups, or keyword density, but no one method has been decided on. We suggest that an alternative technique that uses word semantics to draw on personality can provide an accurate profile of a person. To test this claim, we analyse the works of Shakespeare, Christopher Marlowe, and Elizabeth Cary. We use Word Accumulation Curves, Hierarchical Clustering overlays, Principal Component Analysis, and Linear Discriminant Analysis techniques in combination with RPAS, a multi-faceted text analysis approach that draws on a writer's personality, or self to identify subtle characteristics within a person's writing style. Here we find that RPAS can separate the known authored works of Shakespeare from Marlowe and Cary. Further, it separates their contested works, works suspected of being written by others. While few authorship identification techniques identify self from the way a person writes, we demonstrate that these stylistic characteristics are as applicable 400 years ago as they are today and have the potential to be used within cyberspace for law enforcement purposes.


The effect of a vaginal suppository formulation of dill (Anethum graveolens) in comparison to clotrimazole vaginal tablet on the treatment of vulvovaginal candidiasis.
The goal of this study was to compare the effect of Anethum graveolens (dill) vaginal suppositories and 100 mg clotrimazole vaginal tablets on vulvovaginal Candidiasis. This study was a single centre, single-blind, randomised, placebo-controlled trial, in which 60 women with microbiology-confirmed vulvovaginal candidiasis were randomly assigned to dill and clotrimazole groups. At the end of the study, the estimated prevalence of leucorrhoea, burning, and itching was 23%, 23% and 20% in dill users, respectively. This figure was 20%, 10% and 16.7% for the clotrimazole group, respectively. The difference between the two groups was not significant. 13% of suppository patients, compared with 10% of clotrimazole-treatment patients, had a positive culture, which was not significant (p = .68). According to findings, 2% dill vaginal suppositories were as effective as clotrimazole vaginal tablets in reducing both clinical and microbiological symptoms of Candidiasis. Studies with larger sample sizes are required to confirm current findings. Impact statement What is already known on the subject? Based on results from in vivo and in vitro animal studies, dill (Anethum graveolens) has anti-candida activity. What do the results of this study add? It appears that 2% dill vaginal suppositories were as effective as 100 mg clotrimazole vaginal tablets in reducing both the clinical and microbiological symptoms. What are the implications of these findings for clinical practice and further research? Obstetricians and gynaecologists can offer dill as a useful alternative to chemical drugs, especially in women who are often interested in herbal medicine, or in women who are resistant or are not allowed to use antifungal drugs.


Discovery and Structure-Based Optimization of 2-Ureidothiophene-3-carboxylic Acids as Dual Bacterial RNA Polymerase and Viral Reverse Transcriptase Inhibitors.
We are concerned with the development of novel anti-infectives with dual antibacterial and antiretroviral activities for MRSA/HIV-1 co-infection. To achieve this goal, we exploited for the first time the mechanistic function similarity between the bacterial RNA polymerase (RNAP) "switch region" and the viral non-nucleoside reverse transcriptase inhibitor (NNRTI) binding site. Starting from our previously discovered RNAP inhibitors, we managed to develop potent RT inhibitors effective against several resistant HIV-1 strains with maintained or enhanced RNAP inhibitory properties following a structure-based design approach. A quantitative structure-activity relationship (QSAR) analysis revealed distinct molecular features necessary for RT inhibition. Furthermore, mode of action (MoA) studies revealed that these compounds inhibit RT noncompetitively, through a new mechanism via closing of the RT clamp. In addition, the novel RNAP/RT inhibitors are characterized by a potent antibacterial activity against S. aureus and in cellulo antiretroviral activity against NNRTI-resistant strains. In HeLa and HEK 293 cells, the compounds showed only marginal cytotoxicity.


The historical roots of economic development.
This article reviews an emerging area of research within economics that seeks to better understand contemporary economic outcomes by taking a historical perspective. The field has established that many of the contemporary differences in comparative economic development have their roots in the distant past. The insights gained from this literature are not only of academic importance but also useful for thinking about policies that help to address global development moving forward. I provide examples of recent studies that have begun to take on this important next step in the literature by using insights gleaned from historical analyses to better understand policy and its optimal design.


Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications: a meta-analysis of individual patient data from randomised controlled trials.
Placenta-mediated pregnancy complications include pre-eclampsia, late pregnancy loss, placental abruption, and birth of a small-for-gestational-age (SGA) neonate. These complications are leading causes of maternal, fetal, and neonatal morbidity and mortality in high-income countries. Affected women are at high risk of recurrence in subsequent pregnancies; however, effective strategies to prevent recurrence are absent. Findings from our previous study-level meta-analysis suggested that low-molecular-weight heparin reduced the risk of recurrent placenta-mediated pregnancy complications. However, we identified significant heterogeneity in the results, possibly due to trial design or inclusion criteria. To identify which patients benefit from, and which outcomes are prevented by, low-molecular-weight heparin, we did an individual patient data meta-analysis. We did a systematic review in May, 2013, which identified eight eligible randomised trials done between 2000 and 2013 of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications. We excluded studies on the basis of the wrong population, the study being ongoing, inability to confirm eligibility of participants, intervention stopped too early, and no response from the principal investigator. We requested individual patient data from the study authors for eligible women (women pregnant at the time of the study with a history of previous pregnancy that had been complicated by one or more of the following: pre-eclampsia, placental abruption, birth of an SGA neonate [<10th percentile], pregnancy loss after 16 weeks' gestation, or two losses after 12 weeks' gestation) and recoded, combined, and analysed the data for our meta-analysis. The primary outcome was a composite of early-onset (<34 weeks) or severe pre-eclampsia, birth of an SGA neonate (<5th percentile), late pregnancy loss (≥20 weeks' gestation), or placental abruption leading to delivery, assessed on an intention-to-treat basis. We assessed risk of bias with the Cochrane Risk of Bias tool. This study is registered with PROSPERO, number CRD42013006249. We analysed data from 963 eligible women in eight trials: 480 randomly assigned to low-molecular-weight heparin and 483 randomly assigned to no low-molecular-weight heparin. Overall, the risk of bias was not substantial enough to affect decisions regarding trial inclusion. Participants were mostly white (795/905; 88%) with a mean age of 30·9 years (SD 5·0) and 403/963 (42%) had thrombophilia. In the primary analysis, low-molecular-weight heparin did not significantly reduce the risk of recurrent placenta-mediated pregnancy complications (low-molecular-weight heparin 62/444 [14%] versus no low-molecular-weight heparin 95/443 (22%) absolute difference -8%, 95% CI -17·3 to 1·4, p=0·09; relative risk 0·64, 95% CI 0·36-1·11, p=0·11). We noted significant heterogeneity between single-centre and multicentre trials. In subgroup analyses, low-molecular-weight heparin in multicentre trials reduced the primary outcome in women with previous abruption (p=0·006) but not in any of the other subgroups of previous complications. Low-molecular-weight heparin does not seem to reduce the risk of recurrent placenta-mediated pregnancy complications in at-risk women. However, some decreases in event rates might have been too small for the power of our study to explore. Canadian Institutes of Health Research.


Precision Preventive Medicine of Relapse in Smoking Cessation: Can MRI Inform the Search of Intermediate Phenotypes?
Chronic tobacco smoking remains a major health problem worldwide. Numerous smokers wish to quit but most fail, even if they are helped. The possibility of identifying neuro-biomarkers in smokers at high risk of relapse could be of incredible progress toward personalized prevention therapy. Our aim is to provide a scoping review of this research topic in the field of Magnetic Resonance Imaging (MRI) and to review the studies that investigated if MRI defined markers predicted smoking cessation treatment outcome (abstainers versus relapsers). Based on the available literature, a meta-analysis could not be conducted. We thus provide an overview of the results obtained and take stock of methodological issues that will need to be addressed to pave the way toward precision medicine. Based on the most consistent findings, we discuss the pivotal role of the insula in light of the most recent neurocognitive models of addiction.


Antibiotic-impregnated cement in revision total knee arthroplasty. A prospective cohort study of one hundred and eighty-three knees.
Deep infection following total knee arthroplasty is a devastating complication, and it is very important to prevent it. A prospective cohort study was conducted to evaluate the effect of vancomycin-impregnated cement on the prevention of deep infection after revision total knee arthroplasty performed in a setting in which so-called clean-air measures such as laminar flow and space suits were not available. From 1993 to 2004, 183 first-time revision total knee arthroplasties were performed with fixation of all components with cement. The knees were divided randomly into two groups to evaluate the effect of vancomycin-impregnated cement in the prevention of postoperative infection. In Group 1 (ninety knees), the cement was not mixed with antibiotics; in Group 2 (ninety-three knees), vancomycin-impregnated cement was used for fixation. All of the patients were evaluated preoperatively and intraoperatively and found to be without infection at those times. At an average of eighty-nine months postoperatively, no deep infection had developed in the ninety-three knees in Group 2, whereas a deep infection had developed in six (7%) of the ninety knees in Group 1. This difference between Groups 1 and 2 was significant (p = 0.0130). One superficial wound infection developed in Group 1. Vancomycin-impregnated cement was shown to be effective in the prevention of postoperative deep infection after revision total knee arthroplasty performed with antibiotic prophylaxis but not with so-called clean-air measures. This study provides preliminary evidence to justify larger trials.


Naturalistic Driving: A Framework and Advances in Using Big Data.
Driving is an activity that facilitates physical, cognitive, and social stimulation in older adults, ultimately leading to better physical and cognitive health. However, aging is associated with declines in vision, physical health, and cognitive health, all of which can affect driving ability. One way of assessing driving ability is with the use of sensors in the older adult's own vehicle. This paper provides a framework for driving assessment and addresses how naturalistic driving studies can assist in such assessments. The framework includes driving characteristics (how much driving, speed, position, type of road), actions and reactions (lane changes, intersections, passing, merging, traffic lights, pedestrians, other vehicles), destinations (variety and distance, sequencing and route planning), and driving conditions (time of day and season). Data from a subset of Ottawa drivers from the Candrive study is used to illustrate the use of naturalistic driving data. Challenges in using naturalistic driving big data and the changing technology in vehicles are discussed.


Progressive adaptation of hepatic ketogenesis in mice fed a high-fat diet.
Hepatic ketogenesis provides a vital systemic fuel during fasting because ketone bodies are oxidized by most peripheral tissues and, unlike glucose, can be synthesized from fatty acids via mitochondrial beta-oxidation. Since dysfunctional mitochondrial fat oxidation may be a cofactor in insulin-resistant tissue, the objective of this study was to determine whether diet-induced insulin resistance in mice results in impaired in vivo hepatic fat oxidation secondary to defects in ketogenesis. Ketone turnover (micromol/min) in the conscious and unrestrained mouse was responsive to induction and diminution of hepatic fat oxidation, as indicated by an eightfold rise during the fed (0.50+/-0.1)-to-fasted (3.8+/-0.2) transition and a dramatic blunting of fasting ketone turnover in PPARalpha(-/-) mice (1.0+/-0.1). C57BL/6 mice made obese and insulin resistant by high-fat feeding for 8 wk had normal expression of genes that regulate hepatic fat oxidation, whereas 16 wk on the diet induced expression of these genes and stimulated the function of hepatic mitochondrial fat oxidation, as indicated by a 40% induction of fasting ketogenesis and a twofold rise in short-chain acylcarnitines. Together, these findings indicate a progressive adaptation of hepatic ketogenesis during high-fat feeding, resulting in increased hepatic fat oxidation after 16 wk of a high-fat diet. We conclude that mitochondrial fat oxidation is stimulated rather than impaired during the initiation of hepatic insulin resistance in mice.


The evolution of developmental timing in natural enemy systems.
Natural parasitoid systems exhibit considerable variation in their life history properties yet little is known about the effects of development time on parasitoid fitness or of the conditions that might select for rapid development at the expense of reduced parasitoid growth. In this study the techniques of adaptive dynamics are applied to a discrete time host-parasitoid model to examine the evolution of parasitoid life history strategies. In particular, we explore the conditions that select for variation in parasitoid traits, such as, the timing of parasitoid attack and emergence from the host. The process of evolutionary branching, leading to dimorphism, can occur when the benefits to reproduction of early parasitoid attack are bought at a cost in terms of mortality of late parasitoid emergence from the host. We also find that trends in parasitoid life history traits depend critically on the nature of the underlying population dynamics. Increases in the strength of host density-dependence acts to select for shorter parasitoid development time and lower searching efficiency when the underlying population dynamics are at equilibrium. This trend is reversed when the underlying population dynamics exhibit fluctuations. Here, fluctuations in host density driven by parasitism become more extreme as the strength of host density-dependence decreases and so the parasitoid selects early emergence to avoid the mortality experienced at outbreak host densities. Our results are consistent with the general principle that parasitoids facing high mortality risk favour short development times over size and high searching efficiency, whereas species facing low mortality risks favour size at the cost of increased development time.


Randomized, double-blind, placebo-controlled, linear dose, crossover study to evaluate the efficacy and safety of a green coffee bean extract in overweight subjects.
Adult weight gain and obesity have become worldwide problems. Issues of cost and potential side effects of prescription weight loss drugs have led overweight and obese adults to try nutraceuticals that may aid weight loss. One promising nutraceutical is green coffee extract, which contains high concentrations of chlorogenic acids that are known to have health benefits and to influence glucose and fat metabolism. A 22-week crossover study was conducted to examine the efficacy and safety of a commercial green coffee extract product GCA™ at reducing weight and body mass in 16 overweight adults. Subjects received high-dose GCA (1050 mg), low-dose GCA (700 mg), or placebo in separate six-week treatment periods followed by two-week washout periods to reduce any influence of preceding treatment. Treatments were counterbalanced between subjects. Primary measurements were body weight, body mass index, and percent body fat. Heart rate and blood pressure were also measured. Significant reductions were observed in body weight (-8.04 ± 2.31 kg), body mass index (-2.92 ± 0.85 kg/m(2)), and percent body fat (-4.44% ± 2.00%), as well as a small decrease in heart rate (-2.56 ± 2.85 beats per minute), but with no significant changes to diet over the course of the study. Importantly, the decreases occurred when subjects were taking GCA. Body mass index for six subjects shifted from preobesity to the normal weight range (<25.00 kg/m(2)). The results are consistent with human and animal studies and a meta-analysis of the efficacy of green coffee extract in weight loss. The results suggest that GCA may be an effective nutraceutical in reducing weight in preobese adults, and may be an inexpensive means of preventing obesity in overweight adults.