Are there different cut-off values for staging liver fibrosis using 2D-SWE implemented on different systems from the same manufacturer?
To evaluate the range of liver stiffness (LS) cut-off values for predicting different stages of liver fibrosis (LF) for 2D-SWE-GE implemented on three different systems from General Electric Healthcare (LOGIQ E9, LOGIQ S8, LOGIQ P9). We performed a comparative study evaluating the performance of 2D-SWE-GE (LOGIQ E9, S8, P9) for predicting different stages of LF using Transient Elastography (TE) as the reference method. All patients (with or without chronic hepatopathies) were evaluated by TE, 331 patients were included in the LOGIQ E9 study, 179 in the LOGIQ S8 study and 234 in the LOGIQ P9 study. Reliable liver stiffness measurements (LSM) were defined for TE as the median value of 10 measurements with an interquartile range/median ratio (IQR/M)≤0.30 and for 2D-SWE-GE as the median value of 10 measurements and IQR/M≤0.30. Reliable LSM was obtained by both methods in 91.5% subjects of the LOGIQ E9 group, in 95.5% subjects from the LOGIQ S8 group and in 87.6% subjects in the LOGIQ P9 group. The performance of 2DSWE-GE for predicting F≥2 with LOGIQ E9, LOGIQ S8 and LOGIQ P9 systems were: cut-offs 6.7 kPa, 6.9 kPa and 6.8 kPa; AUCs 0.95, 0.92 and 0.93. For predicting F≥3, the performances were: cut-offs - 8.2 kPa, 8.2 kPa and 7.6 kPa; AUCs - 0.97, 0.93 and 0.94. For predicting F4, the performances were: cut-offs - 9.3 kPa, 9.3 kPa and 9.3 kPa; AUCs - 0.96, 0.91 and 0.91. The LS cut-off values for 2D-SWE-GE implemented on different systems for predicting F≥2, F≥3 and F=4 are not significantly different.


Meaning Making in the Context of Disasters.
Understanding the factors underlying adaptive psychological responses and recovery after disasters has important implications for intervention and prevention efforts. To date, little attention has been paid to successful coping processes in recovering from natural and technological disasters. This article takes a meaning making perspective to explicate how survivors successfully adapt after disasters. Relevant literature is reviewed to illustrate the process of adaptation and resilience after disasters. Studies to date suggest both survivors' global meaning, particularly their religiousness and sense of meaning, and their appraisals and meaning making after the disaster are important influences on their postdisaster resilience. Meanings made in the form of changes in global beliefs and perceived growth have been reported and shown to have inconsistent relations with adjustment. Although much more research is needed, current literature suggests that meaning making processes are central to recovery and resilience after a range of disasters.


Local population density and group composition influence the signal-preference relationship in Enchenopa treehoppers (Hemiptera: Membracidae).
Many animals exhibit social plasticity - changes in phenotype or behaviour in response to experience with conspecifics that change how evolutionary processes like sexual selection play out. Here, we asked whether social plasticity arising from variation in local population density in male advertisement signals and female mate preferences influences the form of sexual selection. We manipulated local density and determined whether this changed how the distribution of male signals overlapped with female preferences - the signal preference relationship. We specifically look at the shape of female mate preference functions, which, when compared to signal distributions, provide hypotheses about the form of sexual selection. We used Enchenopa binotata treehoppers, a group of plant-feeding insects that exhibit natural variation in local densities across individual host plants, populations, species and years. We measured male signal frequency and female preference functions across the density treatments. We found that male signals varied across local social groups, but not according to local density. By contrast, female preferences varied with local density - favouring higher signal frequencies in denser environments. Thus, local density changes the signal-preference relationship and, consequently, the expected form of sexual selection. We found no influence of sex ratio on the signal-preference relationship. Our findings suggest that plasticity arising from variation in local group density and composition can alter the form of sexual selection with potentially important consequences both for the maintenance of variation and for speciation.


Successful topical respiratory tract immunization of primates against Ebola virus.
Ebola virus causes outbreaks of severe viral hemorrhagic fever with high mortality in humans. The virus is highly contagious and can be transmitted by contact and by the aerosol route. These features make Ebola virus a potential weapon for bioterrorism and biological warfare. Therefore, a vaccine that induces both systemic and local immune responses in the respiratory tract would be highly beneficial. We evaluated a common pediatric respiratory pathogen, human parainfluenza virus type 3 (HPIV3), as a vaccine vector against Ebola virus. HPIV3 recombinants expressing the Ebola virus (Zaire species) surface glycoprotein (GP) alone or in combination with the nucleocapsid protein NP or with the cytokine adjuvant granulocyte-macrophage colony-stimulating factor were administered by the respiratory route to rhesus monkeys--in which HPIV3 infection is mild and asymptomatic--and were evaluated for immunogenicity and protective efficacy against a highly lethal intraperitoneal challenge with Ebola virus. A single immunization with any construct expressing GP was moderately immunogenic against Ebola virus and protected 88% of the animals against severe hemorrhagic fever and death caused by Ebola virus. Two doses were highly immunogenic, and all of the animals survived challenge and were free of signs of disease and of detectable Ebola virus challenge virus. These data illustrate the feasibility of immunization via the respiratory tract against the hemorrhagic fever caused by Ebola virus. To our knowledge, this is the first study in which topical immunization through respiratory tract achieved prevention of a viral hemorrhagic fever infection in a primate model.


Human Facial Shape and Size Heritability and Genetic Correlations.
The human face is an array of variable physical features that together make each of us unique and distinguishable. Striking familial facial similarities underscore a genetic component, but little is known of the genes that underlie facial shape differences. Numerous studies have estimated facial shape heritability using various methods. Here, we used advanced three-dimensional imaging technology and quantitative human genetics analysis to estimate narrow-sense heritability, heritability explained by common genetic variation, and pairwise genetic correlations of 38 measures of facial shape and size in normal African Bantu children from Tanzania. Specifically, we fit a linear mixed model of genetic relatedness between close and distant relatives to jointly estimate variance components that correspond to heritability explained by genome-wide common genetic variation and variance explained by uncaptured genetic variation, the sum representing total narrow-sense heritability. Our significant estimates for narrow-sense heritability of specific facial traits range from 28 to 67%, with horizontal measures being slightly more heritable than vertical or depth measures. Furthermore, for over half of facial traits, >90% of narrow-sense heritability can be explained by common genetic variation. We also find high absolute genetic correlation between most traits, indicating large overlap in underlying genetic loci. Not surprisingly, traits measured in the same physical orientation (i.e., both horizontal or both vertical) have high positive genetic correlations, whereas traits in opposite orientations have high negative correlations. The complex genetic architecture of facial shape informs our understanding of the intricate relationships among different facial features as well as overall facial development.


The second-largest subunit of the mouse DNA polymerase alpha-primase complex facilitates both production and nuclear translocation of the catalytic subunit of DNA polymerase alpha.
DNA polymerase alpha-primase is a replication enzyme necessary for DNA replication in all eukaryotes examined so far. Mouse DNA polymerase alpha is made up of four subunits, the largest of which is the catalytic subunit with a molecular mass of 180 kDa (p180). This subunit exists as a tight complex with the second-largest subunit (p68), whose physiological role has remained unclear up until now. We set out to characterize these subunits individually or in combination by using a cDNA expression system in cultured mammalian cells. Coexpression of p68 markedly increased the protein level of p180, with the result that ectopically generated DNA polymerase activity was dramatically increased. Immunofluorescence analysis showed that while either singly expressed p180 or p68 was localized in the cytoplasm, cotransfection of both subunits resulted in colocalization in the nucleus. We identified a putative nuclear localization signal for p180 (residues 1419 to 1437) and found that interaction with p68 is essential for p180 to translocate into the nucleus. These results indicate that association of p180 with p68 is important for both protein synthesis of p180 and translocation into the nucleus, implying that p68 plays a pivotal role in the newly synthesized DNA polymerase alpha complex.


Sex differences in intrinsic aptitude for mathematics and science?: a critical review.
This article considers 3 claims that cognitive sex differences account for the differential representation of men and women in high-level careers in mathematics and science: (a) males are more focused on objects from the beginning of life and therefore are predisposed to better learning about mechanical systems; (b) males have a profile of spatial and numerical abilities producing greater aptitude for mathematics; and (c) males are more variable in their cognitive abilities and therefore predominate at the upper reaches of mathematical talent. Research on cognitive development in human infants, preschool children, and students at all levels fails to support these claims. Instead, it provides evidence that mathematical and scientific reasoning develop from a set of biologically based cognitive capacities that males and females share. These capacities lead men and women to develop equal talent for mathematics and science.


Ionic mechanism underlying recovery of rhythmic activity in adult isolated neurons.
Neurons exhibit long-term excitability changes necessary for maintaining proper cell and network activity in response to various inputs and perturbations. For instance, the adult crustacean pyloric network can spontaneously recover rhythmic activity after complete shutdown resulting from permanent removal of neuromodulatory inputs. Dissociated lobster stomatogastric ganglion (STG) neurons have been shown to spontaneously develop oscillatory activity via excitability changes. Rhythmic electrical stimulation can eliminate these oscillatory patterns in some cells. The ionic mechanisms underlying these changes are only partially understood. We used dissociated crab STG neurons to study the ionic mechanisms underlying spontaneous recovery of rhythmic activity and stimulation-induced activity changes. Similar to lobster neurons, rhythmic activity spontaneously develops in crab STG neurons. Rhythmic hyperpolarizing stimulation can eliminate, but more commonly accelerate, the emergence of stable oscillatory activity depending on Ca(2+) influx at hyperpolarized voltages. Our main finding is that upregulation of a Ca(2+) current and downregulation of a high-threshold K(+) current underlies the spontaneous homeostatic development of oscillatory activity. However, because of a nonlinear dependence on stimulus frequency, hyperpolarization-induced oscillations appear to be inconsistent with a homeostatic regulation of activity. We find no difference in the activity patterns or the underlying ionic currents involved between neurons of the fast pyloric and the slow gastric mill networks during the first 10 days in isolation. Dynamic-clamp experiments confirm that these conductance modifications can explain the observed activity changes. We conclude that spontaneous and stimulation-induced excitability changes in STG neurons can both result in intrinsic oscillatory activity via regulation of the same two conductances.


Pathways to alcohol-induced brain impairment in young people: a review.
Classically, disorders associated with 'alcohol-related brain damage' (ARBD) occur as a result of chronic excessive alcohol misuse and confer significant physical and psychological disability to the individual as well as to the community. These phenotypes are often difficult to detect at early stages and therefore early intervention and treatment is limited. It remains unresolved as to whether there are neurobiological markers of the early stages of such brain damage in young 'at-risk' drinkers, who probably experience 'alcohol-induced brain impairment' prior to the onset of ARBD, per se. This review focuses on neurobiological (in particular, neuropsychological and neuroimaging) markers that are associated with alcohol misuse in young people (13-24 years of age). The findings from this review suggest that a clearer understanding of alcohol misuse (particularly with regards to binge drinking) is needed. Despite this, neurocognitive profile along with supporting neuroimaging evidence appears to be particularly important in the early detection of brain changes that result from excessive alcohol use. In young alcohol misusers, these preventable and potentially reversible deficits may be progressive but if left unresolved such deficits eventually become major contributors to poor outcome (long term) and hamper adherence to treatment. We address five key themes in this review: (i) there are specific drinking patterns in young people; (ii) youth represents a critical period in brain development that is particularly vulnerable to alcohol misuse; (iii) the extent to which there are pre-existing versus alcohol-induced neurobiological changes remains unclear; (iv) vulnerability markers may be mediated by mental health and substance use comorbidities; and (v) cognitive remediation would be a likely candidate for early prevention and treatment as it could help to develop efficient meta-cognitive skills to prevent relapse in young drinkers.


A stakeholder analysis of the perceived outcomes of developing and implementing England's obesity strategy 2008-2011.
International recommendations urge governments to implement population-based strategies to reduce the burden of obesity. This study assesses the development and implementation of the obesity strategy in England 2008-2011, Healthy Weight, Healthy Lives (HWHL). The aim was to identify if stakeholders perceived HWHL to have made any difference to the action to address obesity in England, with the ultimate objective of identifying insights that could inform the development and implementation of future obesity strategies in England and elsewhere. Qualitative study using semi-structured interviews and thematic framework analysis. 40 stakeholders involved in the development and implementation of the obesity strategy were interviewed. Evidence from this study suggests that HWHL was perceived to have made a positive difference to efforts to address obesity in England. It was credited with creating political buy-in, engaging more stakeholders, stimulating and facilitating action, enhancing knowledge and changing attitudes. But it was reported to have failed to fully catalyse action across all government departments and sectors, or to develop adequate mechanisms for learning about the effectiveness of the different elements and actions in the Strategy. Key elements of the Strategy contributing towards to the perceived positive differences included its multi-faceted, inclusive nature; governance structures; monitoring programme to assess progress against national and local targets; child-focus; and funding. The development of the Strategy was said to be stimulated and aided by the prior synthesis of a critical mass of scientific evidence. The English experience of HWHL lends support to the recommendations to develop population-based obesity strategies. It indicates that in order to stimulate comprehensive, inter-sectoral action, obesity strategies need to take a population-based, multi-faceted approach, be implemented through a clear governance structure, follow a systematic process of aligning goals, objectives and agendas between government departments and sectors with a stake in obesity, and have a clear system of reporting changes in obesity rates against a target. In order to design effective policies and to build the case for continued investment, obesity strategies also need to incorporate a national framework for learning and evaluation from the outset.


Trifluridine Induces p53-Dependent Sustained G2 Phase Arrest with Its Massive Misincorporation into DNA and Few DNA Strand Breaks.
Trifluridine (FTD) is a key component of the novel oral antitumor drug TAS-102, which consists of FTD and a thymidine phosphorylase inhibitor. Like 5-fluoro-2'-deoxyuridine (FdUrd), a deoxynucleoside form of 5-fluorouracil metabolite, FTD is sequentially phosphorylated and not only inhibits thymidylate synthase activity, but is also incorporated into DNA. Although TAS-102 was effective for the treatment of refractory metastatic colorectal cancer in clinical trials, the mechanism of FTD-induced cytotoxicity is not completely understood. Here, we show that FTD as well as FdUrd induce transient phosphorylation of Chk1 at Ser345, and that this is followed by accumulation of p53 and p21 proteins in p53-proficient human cancer cell lines. In particular, FTD induced p53-dependent sustained arrest at G2 phase, which was associated with a proteasome-dependent decrease in the Cyclin B1 protein level and the suppression of CCNB1 and CDK1 gene expression. In addition, a p53-dependent increase in p21 protein was associated with an FTD-induced decrease in Cyclin B1 protein. Although numerous ssDNA and dsDNA breaks were induced by FdUrd, few DNA strand breaks were detected in FTD-treated HCT-116 cells despite massive FTD misincorporation into genomic DNA, suggesting that the antiproliferative effect of FTD is not due to the induction of DNA strand breaks. These distinctive effects of FTD provide insights into the cellular mechanism underlying its antitumor effect and may explain the clinical efficacy of TAS-102.


Neuronal oscillations in cortical networks.
Clocks tick, bridges and skyscrapers vibrate, neuronal networks oscillate. Are neuronal oscillations an inevitable by-product, similar to bridge vibrations, or an essential part of the brain's design? Mammalian cortical neurons form behavior-dependent oscillating networks of various sizes, which span five orders of magnitude in frequency. These oscillations are phylogenetically preserved, suggesting that they are functionally relevant. Recent findings indicate that network oscillations bias input selection, temporally link neurons into assemblies, and facilitate synaptic plasticity, mechanisms that cooperatively support temporal representation and long-term consolidation of information.


Rare Copy Number Variants in Array-Based Comparative Genomic Hybridization in Early-Onset Skeletal Fragility.
Early-onset osteoporosis is characterized by low bone mineral density (BMD) and fractures since childhood or young adulthood. Several monogenic forms have been identified but the contributing genes remain inadequately characterized. In search for novel variants and novel candidate loci, we screened a cohort of 70 young subjects with mild to severe skeletal fragility for rare copy-number variants (CNVs). Our study cohort included 15 subjects with primary osteoporosis before age 30 years and 55 subjects with a pathological fracture history and low or normal BMD before age 16 years. A custom-made high-resolution comparative genomic hybridization array with enriched probe density in >1,150 genes important for bone metabolism and ciliary function was used to search for CNVs. We identified altogether 14 rare CNVs. Seven intronic aberrations were classified as likely benign. Five CNVs of unknown clinical significance affected coding regions of genes not previously associated with skeletal fragility (ETV1-DGKB, AGBL2, ATM, RPS6KL1-PGF, and SCN4A). Finally, two CNVs were pathogenic and likely pathogenic, respectively: a 4 kb deletion involving exons 1-4 of COL1A2 (NM_000089.3) and a 12.5 kb duplication of exon 3 in PLS3 (NM_005032.6). Although both genes have been linked to monogenic forms of osteoporosis, COL1A2 deletions are rare and PLS3 duplications have not been described previously. Both CNVs were identified in subjects with significant osteoporosis and segregated with osteoporosis within the families. Our study expands the number of pathogenic CNVs in monogenic skeletal fragility and shows the validity of targeted CNV screening to potentially pinpoint novel candidate loci in early-onset osteoporosis.


Vision During Saccadic Eye Movements.
The perceptual consequences of eye movements are manifold: Each large saccade is accompanied by a drop of sensitivity to luminance-contrast, low-frequency stimuli, impacting both conscious vision and involuntary responses, including pupillary constrictions. They also produce transient distortions of space, time, and number, which cannot be attributed to the mere motion on the retinae. All these are signs that the visual system evokes active processes to predict and counteract the consequences of saccades. We propose that a key mechanism is the reorganization of spatiotemporal visual fields, which transiently increases the temporal and spatial uncertainty of visual representations just before and during saccades. On one hand, this accounts for the spatiotemporal distortions of visual perception; on the other hand, it implements a mechanism for fusing pre- and postsaccadic stimuli. This, together with the active suppression of motion signals, ensures the stability and continuity of our visual experience.


Publication or presentation of results from multicenter clinical trials: evidence from an academic medical center.
Nonpublication of research results threatens the integrity of clinical research, but the extent of nonpublication and factors associated with publication remain poorly documented. We sought to examine rates of publication or presentation of research findings from multicenter clinical trials and determine what factors are associated with dissemination of results. We conducted a follow-up study of 217 prospective, multicenter clinical trials of treatment approved in 1998 by the institutional review board of a large academic medical center, of which 197 had enrolled participants and were not known to be ongoing. Follow-up included searches of the literature and the Internet and telephone and e-mail inquiries to investigators and research sponsors. The main outcome measures were manuscript publication or other presentation of research results. Results of 110 (56%) out of 197 multicenter clinical trials have been published in the peer-reviewed literature. Results of 87 (44%) studies have not been published, and results of 52 (26%) studies have not been disseminated in any form. The rate of dissemination of trial results was highest for studies that were phase 3 (81%), lowest risk (86%), and investigational (76%). The dissemination rate was lowest for studies that were supported by internal funds (50%). However, none of these associations were statistically significant. Results of almost half of the multicenter clinical trials conducted in part at a large academic medical center have never been published. Mechanisms to ensure public dissemination of clinical trial results are needed.


Satisfaction among early and mid-career dentists in a metropolitan dental hospital in China.
A growing body of research has examined career satisfaction among dentists using a standardized instrument, dentist satisfaction survey (DSS). This project examined career satisfaction of early to mid-career dentists in China, a population whose career satisfaction, heretofore, has not been studied. This is an especially critical time to examine career satisfaction because of health care reform measures being implemented in China. A culturally sensitive Chinese-language version of the DSS (CDSS) was developed and electronically administered to 367 early and mid-career dentists in a tertiary dental hospital in Beijing, China. One hundred and seventy respondents completed the survey. The average total career score was 123, with a range of 82-157. Data analysis showed some significant differences in total career score and several subscales based on gender, working hours per week, and years in practice. A stepwise regression model revealed that two variables predicted total career score: working hours per week and gender. Stepwise regression also demonstrated that four subscales significantly predicted the overall professional satisfaction subscale score: respect, delivery of care, income and patient relations. Implications of these results are discussed in light of the health care delivery system and dentist career paths in China.


Galanin and the endocrine pancreas.
Galanin is a 29 amino acid peptide, initially isolated from the porcine small intestine. The peptide has been shown to occur in intrapancreatic nerves in close association to the islets. Its effects on islet hormone secretion and its possible mechanisms behind these effects are reviewed. Galanin has been shown to inhibit basal and stimulated insulin secretion both in vivo and in vitro under a variety of experimental conditions. The peptide has also been shown to inhibit somatostatin secretion and the secretion of pancreatic polypeptide (PP). With regard to glucagon secretion, however, results in the literature are not consistent since both stimulatory and inhibitory effects have been reported. A direct interaction with the pancreatic beta-cells has been proposed behind its inhibitory action on insulin secretion, since galanin inhibits insulin secretion from isolated beta-cells from obese, hyperglycaemic, mice. Galanin has thereby also been shown to induce repolarization and to reduce the free Ca2+ concentration, [Ca2+]i. The reduction in [Ca2+]i is probably not due to a direct interference with the voltage-activated Ca2+ channels, since there is no effect of galanin when these channels are opened by depolarization induced by high concentrations of K+. Instead, preliminary studies indicate that galanin activates the K+ channels that are regulated by ATP, in turn inducing a repolarization-induced reduction in [Ca2+]i resulting in reduced insulin secretion. However, the possibility that galanin inhibits the insulin secretory mechanism at a step distal to the regulation of cytoplasmic free Ca2+ concentration should not be overlooked.


Measures for the integration of health and social care services for long-term health conditions: a systematic review of reviews.
As people are living longer with higher incidences of long-term health conditions, there is a move towards greater integration of care, including integration of health and social care services. Integrated care needs to be comprehensively and systematically evaluated if it is to be implemented widely. We performed a systematic review of reviews to identify measures which have been used to assess integrated care across health and social care services for people living with long-term health conditions. Four electronic databases (PUBMED; MEDLINE; EMBASE; Cochrane library of systematic reviews) were searched in August 2018 for relevant reviews evaluating the integration of health and social care between 1998 and 2018. Articles were assessed according to apriori eligibility criteria. A data extraction form was utilised to collate the identified measures into five categories. Of the 18 articles included, system outcomes and process measures were most frequently identified (15 articles each). Patient or carer reported outcomes were identified in 13 articles while health outcomes were reported in 12 articles. Structural measures were reported in nine articles. Challenges to measuring integration included the identification of a wide range of potential impacts of integration, difficulties in comparing findings due to differences in study design and heterogeneity of types of outcomes, and a need for appropriate, robust measurement tools. Our review revealed no shortage of measures for assessing the structures, processes and outcomes of integrated care. The very large number of available measures and infrequent use of any common set make comparisons between schemes more difficult. The promotion of core measurement sets and stakeholder consultation would advance measurement in this area.


School-Class Co-Ethnic and Immigrant Density and Current Smoking among Immigrant Adolescents.
Although the school-class is known to be an important setting for adolescent risk behavior, little is known about how the ethnic composition of a school-class impacts substance use among pupils with a migration background. Moreover, the few existing studies do not distinguish between co-ethnic density (i.e., the share of immigrants belonging to one's own ethnic group) and immigrant density (the share of all immigrants). This is all the more surprising since a high co-ethnic density can be expected to protect against substance use by increasing levels of social support and decreasing acculturative stress, whereas a high immigrant density can be expected to do the opposite by facilitating inter-ethnic conflict and identity threat. This study analyses how co-ethnic density and immigrant density are correlated with smoking among pupils of Portuguese origin in Luxembourg. A multi-level analysis is used to analyze data from the Luxembourg Health Behavior in School-Aged Children study (N = 4268 pupils from 283 classes). High levels of co-ethnic density reduced current smoking. In contrast, high levels of immigrant density increased it. Thus, in research on the health of migrants, the distinction between co-ethnic density and immigrant density should be taken into account, as both may have opposite effects.


Preventing Chronic Emotional Distress in Stroke Survivors and Their Informal Caregivers.
Chronic emotional distress (e.g., depression, anxiety, post-traumatic stress) is common after stroke and interdependent between patients and their informal caregivers. We measured stroke survivors', caregivers', and neurocritical care nurses' views of primary drivers of distress during the stroke experience, and needs and preferences for the structure, topics, mode of delivery, and timing of an intervention to promote emotional recovery. We conducted semi-structured interviews with 24 patient-caregiver dyads within the Neuroscience Intensive Care Unit (Neuro-ICU). Additionally, we conducted two focus groups with 15 nurses. Interviews and focus groups were audio-recorded, transcribed, and coded using NVivo 11 (QSR International) software. The challenges and impacts of stroke most commonly reported by dyads were: uncertainty about future health, fear of recurrent strokes, negative emotions, and role changes post-stroke. Dyads and nurses agreed that resiliency skills such as mindfulness/focusing on the present, problem solving, gratitude/optimism, self-care, interpersonal communication and developing a supportive team of family, friends, and medical staff are beneficial to optimize recovery. The potential barrier to intervention delivery was accessibility, due to challenges of time and travel to appointments. Participants agreed that starting the intervention at hospitalization and continuing via live video after discharge is an ideal delivery modality. Stroke survivors, caregivers, and Neuro-ICU nurses believe that a resiliency skills-based intervention to prevent chronic emotional distress is necessary and urgent. This qualitative study provides valuable information on the challenges faced by dyads, intervention topics to prioritize, and strategies to maximize feasibility, acceptability, and effect.


Engaging Patient Advocates and Other Stakeholders to Design Measures of Patient-Centered Communication in Cancer Care.
Patient-centered communication (PCC) is an essential component of patient-centered care and contributes to patient satisfaction, health-related quality of life, and other important patient outcomes. The aim of this study was to develop and test survey questions to assess patients' experiences with PCC in cancer care. We used a conceptual model developed by the National Cancer Institute as our framework. The survey questions align with the six core functions of PCC defined in the model: Exchanging Information, Managing Uncertainty, Enabling Patient Self-Management, Fostering Healing Relationships, Making Decisions, and Responding to Emotions. The study focused on colorectal cancer patients. We conducted two rounds of cognitive interviewing to evaluate patients' ability to understand and provide valid answers to the PCC questions. Interviews were conducted in Maryland and North Carolina in 2014. We involved a patient advocacy group, Fight Colorectal Cancer, and a multidisciplinary panel of stakeholders throughout the measurement development process to ensure that the survey questions capture aspects of PCC that are important to patients and meet the needs of potential end users, including researchers, healthcare organizations, and health professionals. Patient and other stakeholder input informed revisions of draft survey questions, including changes to survey instructions, frame of reference for questions, response scales, and language. This study demonstrated the feasibility and value of engaging patients and other stakeholders in a measurement development study. The Patient-Centered Outcomes Research Institute (PCORI) conceptual model of patient-centered outcomes research provides a useful guide for patient engagement in research. Research funders should call for meaningful roles for patients and other stakeholders in health research, including in the development of patient-centered outcomes.


Global localization from monocular SLAM on a mobile phone.
We propose the combination of a keyframe-based monocular SLAM system and a global localization method. The SLAM system runs locally on a camera-equipped mobile client and provides continuous, relative 6DoF pose estimation as well as keyframe images with computed camera locations. As the local map expands, a server process localizes the keyframes with a pre-made, globally-registered map and returns the global registration correction to the mobile client. The localization result is updated each time a keyframe is added, and observations of global anchor points are added to the client-side bundle adjustment process to further refine the SLAM map registration and limit drift. The end result is a 6DoF tracking and mapping system which provides globally registered tracking in real-time on a mobile device, overcomes the difficulties of localization with a narrow field-of-view mobile phone camera, and is not limited to tracking only in areas covered by the offline reconstruction.


Early Doppler-echocardiography evaluation of 597 prosthetic aortic valves.
This study was designed to describe the Doppler-echocardiography normal values in the early postoperative phase for Carpentier-Edwards Perimount Aortic Heart Valve bioprosthesis (CEP), St. Jude Medical (SJM) or Medical Regent (SJMR) Mechanical Heart Valves, evaluated by a single experienced echo-laboratory. Five hundred and ninety-seven consecutive patients in our hospital, who had had a CEP, a SJM or SJMR-17 mm implanted due to aortic stenosis, underwent a control Doppler-echocardiography evaluation 4-7 days after surgery. Hemodynamic performance of SJM, SJMR and CEP were accurately described, evaluating flow-dependent (trans-prosthetic velocities and gradients) and flow-independent (effective orifice area, indexed effective orifice area and Doppler velocity index) Doppler-echocardiography parameters. Of the 597 patients 50.6% were women (n = 302). Mean age was 66.3 +/- 11.7 years. Mean body surface area (BSA) was 1.76 +/- 0.22 m. Mean ejection fraction was 55.3 +/- 10.3%. Two hundred and sixty CEPs and 337 St. Jude mechanical valves (301 SJM and 36 SJMR size-17) were implanted. Comparing size-by-size SJM to CEP, the former were basically less flow obstructive. Our data confirm the wide range of variability, pointing out the need to perform routinely an accurate baseline Doppler-echocardiography evaluation of the hemodynamic profile of prosthetic aortic valves, including flow-dependent and independent parameters, to allow an adequate interpretation at follow-up.


Leadlikeness and structural diversity of synthetic screening libraries.
High program failure rates in the pharmaceutical industry have prompted the development of predictive software that can profile compound libraries as being 'druglike' (resembling existing drugs) and/or 'leadlike' (possessing the structural and physicochemical profile of a quality lead). In recent years, these two notions prompted pharmaceutical companies to clean up their corporate libraries of screening compounds. In order to maintain and expand the size and diversity of these corporate libraries, pharmaceutical companies still continue to add compounds to these, mainly by the acquisition of screening libraries. In this paper, we have analyzed 45 commercially available libraries, offered by suppliers of screening chemistry, for leadlikeness and diversity of the offered structures. To this end we have used a set of structural and physicochemical filters for leadlikeness that was developed in-house. These 45 supplier libraries contained a total of 5.3 million structures, of which 49% (2,592,778 structures) turned out to be unique, and only 12% (677,328 structures) were found to be both unique and leadlike. A diversity analysis revealed that big differences exist between the various offered libraries.


Short-term overfeeding may induce peripheral insulin resistance without altering subcutaneous adipose tissue macrophages in humans.
Chronic low-grade inflammation is a feature of obesity and is postulated to be causal in the development of insulin resistance and type 2 diabetes. The aim of this study was to assess whether overfeeding induces peripheral insulin resistance in lean and overweight humans, and, if so, whether it is associated with increased systemic and adipose tissue inflammation. Thirty-six healthy individuals undertook 28 days of overfeeding by +1,250 kcal/day (45% fat). Weight, body composition, insulin sensitivity (hyperinsulinemic-euglycemic clamp), serum and gene expression of inflammation markers, immune cell activation, fat cell size, macrophage and T-cell numbers in abdominal subcutaneous adipose tissue (flow cytometry and immunohistochemistry) were assessed at baseline and after 28 days. Subjects gained 2.7 +/- 1.6 kg (P < 0.001) and increased fat mass by 1.1 +/- 1.6% (P < 0.001). Insulin sensitivity decreased by 11% from 54.6 +/- 18.7 to 48.9 +/- 15.7 micromol/(kg of FFM)/min (P = 0.01). There was a significant increase in circulating C-reactive protein (P = 0.002) and monocyte chemoattractant protein-1 (P = 0.01), but no change in interleukin-6 and intercellular adhesion molecule-1. There were no changes in fat cell size, the number of adipose tissue macrophages or T-cells, or inflammatory gene expression and no change in circulating immune cell number or expression of their surface activation markers after overfeeding. Weight gain-induced insulin resistance was observed in the absence of a significant inflammatory state, suggesting that inflammation in subcutaneous adipose tissue occurs subsequent to peripheral insulin resistance in humans.


Shape and temperature memory of nanocomposites with broadened glass transition.
Shape-memory polymers can revert to their original shape when they are reheated. The stress generated by shape recovery is a growing function of the energy absorbed during deformation at a high temperature; thus, high energy to failure is a necessary condition for strong shape-memory materials. We report on the properties of composite nanotube fibers that exhibit this particular feature. We observed that these composites can generate a stress upon shape recovery up to two orders of magnitude greater than that generated by conventional polymers. In addition, the nanoparticles induce a broadening of the glass transition and a temperature memory with a peak of recovery stress at the temperature of their initial deformation.


Impact of matric potential and pore size distribution on growth dynamics of filamentous and non-filamentous soil bacteria.
The filamentous growth form is an important strategy for soil microbes to bridge air-filled pores in unsaturated soils. In particular, fungi perform better than bacteria in soils during drought, a property that has been ascribed to the hyphal growth form of fungi. However, it is unknown if, and to what extent, filamentous bacteria may also display similar advantages over non-filamentous bacteria in soils with low hydraulic connectivity. In addition to allowing for microbial interactions and competition across connected micro-sites, water films also facilitate the motility of non-filamentous bacteria. To examine these issues, we constructed and characterized a series of quartz sand microcosms differing in matric potential and pore size distribution and, consequently, in connection of micro-habitats via water films. Our sand microcosms were used to examine the individual and competitive responses of a filamentous bacterium (Streptomyces atratus) and a motile rod-shaped bacterium (Bacillus weihenstephanensis) to differences in pore sizes and matric potential. The Bacillus strain had an initial advantage in all sand microcosms, which could be attributed to its faster growth rate. At later stages of the incubation, Streptomyces became dominant in microcosms with low connectivity (coarse pores and dry conditions). These data, combined with information on bacterial motility (expansion potential) across a range of pore-size and moisture conditions, suggest that, like their much larger fungal counterparts, filamentous bacteria also use this growth form to facilitate growth and expansion under conditions of low hydraulic conductivity. The sand microcosm system developed and used in this study allowed for precise manipulation of hydraulic properties and pore size distribution, thereby providing a useful approach for future examinations of how these properties influence the composition, diversity and function of soil-borne microbial communities.


A review of the thoracic splanchnic nerves and celiac ganglia.
Anatomical variation of the thoracic splanchnic nerves is as diverse as any structure in the body. Thoracic splanchnic nerves are derived from medial branches of the lower seven thoracic sympathetic ganglia, with the greater splanchnic nerve comprising the more cranial contributions, the lesser the middle branches, and the least splanchnic nerve usually T11 and/or T12. Much of the early anatomical research of the thoracic splanchnic nerves revolved around elucidating the nerve root level contributing to each of these nerves. The celiac plexus is a major interchange for autonomic fibers, receiving many of the thoracic splanchnic nerve fibers as they course toward the organs of the abdomen. The location of the celiac ganglia are usually described in relation to surrounding structures, and also show variation in size and general morphology. Clinically, the thoracic splanchnic nerves and celiac ganglia play a major role in pain management for upper abdominal disorders, particularly chronic pancreatitis and pancreatic cancer. Splanchnicectomy has been a treatment option since Mallet-Guy became a major proponent of the procedure in the 1940s. Splanchnic nerve dissection and thermocoagulation are two common derivatives of splanchnicectomy that are commonly used today. Celiac plexus block is also a treatment option to compliment splanchnicectomy in pain management. Endoscopic ultrasonography (EUS)-guided celiac injection and percutaneous methods of celiac plexus block have been heavily studied and are two important methods used today. For both splanchnicectomies and celiac plexus block, the innovation of ultrasonographic imaging technology has improved efficacy and accuracy of these procedures and continues to make pain management for these diseases more successful.


Influence of spironolactone on endogenous steroid metabolism in man.
1. Mild secondary hyperaldosteronism was induced in ten healthy young males by a low sodium diet for 14 days. After 7 days on the diet, five subjects each were treated with spironolactone (group S) or triamterene (group T) daily. 2. The daily negative sodium balance was identical during the first 3 days of medication with both drugs but sodium loss was more severe during the following days in group S. Consequently, the plasma renin activity was higher during the last days of spironolactone compared with triamterene medication. 3. Changes in plasma electrolytes were similar in both groups. 4. No influence of either drug on the synthesis chain leading to cortisol was observed. 5. Plasma concentrations of deoxycorticosterone and corticosterone, however, increased considerably in group S, whereas triamterene did not influence these steroids. 6. Whereas triamterene induced a prompt increase of plasma aldosterone, an increase was delayed for the first 3 days of treatment with spironolactone. Later, plasma aldosterone concentrations rose rapidly in group S and were no longer different from those in group T. 7. Results are interpreted as being due to an initial inhibition of aldosterone synthesis by spironolactone, which is finally compensated, at least in part, by increased activation of the renin-angiotensin system.


A cornea substitute derived from fish scale: 6-month followup on rabbit model.
A fish scale-derived cornea substitute (Biocornea) is proposed as an alternative for human donor corneal tissue. We adopt a regenerative medicine approach to design a primary alternative to the use of fish scale for restoring sight by corneal replacement. Biocornea with corneal multilayer arrangement collagen was implanted to rabbits by pocket implantation. Our study demonstrated the safety and detailed morphologic and physiologic results from the 6 months of followup of rabbit model. In the peripheral Biocornea, the collagen fibrils were arranged in reticular fashion. Slit lamp examination showed that haze and an ulcer were not observed in all groups at 3 months postoperatively while all corneas with Biocornea were clear at both 3 months and 6 months postoperatively. The interface of Biocornea and stromal tissue were filled successfully and without observable immune cells at postoperative day 180. Moreover, the Biocornea was not dissolved and degenerated but remained transparent and showed no apparent fragmentation. Our study demonstrated that the Biocornea derived from fish scale as a good substitute had high biocompatibility and support function after a long-term evaluation. This revealed that the new approach of using Biocornea may yield an ideal artificial cornea substitute for long-term inlay placement.


The landscape of recombination in African Americans.
Recombination, together with mutation, gives rise to genetic variation in populations. Here we leverage the recent mixture of people of African and European ancestry in the Americas to build a genetic map measuring the probability of crossing over at each position in the genome, based on about 2.1 million crossovers in 30,000 unrelated African Americans. At intervals of more than three megabases it is nearly identical to a map built in Europeans. At finer scales it differs significantly, and we identify about 2,500 recombination hotspots that are active in people of West African ancestry but nearly inactive in Europeans. The probability of a crossover at these hotspots is almost fully controlled by the alleles an individual carries at PRDM9 (P value < 10(-245)). We identify a 17-base-pair DNA sequence motif that is enriched in these hotspots, and is an excellent match to the predicted binding target of PRDM9 alleles common in West Africans and rare in Europeans. Sites of this motif are predicted to be risk loci for disease-causing genomic rearrangements in individuals carrying these alleles. More generally, this map provides a resource for research in human genetic variation and evolution.


Glycan Profiles of gp120 Protein Vaccines from Four Major HIV-1 Subtypes Produced from Different Host Cell Lines under Non-GMP or GMP Conditions.
Envelope (Env) glycoprotein of human immunodeficiency virus type 1 (HIV-1) is an important target for the development of an HIV vaccine. Extensive glycosylation of Env is an important feature that both protects the virus from antibody responses and serves as a target for some highly potent broadly neutralizing antibodies. Therefore, analysis of glycans on recombinant Env proteins is highly significant. Here, we present glycosylation profiles of recombinant gp120 proteins from four major clades of HIV-1 (A, B, C, and AE), produced either as research-grade material in 293 and CHO cells or as two independent lots of clinical material under good manufacturing practice (GMP) conditions. Almost all potential N-linked glycosylation sites were at least partially occupied in all proteins. The occupancy rates were largely consistent among proteins produced under different conditions, although a few sites showed substantial variability even between the two GMP lots. Our data confirmed previous studies in the field, showing an abundance of oligomannose on Env protein, with 40 to 50% of glycans being Man5 to Man9 on all four proteins under all production conditions. Overall, the differences in occupancy and glycan forms among different Env subtypes produced under different conditions were less dramatic than anticipated, and antigenicity analysis with a panel of six monoclonal antibodies, including antibodies that recognize glycan forms, showed that all four gp120s maintained their antibody-binding profiles. Such findings have major implications for the final production of a clinical HIV vaccine with Env glycoprotein components.IMPORTANCE HIV-1 Env protein is a major target for the development of an HIV-1 vaccine. Env is covered with a large number of sugar-based glycan forms; about 50% of the Env molecular weight is composed of glycans. Glycan analysis of recombinant Env is important for understanding its roles in viral pathogenesis and immune responses. The current report presents the first extensive comparison of glycosylation patterns of recombinant gp120 proteins from four major clades of HIV-1 produced in two different cell lines, grown either under laboratory conditions or at 50-liter GMP scale in different lots. Information learned in this study is valuable for the further design and production of HIV-1 Env proteins as the critical components of HIV-1 vaccine formulations.


Adenovirus-mediated ex vivo gene transfer of basic fibroblast growth factor promotes collateral development in a rabbit model of hind limb ischemia.
Adenovirus-mediated ex vivo gene transfer of basic fibroblast growth factor (bFGF), a new strategy for the treatment of chronic vascular occlusive disease, was examined in a rabbit model of hind limb ischemia. The left femoral artery was completely excised to induce an ischemic state in the hind limb of male rabbits. Simultaneously, a skin section was resected from the wound, and host fibroblasts were cultured. The cultured fibroblasts were infected with adenovirus vector containing modified human bFGF cDNA with the secretory signal sequence (AxCAMAssbFGF) or LacZ cDNA (AxCALacZ). At 21 days after femoral artery excision, the gene-transduced fibroblasts were administered through the left internal iliac artery. The fibroblasts significantly accumulated in the ischemic hind limb, and the AxCAMAssbFGF-treated cells secreted bFGF for less than 14 days without elevation of systemic bFGF level. At 28 days after cell administration, calf blood pressure ratio, angiographic score, capillary density of muscle tissue and blood flow of the left internal iliac artery were determined, and animals with AxCAMAssbFGF-treated cells showed significantly greater development of collateral vessels, as compared with those with AxCALacZ-treated cells. These findings suggest that adenovirus-mediated ex vivo gene transfer of bFGF was effective for improvement of chronic limb ischemia.


Suppressing the dendritic growth of zinc in an ionic liquid containing cationic and anionic zinc complexes for battery applications.
Metallic zinc is a promising negative electrode for high energy rechargeable batteries due to its abundance, low-cost and non-toxic nature. However, the formation of dendritic zinc and low Columbic efficiency in aqueous alkaline solutions during charge/discharge processes remain a great challenge. Here we demonstrate that the dendritic growth of zinc can be effectively suppressed in an ionic liquid electrolyte containing highly concentrated cationic and anionic zinc complexes obtained by dissolving zinc oxide and zinc trifluoromethylsulfonate in a protic ionic liquid, 1-ethylimidazolium trifluoromethylsulfonate. The presence of both cationic and anionic zinc complexes alters the interfacial structure at the electrode/electrolyte interface and influences the nucleation and growth of zinc, leading to compact, homogeneous and dendrite-free zinc coatings. This study also provides insights into the development of highly concentrated metal salts in ionic liquids as electrolytes to deposit dendrite-free zinc as an anode material for energy storage applications.


Hepatitis C treatment completion in individuals with psychiatric comorbidity and depression.
Hepatitis C virus is a common bloodborne pathogen. Patient, provider, and health care system factors combine to constrain access to treatment and have led to low rates of treatment initiation and continuation among medically eligible individuals. Behavioral health comorbidity, which is common in the patient population, has historically been an exclusion criterion and is one such barrier to care. We implemented an interdisciplinary nurse-managed primary care-based hepatitis C evaluation and treatment program to address behavioral health needs concurrently in an effort to increase treatment initiation and continuation rates among comorbid individuals. We found no association between having a psychiatric or substance use history and treatment discontinuation in our patient cohort. Likewise, there was no association in our cohort between becoming depressed or anxious while undergoing treatment and treatment discontinuation. The results of our study concur with others that have shown that addressing behavioral health comorbidities concurrently with hepatitis C evaluation and treatment may improve treatment continuation rates among comorbid patients, thereby helping to remove barriers to treatment of chronic hepatitis C.


Prioritizing Wetlands for Waterbirds in a Boom and Bust System: Waterbird Refugia and Breeding in the Murray-Darling Basin.
Dryland rivers have considerable flow variability, producing complex ecosystems, processes, and communities of organisms that vary over space and time. They are also among the more vulnerable of the world's ecosystems. A key strategy for conservation of dryland rivers is identifying and maintaining key sites for biodiversity conservation, particularly protecting the quantity and quality of flow and flooding regimes. Extreme variability considerably challenges freshwater conservation planning. We systematically prioritised wetlands for waterbirds (simultaneously for 52 species), across about 13.5% of the Murray-Darling Basin (1,061,469 km2), using a 30-year record of systematic aerial surveys of waterbird populations. Nine key wetlands in this area, primarily lakes, floodplains, and swamps, consistently contributed to a representation target (80%) of total abundances of all 52 waterbird species. The long temporal span of our data included dramatic availability (i.e., booms) and scarcity (i.e., busts) of water, providing a unique opportunity to test prioritisation at extremes of variation. These extremes represented periods when waterbirds were breeding or concentrating on refugia, varying wetland prioritisation. In dry years, important wetlands for waterbirds were riverine and lacustrine (12 wetlands) but this changed in wet years to lacustrine and palustrine (8 wetlands). Such variation in ecosystem condition substantially changes the relative importance of individual wetlands for waterbirds during boom and bust phases. Incorporating this variability is necessary for effective conservation of Murray-Darling Basin waterbirds, with considerable generality for other similarly variable systems around the world.


An Advanced Practice Provider Initiative for Delirium Management in the ICU.
Delirium is the most common neuropsychiatric challenge in cancer patients, particularly in the critically ill population. Without a screening method and constant vigilance by providers, delirium is often misdiagnosed. The purpose of our pilot study was to determine if an educational program targeting critical care medicine advanced practice providers (APPs) and fellows in an oncologic intensive care unit would increase APP knowledge of delirium and their level of comfort with delirium screening and management. Thirty-one APPs and fellows participated in the program. Scores on knowledge-based delirium assessments increased significantly after the intervention and at the 3-month follow-up (p < .0001 and p < .0225, respectively). Providers' comfort with delirium screening and management also improved after the intervention (p = .0020 and p < .0001, respectively) and decreased slightly at the 3-month follow-up (p = .1764 and p = .9840, respectively). A brief and focused APP-led educational initiative successfully improved knowledge of delirium and comfort with screening and management.


Neuroprotective signaling and the aging brain: take away my food and let me run.
It is remarkable that neurons are able to survive and function for a century or more in many persons that age successfully. A better understanding of the molecular signaling mechanisms that permit such cell survival and synaptic plasticity may therefore lead to the development of new preventative and therapeutic strategies for age-related neurodegenerative disorders. We all know that overeating and lack of exercise are risk factors for many different age-related diseases including cardiovascular disease, diabetes and cancers. Our recent studies have shown that dietary restriction (reduced calorie intake) can increase the resistance of neurons in the brain to dysfunction and death in experimental models of Alzheimer's disease, Parkinson's disease, Huntington's disease and stroke. The mechanism underlying the beneficial effects of dietary restriction involves stimulation of the expression of 'stress proteins' and neurotrophic factors. The neurotrophic factors induced by dietary restriction may protect neurons by inducing the production of proteins that suppress oxyradical production, stabilize cellular calcium homeostasis and inhibit apoptotic biochemical cascades. Interestingly, dietary restriction also increases numbers of newly-generated neural cells in the adult brain suggesting that this dietary manipulation can increase the brain's capacity for plasticity and self-repair. Work in other laboratories suggests that physical and intellectual activity can similarly increase neurotrophic factor production and neurogenesis. Collectively, the available data suggest the that dietary restriction, and physical and mental activity, may reduce both the incidence and severity of neurodegenerative disorders in humans. A better understanding of the cellular and molecular mechanisms underlying these effects of diet and behavior on the brain is also leading to novel therapeutic agents that mimick the beneficial effects of dietary restriction and exercise.


Dietary treatment of urinary risk factors for renal stone formation. A review of CLU Working Group.
Diet interventions may reduce the risk of urinary stone formation and its recurrence, but there is no conclusive consensus in the literature regarding the effectiveness of dietary interventions and recommendations about specific diets for patients with urinary calculi. The aim of this study was to review the studies reporting the effects of different dietary interventions for the modification of urinary risk factors in patients with urinary stone disease. A systematic search of the Pubmed database literature up to July 1, 2014 for studies on dietary treatment of urinary risk factors for urinary stone formation was conducted according to a methodology developed a priori. Studies were screened by titles and abstracts for eligibility. Data were extracted using a standardized form and the quality of evidence was assessed. Evidence from the selected studies were used to form evidence-based guideline statements. In the absence of sufficient evidence, additional statements were developed as expert opinions. General measures: Each patient with nephrolithiasis should undertake appropriate evaluation according to the knowledge of the calculus composition. Regardless of the underlying cause of the stone disease, a mainstay of conservative management is the forced increase in fluid intake to achieve a daily urine output of 2 liters. HYPERCALCIURIA: Dietary calcium restriction is not recommended for stone formers with nephrolithiasis. Diets with a calcium content ≥ 1 g/day (and low protein-low sodium) could be protective against the risk of stone formation in hypercalciuric stone forming adults. Moderate dietary salt restriction is useful in limiting urinary calcium excretion and thus may be helpful for primary and secondary prevention of nephrolithiasis. A low-normal protein intake decrease calciuria and could be useful in stone prevention and preservation of bone mass. Omega-3 fatty acids and bran of different origin decreases calciuria, but their impact on the urinary stone risk profile is uncertain. Sports beverage do not affect the urinary stone risk profile. HYPEROXALURIA: A diet low in oxalate and/or a calcium intake normal to high (800-1200 mg/day for adults) reduce the urinary excretion of oxalate, conversely a diet rich in oxalates and/or a diet low in calcium increase urinary oxalate. A restriction in protein intake may reduce the urinary excretion of oxalate although a vegetarian diet may lead to an increase in urinary oxalate. Adding bran to a diet low in oxalate cancels its effect of reducing urinary oxalate. Conversely, the addition of supplements of fruit and vegetables to a mixed diet does not involve an increased excretion of oxalate in the urine. The intake of pyridoxine reduces the excretion of oxalate. HYPERURICOSURIA: In patients with renal calcium stones the decrease of the urinary excretion of uric acid after restriction of dietary protein and purine is suggested although not clearly demonstrated. HYPOCITRATURIA: The administration of alkaline-citrates salts is recommended for the medical treatment of renal stone-formers with hypocitraturia, although compliance to this treatment is limited by gastrointestinal side effects and costs. Increased intake of fruit and vegetables (excluding those with high oxalate content) increases citrate excretion and involves a significant protection against the risk of stone formation. Citrus (lemons, oranges, grapefruit, and lime) and non citrus fruits (melon) are natural sources of dietary citrate, and several studies have shown the potential of these fruits and/or their juices in raising urine citrate levels. There are enought basis to advice an adequate fluid intake also in children. Moderate dietary salt restriction and implementation of potassium intake are useful in limiting urinary calcium excretion whereas dietary calcium restriction is not recommended for children with nephrolithiasis. It seems reasonable to advice a balanced consumption of fruit and vegetables and a low consumption of chocolate and cola according to general nutritional guidelines, although no studies have assessed in pediatric stone formers the effect of fruit and vegetables supplementation on urinary citrate and the effects of chocolate and cola restriction on urinary oxalate in pediatric stone formers. Despite the low level of scientific evidence, a low-protein (< 20 g/day) low-salt (< 2 g/day) diet with high hydration (> 3 liters/day) is strongly advised in children with cystinuria. ELDERLY: In older patients dietary counseling for renal stone prevention has to consider some particular aspects of aging. A restriction of sodium intake in association with a higher intake of potassium, magnesium and citrate is advisable in order to reduce urinary risk factors for stone formation but also to prevent the loss of bone mass and the incidence of hypertension, although more hemodynamic sensitivity to sodium intake and decreased renal function of the elderly have to be considered. A diet rich in calcium (1200 mg/day) is useful to maintain skeletal wellness and to prevent kidney stones although an higher supplementation could involve an increase of risk for both the formation of kidney stones and cardiovascular diseases. A lower content of animal protein in association to an higher intake of plant products decrease the acid load and the excretion of uric acid has no particular contraindications in the elderly patients, although overall nutritional status has to be preserved.


Puerarin facilitates T-tubule development of murine embryonic stem cell-derived cardiomyocytes.
The embryonic stem cell-derived cardiomyocytes (ES-CM) is one of the promising cell sources for repopulation of damaged myocardium. However, ES-CMs present immature structure, which impairs their integration with host tissue and functional regeneration. This study used murine ES-CMs as an in vitro model of cardiomyogenesis to elucidate the effect of puerarin, the main compound found in the traditional Chinese medicine the herb Radix puerariae, on t-tubule development of murine ES-CMs. Electron microscope was employed to examine the ultrastructure. The investigation of transverse-tubules (t-tubules) was performed by Di-8-ANEPPS staining. Quantitative real-time PCR was utilized to study the transcript level of genes related to t-tubule development. We found that long-term application of puerarin throughout cardiac differentiation improved myofibril array and sarcomeres formation, and significantly facilitated t-tubules development of ES-CMs. The transcript levels of caveolin-3, amphiphysin-2 and junctophinlin-2, which are crucial for the formation and development of t-tubules, were significantly upregulated by puerarin treatment. Furthermore, puerarin repressed the expression of miR-22, which targets to caveolin-3. Our data showed that puerarin facilitates t-tubule development of murine ES-CMs. This might be related to the repression of miR-22 by puerarin and upregulation of Cav3, Bin1 and JP2 transcripts.


Cognitive and Physical Activities Impair Perception of Smartphone Vibrations.
Vibration feedback is common in everyday devices, from virtual reality systems to smartphones. However, cognitive and physical activities may impede our ability to sense vibrations from devices. In this study, we develop and characterize a smartphone platform to investigate how a shape-memory task (cognitive activity) and walking (physical activity) impair human perception of smartphone vibrations. We measured how Apple's Core Haptics Framework parameters can be used for haptics research, namely how hapticIntensity modulates amplitudes of 230 Hz vibrations. A 23-person user study found that physical ( ) and cognitive ( p=0.004) activity increase vibration perception thresholds. Cognitive activity also increases vibration response time ( ). This work also introduces a smartphone platform that can be used for out-of-lab vibration perception testing. Researchers can use our smartphone platform and results to design better haptic devices for diverse, unique populations.


A tale of two trials: a comparison of the post-acute coronary syndrome lipid-lowering trials A to Z and PROVE IT-TIMI 22.
The Aggrastat to Zocor (A to Z) and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT) trials compared intensive and moderate statin therapy after acute coronary syndromes, with seemingly disparate results. We analyzed the design, implementation, and results of the two trials in an attempt to clarify the effects of early intensive statin therapy. Study design, end points, and definitions were compared. In each trial, comparisons were made between intensive and moderate arms for both trials' primary end points and death/myocardial infarction. Analyses were performed over various time points: at the end of the trials, < or =4 months, and >4 months. Subjects in A to Z had higher-risk demographics. More PROVE IT subjects were enrolled in the United States and underwent prerandomization revascularization. The low-density lipoprotein (LDL) difference was greater in A to Z than in PROVE IT early (< or =4 months) but less late. Significant C-reactive protein reduction was earlier in PROVE IT. With common end points, event rates were higher in A to Z, and early favorable separation of event curves was seen in PROVE IT but not in A to Z. Clinical end point rates and reductions were similar in both trials after 4 months. An early benefit was seen in PROVE IT but not in A to Z. Late-phase results were similar. Factors that may explain this disparity include the intensity of therapy in the early phase, timing, and magnitude of LDL and C-reactive protein lowering, differences in early revascularization, and the play of chance. Taken together, the results of these trials support a strategy of early intensive statin therapy coupled with revascularization when appropriate in patients after acute coronary syndrome.


Secondary prevention of fractures after hip fracture: a qualitative study of effective service delivery.
There is variation in how services to prevent secondary fractures after hip fracture are delivered and no consensus on best models of care. This study identifies healthcare professionals' views on effective care for the prevention of these fractures. It is hoped this will provide information on how to develop services. Hip fracture patients are at high risk of subsequent osteoporotic fractures. Whilst fracture prevention services are recommended, there is variation in delivery and no consensus on best models of care. This study aims to identify healthcare professionals' views on effective care for prevention of secondary fracture after hip fracture. Forty-three semi-structured interviews were undertaken with healthcare professionals involved in delivering fracture prevention across 11 hospitals in one English region. Interviews explored views on four components of care: (1) case finding, (2) osteoporosis assessment, (3) treatment initiation, and (4) monitoring and coordination. Interviews were audio-recorded, transcribed, anonymised and coded using NVivo software. Case finding: a number of approaches were discussed. Multiple methods ensured there was a 'backstop' if patients were overlooked. Osteoporosis assessment: there was no consensus on who should conduct this. The location of the dual energy X-ray absorptiometry (DXA) scanner influenced the likelihood of patients receiving a scan. Treatment initiation: it was felt this was best done in inpatients rather request initiation in the post-discharge/outpatients period. Monitoring (adherence): adherence was a major concern, and participants felt more monitoring could be conducted by secondary care. Coordination of care: participants advocated using dedicated coordinators and formal and informal methods of communication. A gap between primary and secondary care was identified and strategies suggested for addressing this. A number of ways of organising effective fracture prevention services after hip fracture were identified. It is hoped that this will help professionals identify gaps in care and provide information on how to develop services.


Granulocyte and monocyte adsorption apheresis for cutaneous allergic vasculitis.
Cutaneous allergic vasculitis (CAV) is characterized clinically by purpuric patches with secondary ulcerations, and histologically by leukocytoclastic vasculitis with neutrophil infiltrates. Granulocyte and monocyte adsorption apheresis (GCAP) is an extracorporeal apheresis instrument using a column containing cellulose acetate beads designed to remove pathogenic granulocytes. Here we report our assessment of the efficacy of GCAP for recurrent leg ulcers in a 49-year-old woman with CAV. She underwent five GCAP treatments at one-week intervals. In each treatment session, 1800 mL of blood was processed. Her leg ulcers responded well and her white blood cell and neutrophil counts and the expression level of CD11b/CD18, a marker for activated neutrophils, on her peripheral neutrophils were reduced from 7500/microL to 6500/microL, 4350/microL to 3315/microL, and 64.9 MFI (mean fluorescence intensity) to 27.0 MFI (normal controls: 10.5 +/- 1.2 MFI) by GCAP, respectively. These results suggest that GCAP is useful for skin disorders with leucocytoclastic vasculitis.


Low overhead and nonlinear-tolerant adaptive zero-guard-interval CO-OFDM.
We propose an adaptive channel estimation (CE) method for zero-guard-interval (ZGI) coherent optical (CO)-OFDM systems, and demonstrate its performance in a single channel 28 Gbaud polarization-division multiplexed ZGI CO-OFDM experiment with only 1% OFDM processing overhead. We systematically investigate its robustness against various transmission impairments including residual chromatic dispersion, polarization-mode dispersion, state of polarization rotation, sampling frequency offset and fiber nonlinearity. Both experimental and numerical results show that the adaptive CE-aided ZGI CO-OFDM is highly robust against these transmission impairments in fiber optical transmission systems.


The reverse Warburg effect: glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts.
We and others have previously identified a loss of stromal caveolin-1 (Cav-1) in cancer-associated fibroblasts (CAFs) as a powerful single independent predictor of breast cancer patient tumor recurrence, metastasis, tamoxifen-resistance, and poor clinical outcome. However, it remains unknown how loss of stromal Cav-1 mediates these effects clinically. To mechanistically address this issue, we have now generated a novel human tumor xenograft model. In this two-component system, nude mice are co-injected with i) human breast cancer cells (MDA-MB-231), and ii) stromal fibroblasts (wild-type (WT) versus Cav-1 (-/-) deficient). This allowed us to directly evaluate the effects of a Cav-1 deficiency solely in the tumor stromal compartment. Here, we show that Cav-1-deficient stromal fibroblasts are sufficient to promote both tumor growth and angiogenesis, and to recruit Cav-1 (+) micro-vascular cells. Proteomic analysis of Cav-1-deficient stromal fibroblasts indicates that these cells upregulate the expression of glycolytic enzymes, a hallmark of aerobic glycolysis (the Warburg effect). Thus, Cav-1-deficient stromal fibroblasts may contribute towards tumor growth and angiogenesis, by providing energy-rich metabolites in a paracrine fashion. We have previously termed this new idea the "Reverse Warburg Effect". In direct support of this notion, treatment of this xenograft model with glycolysis inhibitors functionally blocks the positive effects of Cav-1-deficient stromal fibroblasts on breast cancer tumor growth. Thus, pharmacologically-induced metabolic restriction (via treatment with glycolysis inhibitors) may be a promising new therapeutic strategy for breast cancer patients that lack stromal Cav-1 expression. We also identify the stromal expression of PKM2 and LDH-B as new candidate biomarkers for the "Reverse Warburg Effect" or "Stromal-Epithelial Metabolic Coupling" in human breast cancers.


Cosmid based mutagenesis causes genetic instability in Streptomyces coelicolor, as shown by targeting of the lipoprotein signal peptidase gene.
Bacterial lipoproteins are extracellular proteins tethered to cell membranes by covalently attached lipids. Deleting the lipoprotein signal peptidase (lsp) gene in Streptomyces coelicolor results in growth and developmental defects that cannot be restored by reintroducing lsp. This led us to hypothesise that lsp is essential and that the lsp mutant we isolated previously had acquired compensatory secondary mutations. Here we report resequencing of the genomes of wild-type M145 and the cis-complemented ∆lsp mutant (BJT1004) to map and identify these secondary mutations but we show that they do not increase the efficiency of disrupting lsp and are not lsp suppressors. We provide evidence that they are induced by introducing the cosmid St4A10∆lsp, as part of ReDirect PCR mutagenesis protocol, which transiently duplicates a number of important cell division genes. Disruption of lsp using a suicide vector (which does not result in gene duplication) still results in growth and developmental delays and we conclude that loss of Lsp function results in developmental defects due to the loss of all lipoproteins from the cell membrane. Significantly, our results also indicate the use of cosmid libraries for the genetic manipulation of bacteria can lead to phenotypes not necessarily linked to the gene(s) of interest.


The role of decision confidence in advice-taking and trust formation.
In a world where ideas flow freely across multiple platforms, people must often rely on others' advice and opinions without an objective standard to judge whether this information is accurate. The present study explores the hypothesis that an individual's internal decision confidence can be used as a signal to learn the accuracy of others' advice, even in the absence of feedback. According to this "agreement-in-confidence" hypothesis, people can learn about an advisor's accuracy across multiple interactions according to whether the advice offered agrees with their own initial opinions, weighted by the confidence with which these initial opinions are held. We test this hypothesis using a judge-advisor system paradigm to precisely manipulate the profiles of virtual advisors in a perceptual decision-making task. We find that when advisors' and participants' judgments are independent, people can correctly learn advisors' features, like their accuracy and calibration, whether or not objective feedback is available. However, when their judgments (and thus errors) are correlated-as is the case in many real social contexts-predictable distortions in trust can be observed between feedback and feedback-free scenarios. Using agent-based simulations, we explore implications of these individual-level heuristics for network-level patterns of trust and belief formation. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Identification of women with early breast cancer by analysis of p43-positive lymphocytes.
Regular screening mammographies and increasing knowledge of high-risk groups have resulted in an improvement in the rate of detection of smaller malignant lesions. However, uncertain minimal mammographic features frequently require further costly and often uncomfortable investigation, including repeat radiological controls or surgical procedures, before cancerous lesions can be identified. Placental isoferritin (p43), a protein with immunosuppressive effects, has been detected on the surface of lymphocytes taken from peripheral blood in patients with breast cancer. In this study we evaluated the sensitivity and specificity of the expression of p43-positive lymphocytes as a marker in early stage breast cancer and also investigated its expression on T-cell subpopulations. The presence of p43-positive lymphocytes was investigated using the monoclonal antibody CM-H-9 and flow cytometry in 76 women with controversial, non-palpable mammographic findings who were undergoing surgical biopsy. Patients with early breast cancer (n = 48) had significantly higher p43-positive cell values (median 3.83%, range 0.98-19.4) than patients with benign lumps (n = 28, median 1.43%, range 0.17-3.7) or controls (n = 22, median 1.3%, range 0.4-1.87) (P < 0.0001). At a cut-off level of 2% p43-positive cells a sensitivity of 91.7% and a specificity of 89.3% for detection of breast cancer could be reached. While the median ratio of total CD4+/CD8+ cells was 2.6, a ratio of 1.3 was found for the p43-positive subpopulation (P < 0.001), thus indicating a significant link between p43 and CD8+ cells. The determination of p43-positive lymphocytes in peripheral blood could serve as an additional diagnostic tool in patients with controversial mammographic findings and could also reduce the need for cost-intensive and often uncomfortable management of these patients.


Photoactivated capture molecule immobilization in plasmonic nanoapertures in the ultraviolet.
We demonstrate a photoactivated surface coupling scheme for achieving spatial overlap between biomolecules of interest and optical near field excitation. Using aluminium nanoapertures, we obtained increased coupling efficiency of biotinylated capture probe oligos to the photoactivated surface due to ~3× nanoaperture enhancement of UV light. We further validate DNA sensor functionality via the hybridization of Cy-5 labeled target oligos, with up to 8× fluorescence enhancement obtained from a commercial microarray scanner. This generic photoimmobilization strategy is an essential step to realizing miniaturized plasmon enhanced detection arrays by virtue of localizing capture molecules to the region of plasmonic enhancement.


A Novel Model of Meibomian Gland Dysfunction Induced with Complete Freund's Adjuvant in Rabbits.
A novel meibomian gland dysfunction (MGD) model induced by the injection of complete Freund's adjuvant (CFA) in rabbits was developed to facilitate the understanding of the pathophysiology of MGD with meibomitis. In addition, we sought to evaluate treatment with steroid eye drops in this model. Male Japanese white rabbits were subcutaneously injected with CFA into the upper eyelid margin. The eyelid margins of the rabbits were chronologically observed through slit lamp examination. The development of meibomitis was assessed through histopathology. We evaluated the effects of topically applied tobramycin/dexamethasone (Tob/Dex) eye drops on the plugged orifices and telangiectasia. After the injection of CFA, slit lamp examination revealed markedly plugged orifices, telangiectasia around the orifices and a toothpaste-like meibum, as compared with the normal eyelids. Histopathology revealed granulation tissue with infiltration of inflammatory cells, hyperkeratinization of the ductal epithelium, and cystic dilatation of ducts in the meibomian gland. The orifices were plugged with a proteinaceous substance. Tob/Dex eye drops significantly suppressed the plugging and telangiectasia around the orifices. Through the injection of CFA, we successfully established a novel rabbit MGD that mimics the symptoms observed in humans meibomitis. This model should be useful in the evaluation of the efficacy of drug candidates.


Phthalocyanine-peptide conjugates: receptor-targeting bifunctional agents for imaging and photodynamic therapy.
The synthesis of a series of new zinc phthalocyanine-peptide conjugates targeting the gastrin-releasing peptide (GRP) and integrin receptors is reported. Two alternative synthetic methods based on Sonogashira cross-coupling of an iodinated zinc phthalocyanine with acetylenic bombesin or arginine-glycine-aspartic acid (RGD) derivatives, either in solution or on solid phase, are presented. The water-soluble conjugates were screened for their photodynamic efficacy against several cancer cell lines expressing different levels of GRP and integrin receptors, and their intracellular localization was evaluated via confocal fluorescence microscopy. Variations in photocytotoxicity between the conjugates correlate to differences in hydrophobicity as well as receptor-mediated cell uptake. In the case of the phthalocyanine-bombesin conjugate, competition experiments confirm the involvement of the GRP receptor in both the phototherapeutic activity as well as intracellular localization. These findings warrant further in vivo studies to evaluate the potential of this conjugate as photosensitizer for photodynamic therapy (PDT) of cancers overexpressing the GRP receptor.


Insights into the molecular interaction between two polyoxygenated cinnamoylcoumarin derivatives and human serum albumin.
Ligand binding studies on human serum albumin (HSA) are crucial in determining the pharmacological properties of drug candidates. Here, two representatives of coumarin-chalcone hybrids were selected and their binding mechanism was identified via thermodynamics techniques, curve resolution analysis and computational methods at molecular levels. The binding parameters were derived using spectroscopic approaches and the results point to only one pocket located near the Trp214 residue in subdomain IIA of HSA. The protein tertiary structure was altered during ligand binding and formed an intermediate structure to create stronger ligand binding interactions. The best binding mode of the ligand was initially estimated by docking on an ensemble of HSA crystallographic structures and by molecular dynamics (MD) simulations. Per residue interaction energies were calculated over the MD trajectories as well. Reasonable agreement was found between experimental and theoretical results about the nature of binding, which was dominated by hydrogen bonding and van der Waals contributions.


Health and wellbeing outcomes of programs for Indigenous Australians that include strategies to enable the expression of cultural identities: a systematic review.
Indigenous people have long maintained that strong cultural identities are critical to health and wellbeing. The purpose of this systematic review is to examine whether interventions that entail strategies to enable expression of cultural identities for Australian Indigenous peoples are associated with measurable improvements in health and wellbeing. Peer-reviewed articles that reported quantitatively expressed health and wellbeing outcomes involving Indigenous Australian participants only were included. The cultural intervention component was defined and assessed by Indigenous researchers on the team. A narrative analysis was conducted. The protocol was registered on PROSPERO (CRD42015027387). Thirteen articles describing eleven studies were identified, including one randomised control trial (RCT), one cluster RCT and two studies with non-randomised controls. Other studies reported on case series or cross-sectional studies. All except two studies described multiple intervention strategies. Eight studies showed significant improvement in at least one psychosocial, behavioural or clinical measure, with two showing a positive direction of effect and one showing no improvement. Publication bias may discourage researchers to report negative findings of these interventions. Although studies vary in quality, this review provides evidence that interventions that include opportunities for expression of cultural identities can have beneficial effects for Australian Indigenous peoples.


Clinical features of Barré-Lièou syndrome and efficacy of trazodone for its treatment: A retrospective single center study.
Barré-Lièou syndrome (BLS) is a manifestation of various autonomic and secondary symptoms including muscle stiffness, tinnitus, dizziness, and pain in various body parts. Although considered to be caused by hyperactivation of the autonomic nervous system due to trauma, there is currently no firmly established etiology or evidence on the treatment and clinical features of BLS. We retrospectively examined the clinical features of BLS and evaluated the efficacy of trazodone (TZD) for its treatment. We conducted a retrospective analysis of the data of 20 consecutive cases with suspected BLS who were treated in our hospital between 2016 and 2019. BLS symptoms were rated on a 10-point scale, and two groups were defined, that is, a mild-BLS group (BLS scores, 1-5) and a severe-BLS group (BLS scores, 6-10). Univariate analysis of patient factors was performed. The BLS score was 6.0 ± 1.7, and the maximum TZD dose was 80 ± 34 mg/day; nine patients (45%) were TZD free, and no TZD side effects were observed, while all patients had a good clinical outcome. There were significant differences between the mild-BLS and severe-BLS groups in the period from injury to diagnosis (p = 0.015), chest/back pain (p < 0.001), constipation (p = 0.001), and maximum TZD dose (p = 0.008). BLS involves posttraumatic autonomic symptoms accompanied by depression and insomnia. The sympathetic hypersensitivity theory could explain its etiology. TZD could effectively and safely treat BLS, and early diagnosis and treatment can contribute toward good clinical outcomes. Enhanced recognition and understanding of this disease are warranted.


Hospital responses to a data-driven statewide quality improvement project.
The overall success of any continuous quality improvement (CQI) project lies in the ability to measure changes resulting from the project and to show that changes have resulted n improved care. A software tool was developed to categorize hospital responses and activities implemented by hospitals as a result of the Cooperative Cardiovascular Project CCP). Information was captured regarding the hospital's acceptance of data and the educational/interventional strategies implemented. Hospital size, number of acute myocardial infarction patients treated, indicator performances, and type of presentation given (on-site versus regional visit) was entered to allow analysis of factors affecting the response. sixty-one of 107 hospitals responded to the peer review organization. Of those, 49% planned further educational activities and 75% planned to implement some form of CQI activity. Comparison of responses in relation to the type of presentation received suggested that on-site presentations are associated with higher response rates and more intense quality improvement efforts. This also could be attributed to other factors such as hospital size, teaching environment, or number of acute myocardial infarction patients treated. The system developed allowed us to collate hospital improvement efforts as a result of CCP. The system is limited in its ability to identify those activities taking place before CCP. Further development and refinement of the tool is warranted to document quality improvement efforts and determine best strategies for peer review organization intervention.


ATLANTIC DIP: the impact of obesity on pregnancy outcome in glucose-tolerant women.
OBJECTIVE A prospective study of the impact of obesity on pregnancy outcome in glucose-tolerant women. RESEARCH DESIGN AND METHODS The Irish Atlantic Diabetes in Pregnancy network advocates universal screening for gestational diabetes. Women with normoglycemia and a recorded booking BMI were included. Maternal and infant outcomes correlated with booking BMI are reported. RESULTS A total of 2,329 women fulfilled the criteria. Caesarean deliveries increased in overweight (OW) (odds ratio 1.57 [95% CI 1.24-1.98]) and obese (OB) (2.65 [2.03-3.46]) women. Hypertensive disorders increased in OW (2.30 [1.55-3.40]) and OB (3.29 [2.14-5.05]) women. Reported miscarriages increased in OB (1.4 [1.11-1.77]) women. Mean birth weight was 3.46 kg in normal BMI (NBMI), 3.54 kg in OW, and 3.62 kg in OB (P < 0.01) mothers. Macrosomia occurred in 15.5, 21.4, and 27.8% of babies of NBMI, OW, and OB mothers, respectively (P < 0.01). Shoulder dystocia occur in 4% (>4 kg) compared with 0.2% (<4 kg) babies (P < 0.01). Congenital malformation risk increased for OB (2.47 [1.09-5.60]) women. CONCLUSIONS OW and OB glucose-tolerant women have greater adverse pregnancy outcomes.


Social relationships and risk of dementia: A systematic review and meta-analysis of longitudinal cohort studies.
It is unclear to what extent poor social relationships are related to the development of dementia. A comprehensive systematic literature search identified 19 longitudinal cohort studies investigating the association between various social relationship factors and incident dementia in the general population. Relative risks (RRs) with 95% confidence intervals (CIs) were pooled using random-effects meta-analysis. Low social participation (RR: 1.41 (95% CI: 1.13-1.75)), less frequent social contact (RR: 1.57 (95% CI: 1.32-1.85)), and more loneliness (RR: 1.58 (95% CI: 1.19-2.09)) were statistically significant associated with incident dementia. The results of the association between social network size and dementia were inconsistent. No statistically significant association was found for low satisfaction with social network and the onset of dementia (RR: 1.25 (95% CI: 0.96-1.62). We conclude that social relationship factors that represent a lack of social interaction are associated with incident dementia. The strength of the associations between poor social interaction and incident dementia is comparable with other well-established risk factors for dementia, including low education attainment, physical inactivity, and late-life depression.


Association of combination statin and antihypertensive therapy with reduced Alzheimer's disease and related dementia risk.
Hyperlipidemia and hypertension are modifiable risk factors for Alzheimer's disease and related dementias (ADRD). Approximately 25% of adults over age 65 use both antihypertensives (AHTs) and statins for these conditions. While a growing body of evidence found statins and AHTs are independently associated with lower ADRD risk, no evidence exists on simultaneous use for different drug class combinations and ADRD risk. Our primary objective was to compare ADRD risk associated with concurrent use of different combinations of statins and antihypertensives. In a retrospective cohort study (2007-2014), we analyzed 694,672 Medicare beneficiaries in the United States (2,017,786 person-years) who concurrently used both statins and AHTs. Using logistic regression adjusting for age, socioeconomic status and comorbidities, we quantified incident ADRD diagnosis associated with concurrent use of different statin molecules (atorvastatin, pravastatin, rosuvastatin, and simvastatin) and AHT drug classes (two renin-angiotensin system (RAS)-acting AHTs, angiotensin converting enzyme inhibitors (ACEIs) or angiotensin-II receptor blockers (ARBs), vs non-RAS-acting AHTs). Pravastatin or rosuvastatin combined with RAS-acting AHTs reduce risk of ADRD relative to any statin combined with non-RAS-acting AHTs: ACEI+pravastatin odds ratio (OR) = 0.942 (CI: 0.899-0.986, p = 0.011), ACEI+rosuvastatin OR = 0.841 (CI: 0.794-0.892, p<0.001), ARB+pravastatin OR = 0.794 (CI: 0.748-0.843, p<0.001), ARB+rosuvastatin OR = 0.818 (CI: 0.765-0.874, p<0.001). ARBs combined with atorvastatin and simvastatin are associated with smaller reductions in risk, and ACEI with no risk reduction, compared to when combined with pravastatin or rosuvastatin. Among Hispanics, no combination of statins and RAS-acting AHTs reduces risk relative to combinations of statins and non-RAS-acting AHTs. Among blacks using ACEI+rosuvastatin, ADRD odds were 33% lower compared to blacks using other statins combined with non-RAS-acting AHTs (OR = 0.672 (CI: 0.548-0.825, p<0.001)). Among older Americans, use of pravastatin and rosuvastatin to treat hyperlipidemia is less common than use of simvastatin and atorvastatin, however, in combination with RAS-acting AHTs, particularly ARBs, they may be more effective at reducing risk of ADRD. The number of Americans with ADRD may be reduced with drug treatments for vascular health that also confer effects on ADRD.


A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study.
Rasagiline (n-propargyl-1[R]-aminoindan) mesylate is a novel irreversible selective monoamine oxidase type B inhibitor, previously demonstrated to improve symptoms in early Parkinson disease (PD). To determine the safety, tolerability, and efficacy of rasagiline in levodopa-treated patients with PD and motor fluctuations. Multicenter, randomized, placebo-controlled, double-blind, parallel-group study. Parkinson disease patients (N = 472) with at least 21/2 hours of daily "off" (poor motor function) time, despite optimized treatment with other anti-PD medications. Rasagiline, 1.0 or 0.5 mg/d, or matching placebo. Change from baseline in total daily off time measured by patients' home diaries during 26 weeks of treatment, percentage of patients completing 26 weeks of treatment, and adverse event frequency. During the treatment period, the mean adjusted total daily off time decreased from baseline by 1.85 hours (29%) in patients treated with 1.0 mg/d of rasagiline, 1.41 hours (23%) with 0.5 mg/d rasagiline, and 0.91 hour (15%) with placebo. Compared with placebo, patients treated with 1.0 mg/d rasagiline had 0.94 hour less off time per day, and patients treated with 0.5 mg/d rasagiline had 0.49 hour less off time per day. Prespecified secondary end points also improved during rasagiline treatment, including scores on an investigator-rated clinical global impression scale and the Unified Parkinson's Disease Rating Scale (activities of daily living in the off state and motor performance in the "on" state). Rasagiline was well tolerated. Rasagiline improves motor fluctuations and PD symptoms in levodopa-treated PD patients. In light of recently reported benefits in patients with early illness, rasagiline is a promising new treatment for PD.