Autopedophilia.
The most salient dimension of men's sexual orientation is gender: attraction to males versus females. A second dimension is sexual maturity: attraction to children versus adults. A less appreciated dimension is location: attraction to other individuals versus the sexual fantasy of being one of those individuals. Men sexually aroused by the idea or fantasy of being the kinds of individuals to whom they are sexually attracted have an erotic-target identity inversion (ETII). We conducted an online survey to investigate the prevalence and phenomenology of ETIIs among 475 men sexually attracted to children. Autopedophilia, or sexual arousal by the idea of being a child, was common. Furthermore, autopedophilic men tended to be sexually aroused by imagining themselves as the kinds of children (with respect to gender and age) to whom they are sexually attracted. Results support the concept of ETIIs and exemplify the simultaneous importance of three dimensions of male sexual orientation.


Models for structuring a clinical initiative to enhance palliative care in the intensive care unit: a report from the IPAL-ICU Project (Improving Palliative Care in the ICU).
To describe models used in successful clinical initiatives to improve the quality of palliative care in critical care settings. We searched the MEDLINE database from inception to April 2010 for all English language articles using the terms "intensive care," "critical care," or "ICU" and "palliative care"; we also hand-searched reference lists and author files. Based on review and synthesis of these data and the experiences of our interdisciplinary expert Advisory Board, we prepared this consensus report. We critically reviewed the existing data with a focus on models that have been used to structure clinical initiatives to enhance palliative care for critically ill patients in intensive care units and their families. There are two main models for intensive care unit-palliative care integration: 1) the "consultative model," which focuses on increasing the involvement and effectiveness of palliative care consultants in the care of intensive care unit patients and their families, particularly those patients identified as at highest risk for poor outcomes; and 2) the "integrative model," which seeks to embed palliative care principles and interventions into daily practice by the intensive care unit team for all patients and families facing critical illness. These models are not mutually exclusive but rather represent the ends of a spectrum of approaches. Choosing an overall approach from among these models should be one of the earliest steps in planning an intensive care unit-palliative care initiative. This process entails a careful and realistic assessment of available resources, attitudes of key stakeholders, structural aspects of intensive care unit care, and patterns of local practice in the intensive care unit and hospital. A well-structured intensive care unit-palliative care initiative can provide important benefits for patients, families, and providers.


Measurement challenge: protocol for international case-control comparison of mammographic measures that predict breast cancer risk.
For women of the same age and body mass index, increased mammographic density is one of the strongest predictors of breast cancer risk. There are multiple methods of measuring mammographic density and other features in a mammogram that could potentially be used in a screening setting to identify and target women at high risk of developing breast cancer. However, it is unclear which measurement method provides the strongest predictor of breast cancer risk. The measurement challenge has been established as an international resource to offer a common set of anonymised mammogram images for measurement and analysis. To date, full field digital mammogram images and core data from 1650 cases and 1929 controls from five countries have been collated. The measurement challenge is an ongoing collaboration and we are continuing to expand the resource to include additional image sets across different populations (from contributors) and to compare additional measurement methods (by challengers). The intended use of the measurement challenge resource is for refinement and validation of new and existing mammographic measurement methods. The measurement challenge resource provides a standardised dataset of mammographic images and core data that enables investigators to directly compare methods of measuring mammographic density or other mammographic features in case/control sets of both raw and processed images, for the purposes of the comparing their predictions of breast cancer risk. Challengers and contributors are required to enter a Research Collaboration Agreement with the University of Melbourne prior to participation in the measurement challenge. The Challenge database of collated data and images are stored in a secure data repository at the University of Melbourne. Ethics approval for the measurement challenge is held at University of Melbourne (HREC ID 0931343.3).


Quantification of fluorescent reporters in plant cells.
Fluorescent reporters are powerful tools for plant research. Many studies require accurate determination of fluorescence intensity and localization. Here, we describe protocols for the quantification of fluorescence intensity in plant cells from confocal laser scanning microscope images using semiautomated software and image analysis techniques.


Differential association of Orc1 and Sir2 proteins to telomeric domains in Plasmodium falciparum.
Telomeres have the capacity to recruit proteins that facilitate the spreading of heterochromatin into subtelomeric DNA regions. In the human protozoan pathogen Plasmodium falciparum, the telomere-associated protein Sir2 has been shown to control the silencing of members of virulence genes at some, but not all, chromosome-end loci, indicating that additional proteins are involved in telomere position effect. Here, we identified, in P. falciparum, a novel telomere-associated protein that displays homology with the origin-of-recognition-complex 1 protein Orc1. Antibodies raised against this P. falciparum protein localized to telomeric clusters in the nuclear periphery and the nucleolus. It was found that, prior to DNA replication, P. falciparum Orc1 and Sir2 undergo drastic subcellular reorganization, such as dissociation from the telomere cluster and spreading into the nucleus and parasite cytoplasm. Relocation of Orc1 and Sir2 was also linked to the partial dissociation of telomere clusters. Super gel-shift and chromatin-immunoprecipitation experiments showed the physical association of Orc1 with telomere repeats but revealed a differential association with adjacent non-coding repeat DNA elements. Our data suggest that Plasmodium telomeres might fold back and that Orc1 cooperates with Sir2 in telomeric silencing.


Effects of the glucocorticoid betamethasone on the interaction of Candida albicans with human epithelial cells.
The glucocorticoid betamethasone (BM) is frequently employed in clinical practice because of its anti-inflammatory and immunosuppressive properties. In this study, we investigated the effect of BM (1 and 2 mM) on the ability of Candida albicans to adhere to, invade and damage oral, intestinal or vaginal epithelial cells, as well as to elicit cytokine and chemokine release. BM at 2 mM concentration stimulated adherence of C. albicans to vaginal cells and facilitated the invasion of intestinal and vaginal epithelia without influencing the growth rate of invading C. albicans hyphae at any type of epithelia and BM concentrations tested. In addition, BM at 2 mM concentration also augmented C. albicans-initiated cell damage of oral and intestinal cells. Furthermore, BM exposure decreased IL-6 cytokine and IL-8 chemokine release from oral and vaginal epithelial cells and also IL-6 release from intestinal epithelium after infection with C. albicans. These observations suggest that high-dose applications of BM may predispose patients to various epithelial C. albicans infections.


The impact of colonoscopy indication on polyp detection rate.
Adenoma/polyp detection rates are considered to be among the most important quality indicators of colonoscopy and are key measures of a quality procedure. However, they are designed for use in the screening setting and are not amenable to other colonoscopy indications. Little is known about their significance in other colonoscopy indications. We aimed to evaluate the impact of the various indications on polyp detection rate (PDR). This was a retrospective, single-center study. Electronic reports of index colonoscopy procedures with adequate bowel preparation over a 10-year period were reviewed. Patients were divided into 7 groups based on the study indication. PDR was determined for each group and was compared to that of a control group, the screening indication group. Adjustment was made for potential confounders such as age, sex, and procedural setting. A total of 13,054 patients were considered suitable for the study. PDR was greatest in the positive fecal occult blood test group, with a value of 33.1% (P<0.01). Overall, the remaining groups showed similar PDRs compared with screening (22.1% vs. 20.4%; P=0.15). This trend persisted in a multivariate analysis, which showed the odds ratio in the positive fecal occult blood test group to be significantly higher, with a value of 1.955 (1.759-2.172, P<0.001) compared with the screening group. PDR was highest for the positive fecal occult blood test indication, but was not affected significantly by most indications. Further randomized studies are warranted to confirm these findings and help calculate recommended thresholds for "overall" PDR.


Relational Integration in the Human Brain: A Review and Synthesis.
Relational integration is required when multiple explicit representations of relations between entities must be jointly considered to make inferences. We provide an overview of the neural substrate of relational integration in humans and the processes that support it, focusing on work on analogical and deductive reasoning. In addition to neural evidence, we consider behavioral and computational work that has informed neural investigations of the representations of individual relations and of relational integration. In very general terms, evidence from neuroimaging, neuropsychological, and neuromodulatory studies points to a small set of regions (generally left lateralized) that appear to constitute key substrates for component processes of relational integration. These include posterior parietal cortex, implicated in the representation of first-order relations (e.g., A:B); rostrolateral pFC, apparently central in integrating first-order relations so as to generate and/or evaluate higher-order relations (e.g., A:B::C:D); dorsolateral pFC, involved in maintaining relations in working memory; and ventrolateral pFC, implicated in interference control (e.g., inhibiting salient information that competes with relevant relations). Recent work has begun to link computational models of relational representation and reasoning with patterns of neural activity within these brain areas.


Climate change and the geographic distribution of infectious diseases.
Our ability to predict the effects of climate change on the spread of infectious diseases is in its infancy. Numerous, and in some cases conflicting, predictions have been developed, principally based on models of biological processes or mapping of current and historical disease statistics. Current debates on whether climate change, relative to socioeconomic determinants, will be a major influence on human disease distributions are useful to help identify research needs but are probably artificially polarized. We have at least identified many of the critical geophysical constraints, transport opportunities, biotic requirements for some disease systems, and some of the socioeconomic factors that govern the process of migration and establishment of parasites and pathogens. Furthermore, we are beginning to develop a mechanistic understanding of many of these variables at specific sites. Better predictive understanding will emerge in the coming years from analyses regarding how these variables interact with each other.


Use of anticoagulant agents and risk of bleeding among patients admitted with myocardial infarction: a report from the NCDR ACTION Registry--GWTG (National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network Registry--Get With the Guidelines).
The aim of this study was to evaluate anticoagulant use patterns and bleeding risk in a contemporary population of patients with acute coronary syndrome. Current practice guidelines support the use of unfractionated heparin, low molecular weight heparin, bivalirudin, or fondaparinux in non-ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI). Little is known about how these agents are selected in clinical practice. Between January 2007 and June 2009, data were captured for 72,699 patients with NSTEMI and 48,943 patients with STEMI at 360 U.S. hospitals for the NCDR ACTION Registry-GWTG (National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines). Patients were categorized based on anticoagulant strategy selected during hospitalization and their CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of ACC/AHA [American College of Cardiology/American Heart Association] Guidelines) bleeding risk category. At least 1 anticoagulant was administered to 66,279 patients (91.2%) with NSTEMI and 46,149 patients (94.3%) with STEMI. Among STEMI patients, unfractionated heparin was most commonly used (66%), followed by bivalirudin (14%) and low molecular weight heparin (8%). In NSTEMI patients, unfractionated heparin was also the most commonly used anticoagulant (42%), followed by low molecular weight heparin (27%) and then bivalirudin (13%). There were significant differences in anticoagulant use by age, risk factors, concomitant medications, and invasive care. There was a 5-fold difference in the rate of bleeding between patients in the lowest and highest CRUSADE bleeding risk groups, which was consistently observed in most anticoagulant groups. There is a wide variability in the use of anticoagulant regimens with significant differences according to baseline characteristics and concomitant therapies. Major bleeding is common, though a great degree of the variability in the rate of bleeding is largely based on differences in baseline characteristics, comorbidities, and invasive treatment strategies, rather than specific anticoagulant regimens.


Controlling the morphology of metal-organic frameworks and porous carbon materials: metal oxides as primary architecture-directing agents.
Owing to their large ratio of surface area to mass and volume, metal-organic frameworks and porous carbons have revolutionized many applications that rely on chemical and physical interactions at surfaces. However, a major challenge today is to shape these porous materials to translate their enhanced performance from the laboratory into macroscopic real-world applications. In this review, we give a comprehensive overview of how the precise morphology control of metal oxides can be transferred to metal-organic frameworks and porous carbon materials. As such, tailored material structures can be designed in 0D, 1D, 2D, and 3D with considerable implications for applications such as in energy storage, catalysis and nanomedicine. Therefore, we predict that major research advances in morphology control of metal-organic frameworks and porous carbons will facilitate the use of these materials in addressing major needs of the society, especially the grand challenges of energy, health, and environment.


Premature chromosome condensation is induced by a point mutation in the hamster RCC1 gene.
At the nonpermissive temperature, premature chromosome condensation (PCC) occurs in tsBN2 cells derived from the BHK cell line, which can be converted to the Ts+ phenotype by the human RCC1 gene. To prove that the RCC1 gene is the mutant gene in tsBN2 cells, which have RCC1 mRNA and protein of the same sizes as those of BHK cells, RCC1 cDNAs were isolated from BHK and tsBN2 cells and sequenced to search for mutations. The hamster (BHK) RCC1 cDNA encodes a protein of 421 amino acids homologous to the human RCC1 protein. In a comparison of the base sequences of BHK and BN2 RCC1 cDNAs, a single base change, cytosine to thymine (serine to phenylalanine), was found in the 256th codon of BN2 RCC1 cDNA. The same transition was verified in the RCC1 genomic DNA by the polymerase chain reaction method. BHK RCC1 cDNA, but not tsBN2 RCC1 cDNA, complemented the tsBN2 mutation, although both have the same amino acid sequence except for one amino acid at the 256th codon. This amino acid change, serine to phenylalanine, was estimated to cause a profound structural change in the RCC1 protein.


Estimating detection-effort curves for plants using search experiments.
Recent studies suggest that plant detection is not perfect, even for large, highly visible plants. However, this is often not taken into account during plant surveys where failing to detect a plant when present can result in poor management and biodiversity outcomes. Including knowledge of imperfect detectability into survey design and evaluation is hampered by the paucity of empirical data, and in particular, how detectability will change with search effort, plant size and abundance, the surrounding vegetation, or observer experience. We carried out a search experiment to measure the detection-effort curve for the invasive species orange hawkweed (Hieracium aurantiacum) in Victoria, Australia. The probability that hawkweed was detected increased with increasing search effort and the number of plants at the location. While detection probability varied between observers, experience appeared to have little effect. Accounting for imperfect detectability in plant surveys holds much promise for improved survey design and biodiversity outcomes, and we encourage other researchers to undertake similar experiments to further our understanding of plant detectability.


Methods of discovery and techniques to study endophytic fungi producing fuel-related hydrocarbons.
One promising area in the search for renewable bio-fuels is the discovery of microorganisms that produce fuel-related hydrocarbons (mycodiesel) that is in stark contrast to yeast fermentation that utilizes expensive sugars or starch to produce ethanol, which is a proven and useful source of fuel, but by no means is it ideal. Recently, a number of endophytic fungi have been isolated and described that make compounds such as mono- terpenoids, alkanes, cyclohexanes, cyclopentanes, and alkyl alcohols/ketones, benzenes and polyaromatic hydrocarbons. Many of these compounds are either identical to or are closely related to those specific classes of molecules that are found in diesel. Most importantly, these organisms make hydrocarbons while utilizing cellulosic polymers found in all plant-based agricultural wastes. Also discussed are some novel methods and techniques to quantitatively and qualitatively study hydrocarbon production by these microbes. Two models are discussed for identifying potential fuel-related compounds, scaling up production of them and advanced engine testing. Finally, it seems possible that endophytic fungi may have an additional attribute of having contributed to the formation of crude oil in the first place and a description of the paleobiosphere, to test this hypothesis, is in this review.


Comparative effects of two different artificial body fluids on Candida albicans adhesion to soft lining materials.
This study investigated the C. albicans adhesion to cold- and heat-polymerized soft lining materials that were initially incubated in two different artificial body fluids, namely saliva and nasal secretion, and examined the surface roughness the materials (cold and heat polymerized soft liner) tested in vitro. Cold (Visco Gel) and heat-polymerized (Molloplast B) soft liner specimens (N=32, n=8 per group) (10x10x1.5 mm) were randomly produced to express the relationship between surface roughness and contamination, and influence of body fluids, and incubated in 1.5 ml contaminated solutions for 2 h. After fixation, all of materials were evaluated under optical microscope (x400) and SEM. Surface roughness measurements were examined with profilometre for each material. Data were analyzed using two-way ANOVA, Tukey's HSD and Dunnett T3 tests (alpha=0.05). Material type (p<0.05) and contamination media (p<0.05) showed a significant influence on the C. albicans adherence. The surface roughness of cold polymerized soft liner (Visco Gel) was significantly higher than heat-polymerized soft liner (Molloplast B) (p<0.05).


Effect of 8 days of a hypergravity condition on the sprinting speed and lower-body power of elite rugby players.
-Sprinting speed and lower-body power are considered to be key physical abilities for rugby players. A method of improving the lower-body power of athletes is simulated hypergravity. This method involves wearing a weighted vest at all times during the day for an extended period of time. There are no studies that have examined the effect of hypergravity on speed or the benefit for rugby players. An experimental group (n = 8) and a control group (n = 7) of national team rugby players took part in the study, which consisted of rugby, conditioning, speed, and strength sessions. The experimental group wore a weighted vest equating to 12% of their body mass for 8 days. All players were tested for speed and lower-body power before, 2 days after, and 9 days after the intervention. Speed testing involved the athletes completing 40-m sprints with timing lights and high-speed video cameras assessing acceleration and maximal velocity sprinting kinematics. Lower-body power was assessed using weighted countermovement jumps (CMJs). No group differences were found for sprinting speed at any point. The experimental group displayed a large decrease in acceleration ground contact time (-0.01 ± 0.005 s, d = 1.07) and a moderate increase in 15-kg CMJ velocity (0.07 ± 0.11 m·s, d = 0.71). Individual responses showed that players in the experimental group had both negative and positive speed and power responses to the training intervention. Simulated hypergravity for 8 days is likely ineffective at improving sprinting speed while undergoing standard rugby training.


An open randomized comparison of clinical effectiveness of protocol-driven opioid analgesia, celiac plexus block or thoracoscopic splanchnicectomy for pain management in patients with pancreatic and other abdominal malignancies.
In inoperable malignancy, pain relief with opioids is often inadequate. Nerve block procedures may improve symptom control. Our aim was to assess celiac plexus block (CPB) and thoracoscopic splanchnicectomy (TS) in patients receiving appropriate medical management (MM). Patients with confirmed irresectable malignancy of the pancreas or upper abdominal viscera who required opioid analgesia were randomized to MM alone, MM+CPB, or MM+TS. Randomization was stratified by treatment centre, tumour type and previous opioid medication. The primary endpoint was pain relief at 2 months. 65 patients (58 pancreas cancer) were randomized, 18 withdrew or died within 2 months. Effective pain relief was achieved in only one third of subjects at 2 weeks, and just under half at 2 months (MM: 6/19 and 5/12 evaluable patients; CPB: 5/14 and 5/9; TS 4/14 and 4/11). There were no significant differences between the groups in pain scores or opioid consumption, and there was no correlation between continued use of opioids and effective pain relief. Previous randomized studies have shown small differences in pain scores, but no difference in opioid consumption and quality of life. The absence of any benefit from interventions in the present study questions their value.


Pattern-oriented modeling of agent-based complex systems: lessons from ecology.
Agent-based complex systems are dynamic networks of many interacting agents; examples include ecosystems, financial markets, and cities. The search for general principles underlying the internal organization of such systems often uses bottom-up simulation models such as cellular automata and agent-based models. No general framework for designing, testing, and analyzing bottom-up models has yet been established, but recent advances in ecological modeling have come together in a general strategy we call pattern-oriented modeling. This strategy provides a unifying framework for decoding the internal organization of agent-based complex systems and may lead toward unifying algorithmic theories of the relation between adaptive behavior and system complexity.


Midline episiotomies: more harm than good?
The association between episiotomy and severe (third- and fourth-degree) perineal lacerations was studied in 24,114 women. The overall rates of severe lacerations were 8.3 and 1.5% for primiparous and multiparous women, respectively. Women who had midline episiotomies were nearly 50 times more likely and women who had mediolateral episiotomies were over eight times more likely to suffer a severe laceration than were women who did not undergo an episiotomy. Severe lacerations were also more common after use of forceps, in occiput transverse and posterior presentations, among women with smaller pelvic outlet measurements or lower prepregnant weight, and with larger fetuses. The same factors that caused a woman to have an increased risk of laceration also made performance of an episiotomy more likely. After statistical adjustment for these risk factors, mediolateral episiotomy was associated with a 2.5-fold reduction in the risk of severe lacerations among primiparous women, and a statistically nonsignificant 2.4-fold increase among multiparous women, compared with no episiotomy. Midline episiotomy was associated with statistically significant 4.2- and 12.8-fold increases in the risk of lacerations among primiparous and multiparous women, respectively. We conclude that the risks and benefits of midline episiotomy should be evaluated in a randomized clinical trial that compares policies of "usual" versus conservative use of episiotomy.


Estimating the burden of disease attributable to injecting drug use as a risk factor for HIV, hepatitis C, and hepatitis B: findings from the Global Burden of Disease Study 2013.
Previous estimates of the burden of HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) among people who inject drugs have not included estimates of the burden attributable to the consequences of past injecting. We aimed to provide these estimates as part of the Global Burden of Disease (GBD) Study 2013. We modelled the burden of HBV and HCV (including cirrhosis and liver cancer burden) and HIV at the country, regional, and global level. We extracted United Nations data on the proportion of notified HIV cases by transmission route, and estimated the contribution of injecting drug use (IDU) to HBV and HCV disease burden by use of a cohort method that recalibrated individuals' history of IDU, and accumulated risk of HBV and HCV due to IDU. We estimated data on current IDU from a meta-analysis of HBV and HCV incidence among injecting drug users and country-level data on the incidence of HBV and HCV between 1990 and 2013. We calculated estimates of burden of disease through years of life lost (YLL), years of life lived with disability (YLD), deaths, and disability-adjusted life-years (DALYs), with 95% uncertainty intervals (UIs) calculated for each metric. In 2013, an estimated 10·08 million DALYs were attributable to previous exposure to HIV, HBV, and HCV via IDU, a four-times increase since 1990. In total in 2013, IDU was estimated to cause 4·0% (2·82 million DALYs, 95% UI 2·4 million to 3·8 million) of DALYs due to HIV, 1·1% (216 000, 101 000-338 000) of DALYs due to HBV, and 39·1% (7·05 million, 5·88 million to 8·15 million) of DALYs due to HCV. IDU-attributable HIV burden was highest in low-to-middle-income countries, and IDU-attributable HCV burden was highest in high-income countries. IDU is a major contributor to the global burden of disease. Effective interventions to prevent and treat these important causes of health burden need to be scaled up. Bill & Melinda Gates Foundation and Australian National Health and Medical Research Council.


Optical clearing and fluorescence deep-tissue imaging for 3D quantitative analysis of the brain tumor microenvironment.
Three-dimensional visualization of the brain vasculature and its interactions with surrounding cells may shed light on diseases where aberrant microvascular organization is involved, including glioblastoma (GBM). Intravital confocal imaging allows 3D visualization of microvascular structures and migration of cells in the brain of mice, however, with limited imaging depth. To enable comprehensive analysis of GBM and the brain microenvironment, in-depth 3D imaging methods are needed. Here, we employed methods for optical tissue clearing prior to 3D microscopy to visualize the brain microvasculature and routes of invasion of GBM cells. We present a workflow for ex vivo imaging of optically cleared brain tumor tissues and subsequent computational modeling. This workflow was used for quantification of the microvasculature in relation to nuclear or cellular density in healthy mouse brain tissues and in human orthotopic, infiltrative GBM8 and E98 glioblastoma models. Ex vivo cleared mouse brain tissues had a >10-fold imaging depth as compared to intravital imaging of mouse brain in vivo. Imaging of optically cleared brain tissue allowed quantification of the 3D microvascular characteristics in healthy mouse brains and in tissues with diffuse, infiltrative growing GBM8 brain tumors. Detailed 3D visualization revealed the organization of tumor cells relative to the vasculature, in both gray matter and white matter regions, and patterns of multicellular GBM networks collectively invading the brain parenchyma. Optical tissue clearing opens new avenues for combined quantitative and 3D microscopic analysis of the topographical relationship between GBM cells and their microenvironment.


The lung microbiome.
Historically, our understanding of lung microbiology has relied on insight gained through culture-based diagnostic approaches that employ selective culture conditions to isolate specific pathogens. The relatively recent development of culture-independent microbiota-profiling techniques, particularly 16S rRNA (ribosomal ribonucleic acid) gene amplicon sequencing, has enabled more comprehensive characterisation of the microbial content of respiratory samples. The widespread application of such techniques has led to a fundamental shift in our view of respiratory microbiology. Rather than a sterile lung environment that can become colonised by microbes during infection, it appears that a more nuanced balance exists between what we consider respiratory health and disease, mediated by mechanisms that influence the clearance of microbes from the lungs. Where airway defences are compromised, the ongoing transient exposure of the lower airways to microbes can lead to the establishment of complex microbial communities within the lung. Importantly, the characteristics of these communities, and the manner in which they influence lung pathogenesis, can be very different from those of their constituent members when viewed in isolation. The lung microbiome, a construct that incorporates microbes, their genetic material, and the products of microbial genes, is increasingly central to our understanding of the regulation of respiratory physiology and the processes that underlie lung pathogenesis.


Bioresorbable silicon electronic sensors for the brain.
Many procedures in modern clinical medicine rely on the use of electronic implants in treating conditions that range from acute coronary events to traumatic injury. However, standard permanent electronic hardware acts as a nidus for infection: bacteria form biofilms along percutaneous wires, or seed haematogenously, with the potential to migrate within the body and to provoke immune-mediated pathological tissue reactions. The associated surgical retrieval procedures, meanwhile, subject patients to the distress associated with re-operation and expose them to additional complications. Here, we report materials, device architectures, integration strategies, and in vivo demonstrations in rats of implantable, multifunctional silicon sensors for the brain, for which all of the constituent materials naturally resorb via hydrolysis and/or metabolic action, eliminating the need for extraction. Continuous monitoring of intracranial pressure and temperature illustrates functionality essential to the treatment of traumatic brain injury; the measurement performance of our resorbable devices compares favourably with that of non-resorbable clinical standards. In our experiments, insulated percutaneous wires connect to an externally mounted, miniaturized wireless potentiostat for data transmission. In a separate set-up, we connect a sensor to an implanted (but only partially resorbable) data-communication system, proving the principle that there is no need for any percutaneous wiring. The devices can be adapted to sense fluid flow, motion, pH or thermal characteristics, in formats that are compatible with the body's abdomen and extremities, as well as the deep brain, suggesting that the sensors might meet many needs in clinical medicine.


Tissue specificity of histone phosphorylation.
The incorporation of (32)P-phosphate into histone fractions isolated from normal, hepatectomized, and Novikoff hepatoma-bearing rats was investigated. Varying degrees of phosphorylation were exhibited by different histone fractions. The phosphorylation of histones is tissue specific and appears to be correlated with metabolic cell functions, that is, it decreases with increasing mitotic activity of the cells.


Patient Engagement and Coaching for Health: The PEACH study--a cluster randomised controlled trial using the telephone to coach people with type 2 diabetes to engage with their GPs to improve diabetes care: a study protocol.
The PEACH study is based on an innovative 'telephone coaching' program that has been used effectively in a post cardiac event trial. This intervention will be tested in a General Practice setting in a pragmatic trial using existing Practice Nurses (PN) as coaches for people with type 2 diabetes (T2D). Actual clinical care often fails to achieve standards, that are based on evidence that self-management interventions (educational and psychological) and intensive pharmacotherapy improve diabetes control. Telephone coaching in our study focuses on both. This paper describes our study protocol, which aims to test whether goal focused telephone coaching in T2D can improve diabetes control and reduce the treatment gap between guideline based standards and actual clinical practice. In a cluster randomised controlled trial, general practices employing Practice Nurses (PNs) are randomly allocated to an intervention or control group. We aim to recruit 546 patients with poorly controlled T2D (HbA1c >7.5%) from 42 General Practices that employ PNs in Melbourne, Australia. PNs from General Practices allocated to the intervention group will be trained in diabetes telephone coaching focusing on biochemical targets addressing both patient self-management and engaging patients to work with their General Practitioners (GPs) to intensify pharmacological treatment according to the study clinical protocol. Patients of intervention group practices will receive 8 telephone coaching sessions and one face-to-face coaching session from existing PNs over 18 months plus usual care and outcomes will be compared to the control group, who will only receive only usual care from their GPs. The primary outcome is HbA1c levels and secondary outcomes include cardiovascular disease risk factors, behavioral risk factors and process of care measures. Understanding how to achieve comprehensive treatment of T2D in a General Practice setting is the focus of the PEACH study. This study explores the potential role for PNs to help reduce the treatment and outcomes gap in people with T2D by using telephone coaching. The intervention, if found to be effective, has potential to be sustained and embedded within real world General Practice.


A novel small molecule TLR4 antagonist (IAXO-102) negatively regulates non-hematopoietic toll like receptor 4 signalling and inhibits aortic aneurysms development.
The toll-like receptors (TLRs), including TLR4, have been shown to play a crucial role in vascular inflammatory diseases, such as atherosclerosis and aneurysm. The main goal of this study was to determine the potential of IAXO-102 (Innaxon, Tewkesbury), a novel small molecule TLR4 antagonist, to modulate non-hematopoietic TLR4 proinflammatory signalling and inhibit experimental abdominal aortic aneurysm (AAA) development. Human umbilical vein endothelial cells (HUVEC) and Angiotensin II-induced experimental AAA development were our in vitro and in vivo models respectively. Western blotting, antibody array and ELISA approaches were used to explore the effect of IAXO-102 on TLR4 functional activity on two levels: modulation of TLR4-induced mitogen activated protein kinases (MAPK) and p65 NF-kB phosphorylation and expression of TLR4 dependent proinflammatory proteins. Following activation of TLR4, in vitro/in vivo data revealed that IAXO-102 inhibited MAPK and p65 NF-kB phosphorylation associated with down regulation of the expression of TLR4 and TLR4 dependent proinflammatory proteins. Furthermore, IAXO-102 decreased Angiotensin II-induced aortic expansion, rupture and incidence of AAA. These results demonstrate the ability of IAXO-102 to negatively regulate TLR4 signalling and to inhibit experimental AAA development, suggesting the potential therapeutic use of this TLR4 antagonist for pharmacological intervention of AAA.


What supports physiotherapists' use of research in clinical practice? A qualitative study in Sweden.
Evidence-based practice has increasingly been recognized as a priority by professional physiotherapy organizations and influential researchers and clinicians in the field. Numerous studies in the past decade have documented that physiotherapists hold generally favorable attitudes to evidence-based practice and recognize the importance of using research to guide their clinical practice. Research has predominantly investigated barriers to research use. Less is known about the circumstances that actually support use of research by physiotherapists. This study explores the conditions at different system levels that physiotherapists in Sweden perceive to be supportive of their use of research in clinical practice. Patients in Sweden do not need a referral from a physician to consult a physiotherapist and physiotherapists are entitled to choose and perform any assessment and treatment technique they find suitable for each patient. Eleven focus group interviews were conducted with 45 physiotherapists, each lasting between 90 and 110 minutes. An inductive approach was applied, using topics rather than questions to allow the participants to generate their own questions and pursue their own priorities within the framework of the aim. The data were analyzed using qualitative content analysis. Analysis of the data yielded nine favorable conditions at three system levels supporting the participant's use of research in clinical practice: two at the individual level (attitudes and motivation concerning research use; research-related knowledge and skills), four at the workplace level (leadership support; organizational culture; research-related resources; knowledge exchange) and three at the extra-organizational level (evidence-based practice guidelines; external meetings, networks, and conferences; academic research and education). Supportive conditions for physiotherapists' use of research exist at multiple interdependent levels, including the individual, workplace, and extra-organizational levels. Research use in physiotherapy appears to be an interactive and interpretative social process that involves a great deal of interaction with various people, including colleagues and patients.


Antibiotic treatment for Burkholderia cepacia complex in people with cystic fibrosis experiencing a pulmonary exacerbation.
Chronic pulmonary infection is one of the hallmarks of lung disease in cystic fibrosis. Infections dominated by organisms of the Burkholderia cepacia complex, a group of at least 17 closely-related species of gram-negative bacteria, are particularly difficult to treat. These infections may be associated with a fulminant necrotising pneumonia, and are greatly feared by patients. Burkholderia cepacia bacteria are innately resistant to many common antibiotics and able to acquire resistance against many more. Since strict patient segregation was introduced to cystic fibrosis medical care, the incidence of the more virulent epidemic strains has fallen, and new infections are more likely to be with environmentally-acquired strains which seem to exhibit less virulence. Nonetheless, exacerbations of respiratory symptoms require effective therapy directed against the dominant bacterial species. Although evidence-based guidelines exist for the treatment of respiratory exacerbations involving Pseudomonas aeruginosa, the most common chronic infection in cystic fibrosis, these cannot be directly extended to Burkholderia cepacia complex infections. The aim of this review is to assess the available trial evidence for choice and application of treatments for Burkholderia cepacia complex infections. To assess the effectiveness and safety of different antibiotic regimens in people with cystic fibrosis experiencing an exacerbation, who are chronically infected with organisms of the Burkholderia cepacia complex. We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews.Date of latest search: 29 November 2011. Randomised and quasi-randomised controlled trials of treatments for exacerbations of pulmonary symptoms in cystic fibrosis patients chronically infected with organisms of the Burkholderia cepacia complex. No relevant trials were identified. No trials were included in this review. Burkholderia cepacia complex infections present a significant challenge for cystic fibrosis clinicians and patients alike. The incidence is likely to increase as the cystic fibrosis population ages and the problem of how to manage and treat these infections becomes more important. There is a lack of trial evidence to guide decision making and no conclusions can be drawn from this review about the optimal antibiotic regimens for cystic fibrosis patients with chronic Burkholderia cepacia complex infections. Clinicians must continue to assess each patient individually, taking into account in vitro antibiotic susceptibility data, previous clinical responses and their own experience. There is a clear need for multi-centre randomised clinical trials to assess the effectiveness of different antibiotic regimens in cystic fibrosis patients infected with organisms of the Burkholderia cepacia complex.


Psychometric evaluation of the 4C tinnitus management questionnaire for patients with tinnitus alone or tinnitus combined with hyperacusis.
To assess the psychometric properties of a new questionnaire evaluating patients' confidence in managing their tinnitus, the 4C tinnitus management questionnaire (4C), which was designed to be used in the process of cognitive behavioural therapy. Retrospective cross-sectional based on patient records. 99 consecutive patients who sought help for tinnitus (with or without hyperacusis) from an audiology clinic in the UK. Pure tone average (PTA) hearing thresholds, Uncomfortable Loudness Levels (ULLs), and responses to the 4C questionnaire, Tinnitus Handicap Inventory (THI), Hyperacusis Questionnaire (HQ), and Screening for Anxiety and Depression in Tinnitus (SAD-T) questionnaire were gathered from the records of patients held at the audiology department. Cronbach's alpha for the 4C was 0.91, indicating high internal consistency. Exploratory factor analysis suggested a one-factor solution. Discriminant validity was supported by weak correlations between 4C scores and PTA across ears and ULLmin (the across-frequency average ULL for the ear with lower average ULL). Convergent validity was supported by moderate correlations between 4C scores and scores for the THI, HQ, and SAD-T. The 4C is an internally consistent questionnaire with high convergent and discriminant validity, which can be used to assess patients' confidence in managing their tinnitus.


Neuronal expression of the rat M1 muscarinic acetylcholine receptor gene is regulated by elements in the first exon.
Muscarinic acetylcholine receptor genes are members of the G-protein coupled receptor superfamily. Each member of this family studied to date appears to have a distinct expression profile, however the mechanisms determining these expression patterns remain largely unknown. We have previously isolated a genomic clone containing the M1 muscarinic receptor gene and determined its gene structure [Pepitoni, Wood and Buckley (1997) J. Biol. Chem. 272, 17112-17117]. We have now identified DNA elements responsible for driving cell specific expression in transient transfection assays of immortalized cell lines. A region of the gene spanning 974 nucleotides and containing 602 nucleotides of the first exon is sufficient to drive specific expression in cell lines. Like the M4 and M2 gene promoters, the M1 promoter contains an Sp1 motif which can recruit transcription factor Sp1 and at least one other protein, although this site does not appear to be functionally important for M1 expression in our assay. We have identified a region within the first exon of the M1 gene that regulates expression in cell lines, contains several positive and negative acting elements and is able to drive expression of a heterologous promoter. A polypyrimidine/polypurine tract and a sequence conserved between M1 genes of various species act in concert to enhance M1 transcription and are able to activate a heterologous promoter. We show that DNA binding proteins interact in vitro with single-stranded DNA derived from these regions and suggest that topology of the DNA is important for regulation of M1 expression.


Rising PSA in nonmetastatic prostate cancer.
Rising prostate-specific antigen (PSA) in nonmetastatic prostate cancer occurs in two main clinical settings: (1) rising PSA to signal failed initial local therapy and (2) rising PSA in the setting of early hormone-refractory prostate cancer prior to documented clinical metastases. Most urologists and radiation oncologists are very familiar with the initial very common clinical scenario, commonly called "biochemical recurrence." In fact, up to 70,000 men each year will have a PSA-only recurrence after failed definitive therapy. The ideal salvage therapy for these men is not clear and includes salvage local therapies and systemic approaches, of which the mainstay is hormonal therapy. Treatment needs to be individualized based upon the patient's risk of progression and the likelihood of success and the risks involved with the therapy. It is unknown how many men per year progress with rising PSA while on hormonal therapy without documented metastases. This rising PSA disease state is sometimes called, "PSA-only hormone-refractory prostate cancer." As in the setting of initial biochemical recurrence, evidence-based treatment options are limited, and taking a risk-stratified approach is justified. In this article, we will explore these prostate cancer disease states with an emphasis on practical, clinically applicable approaches.


Recombination in Streptococcus pneumoniae Lineages Increase with Carriage Duration and Size of the Polysaccharide Capsule.
Streptococcus pneumoniae causes a high burden of invasive pneumococcal disease (IPD) globally, especially in children from resource-poor settings. Like many bacteria, the pneumococcus can import DNA from other strains or even species by transformation and homologous recombination, which has allowed the pneumococcus to evade clinical interventions such as antibiotics and pneumococcal conjugate vaccines (PCVs). Pneumococci are enclosed in a complex polysaccharide capsule that determines the serotype; the capsule varies in size and is associated with properties including carriage prevalence and virulence. We determined and quantified the association between capsule and recombination events using genomic data from a diverse collection of serotypes sampled in Malawi. We determined both the amount of variation introduced by recombination relative to mutation (the relative rate) and how many individual recombination events occur per isolate (the frequency). Using univariate analyses, we found an association between both recombination measures and multiple factors associated with the capsule, including duration and prevalence of carriage. Because many capsular factors are correlated, we used multivariate analysis to correct for collinearity. Capsule size and carriage duration remained positively associated with recombination, although with a reduced P value, and this effect may be mediated through some unassayed additional property associated with larger capsules. This work describes an important impact of serotype on recombination that has been previously overlooked. While the details of how this effect is achieved remain to be determined, it may have important consequences for the serotype-specific response to vaccines and other interventions. The capsule determines >90 different pneumococcal serotypes, which vary in capsule size, virulence, duration, and prevalence of carriage. Current serotype-specific vaccines elicit anticapsule antibodies. Pneumococcus can take up exogenous DNA by transformation and insert it into its chromosome by homologous recombination. This mechanism has disseminated drug resistance and generated vaccine escape variants. It is hence crucial to pneumococcal evolutionary response to interventions, but there has been no systematic study quantifying whether serotypes vary in recombination and whether this is associated with serotype-specific properties such as capsule size or carriage duration. Larger capsules could physically inhibit DNA uptake, or given the longer carriage duration for larger capsules, this may promote recombination. We find that recombination varies among capsules and is associated with capsule size, carriage duration, and carriage prevalence and negatively associated with invasiveness. The consequence of this work is that serotypes with different capsules may respond differently to selective pressures like vaccines.


Anticorrosive, Ultralight, and Flexible Carbon-Wrapped Metallic Nanowire Hybrid Sponges for Highly Efficient Electromagnetic Interference Shielding.
Metal-based materials with exceptional intrinsic conductivity own excellent electromagnetic interference (EMI) shielding performance. However, high density, corrosion susceptibility, and poor flexibility of the metal severely restrict their further applications in the areas of aircraft/aerospace, portable and wearable smart electronics. Herein, a lightweight, flexible, and anticorrosive silver nanowire wrapped carbon hybrid sponge (Ag@C) is fabricated and employed as ultrahigh efficiency EMI shielding material. The interconnected Ag@C hybrid sponges provide an effective way for electron transport, leading to a remarkable conductivity of 363.1 S m-1 and superb EMI shielding effectiveness of around 70.1 dB in the frequency range of 8.2-18 GHz, while the density is as low as 0.00382 g cm-3 , which are among the best performances for electrically conductive sponges/aerogels/foams by far. More importantly, the Ag@C sponge surprisingly exhibits super-hydrophobicity and strong corrosion resistance. In addition, the hybrid sponges possess excellent mechanical resilience even with a large strain (90% reversible compressibility) and an outstanding cycling stability, which is far better than the bare metallic aerogels, such as silver nanowire aerogels and copper nanowire foams. This strategy provides a facile methodology to fabricate lightweight, flexible, and anticorrosive metal-based sponge for highly efficient EMI shielding applications.


Atomistic study of energy funneling in the light-harvesting complex of green sulfur bacteria.
Phototrophic organisms such as plants, photosynthetic bacteria, and algae use microscopic complexes of pigment molecules to absorb sunlight. Within the light-harvesting complexes, which frequently have several functional and structural subunits, the energy is transferred in the form of molecular excitations with very high efficiency. Green sulfur bacteria are considered to be among the most efficient light-harvesting organisms. Despite multiple experimental and theoretical studies of these bacteria, the physical origin of the efficient and robust energy transfer in their light-harvesting complexes is not well understood. To study excitation dynamics at the systems level, we introduce an atomistic model that mimics a complete light-harvesting apparatus of green sulfur bacteria. The model contains approximately 4000 pigment molecules and comprises a double wall roll for the chlorosome, a baseplate, and six Fenna-Matthews-Olson trimer complexes. We show that the fast relaxation within functional subunits combined with the transfer between collective excited states of pigments can result in robust energy funneling to the initial excitation conditions and temperature changes. Moreover, the same mechanism describes the coexistence of multiple time scales of excitation dynamics frequently observed in ultrafast optical experiments. While our findings support the hypothesis of supertransfer, the model reveals energy transport through multiple channels on different length scales.


NIPA defines an SCF-type mammalian E3 ligase that regulates mitotic entry.
The regulated oscillation of protein expression is an essential mechanism of cell cycle control. The SCF class of E3 ubiquitin ligases is involved in this process by targeting cell cycle regulatory proteins for degradation by the proteasome, with the F-box subunit of the SCF specifically recruiting a given substrate to the SCF core. Here we identify NIPA (nuclear interaction partner of ALK) as a human F-box-containing protein that defines an SCF-type E3 ligase (SCF(NIPA)) controlling mitotic entry. Assembly of this SCF complex is regulated by cell-cycle-dependent phosphorylation of NIPA, which restricts substrate ubiquitination activity to interphase. We show nuclear cyclin B1 to be a substrate of SCF(NIPA). Inactivation of NIPA by RNAi results in nuclear accumulation of cyclin B1 in interphase, activation of cyclin B1-Cdk1 kinase activity, and premature mitotic entry. Thus, SCF(NIPA)-based ubiquitination may regulate S-phase completion and mitotic entry in the mammalian cell cycle.


Piezoelectric-transducer-based optoelectronic frequency synchronizer for control of pulse delay in a femtosecond passively mode-locked Ti:sapphire laser.
We propose a piezoelectric transducer-(PZT-) based optoelectronic frequency synchronizer to control simultaneously change in the repetition rate, the relative pulse delay, and the phase noise of a passively mode-locked femtosecond Ti:sapphire laser with an intracavity saturable Bragg reflector absorber with respect to an electronic frequency reference. An optoelectronic phase-locked-loop-based PZT feedback controller with a proportional, integral, and differential (PID) circuit and a tunable voltage regulator is designed to achieve frequency synchronization, phase-noise suppression, and delay-time tuning. When the controlling voltage is tuned from -2.6 to 2.6 V, the maximum pulse-delay range, tuning slope, and tuning resolution of the laser pulse-train are 11.3 ns, 2.3 ps/mV, and 1.2 ps, respectively. Setting the gain constant of the PID circuit at 10 or larger causes the delay-time tuning function to be linearly proportional to the controlling voltage. In the delay-time tuning mode the uncorrelated single-side-band phase-noise density of the frequency-synchronized laser is approximately -120 dBc/Hz at an offset frequency of 5 kHz, which is only 7 dBc/Hz higher than that of the electrical frequency reference. The proposed system also supports linear,continuous switching,and programmable control of the delay time of Ti:sapphire laser pulses when they are frequency synchronized to external reference clocks.


The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance.
Recent genome-wide association studies demonstrated that common variants of solute carrier family 30 member 8 gene (SLC30A8) increase susceptibility to type 2 diabetes. SLC30A8 encodes zinc transporter-8 (ZnT8), which delivers zinc ion from the cytoplasm into insulin granules. Although it is well known that insulin granules contain high amounts of zinc, the physiological role of secreted zinc remains elusive. In this study, we generated mice with β cell-specific Slc30a8 deficiency (ZnT8KO mice) and demonstrated an unexpected functional linkage between Slc30a8 deletion and hepatic insulin clearance. The ZnT8KO mice had low peripheral blood insulin levels, despite insulin hypersecretion from pancreatic β cells. We also demonstrated that a substantial amount of the hypersecreted insulin was degraded during its first passage through the liver. Consistent with these findings, ZnT8KO mice and human individuals carrying rs13266634, a major risk allele of SLC30A8, exhibited increased insulin clearance, as assessed by c-peptide/insulin ratio. Furthermore, we demonstrated that zinc secreted in concert with insulin suppressed hepatic insulin clearance by inhibiting clathrin-dependent insulin endocytosis. Our results indicate that SLC30A8 regulates hepatic insulin clearance and that genetic dysregulation of this system may play a role in the pathogenesis of type 2 diabetes.


Revealing the maternal demographic history of Panthera leo using ancient DNA and a spatially explicit genealogical analysis.
Understanding the demographic history of a population is critical to conservation and to our broader understanding of evolutionary processes. For many tropical large mammals, however, this aim is confounded by the absence of fossil material and by the misleading signal obtained from genetic data of recently fragmented and isolated populations. This is particularly true for the lion which as a consequence of millennia of human persecution, has large gaps in its natural distribution and several recently extinct populations. We sequenced mitochondrial DNA from museum-preserved individuals, including the extinct Barbary lion (Panthera leo leo) and Iranian lion (P. l. persica), as well as lions from West and Central Africa. We added these to a broader sample of lion sequences, resulting in a data set spanning the historical range of lions. Our Bayesian phylogeographical analyses provide evidence for highly supported, reciprocally monophyletic lion clades. Using a molecular clock, we estimated that recent lion lineages began to diverge in the Late Pleistocene. Expanding equatorial rainforest probably separated lions in South and East Africa from other populations. West African lions then expanded into Central Africa during periods of rainforest contraction. Lastly, we found evidence of two separate incursions into Asia from North Africa, first into India and later into the Middle East. We have identified deep, well-supported splits within the mitochondrial phylogeny of African lions, arguing for recognition of some regional populations as worthy of independent conservation. More morphological and nuclear DNA data are now needed to test these subdivisions.


User Experiences With and Recommendations for Mobile Health Technology for Hypertensive Disorders of Pregnancy: Mixed Methods Study.
Hypertensive disorders of pregnancy (HDP) are a primary cause of adverse maternal and neonatal outcomes worldwide. For women at risk of hypertensive complications, guidelines recommend frequent surveillance of blood pressure and signs of preeclampsia. Clinic visits range from every 2 weeks to several times a week. Given the wide ubiquity of smartphones and computers in most countries and a growing attention for self-management, digital technologies, including mobile health (mHealth), constitute a promising component of monitoring (self-measured) blood pressure during pregnancy. Currently, little is known about the experiences of women using such platforms and how mHealth can be aligned with their needs and preferences. The objectives were twofold: (1) to explore the experiences of Dutch women who had an increased risk of HDP with a blended care approach (mHealth combined with face-to-face care) for remote self-monitoring of blood pressure and preeclampsia symptoms and (2) to formulate recommendations for the use and integration of mHealth in clinical care. Alongside a prospective blended care study (SAFE@home study) that monitors pregnant women at increased risk of HPD with mHealth technology, a mixed methods study was conducted, including questionnaires (n=52) and interviews (n=11). Results were analyzed thematically. Of the 4 themes, 2 themes were related to the technologies themselves (expectations, usability), and 2 themes were related to the interaction and use of mHealth (autonomy and responsibilities of patients, responsibilities of health care professionals). First, the digital platform met the expectations of patients, which contributed to user satisfaction. Second, the platform was considered user-friendly, and patients favored different moments and frequencies for measuring their blood pressure. Third, patient autonomy was mentioned in terms of increased insight about their own condition and being able to influence clinical decision making. Fourth, clinical expertise of health care professionals was considered essential to interpret the data, which translates to subsequent responsibilities for clinical management. Data from the questionnaires and interviews corresponded. Blended care using an mHealth tool to monitor blood pressure in pregnancy was positively evaluated by its users. Insights from participants led to 7 recommendations for designing and implementing similar interventions and to enhance future, morally sound use of digital technologies in clinical care.


Absolute optical ranging using low coherence interferometry.
We describe a method for measuring submicrometer distances with an asymmetric fiber Michelson interferometer having an LED as a source of radiation. By measuring the phase slope of the Fourier components in the frequency domain, it is possible to locate the position of reflections with nanometer precision even in the presence of sample dispersion. The method is compatible with time domain sampling at the Nyquist rate which assures efficiency in data acquisition and processing.


Evaluation of sprayed hypochlorous acid solutions for their virucidal activity against avian influenza virus through in vitro experiments.
Hypochlorous acid (HOCl) solutions were evaluated for their virucidal ability against a low pathogenic avian influenza virus (AIV), H7N1. HOCl solutions containing 50, 100 and 200 ppm chlorine (pH 6) or their sprayed solutions (harvested in dishes placed at 1 or 30 cm distance between the spray nozzle and dish) were mixed with the virus with or without organic materials (5% fetal bovine serum: FBS). Under plain diluent conditions (without FBS), harvested solutions of HOCl after spraying could decrease the AIV titer by more than 1,000 times, to an undetectable level (< 2.5 log10TCID50/ml) within 5 sec, with the exception of the 50 ppm solution harvested after spraying at the distance of 30 cm. Under the dirty conditions (in the presence of 5% FBS), they lost their virucidal activity. When HOCl solutions were sprayed directly on the virus on rayon sheets for 10 sec, the solutions of 100 and 200 ppm could inactivate AIV immediately after spraying, while 50 ppm solution required at least 3 min of contact time. In the indirect spray form, after 10 sec of spraying, the lids of the dishes were opened to expose the virus on rayon sheets to HOCl. In this form, the 200 ppm solution inactivated AIV within 10 min of contact, while 50 and 100 ppm could not inactivate it. These data suggest that HOCl can be used in spray form to inactivate AIV at the farm level.


Implementation of Geometry-Dependent Charge Flux into the Polarizable AMOEBA+ Potential.
Molecular dynamics (MD) simulations employing classical force fields (FFs) have been widely used to model molecular systems. The important ingredient of the current FFs, atomic charge, remains fixed during MD simulations despite the atomic environment or local geometry changes. This approximation hinders the transferability of the potential being used in multiple phases. Here we implement a geometry-dependent charge flux (GDCF) model into the multipole-based AMOEBA+ polarizable potential. The CF in the current work explicitly depends on the local geometry (bond and angle) of the molecule. To our knowledge, this is the first study that derives energy and force expressions due to GDCF in a multipole-based polarizable FF framework. Due to the inclusion of GDCF, the AMOEBA+ water model is noticeably improved in terms of describing the monomer properties, cluster binding/interaction energy, and a variety of liquid properties, including the infrared spectra that previous flexible water models were not able to capture.


Difficulties and possible solutions in the genetic management of mtDNA disease in the preimplantation embryo.
Families who have had a child die of a severe, maternally inherited mitochondrial DNA (mtDNA) disease are usually desperate to avoid having further affected children. Here we discuss the problems of applying classical genetic management to mtDNA diseases (Poulton and Turnbull, 2000) and the biology underlying these problems. We explain why these disorders have lagged so far behind the genetics revolution. We then outline the directions in which management is likely to develop, including the use of preimplantation genetic diagnosis (PGD).


Repression of competition favours cooperation: experimental evidence from bacteria.
Repression of competition (RC) within social groups has been suggested as a key mechanism driving the evolution of cooperation, because it aligns the individual's proximate interest with the interest of the group. Despite its enormous potential for explaining cooperation across all levels of biological organization, ranging from fair meiosis, to policing in insect societies, to sanctions in mutualistic interactions between species, there has been no direct experimental test of whether RC favours the spread of cooperators in a well-mixed population with cheats. To address this, we carried out an experimental evolution study to test the effect of RC upon a cooperative trait - the production of iron-scavenging siderophore molecules - in the bacterium Pseudomonas aeruginosa. We found that cooperation was favoured when competition between siderophore producers and nonsiderophore-producing cheats was repressed, but not in a treatment where competition between the two strains was permitted. We further show that RC altered the cost of cooperation, but did not affect the relatedness among interacting individuals. This confirms that RC per se, as opposed to increased relatedness, has driven the observed increase in bacterial cooperation.


Expanding the spectrum of EEF1D neurodevelopmental disorders: Biallelic variants in the guanine exchange domain.
Protein translation is an essential cellular process and dysfunctional protein translation causes various neurodevelopmental disorders. The eukaryotic translation elongation factor 1A (eEF1A) delivers aminoacyl-tRNA to the ribosome, while the eEF1B complex acts as a guanine exchange factor (GEF) of GTP for GDP indirectly catalyzing the release of eEF1A from the ribosome. The gene EEF1D encodes the eEF1Bδ subunit of the eEF1B complex. EEF1D is alternatively spliced giving rise to one long and three short isoforms. Two different homozygous, truncating variants in EEF1D had been associated with severe intellectual disability and microcephaly in two families. The published variants only affect the long isoform of EEF1D that acts as a transcription factor of heat shock element proteins. By exome sequencing, we identified two different homozygous variants in EEF1D in two families with severe developmental delay, severe microcephaly, spasticity, and failure to thrive with optic atrophy, poor feeding, and recurrent aspiration pneumonia. The EEF1D variants reported in this study are localized in the C-terminal GEF domain, suggesting that a disturbed protein translation machinery might contribute to the neurodevelopmental phenotype. Pathogenic variants localized in both the alternatively spliced domain or the GEF domain of EEF1D cause a severe neurodevelopmental disorder with microcephaly and spasticity.


Testicular cancer survivorship: research strategies and recommendations.
Testicular cancer represents the most curable solid tumor, with a 10-year survival rate of more than 95%. Given the young average age at diagnosis, it is estimated that effective treatment approaches, in particular, platinum-based chemotherapy, have resulted in an average gain of several decades of life. This success, however, is offset by the emergence of considerable long-term morbidity, including second malignant neoplasms, cardiovascular disease, neurotoxicity, nephrotoxicity, pulmonary toxicity, hypogonadism, decreased fertility, and psychosocial problems. Data on underlying genetic or molecular factors that might identify those patients at highest risk for late sequelae are sparse. Genome-wide association studies and other translational molecular approaches now provide opportunities to identify testicular cancer survivors at greatest risk for therapy-related complications to develop evidence-based long-term follow-up guidelines and interventional strategies. We review research priorities identified during an international workshop devoted to testicular cancer survivors. Recommendations include 1) institution of lifelong follow-up of testicular cancer survivors within a large cohort setting to ascertain risks of emerging toxicities and the evolution of known late sequelae, 2) development of comprehensive risk prediction models that include treatment factors and genetic modifiers of late sequelae, 3) elucidation of the effect(s) of decades-long exposure to low serum levels of platinum, 4) assessment of the overall burden of medical and psychosocial morbidity, and 5) the eventual formulation of evidence-based long-term follow-up guidelines and interventions. Just as testicular cancer once served as the paradigm of a curable malignancy, comprehensive follow-up studies of testicular cancer survivors can pioneer new methodologies in survivorship research for all adult-onset cancer.


Epizootic and zoonotic helminths of the bobcat (Lynx rufus) in Illinois and a comparison of its helminth component communities across the American Midwest.
A total of 6257 helminths of 19 taxa were recovered from the digestive tract and lungs of 67 bobcats in Illinois. Infections caused by Alaria mustelae, Diphyllobothrium latum, and Macracanthorhynchus ingens are reported for the first time in bobcats. From all the taxa recovered, only three species occurred in high prevalence and caused intense infections: Taenia rileyi, Alaria marcianae, and Toxocara cati, with prevalence and mean intensity of 70% and 6; 42% and 193, and 25% and 14 individuals, respectively. Prevalence lower than 15% of 14 helminth species suggests bobcats are not continuously exposed to infective stages of a single parasite, and may be exposed to a large variety of generalists during their lifespan. No significant difference in parasite species according to host sex or age was detected, except for Diphyllobothrium spp., which were found more frequently in females and in trapped bobcats, and the hookworm, Ancylostoma caninum, which infected juveniles more frequently. Average species richness per infracommunity was 2.4 (±1.2), and the parasite component community showed low qualitative similarity with neighbor communities. The taxa A. caninum, Alaria spp., Diphyllobothrium spp., Paragonimus kellicotti, and T. cati are etiological agents of epizootic and zoonotic diseases.


Spatiotemporal interpolation and quality of apparent motion.
We investigate the conditions under which stimuli in apparent (sampled) motion are indistinguishable from those in smooth motion and compare this discrimination with the precision achieved by the visual system in interpolating apparent motion. In an initial experiment, observers were required to discriminate smooth from apparent motion, at variable step sizes, contrasts, velocities, and stimulus types (broadband line or bar stimuli and grating patches of different spatial frequency). Thresholds for discriminating smooth from sampled motion were approximately 40 arc min under optimal conditions, corresponding to the diameter of foveal photoreceptors. The tolerated step size between stations increased with velocity, more so for low- than for high-spatial-frequency stimuli. Tolerated step size decreased with presentation duration and with stimulus contrast. A separate experiment examined precision of interpolation. Vernier offsets were produced through temporal delays along the trajectory of an apparent motion, and thresholds for the discrimination of direction of offset were measured as a function of speed of motion and of distance between stations of apparent motion. Perfect interpolation was achieved for distances between stations of approximately 2 arc min. A model based on spatiotemporal filtering at an early stage of processing accounts well for the results of both types of experiments.


Effectiveness of a Piezoelectric-Assisted Distraction Osteogenesis Procedure for the Treatment of Ankylosed Permanent Front Teeth.
A common complication of tooth replantation after traumatic avulsion is tooth ankylosis causing dental malpositioning, partial loss of function, tipping of adjacent teeth and worsening of aesthetics. The aim of this study is to evaluate the effects of a repositioning procedure of such ankylosed permanent front teeth by a distraction osteogenesis procedure. Five patients (mean age 13.4 years), with an ankylosed permanent front tooth in the anterior area, were enrolled in the present study. After the pre-operatory orthodontic preparation, each selected site was treated with single-tooth dento-alveolar block osteotomy surgery performed with a piezoelectric surgery device with ultrasonic cuts on the buccal side. Subsequently, a custom distraction device, made by a resin splint and a sector expansion screw, was set in such a way it delivered a force with direction and sense towards the planned position of the tooth as well as the osteotomy's incision. After a latency period of 14 days, the distraction of the dento-alveolar block was started with a rate of distraction of 0.8 mm per day. The average shift obtained by the ankylosed teeth was 7.8 ± 0.75 mm (±SD), and the ankylosed tooth was regularly positioned into the occlusion in 20.4 ± 1.85 days (±SD), with a slight relapse (±0.5 mm) observed after 1 year. This study indicates that a therapeutic approach combining piezoelectric surgery and orthodontic therapy may be useful for the treatment of ankylosed permanent teeth in the frontal area with a long-term follow-up over 5 years.


Isolation of the floral morph-related genes in heterostylous flax (Linum grandiflorum): the genetic polymorphism and the transcriptional and post-transcriptional regulations of the S locus.
Heterostylous species have two types of flowers, thrum and pin morphs, and these are controlled by a single diallelic locus designated the 'S locus'; fertilization between these two types of flowers is successful. The S gene and the molecular mechanism by which it operates remain to be uncovered, although heterostyly has been studied since the time of Darwin. We compared transcripts and proteins of the thrum and pin flowers of heterostylous flax (Linum grandiflorum) to characterize the molecular differences between them and to elucidate the molecular machinery of heterostyly. Twelve floral morph-related genes were eventually isolated by an integrated study of subtraction and 2D-PAGE analyses, and four genes, TSS1, LgAP1, LgMYB21 and LgSKS1, were predicted to be related to heterostyly. TSS1, a thrum style-specific gene, showed some features suitable for the S gene. Although its biological function is unclear, TSS1 was expressed only in the thrum style and is probably linked to the S locus. LgMYB21, another thrum style gene, would be involved in floral morphogenesis. LgMYB21 was highly expressed in the thrum style, which is shorter than the pin style, and its overexpression in Arabidopsis reduced pistil length. Furthermore, a comparison of transcript and protein accumulations showed no differences in the mRNA accumulation of some thrum-specific proteins, including LgSKS1, suggesting that these are regulated by floral morph-specific post-transcriptional regulation. The Linum S locus regulates not only S specificity but also many floral phenotypes. Dynamic regulation of transcripts and proteins would be necessary for the pleiotropic function of the Linum S locus.


Microbial content of commercial South African high-moisture dried fruits.
The aim was to evaluate commercially available South African high-moisture dried fruits (HMDF) for the microbial, moisture and SO2 contents, as well as aw and pH. The microbial content of commercially available HMDF was evaluated using nine different growth media. The moisture content, aw) SO2 and pH of each product were determined using standard analytical methods. It was found that the highest total aerobic counts were generated from high-moisture dried (HMD) prunes and raisins. The most frequent spoilers were members of the genus Bacillus. Fungal counts were also very high in the apricot products, exceeding the limit of 1000 CFU g(-1) as set by HMDF producers. Members of the genus Staphylococcus were found in the HMD raisins and Salmonella and thermoduric organisms were isolated from the HMD prunes. The microbial levels of South African HMDF were within the limits set, with the exception of apricots. The study shows the presence of Salmonella, Staphylococcus and Clostridium in South African HMDF. The presence of thermoduric organisms indicated that the current pasteurization process is not adequate and that the addition of preservatives would be an additional method to ensure safety and quality.


The Medial Temporal Lobe Is Critical for Spatial Relational Perception.
The medial temporal lobe (MTL) is traditionally considered to be a system that is specialized for long-term memory. Recent work has challenged this notion by demonstrating that this region can contribute to many domains of cognition beyond long-term memory, including perception and attention. One potential reason why the MTL (and hippocampus specifically) contributes broadly to cognition is that it contains relational representations-representations of multidimensional features of experience and their unique relationship to one another-that are useful in many different cognitive domains. Here, we explore the hypothesis that the hippocampus/MTL plays a critical role in attention and perception via relational representations. We compared human participants with MTL damage to healthy age- and education-matched individuals on attention tasks that varied in relational processing demands. On each trial, participants viewed two images (rooms with paintings). On "similar room" trials, they judged whether the rooms had the same spatial layout from a different perspective. On "similar art" trials, they judged whether the paintings could have been painted by the same artist. On "identical" trials, participants simply had to detect identical paintings or rooms. MTL lesion patients were significantly and selectively impaired on the similar room task. This work provides further evidence that the hippocampus/MTL plays a ubiquitous role in cognition by virtue of its relational and spatial representations and highlights its important contributions to rapid perceptual processes that benefit from attention.


Alternative models of DSM-5 PTSD: Examining diagnostic implications.
The factor structure of DSM-5 posttraumatic stress disorder (PTSD) has been extensively debated with evidence supporting the recently proposed seven-factor Hybrid model. However, despite myriad studies examining PTSD symptom structure few have assessed the diagnostic implications of these proposed models. This study aimed to generate PTSD prevalence estimates derived from the 7 alternative factor models and assess whether pre-established risk factors associated with PTSD (e.g., transportation accidents and sexual victimisation) produce consistent risk estimates. Seven alternative models were estimated within a confirmatory factor analytic framework using the PTSD Checklist for DSM-5 (PCL-5). Data were analysed from a Malaysian adolescent community sample (n = 481) of which 61.7% were female, with a mean age of 17.03 years. The results indicated that all models provided satisfactory model fit with statistical superiority for the Externalising Behaviours and seven-factor Hybrid models. The PTSD prevalence estimates varied substantially ranging from 21.8% for the DSM-5 model to 10.0% for the Hybrid model. Estimates of risk associated with PTSD were inconsistent across the alternative models, with substantial variation emerging for sexual victimisation. These findings have important implications for research and practice and highlight that more research attention is needed to examine the diagnostic implications emerging from the alternative models of PTSD.


Genetic Contributions to The Association Between Adult Height and Head and Neck Cancer: A Mendelian Randomization Analysis.
With the aim to dissect the effect of adult height on head and neck cancer (HNC), we use the Mendelian randomization (MR) approach to test the association between genetic instruments for height and the risk of HNC. 599 single nucleotide polymorphisms (SNPs) were identified as genetic instruments for height, accounting for 16% of the phenotypic variation. Genetic data concerning HNC cases and controls were obtained from a genome-wide association study. Summary statistics for genetic association were used in complementary MR approaches: the weighted genetic risk score (GRS) and the inverse-variance weighted (IVW). MR-Egger regression was used for sensitivity analysis and pleiotropy evaluation. From the GRS analysis, one standard deviation (SD) higher height (6.9 cm; due to genetic predisposition across 599 SNPs) raised the risk for HNC (Odds ratio (OR), 1.14; 95% Confidence Interval (95%CI), 0.99-1.32). The association analyses with potential confounders revealed that the GRS was associated with tobacco smoking (OR = 0.80, 95% CI (0.69-0.93)). MR-Egger regression did not provide evidence of overall directional pleiotropy. Our study indicates that height is potentially associated with HNC risk. However, the reported risk could be underestimated since, at the genetic level, height emerged to be inversely associated with smoking.


Studies of carbohydrate and lipid metabolism in women developing hypertension on oral contraceptives.
Metabolic studies in 100 women developing hypertension on combined oestrogen-progestogen oral contraceptives have been compared with similar studies in normotensive women on oral contraceptives, matched for age and duration of contraceptive use, and in women not taking contraceptives.The metabolic changes known to be induced by oral contraceptives-impaired glucose tolerance, elevated blood pyruvate levels, and raised serum lipid concentrations-were found to be exaggerated in the matched hypertensive group, largely due to pronounced abnormalities in 33 subjects with diastolic blood pressures over 110 mm Hg.Women developing severe hypertension were older, more obese, and of higher parity than those with mild hypertension and there was a high incidence of previous toxaemia of pregnancy in the hypertensive group.The results show that in women on oral contraceptives changes in blood pressure and in metabolic functions tend to be correlated with one another, and are consistent with the hypothesis that oral contraception induces a primary biochemical effect whose expression in the individual is determined by intrinsic factors including genetic constitution, age, weight, and parity.


Physical and genetic interactions of yeast Cwc21p, an ortholog of human SRm300/SRRM2, suggest a role at the catalytic center of the spliceosome.
In Saccharomyces cerevisiae, Cwc21p is a protein of unknown function that is associated with the NineTeen Complex (NTC), a group of proteins involved in activating the spliceosome to promote the pre-mRNA splicing reaction. Here, we show that Cwc21p binds directly to two key splicing factors-namely, Prp8p and Snu114p-and becomes the first NTC-related protein known to dock directly to U5 snRNP proteins. Using a combination of proteomic techniques we show that the N-terminus of Prp8p contains an intramolecular fold that is a Snu114p and Cwc21p interacting domain (SCwid). Cwc21p also binds directly to the C-terminus of Snu114p. Complementary chemical cross-linking experiments reveal reciprocal protein footprints between the interacting Prp8 and Cwc21 proteins, identifying the conserved cwf21 domain in Cwc21p as a Prp8p binding site. Genetic and functional interactions between Cwc21p and Isy1p indicate that they have related functions at or prior to the first catalytic step of splicing, and suggest that Cwc21p functions at the catalytic center of the spliceosome, possibly in response to environmental or metabolic changes. We demonstrate that SRm300, the only SR-related protein known to be at the core of human catalytic spliceosomes, is a functional ortholog of Cwc21p, also interacting directly with Prp8p and Snu114p. Thus, the function of Cwc21p is likely conserved from yeast to humans.


Short-term dynamics of synaptic transmission within the excitatory neuronal network of rat layer 4 barrel cortex.
The short-term plasticity of synaptic transmission between excitatory neurons within a barrel of layer 4 rat somatosensory neocortex was investigated. Action potentials in presynaptic neurons at frequencies ranging from 1 to 100 Hz evoked depressing postsynaptic excitatory postsynaptic potentials (EPSPs). Recovery from synaptic depression followed an exponential time course with best-fit parameters that differed greatly between individual synaptic connections. The average maximal short-term depression was close to 0.5 with a recovery time constant of around 500 ms. Analysis of each individual sweep showed that there was a correlation between the amplitude of the response to the first and second action potentials such that large first EPSPs were followed by smaller than average second EPSPs and vice versa. Short-term depression between excitatory layer 4 neurons can thus be termed use dependent. A simple model describing use-dependent short-term plasticity was able to closely simulate the experimentally observed dynamic behavior of these synapses for regular spike trains. More complex irregular trains of 10 action potentials occurring within 500 ms were initially well described, but during the train errors increased. Thus for short periods of time the dynamic behavior of these synapses can be predicted accurately. In conjunction with data describing the connectivity, this forms a first step toward computational modeling of the excitatory neuronal network of layer 4 barrel cortex. Simulation of whisking-evoked activity suggests that short-term depression may provide a mechanism for enhancing the detection of objects within the whisker space.


What's in a smile? Maternal brain responses to infant facial cues.
Our goal was to determine how a mother's brain responds to her own infant's facial expressions, comparing happy, neutral, and sad face affect. In an event-related functional MRI study, 28 first-time mothers were shown novel face images of their own 5- to 10-month-old infant and a matched unknown infant. Sixty unique stimuli from 6 categories (own-happy, own-neutral, own-sad, unknown-happy, unknown-neutral, and unknown-sad) were presented randomly for 2 seconds each, with a variable 2- to 6-second interstimulus interval. Key dopamine-associated reward-processing regions of the brain were activated when mothers viewed their own infant's face compared with an unknown infant's face. These included the ventral tegmental area/substantia nigra regions, the striatum, and frontal lobe regions involved in (1) emotion processing (medial prefrontal, anterior cingulate, and insula cortex), (2) cognition (dorsolateral prefrontal cortex), and (3) motor/behavioral outputs (primary motor area). Happy, but not neutral or sad own-infant faces, activated nigrostriatal brain regions interconnected by dopaminergic neurons, including the substantia nigra and dorsal putamen. A region-of-interest analysis revealed that activation in these regions was related to positive infant affect (happy > neutral > sad) for each own-unknown infant-face contrast. When first-time mothers see their own infant's face, an extensive brain network seems to be activated, wherein affective and cognitive information may be integrated and directed toward motor/behavioral outputs. Dopaminergic reward-related brain regions are activated specifically in response to happy, but not sad, infant faces. Understanding how a mother responds uniquely to her own infant, when smiling or crying, may be the first step in understanding the neural basis of mother-infant attachment.


Humoral trophic influence on cardiovascular structural changes in hypertension.
Since the early development of structural cardiovascular change in spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP) indicated the involvement of non-pressure-dependent factors in this process in hypertension, smooth muscle cells (SMC) from the aorta of SHR, SHRSP, and normotensive Wistar-Kyoto rats (WKY) were investigated under tissue culture conditions free from blood pressure and humoral factors in vivo. By the observation of such factors as growth rate and DNA or protein synthesis vascular SMC from these rats with genetic hypertension were proved to have intrinsically greater growth activity independently of blood pressure. Although serum from SHR and SHRSP had no specific stimulative effect on SMC growth, circulating epinephrine may accelerate cardiovascular structural changes because isoproterenol added to the culture media enhanced ornithine decarboxylase (ODC) activity. Moreover, SMC from SHR and SHRSP showed greater thymidine incorporation than those from WKY even in response to lower extracellular Na+ concentration. Local nutritional conditions of SMC, which were proved to have a great effect on the morphology and structure of cultured SMC, may be a basic determinant of the development of hypertension-induced structural vascular changes or lesions.


Effect of Ajwa Dates Consumption to Inhibit the Progression of Preeclampsia Threats on Mean Arterial Pressure and Roll-Over Test.
Preeclampsia is the major problem and the main leading cause of fetal and maternal mortality worldwide. The early prediction of preeclampsia in pregnant women is required to prevent the occurrence of preeclampsia. The mean arterial pressure (MAP) and roll-over test (ROT) are the combination of measurement which can be used to predict preeclampsia. On the contrary, Ajwa dates were reported to have an enormous activity which contributes to its role in improving health conditions. In this study, we aimed to evaluate the effect of daily consumption of seven Ajwa dates on prevention of preeclampsia, through MAP and ROT changes. Forty pregnant women (n = 40) were randomly assigned into the control group (n = 10) and the intervention group which received a daily intake of Ajwa dates (n = 30). The MAP and ROT were assessed before and after the 8-week intervention period. The intervention group showed the significant reduction in MAP and ROT following the 8-week intervention period (p < 0.05). Daily consumption of seven Ajwa dates has a remarkable potential to decrease the MAP and ROT in pregnant women at risk of developing preeclampsia, and thus, it can contribute to prevent the development of preeclampsia.


Predicting the Susceptibility of Meningococcal Serogroup B Isolates to Bactericidal Antibodies Elicited by Bivalent rLP2086, a Novel Prophylactic Vaccine.
Bivalent rLP2086 (Trumenba), a vaccine for prevention of Neisseria meningitidis serogroup B (NmB) disease, was licensed for use in adolescents and young adults after it was demonstrated that it elicits antibodies that initiate complement-mediated killing of invasive NmB isolates in a serum bactericidal assay with human complement (hSBA). The vaccine consists of two factor H binding proteins (fHBPs) representing divergent subfamilies to ensure broad coverage. Although it is the surrogate of efficacy, an hSBA is not suitable for testing large numbers of strains in local laboratories. Previously, an association between the in vitro fHBP surface expression level and the susceptibility of NmB isolates to killing was observed. Therefore, a flow cytometric meningococcal antigen surface expression (MEASURE) assay was developed and validated by using an antibody that binds to all fHBP variants from both fHBP subfamilies and accurately quantitates the level of fHBP expressed on the cell surface of NmB isolates with mean fluorescence intensity as the readout. Two collections of invasive NmB isolates (n = 1,814, n = 109) were evaluated in the assay, with the smaller set also tested in hSBAs using individual and pooled human serum samples from young adults vaccinated with bivalent rLP2086. From these data, an analysis based on fHBP variant prevalence in the larger 1,814-isolate set showed that >91% of all meningococcal serogroup B isolates expressed sufficient levels of fHBP to be susceptible to bactericidal killing by vaccine-induced antibodies.IMPORTANCE Bivalent rLP2086 (Trumenba) vaccine, composed of two factor H binding proteins (fHBPs), was recently licensed for the prevention of N. meningitidis serogroup B (NmB) disease in individuals 10 to 25 years old in the United States. This study evaluated a large collection of NmB isolates from the United States and Europe by using a flow cytometric MEASURE assay to quantitate the surface expression of the vaccine antigen fHBP. We find that expression levels and the proportion of strains above the level associated with susceptibility in an hSBA are generally consistent across these geographic regions. Thus, the assay can be used to predict which NmB isolates are susceptible to killing in the hSBA and therefore is able to demonstrate an fHBP vaccine-induced bactericidal response. This work significantly advances our understanding of the potential for bivalent rLP2086 to provide broad coverage against diverse invasive-disease-causing NmB isolates.


Effect of n-3 PUFA supplementation on cognitive function throughout the life span from infancy to old age: a systematic review and meta-analysis of randomized controlled trials.
n-3 PUFAs play an important role in cognitive function. The objective was to investigate the effect of n-3 PUFA supplements on cognitive development, function, and decline throughout the life span. The study included randomized controlled trials and provided ≥3 mo of treatment. Potential studies were independently screened in duplicate, and study characteristics and outcomes were extracted. A meta-analysis was performed by using fixed- or random-effects models. The results are presented as standardized mean differences (SMDs) with 95% CIs. Of the 3692 citations retrieved, 34 studies of a total of 12,999 participants (1031 infants, 1517 children, 3657 adults, and 6794 elderly individuals) were included. Compared with placebo, n-3 PUFA supplements significantly improved cognitive development in infants, including the Mental Development Index (SMD: 0.33; 95% CI: 0.15, 0.52), the Psychomotor Development Index (0.27; 95% CI: 0.09, 0.45), and language (0.27; 95% CI: 0.13, 0.42), motor (0.29; 95% CI: 0.14, 0.43), and cognitive (0.31; 95% CI: 0.16, 0.45) abilities. However, n-3 PUFAs did not promote cognitive function in terms of composite memory, executive function, and processing speed domains in children, adults, or the elderly, except for the attention domain. No association was found between n-3 PUFA intake and improvements in cognitive performance in terms of recognition, immediate and delayed word recall, digit span backward and forward tests, rapid visual information processing, verbal fluency, and simple and choice reaction times. In addition, n-3 PUFA supplements were not associated with improvements in cognitive decline or with any effects on Alzheimer disease in elderly people. n-3 PUFA supplements may significantly improve cognitive development in infants but do not improve cognitive performance in children, adults, or the elderly. n-3 PUFA intake, especially that of DHA supplements, may benefit cognitive development during infancy.