Excitatory synaptic transmission between interneurons and motoneurons in chick spinal cord cell cultures.
We have examined the development of synaptic transmission between interneurons and motoneurons in spinal cord cell cultures. Unitary excitatory synaptic currents and complex bursts of excitatory currents develop rapidly: EPSCs (excitatory postsynaptic currents) were detected in 100% of the motoneurons by the 4th day after plating. Inhibitory synaptic currents develop more slowly: IPSCs (inhibitory postsynaptic currents) were detected in only 10% of the motoneurons on day 5 and 40% on day 8. During the 1st and 2nd days in vitro, 24% of the motoneurons tested were dye (Lucifer Yellow) coupled to nearby interneurons. The incidence of dye coupling declined during the first week in culture. No coupling was observed between motoneurons. Our data imply that both G1 and G2 receptors are activated at each synapse. The amplitude of spontaneous excitatory synaptic currents did not change when the motoneuron was hyperpolarized from -50 to -80 mV. This behavior is similar to that of currents induced by glutamate, an agonist that activates 2 types of receptors (G1 and G2) on motoneurons. In addition, a concentration of 2-amino-5-phosphonovaleric acid sufficient to inhibit all G1 receptors only partially inhibited the excitatory synaptic currents. Given the conductance of G1 and G2 channels and the ratio of channels activated during unitary EPSCs, we estimate that as few as 25 G1 channels and 5 G2 channels may mediate excitatory interaction between interneurons and motoneurons during the first week in culture.


Understanding the evolution and spread of chikungunya virus in the Americas using complete genome sequences.
Local transmission of chikungunya virus (CHIKV) was first detected in the Americas in December 2013, after which it spread rapidly throughout the Caribbean islands and American mainland, causing a major chikungunya fever epidemic. Previous phylogenetic analysis of CHIKV from a limited number of countries in the Americas suggests that an Asian genotype strain was responsible, except in Brazil where both Asian and East/Central/South African (ECSA) lineage strains were detected. In this study, we sequenced thirty-three complete CHIKV genomes from viruses isolated in 2014 from fourteen Caribbean islands, the Bahamas and two mainland countries in the Americas. Phylogenetic analyses confirmed that they all belonged to the Asian genotype and clustered together with other Caribbean and mainland sequences isolated during the American outbreak, forming an 'Asian/American' lineage defined by two amino acid substitutions, E2 V368A and 6K L20M, and divided into two well-supported clades. This lineage is estimated to be evolving at a mean rate of 5 × 10-4 substitutions per site per year (95% higher probability density, 2.9-7.9 × 10-4) and to have arisen from an ancestor introduced to the Caribbean (most likely from Oceania) in about March 2013, 9 months prior to the first report of CHIKV in the Americas. Estimation of evolutionary rates for individual gene regions and selection analyses indicate that (in contrast to the Indian Ocean Lineage that emerged from the ECSA genotype followed by adaptive evolution and with a significantly higher substitution rate) the evolutionary dynamics of the Asian/American lineage are very similar to the rest of the Asian genotype and natural selection does not appear to have played a major role in its emergence. However, several codon sites with evidence of positive selection were identified within the non-structural regions of Asian genotype sequences outside of the Asian/American lineage.


In vivo imaging of prostate cancer using [68Ga]-labeled bombesin analog BAY86-7548.
A novel [(68)Ga]-labeled DOTA-4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 peptide (BAY86-7548) having high affinity to bombesin receptor subtype II to detect primary and metastatic prostate carcinoma using positron emission tomography/computed tomography (PET/CT) was synthesized and evaluated for prostate cancer. In this first human study with BAY86-7548, 14 men scheduled for radical prostatectomy (n = 11) or with biochemical recurrence after surgery or hormonal therapy (n = 3) were enrolled. The patients received an intravenous injection of BAY86-7548 followed by over 60-minute dynamic imaging of prostate gland (n = 10) and/or subsequent whole-body imaging (n = 14). The visual assessment of PET/CT images included evaluation of intraprostatic (12 subsextants) and pelvic nodal uptake of BAY86-7548 in 11 surgical patients and detection of potential metastatic foci in all patients. In patients with biochemical recurrence, results were compared with those of either [(11)C]-acetate (n = 2) or [(18)F]-fluoromethylcholine (n = 1) PET/CT. We found a sensitivity, specificity, and accuracy of 88%, 81% and 83%, respectively, for detection of primary PCa and sensitivity of 70% for metastatic lymph nodes using histology as gold standard. BAY86-7548 correctly detected local recurrence in prostate bed and showed nodal relapse in accordance with [(11)C]-acetate PET/CT in 2 patients with biochemical relapse. In the third hormone refractory patient, BAY86-7548 failed to show multiple bone metastases evident on [(18)F]-fluoromethylcholine PET/CT. BAY86-7548 PET/CT is a promising molecular imaging technique for detecting intraprostatic prostate cancer.


Modeling the Mechanical Microenvironment of Coiled Cerebral Aneurysms.
Successful occlusion of cerebral aneurysms using coil embolization is contingent upon stable thrombus formation, and the quality of the thrombus depends upon the biomechanical environment. The goal of this study was to investigate how coil embolization alters the mechanical micro-environment within the aneurysm dome. Inertialess particles were injected in three-dimensional, computational simulations of flow inside patient aneurysms using patient-specific boundary conditions. Coil embolization was simulated as a homogenous porous medium of known permeability and inertial constant. Lagrangian particle tracking was used to calculate the residence time and shear stress history for particles in the flow before and after treatment. The percentage of particles entering the aneurysm dome correlated with the neck surface area before and after treatment (pretreatment: R2 = 0.831, P < 0.001; post-treatment: R2 = 0.638, P < 0.001). There was an inverse relationship between the change in particles entering the dome and coil packing density (R2 = 0.600, P < 0.001). Following treatment, the particles with the longest residence times tended to remain within the dome even longer while accumulating lower shear stress. A significant correlation was observed between the treatment effect on residence time and the ratio of the neck surface area to porosity (R2 = 0.390, P = 0.007). The results of this study suggest that coil embolization triggers clot formation within the aneurysm dome via a low shear stress-mediated pathway. This hypothesis links independently observed findings from several benchtop and clinical studies, furthering our understanding of this treatment strategy.


Effect of inclusion rate of Fermenten on performance, carcass traits, and apparent total tract digestibility of growing Angus crossbred steers.
In Phase 1 (days 0 to 56) of a two-phase experiment, 81 steers (initial BW = 189 ± 22 kg) were arranged in a generalized randomized block design, allocated to nine pens (nine steers per pen) and assigned to one of three dietary treatments. Treatments consisted of different inclusion rates of Fermenten (FER) in a backgrounding diet fed ad libitum, and were as follows: 0% (CON), 2%, or s FER in the diet DM. Steer was considered the experimental unit, and individual DMI was measured using the GrowSafe system. In Phase 2 (days 57 to 112), treatments were discontinued and steers were relocated to a paddock with free access to a common basal diet, to assess potential residual effects of FER. Effect of treatment was measured on performance, concentration of serum urea nitrogen (SUN), NEFA and glucose, and apparent total tract digestibility of nutrients. On day 56, steers fed 4% FER had lesser (P = 0.01) BW than 2% FER steers. Steers fed CON also tended (P = 0.08) to have greater BW than 4% FER steers. ADG was not different (P = 0.96) between CON and 2% FER steers, whereas steers in the 4% FER treatment had lesser (P ≤ 0.01) ADG than CON and 2% FER. Steers in the 4% FER treatment had lesser (P = 0.04) DMI than CON, and were less feed efficient (P ≤ 0.04) than 2% FER and CON steers. However, DMI as a percentage of the BW did not differ (P = 0.07) across treatments. A treatment effect was observed for final BW on day 112 (P = 0.05), where 4% FER tended (P = 0.07) to have lesser BW than CON. In Phase 2, ADG was not different (P = 0.18) among treatments. However, overall ADG (days 0 to 112) was lesser (P = 0.02) for steers fed 4% FER when compared with CON. There was no difference (P ≥ 0.12) in longissimus muscle area gain or 12th rib fat depth gain. There was a treatment × day interaction for serum concentrations of glucose (P < 0.001), NEFA (P < 0.001), and SUN (P < 0.001). Steers fed 4% FER had greater (P < 0.001) DM, OM, NDF, ADF, and CP apparent total tract digestibility than CON. Similarly, 4% FER steers had greater (P ≤ 0.02) DM, OM, NDF, and ADF digestibility than 2% FER. Results show that although inclusion of FER increased apparent total tract digestibility of nutrients, DMI and overall performance of growing beef cattle were negatively affected, mainly when FER was included at 4% of the diet DM.


Determining surface orientations of transparent objects based on polarization degrees in visible and infrared wavelengths.
Techniques for modeling an object through observation are very important in object recognition and virtual reality. A wide variety of techniques have been developed for modeling objects with opaque surfaces, whereas less attention has been paid to objects with transparent surfaces. A transparent surface has only surface reflection; it has little body reflection. We present a new method for obtaining surface orientations of transparent surfaces through analysis of the degree of polarization in surface reflection and emission in visible and far-infrared wavelengths, respectively. This parameter, the polarization degree of reflected light at the visible wavelengths, is used for determining the surface orientation at a surface point. The polarization degree at visible wavelengths provides two possible solutions, and the proposed method uses the polarization degree at far-infrared wavelengths to resolve this ambiguity.


Lombard effect onset times reveal the speed of vocal plasticity in a songbird.
Animals that use vocal signals to communicate often compensate for interference and masking from background noise by raising the amplitude of their vocalisations. This response has been termed the Lombard effect. However, despite more than a century of research, little is known how quickly animals can adjust the amplitude of their vocalisations after the onset of noise. The ability to respond quickly to increases in noise levels would allow animals to avoid signal masking and ensure their calls continue to be heard, even if they are interrupted by sudden bursts of high-amplitude noise. We tested how quickly singing male canaries (Serinus canaria) exhibit the Lombard effect by exposing them to short playbacks of white noise and measuring the speed of their responses. We show that canaries exhibit the Lombard effect in as little as 300 ms after the onset of noise and are also able to increase the amplitude of their songs mid-song and mid-phrase without pausing. Our results demonstrate high vocal plasticity in this species and suggest that birds are able to adjust the amplitude of their vocalisations very rapidly to ensure they can still be heard even during sudden changes in background noise levels.


Interactions between melatonin and estrogen may regulate cerebrovascular function in women: clinical implications for the effective use of HRT during menopause and aging.
A number of clinical trials associated with the Women's Health Initiative (WHI) have assessed the potential benefits of hormone replacement therapy (HRT) for protection against the development of cardiovascular disease and memory loss in menopausal women. The results of the WHI Memory Study suggest that HRT increases the risk of stroke and dementia in menopausal women. This finding has called into question the results of hundreds of basic science studies that have suggested that estrogen could protect brain cells from damage and improve cognition. A number of researchers have argued that inappropriate formulation, improper dosing, a limited study population, and poor timing of administration likely contributed to the reported findings from the clinical trial. Regarding appropriate formulation, it has been suggested that interactions between estrogen and other hormones should be considered for further investigation. A review of the literature has led us to conclude that a thorough investigation into such hormonal interactions is warranted. We hypothesize that the increased risk of cerebrovascular disease observed in menopausal women may, in part, be due to changes in the circulating levels of melatonin and estrogen and their modulatory affects on many relevant endothelial cell biological activities, such as regulation of vascular tone, adhesion to leukocytes, and angiogenesis, among others. Our hypothesis is supported by numerous studies demonstrating the reciprocal inhibitory effects of melatonin and estrogen on vascular tone, neuroprotection, and receptor expression. We believe that a thorough analysis of the distribution, localization, expression, quantification, and characterization of hormonal receptor subtypes, as well as changes in structural morphology in diseased and normal, healthy cerebrovascular tissue, will substantially aid in our understanding of the effects of HRT on the cerebrovascular circulation. The application of new molecular biological techniques such as tissue microarray analysis, gene and protein arrays, and multi-photon confocal microscopy may be of tremendous benefit in this regard.


A case-control study of lung cancer in relation to silica exposure and silicosis in a rural area in Japan.
In southeast Okayama Prefecture, Japan, there have been reports of a high prevalence of silicosis among refractory brick production workers. Recently, a high mortality rate of lung cancer among the local residents has been observed. Therefore, a population based case-control study was conducted concerning the relationship between silica, silicosis, and lung cancer using multiple cancer controls. Cases and controls were restricted to male subjects and information was obtained from death certificates from 1986 to 1993 in the area. Three categories of deceased control groups were selected: a series of deaths from liver cancer, colon cancer, and cancers of other organs, which was assumed not to be related to silica exposure. Age and smoking habits were adjusted by stratified analysis using the Mantel-Haenszel odds ratio estimates. Unconditional logistic regression analysis was also conducted to control potential confounding factors; such as age and smoking habits. The age-, smoking-adjusted odds ratios were 1.94 (0.94-4.43) for the colon cancer control group, 2.13 (1.19-3.85) for the other cancer control group related to silica exposure, and 2.94 (1.30-8.90) and 2.69 (1.43-5.37) related to silicosis, respectively. The direct weighted average using the estimates for colon and the other cancer controls was 2.06 (1.29-3.29) for silica exposure, and 2.77 (1.60-4.77) for silicosis. Histological or cytological types of lung cancer cases were obtained from 64.1% of the subjects (118/184). As for the histologic type of lung cancer, small cell carcinoma was higher among those who had been silica-exposed workers than the unexposed lung cancer cases and the data from the general Japanese population. On chest x-ray findings, elevated lung cancer mortality compared with cancers other than lung cancer was demonstrated among patients without large opacities. Silica exposure increased the lung cancer mortality in the area. A high lung cancer mortality rate in the area could be explained by silica exposure and silicosis prevalence in this area.


Mesh erosion in robotic sacrocolpopexy.
This study aimed to compare the incidence of mesh erosion after robotic sacrocolpopexy between women undergoing total and those undergoing supracervical hysterectomy (SH). This is a retrospective cohort study of women who underwent sacrocolpopexy and concomitant hysterectomy using the DaVinci surgical robot between May 2007 and December 2010 at 2 sites. Baseline data were gathered before surgery. The primary outcome was mesh erosion identified during 3 months of follow-up. A total of 102 women underwent sacrocolpopexy, of whom 45 were with concomitant SH and 57 were with total hysterectomy (TH). Their mean age was 58 years, mean body mass index was 26.8 kg/m, 98% were white, 6% smoked, and 25% were on systemic hormone replacement therapy. Mean preoperative Ba = +1.4, C = -2.2. These were not different between the 2 groups or by site. Within 3 months of surgery, mesh erosion was diagnosed in 8 women, all of whom had TH. No mesh erosions occurred in the SH group (14% vs 0%). Total hysterectomy mesh erosion rate at site 1 was 37% compared with 3% [corrected] at site 2. Mesh type was the only identifiable difference between sites: self-cut polypropylene at site 1, precut polypropylene at site 2. Two women in the SH had abnormal uterine pathology: 1 endometrial adenocarcinoma and 1 focus of hyperplasia with atypia. No mesh erosions were associated with SH within the first 3 months. In TH, the graft material used may be a modifiable factor needing further investigation. Unexpected abnormal uterine pathologic diagnosis remains a possibility with SH. Longer-term follow-up and a randomized trial are warranted to answer these questions.


Hepatitis B Virus Incidence and Risk Factors Among Human Immunodeficiency Virus-1 Negative Men Who Have Sex With Men in Kenya.
No data exist on hepatitis B virus (HBV) incidence among African men who have sex with men (MSM). We tested plasma samples archived between 2005 and 2014 for HBV core antibody or surface antigen seroconversion in a cohort of 312 initially human immunodeficiency virus (HIV)-1-negative MSM with no evidence of prior HBV infection. Hepatitis B virus incidence was 6.0/100 person-years (95% confidence interval [CI], 3.9-9.1). Hepatitis B virus acquisition was associated with being uncircumcised (adjusted incidence rate ratio [aIRR], 5.0; 95% CI, 1.5-16.8), recent HIV-1 acquisition (aIRR, 2.9; 95% CI, 1.1-7.7), rape (aIRR, 5.0; 95% CI, 1.2-20.4), and any tertiary education (aIRR, 3.2; 95% CI, 1.1-9.7). African MSM have a substantial risk of HBV acquisition and require vaccination urgently.


Introduction of the harmonised respiratory physiotherapy curriculum.
Building on the core syllabus for postgraduate training in respiratory physiotherapy, published in 2014, the European Respiratory Society (ERS) respiratory physiotherapy task force has developed a harmonised and structured postgraduate curriculum for respiratory physiotherapy training. The curriculum outlines the knowledge, skills and attitudes which must be mastered by a respiratory physiotherapist working with adult or paediatric patients, together with guidance for minimal clinical exposures, and forms of learning and assessment. This article presents the rationale, methodology and content of the ERS respiratory physiotherapy curriculum. The full curriculum can be found in the supplementary material.


Predicting protein-protein interactions from protein sequences by a stacked sparse autoencoder deep neural network.
Protein-protein interactions (PPIs) play an important role in most of the biological processes. How to correctly and efficiently detect protein interaction is a problem that is worth studying. Although high-throughput technologies provide the possibility to detect large-scale PPIs, these cannot be used to detect whole PPIs, and unreliable data may be generated. To solve this problem, in this study, a novel computational method was proposed to effectively predict the PPIs using the information of a protein sequence. The present method adopts Zernike moments to extract the protein sequence feature from a position specific scoring matrix (PSSM). Then, these extracted features were reconstructed using the stacked autoencoder. Finally, a novel probabilistic classification vector machine (PCVM) classifier was employed to predict the protein-protein interactions. When performed on the PPIs datasets of Yeast and H. pylori, the proposed method could achieve average accuracies of 96.60% and 91.19%, respectively. The promising result shows that the proposed method has a better ability to detect PPIs than other detection methods. The proposed method was also applied to predict PPIs on other species, and promising results were obtained. To evaluate the ability of our method, we compared it with the-state-of-the-art support vector machine (SVM) classifier for the Yeast dataset. The results obtained via multiple experiments prove that our method is powerful, efficient, feasible, and make a great contribution to proteomics research.


Compiler-aided systematic construction of large-scale DNA strand displacement circuits using unpurified components.
Biochemical circuits made of rationally designed DNA molecules are proofs of concept for embedding control within complex molecular environments. They hold promise for transforming the current technologies in chemistry, biology, medicine and material science by introducing programmable and responsive behaviour to diverse molecular systems. As the transformative power of a technology depends on its accessibility, two main challenges are an automated design process and simple experimental procedures. Here we demonstrate the use of circuit design software, combined with the use of unpurified strands and simplified experimental procedures, for creating a complex DNA strand displacement circuit that consists of 78 distinct species. We develop a systematic procedure for overcoming the challenges involved in using unpurified DNA strands. We also develop a model that takes synthesis errors into consideration and semi-quantitatively reproduces the experimental data. Our methods now enable even novice researchers to successfully design and construct complex DNA strand displacement circuits.


Influence of anti-Nogo-A antibody treatment on the reorganization of callosal connectivity of the premotor cortical areas following unilateral lesion of primary motor cortex (M1) in adult macaque monkeys.
Following unilateral lesion of the primary motor cortex, the reorganization of callosal projections from the intact hemisphere to the ipsilesional premotor cortex (PM) was investigated in 7 adult macaque monkeys, in absence of treatment (control; n = 4) or treated with function blocking antibodies against the neurite growth inhibitory protein Nogo-A (n = 3). After functional recovery, though incomplete, the tracer biotinylated dextran amine (BDA) was injected in the ipsilesional PM. Retrogradely labelled neurons were plotted in the intact hemisphere and their number was normalized with respect to the volume of the core of BDA injection sites. (1) The callosal projections to PM in the controls originate mainly from homotypic PM areas and, but to a somewhat lesser extent, from the mesial cortex (cingulate and supplementary motor areas). (2) In the lesioned anti-Nogo-A antibody-treated monkeys, the normalized number of callosal retrogradely labelled neurons was up to several folds higher than in controls, especially in the homotypic PM areas. (3) Except one control with a small lesion and a limited, transient deficit, the anti-Nogo-A antibody-treated monkeys recovered to nearly baseline levels of performance (73-90 %), in contrast to persistent deficits in the control monkeys. These results are consistent with a sprouting and/or sparing of callosal axons promoted by the anti-Nogo-A antibody treatment after lesion of the primary motor cortex, as compared to untreated monkeys.


Hypertension treatment in the Asia-Pacific: the role of and treatment strategies with nebivolol.
Hypertension is a common disease, and hypertensive patients are at increased risk of cardiovascular events. The prevalence and socioeconomic burden of hypertension in the Asia-Pacific region are predicted to increase in the coming decades. Effective blood pressure lowering reduces overall cardiovascular morbidity and mortality in patients, yet doubt has been raised regarding the use of (mainly older generation) β-blockers as initial therapy in hypertension. Consequently, several international treatment guidelines do not recommend β-blockers for the treatment of hypertension. However, in contrast to first-generation and second-generation β-blockers, the third-generation, vasodilating β-blocker nebivolol has a considerably better metabolic, haemodynamic and side effect profile. In addition to providing effective blood pressure control similar to other β-blockers and drugs from other antihypertensive classes, nebivolol exerts a dual mechanism for increasing the bioavailability of the naturally occurring vasodilator nitric oxide. The clinical benefits and significance of enhancing nitric oxide levels in hypertensive patients have been shown in direct comparisons of nebivolol with other β-blockers. While β-blockers generally provide comparable blood pressure reductions, only nebivolol demonstrated enhanced vasodilation and blood flow by increasing the expression of endothelial nitric oxide synthase and therefore increasing nitric oxide release from the endothelium. In contrast to other β-blockers, therefore, it has been suggested that nebivolol has beneficial effects in several hypertensive subgroups due to its vasodilating properties. Considering the existing data, it may be timely for treatment guidelines to recommend third-generation vasodilating β-blockers as a first-line option for the pharmacotherapy of hypertension.


Increasing the frequency of physical activity very brief advice by nurses to cancer patients. A mixed methods feasibility study of a training intervention.
To examine the impact, acceptability, practicability and implementation of a training intervention, designed using the Behaviour Change Wheel, on the delivery of very brief advice on physical activity, by nurses to cancer patients. A mixed methods feasibility study. A purposeful sample of nurses (n = 62) were recruited across two delivery arms, face-to-face (n = 55) and online (n = 7). Frequency of delivery of physical activity advice was collected at baseline with follow-up at 12 weeks. The 'capability, opportunity and motivation' of nurses to deliver very brief advice was measured via questionnaire. Semi-structured phone interviews (n = 14) were completed and analyzed thematically. A cost consequence analysis was undertaken. The intervention improved the 'capability, opportunity and motivation' of nurses resulting in a change in knowledge, attitudes and beliefs towards physical activity. The intervention was both acceptable and practical. Face-to-face was the preferred mode of delivery, however there was also value in the online option. The cost of delivery per participant was £33.87 for face-to-face delivery, and £103.83 for online delivery inflated due to low recruitment numbers. A significant improvement was seen in delivery of very brief advice at 12 weeks (Z = -4.39, P ≤ 0.01). The intervention is acceptable, practical and improves delivery of very brief advice on physical activity by nurses to cancer patients in the short-term. Both face-to-face and online delivery should be considered.


Advanced airway management in combat casualties by medics at the point of injury: a sub-group analysis of the reach study.
background: Optimal airway management protocols for the prehospital battlefield setting have not been defined. Airway management strategies in this environment must take into account the injury patterns, the environment and training requirements of military prehospital providers. This is a post-hoc, sub-group analysis of the Registry of Emergency Airways Arriving at Combat Hospitals or REACH database. This study examines only those patients who had advanced airways placed for trauma by an enlisted military medic at the point of injury. results: Twenty (100%) of the patients had a traumatic injury, 19 (95%) were male, and 13 (65%) had a gun shot wounds (GSWs) as the mechanism of injury. The majority, 12 (60%) patients had an esophageal-tracheal airway device placed. Of the remaining patients, four (20%) underwent endotracheal intubation, three (15%) had a surgical cricothyroidotomy performed, and one (5%) had a Laryngeal Mask Airway (LMA) placed. Seventeen (85%) of the twenty patients were dead on arrival or died shortly after arrival at the Combat Support Hospital (CSH). All of the patients that died had a Glasgow Coma Scale (GCS) of three upon arrival. The Glasgow Coma Scale provides a score in the range 3-15; patients with scores of 3-8 are usually said to be in a coma. Three patients in this group survived to transfer from the CSH. Two of the transfers were lost to follow up, one with a GSW to the head and GCS of three, the other with a GCS of five from injuries sustained in an explosion. The third patient had a surgical cricothyroidotomy (SC) performed in the field for an expanding neck hematoma and recovered fully following surgery. conclusions: Casualties that tolerate invasive airway management without sedation in the context of trauma prognosticates a very high mortality. Airway management algorithms for military providers should reflect the casualties encountered on the battlefield not patients in cardiac arrest which predominate in the civilian EMS airway management practice. Further data are needed to understand the injuries encountered on the battlefield and to develop airway management solutions that optimize outcomes of patients with battlefield trauma.


Immunostimulatory effect of kumquat (Fortunella crassifolia) and its constituents, β-cryptoxanthin and R-limonene.
Natural killer (NK) cells play an important role in the innate immune system by eliminating cancer cells and virally infected cells. Aging and stress attenuate the activity of NK cells, thereby increasing the risk of various diseases. In this study, we demonstrated that the consumption of a small number of kumquats in an in vivo model could suppress elevated plasma corticosterone levels and reverse the decline in splenocyte cytotoxicity caused by restraint stress. Our results identified β-cryptoxanthin (BCX) as an active kumquat component with a NK cell-activating effect, and R-limonene as an active component that mediates not only the anti-stress effect but also NK cell activation by oral administration. In addition, BCX, R-limonene, and R-limonene metabolites were found to enhance IFN-γ production in KHYG-1 cells, a human NK cell line. Collectively, our findings suggest that the ingestion of a few kumquats on a daily basis can help to combat stress and enhance NK cell activity.


Racial and ethnic disparities in influenza vaccination among elderly adults.
To examine whether access to care factors account for racial/ethnic disparities in influenza vaccination among elderly adults in the United States. Indicators of access to care (predisposing, enabling, environmental/system, and health need) derived from Andersen's behavioral model were identified in the National Health Interview Survey questionnaire. The relationship of these indicators to influenza vaccination and race/ethnicity was assessed with multiple logistic regression models. Significant differences in vaccination were observed between non-Hispanic (NH) whites (66%) and Hispanics (50%, P<.001) and between NH whites (66%) and NH blacks (46%, P<.001). Controlling for predisposing and enabling access to care indicators, education, marital status, regular source of care, and number of doctor visits, reduced the prevalence odds ratios (POR) comparing Hispanics to non-Hispanic whites from 1.89 to 1.27. For NH blacks, controlling for access to care indicators changed the POR only from 2.24 (95% CI, 1.9 to 2.7) to 1.93 (95% CI, 1.6 to 2.4). This study confirmed the existence of sizable racial/ethnic differences in influenza vaccination among elderly adults. These disparities were only partially explained by differences in indicators of access to care, especially among non-Hispanic blacks for whom large disparities remained. Factors not available in the National Health Interview Survey, such as patient attitudes and provider performance, should be investigated as possible explanations for the racial/ethnic disparity in influenza vaccination among non-Hispanic blacks.


Prediction of the Transporter-Mediated Drug-Drug Interaction Potential of Dabrafenib and Its Major Circulating Metabolites.
The BRAF inhibitor dabrafenib was recently approved for the treatment of certain BRAF V600 mutation-positive tumors, either alone or in combination therapy with the mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 inhibitor, trametinib. This article presents the dabrafenib transporter-mediated drug-drug interaction (DDI) risk assessment, which is currently an important part of drug development, regulatory submission, and drug registration. Dabrafenib and its major circulating metabolites (hydroxy-, carboxy-, and desmethyl-dabrafenib) were investigated as inhibitors of the clinically relevant transporters P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, and OAT3. The DDI Guidance risk assessment decision criteria for inhibition of BCRP, OATP1B1 and OAT3 were slightly exceeded and therefore a minor DDI effect resulting from inhibition of these transporters remained possible. Biliary secretion is the major excretion pathway of dabrafenib-related material (71.1% of orally administered radiolabeled dose recovered in feces), whereas urinary excretion was observed as well (22.7% of the dose). In vitro uptake into human hepatocytes of the dabrafenib metabolites, but not of dabrafenib parent compound, was mediated, at least in part, by hepatic uptake transporters. The transporters responsible for uptake of the pharmacologically active hydroxy- and desmethyl dabrafenib could not be identified, whereas carboxy-dabrafenib was a substrate of several OATPs. Dabrafenib, hydroxy-, and desmethyl-dabrafenib were substrates of P-gp and BCRP, whereas carboxy-dabrafenib was not. Although a small increase in exposure to carboxy-dabrafenib upon inhibition of OATPs and an increase in exposure to desmethyl-dabrafenib upon inhibition of P-gp or BCRP cannot be excluded, the clinical significance of such increases is likely to be low.


Exploring the mediating role of energy balance-related behaviours in the association between sleep duration and obesity in European adults. The SPOTLIGHT project.
Sleep restriction is a risk factor for weight gain and obesity. Few studies have formally investigated the mediating role of energy balance-related behaviours in the sleep - obesity association. The aim of this study was to explore the mediating role of physical activity, sedentary behaviours and dietary habits in the association of sleep duration with obesity in adults in five European urban regions. Data on self-reported sleep duration, energy balance-related behaviours, height and weight and other covariates were collected between February and September 2014 from participants to the SPOTLIGHT survey (N=5900, mean age 52years). Participants were recruited from 60 urban neighbourhoods in Belgium, France, Hungary, the Netherlands and the United Kingdom. Multilevel logistic regression analyses were used to assess the associations of sleep duration, energy balance-related behaviours and obesity and mediating effects were calculated using MacKinnon's product-of-coefficients method. Results indicated that a 1h increase in sleeping time was associated with a 14% lower likelihood of being obese (OR=0.86, 95%CI=0.80; 0.93). Only work-related sedentary behaviour was identified as a statistically significant mediator in the association between sleep duration and obesity for the total sample, and youngest and oldest age group. We did not find evidence for a mediating role of dietary habits and physical activities.


Haptic Shared Control in Tele-Manipulation: Effects of Inaccuracies in Guidance on Task Execution.
Haptic shared control is a promising approach to improve tele-manipulated task execution, by making safe and effective control actions tangible through guidance forces. In current research, these guidance forces are most often generated based on pre-generated, errorless models of the remote environment. Hence such guidance forces are exempt from the inaccuracies that can be expected in practical implementations. The goal of this research is to quantify the extent to which task execution is degraded by inaccuracies in the model on which haptic guidance forces are based. In a human-in-the-loop experiment, subjects (n = 14) performed a realistic tele-manipulated assembly task in a virtual environment. Operators were provided with various levels of haptic guidance, namely no haptic guidance (conventional tele-manipulation), haptic guidance without inaccuracies, and haptic guidance with translational inaccuracies (one large inaccuracy, in the order of magnitude of the task, and a second smaller inaccuracy). The quality of natural haptic feedback (i.e., haptic transparency) was varied between high and low to identify the operator's ability to detect and cope with inaccuracies in haptic guidance. The results indicate that haptic guidance is beneficial for task execution when no inaccuracies are present in the guidance. When inaccuracies are present, this may degrade task execution, depending on the magnitude and the direction of the inaccuracy. The effect of inaccuracies on overall task performance is dominated by effects found for the Constrained Translational Movement, due to its potential for jamming. No evidence was found that a higher quality of haptic transparency helps operators to detect and cope with inaccuracies in the haptic guidance.


Prevalence of lymphocytic choriomeningitis virus infection in a human population of Argentina.
The activity of lymphocytic choriomeningitis virus (LCMV) in the endemic area of Argentine hemorrhagic fever has been previously reported and represents the first evidence of the coexistence of two arenaviruses pathogenic for humans, Junin and LCMV, in the same geographic area. Data are presented on the prevalence of LCMV human infection in a 10,000-km2 area located in Santa Fe Province, Argentina. Study subjects were males, 15-65 years old, living and/or working in the rural area of 41 localities. One serum sample was obtained from each 7,227 volunteers from a total population of 21,340 individuals with the described features. Antibodies to LCMV were assessed by means of an indirect immunofluorescence assay. These antibodies were found in 172 serum samples, with titers ranging from 1:8 to 1:128 (geometric mean titer = 15.03), and a mean percentage of infection of 2.38%. A significantly different distribution of positive individuals was found between the eastern (1.54%) and western (3.07%) borders of the region studied (P < 0.0003). The higher percentage of infection on the western side was due to the existence of two clusters of counties with a mean percentage of 6.06% that was significantly different from the 1.67% obtained in the rest of the study area (P < 0.0003). These results provide new information on the LCMV activity in Argentina, and update the evidence on the coexistence of two arenaviruses in the same region of Argentina. This circumstance increases the probability of generation of viral reassortants with changes that could determine the need for new therapeutic and/or preventive strategies for arenaviral diseases.


Invading the yeast nucleus: a nuclear localization signal at the C terminus of Ty1 integrase is required for transposition in vivo.
Retrotransposon Ty1 faces a formidable cell barrier during transposition--the yeast nuclear membrane which remains intact throughout the cell cycle. We investigated the mechanism by which transposition intermediates are transported from the cytoplasm (the presumed site of Ty1 DNA synthesis) to the nucleus, where they are integrated into the genome. Ty1 integrase has a nuclear localization signal (NLS) at its C terminus. Both full-length integrase and a C-terminal fragment localize to the nucleus. C-terminal deletion mutants in Ty1 integrase were used to map the putative NLS to the last 74 amino acid residues of integrase. Mutations in basic segments within this region decreased retrotransposition at least 50-fold in vivo. Furthermore, these mutant integrase proteins failed to localize to the nucleus. Production of virus-like particles, reverse transcriptase activity, and complete in vitro Ty1 integration resembled wild-type levels, consistent with failure of the mutant integrases to enter the nucleus.


Different amino acid substitutions at the same position in rhodopsin lead to distinct phenotypes.
Identification of a novel rhodopsin mutation in a family with retinitis pigmentosa and comparison of the clinical phenotype to a known mutation at the same amino acid position. Screening for mutations in rhodopsin was performed in 78 patients with retinitis pigmentosa. All exons and flanking intronic regions were amplified by PCR, sequenced, and compared to the reference sequence derived from the National Center for Biotechnology Information (NCBI, Bethesda, MD) database. Patients were characterized clinically according to the results of best corrected visual acuity testing (BCVA), slit lamp examination (SLE), funduscopy, Goldmann perimetry (GP), dark adaptometry (DA), and electroretinography (ERG). Structural analyses of the rhodopsin protein were performed with the Swiss-Pdb Viewer program available on-line (http://www.expasy.org.spdvbv/ provided in the public domain by Swiss Institute of Bioinformatics, Geneva, Switzerland). A novel rhodopsin mutation (Gly90Val) was identified in a Swiss family of three generations. The pedigree indicated autosomal dominant inheritance. No additional mutation was found in this family in other autosomal dominant genes. The BCVA of affected family members ranged from 20/25 to 20/20. Fundus examination showed fine pigment mottling in patients of the third generation and well-defined bone spicules in patients of the second generation. GP showed concentric constriction. DA demonstrated monophasic cone adaptation only. ERG revealed severely reduced rod and cone signals. The clinical picture is compatible with retinitis pigmentosa. A previously reported amino acid substitution at the same position in rhodopsin leads to a phenotype resembling night blindness in mutation carriers, whereas patients reported in the current study showed the classic retinitis pigmentosa phenotype. The effect of different amino acid substitutions on the three-dimensional structure of rhodopsin was analyzed by homology modeling. Distinct distortions of position 90 (shifts in amino acids 112 and 113) and additional hydrogen bonds were found. Different amino acid substitutions at position 90 of rhodopsin can lead to night blindness or retinitis pigmentosa. The data suggest that the property of the substituted amino acid distinguishes between the phenotypes.


Chronic persistent cough in the community: a questionnaire survey.
Chronic cough is a common symptom which causes significant levels of morbidity. It is becoming increasingly well characterised by research taking place in specialist cough clinics, where successful treatment rates are high. However, there is a paucity of data regarding the symptom complex of chronic cough in the community. This report details the results of a postal questionnaire survey sent to individuals requesting further information on chronic cough. 856 chronic cough questionnaires were sent out to members of the public who requested an information sheet following a national UK radio broadcast. Information regarding demography, history of cough, previous treatment and physical, psychological and social effects of the cough was elicited. 373 completed questionnaires were returned. Mean age was 65.3 years (SD 12.0, range 9-88 years). 73% were female and 2% current smokers. Median duration of cough was 6.5 years. 66% had no other coexisting respiratory diagnosis, whilst 24% reported asthma. Of those who responded, 91% had consulted a general practitioner regarding the cough and of them, 85% had been prescribed some sort of treatment. 61% had seen at least one hospital specialist. Commonly reported associated physical symptoms included breathlessness (55%), wheeze (37%), fatigue (72%) and disturbed sleep (70%). Incontinence occurred in 55% of women. Similarly, the majority reported psychological effects such as anger or frustration (83%), anxiety (69%) and depression (55%). 64% felt that the cough interfered with their social life. Chronic cough causes a high level of morbidity in the community, which results in a correspondingly high rate of healthcare utilisation. Demography and symptomatology seems to be similar to that reported from specialist centres, but successful treatment of the cough was uncommon, despite a high number of medical consultations in both primary and secondary care. If understanding of this debilitating but eminently treatable condition is enhanced, management of chronic cough will improve and many patients will be helped.


Plant-soil feedbacks: a meta-analytical review.
Plants can change soil biology, chemistry and structure in ways that alter subsequent plant growth. This process, referred to as plant-soil feedback (PSF), has been suggested to provide mechanisms for plant diversity, succession and invasion. Here we use three meta-analytical models: a mixed model and two Bayes models, one correcting for sampling dependence and one correcting for sampling and hierarchical dependence (delta-splitting model) to test these hypotheses. All three models showed that PSFs have medium to large negative effects on plant growth, and especially grass growth, the life form for which we had the most data. This supports the hypothesis that PSFs, through negative frequency dependence, maintain plant diversity, especially in grasslands. PSFs were also large and negative for annuals and natives, but the delta-splitting model indicated that more studies are needed for these results to be conclusive. Our results support the hypotheses that PSFs encourage successional replacements and plant invasions. Most studies were performed using monocultures of grassland species in greenhouse conditions. Future research should examine PSFs in plant communities, non-grassland systems and field conditions.


Toward toxicity testing of nanomaterials in the 21st century: a paradigm for moving forward.
A challenge-facing hazard identification and safety evaluation of engineered nanomaterials being introduced to market is the diversity and complexity of the types of materials with varying physicochemical properties, many of which can affect their toxicity by different mechanisms. In general, in vitro test systems have limited usefulness for hazard identification of nanoparticles due to various issues. Meanwhile, conducting chronic toxicity/carcinogenicity studies in rodents for every new nanomaterial introduced into the commerce is impractical if not impossible. New toxicity testing systems which rely on predictive, high-throughput technologies may be the ultimate goal of evaluating the potential hazard of nanomaterials. However, at present, this approach alone is unlikely to succeed in evaluating the toxicity of the wide array of nanomaterials and requires validation from in vivo studies. This article proposes a paradigm for toxicity testing and elucidation of the molecular mechanisms of reference materials for specific nanomaterial classes/subclasses using short-term in vivo animal studies in conjunction with high-throughput screenings and mechanism-based short-term in vitro assays. The hazard potential of a particular nanomaterial can be evaluated by conducting only in vitro high-throughput assays and mechanistic studies and comparing the data with those of the reference materials in the specific class/subclass-an approach in line with the vision for 'Toxicity Testing in the 21st Century' of chemicals. With well-designed experiments, testing nanomaterials of varying/selected physicochemical parameters may be able to identify the physicochemical parameters contributing to toxicity. The data so derived could be used for the development of computer model systems to predict the hazard potential of specific nanoparticles based on property-activity relationships.


2-Methoxyestradiol, an estradiol metabolite, inhibits neointima formation and smooth muscle cell growth via double blockade of the cell cycle.
2-Methoxyestradiol (2-ME), an endogenous metabolite of estradiol with no affinity for estrogen receptors, is a potent anticarcinogenic agent (in phase II clinical trials) and mediates the inhibitory effects of estradiol on smooth muscle cell (SMC) growth. Here we studied the intracellular mechanisms by which 2-ME inhibits SMC growth and whether 2-ME prevents injury-induced neointima formation. 2-ME concentrations that inhibit proliferation of cycling human aortic SMCs by >or=50% blocked cell-cycle progression in G(0)/G(1) and in G(2)/M phase, as determined by flow cytometry. Consistent with the cell-cycle effects, at a molecular level (Western blots), 2-ME inhibited cyclin D(1) and cyclin B(1) expression; cyclin-dependent kinase (cdk)-1 and cdk-2 activity; and retinoblastoma protein (pRb), extracellular signal-regulated kinase (ERK) 1/2, and Akt phosphorylation. 2-ME also upregulated the Cdk inhibitor p27 and interfered with tubulin polymerization. Moreover, 2-ME augmented COX-2 expression, suggesting that it may also inhibit SMC growth via prostaglandin formation. In rats, treatment with 2-ME abrogated injury-induced neointima formation; decreased proliferating SMCs; downregulated expression of proliferating-cell nuclear antigen (PCNA), c-myc, cyclin D(1), cyclin B(1), phosphorylated Akt, phosphorylated ERK1/2, p21, and pRb; inhibited cdk-1 and cdk-4 activity; and upregulated expression of cyclooxygenase (COX)-2 and p27. Caspase-3 cleavage assay and fluorescence-activated cell-sorting (FACS) analysis showed no evidence of apoptosis in 2-ME-treated SMCs, and TUNEL staining in carotid segments showed no evidence of 2-ME-induced apoptosis in vivo. The antimitotic effects of 2-ME on SMCs are mediated by the inhibition of key cell-cycle regulatory proteins and effects on tubulin polymerization and COX-2 upregulation. These effects of 2-ME most likely contribute to the antivasoocclusive actions of this endogenous compound.


Lipoxin A4 prevents tight junction disruption and delays the colonization of cystic fibrosis bronchial epithelial cells by Pseudomonas aeruginosa.
The specialized proresolution lipid mediator lipoxin A4 (LXA4) is abnormally produced in cystic fibrosis (CF) airways. LXA4 increases the CF airway surface liquid height and stimulates airway epithelial repair and tight junction formation. We report here a protective effect of LXA4 (1 nM) against tight junction disruption caused by Pseudomonas aeruginosa bacterial challenge together with a delaying action against bacterial invasion in CF airway epithelial cells from patients with CF and immortalized cell lines. Bacterial invasion and tight junction integrity were measured by gentamicin exclusion assays and confocal fluorescence microscopy in non-CF (NuLi-1) and CF (CuFi-1) bronchial epithelial cell lines and in primary CF cultures, grown under an air/liquid interface, exposed to either a clinical or laboratory strains of P. aeruginosa LXA4 delayed P. aeruginosa invasion and transepithelial migration in CF and normal bronchial epithelial cell cultures. These protective effects of LXA4 were inhibited by the ALX/FPR2 lipoxin receptor antagonist BOC-2. LXA4 prevented the reduction in mRNA biosynthesis and protein abundance of the tight junction protein ZO-1 and reduced tight junction disruption induced by P. aeruginsosa inoculation. In conclusion, LXA4 plays a protective role in bronchial epithelium by stimulating tight junction repair and by delaying and reducing the invasion of CF bronchial epithelial cells by P. aeruginsosa.


Evolutionary characters, phenotypes and ontologies: curating data from the systematic biology literature.
The wealth of phenotypic descriptions documented in the published articles, monographs, and dissertations of phylogenetic systematics is traditionally reported in a free-text format, and it is therefore largely inaccessible for linkage to biological databases for genetics, development, and phenotypes, and difficult to manage for large-scale integrative work. The Phenoscape project aims to represent these complex and detailed descriptions with rich and formal semantics that are amenable to computation and integration with phenotype data from other fields of biology. This entails reconceptualizing the traditional free-text characters into the computable Entity-Quality (EQ) formalism using ontologies. We used ontologies and the EQ formalism to curate a collection of 47 phylogenetic studies on ostariophysan fishes (including catfishes, characins, minnows, knifefishes) and their relatives with the goal of integrating these complex phenotype descriptions with information from an existing model organism database (zebrafish, http://zfin.org). We developed a curation workflow for the collection of character, taxonomic and specimen data from these publications. A total of 4,617 phenotypic characters (10,512 states) for 3,449 taxa, primarily species, were curated into EQ formalism (for a total of 12,861 EQ statements) using anatomical and taxonomic terms from teleost-specific ontologies (Teleost Anatomy Ontology and Teleost Taxonomy Ontology) in combination with terms from a quality ontology (Phenotype and Trait Ontology). Standards and guidelines for consistently and accurately representing phenotypes were developed in response to the challenges that were evident from two annotation experiments and from feedback from curators. The challenges we encountered and many of the curation standards and methods for improving consistency that we developed are generally applicable to any effort to represent phenotypes using ontologies. This is because an ontological representation of the detailed variations in phenotype, whether between mutant or wildtype, among individual humans, or across the diversity of species, requires a process by which a precise combination of terms from domain ontologies are selected and organized according to logical relations. The efficiencies that we have developed in this process will be useful for any attempt to annotate complex phenotypic descriptions using ontologies. We also discuss some ramifications of EQ representation for the domain of systematics.


Neonatal ghrelin programs development of hypothalamic feeding circuits.
A complex neural network regulates body weight and energy balance, and dysfunction in the communication between the gut and this neural network is associated with metabolic diseases, such as obesity. The stomach-derived hormone ghrelin stimulates appetite through interactions with neurons in the arcuate nucleus of the hypothalamus (ARH). Here, we evaluated the physiological and neurobiological contribution of ghrelin during development by specifically blocking ghrelin action during early postnatal development in mice. Ghrelin blockade in neonatal mice resulted in enhanced ARH neural projections and long-term metabolic effects, including increased body weight, visceral fat, and blood glucose levels and decreased leptin sensitivity. In addition, chronic administration of ghrelin during postnatal life impaired the normal development of ARH projections and caused metabolic dysfunction. Consistent with these observations, direct exposure of postnatal ARH neuronal explants to ghrelin blunted axonal growth and blocked the neurotrophic effect of the adipocyte-derived hormone leptin. Moreover, chronic ghrelin exposure in neonatal mice also attenuated leptin-induced STAT3 signaling in ARH neurons. Collectively, these data reveal that ghrelin plays an inhibitory role in the development of hypothalamic neural circuits and suggest that proper expression of ghrelin during neonatal life is pivotal for lifelong metabolic regulation.


Caffeinated and caffeine-free beverages and risk of type 2 diabetes.
Consumption of caffeinated beverages such as coffee and tea has been associated with a lower risk of type 2 diabetes (T2D). Paradoxically, short-term metabolic studies have shown that caffeine impairs postprandial glycemic control. The objective was to prospectively examine the association of caffeinated compared with caffeine-free beverages, including coffee, tea, sugar-sweetened beverages (SSBs), and carbonated artificially sweetened beverages (ASBs), with T2D risk. We prospectively observed 74,749 women from the Nurses' Health Study (NHS, 1984-2008) and 39,059 men from the Health Professionals Follow-Up Study (HPFS, 1986-2008) who were free of diabetes, cardiovascular diseases, and cancer at baseline. We documented 7370 incident cases of T2D during 24 y of follow-up in the NHS and 2865 new cases during 22 y of follow-up in the HPFS. After major lifestyle and dietary risk factors were controlled for, caffeinated and caffeine-free SSB intake was significantly associated with a higher risk of T2D in the NHS (RR per serving: 13% for caffeinated SSBs, 11% for caffeine-free SSBs; P < 0.05) and in the HPFS (RR per serving: 16% for caffeinated SSBs, 23% for caffeine-free SSBs; P < 0.01). Only caffeine-free ASB intake in NHS participants was associated with a higher risk of T2D (RR: 6% per serving; P < 0.001). Conversely, the consumption of caffeinated and decaffeinated coffee was associated with a lower risk of T2D [RR per serving: 8% for both caffeinated and decaffeinated coffee in the NHS (P < 0.0001) and 4% for caffeinated and 7% for decaffeinated coffee in the HPFS (P < 0.01)]. Only caffeinated tea was associated with a lower T2D risk among NHS participants (RR per serving: 5%; P < 0.0001). Irrespective of the caffeine content, SSB intake was associated with a higher risk of T2D, and coffee intake was associated with a lower risk of T2D.


The decision-making process of young adult women with cancer who considered fertility cryopreservation.
To provide an in-depth description of the decision-making process that women who are diagnosed with cancer undergo as they decide whether to accept or decline fertility cryopreservation. A qualitative, grounded theory approach. Twenty-seven women (mean age = 29 years) who were diagnosed with cancer and were eligible for egg, embryo, or ovarian tissue cryopreservation were recruited from the Internet and two university centers. Each woman participated in a semistructured interview by phone (n = 21) or e-mail (n = 6). Data were analyzed using the constant-comparative method to inductively ascertain the women's decision-making process. NVivo 8 software was used to assist with data retrieval and analysis. The decision-making process consists of four major phases that women experience to actively formulate a decision: identify, contemplate, resolve, and engage. In the identify phase, women acquire knowledge and experience a "double hit" scenario that is often devastating. Within the contemplate phase, five interrelated dimensions emerged including constructing and/or endorsing preferences and values and undergoing decisional debriefing sessions. A decision is reached in the resolve phase and carried out in the engage phase. Among the participants, 14 declined fertility cryopreservation and 13 accepted egg and/or embryo cryopreservation. The descriptive theoretical framework clarifies the underlying processes that women with cancer undergo to decide about fertility cryopreservation. Quality of care for women with cancer can be improved by implementing appropriately timed information and tailored developmental and contextual counseling to support decision making.


Clinical Utility of Multisensory Environments for People With Intellectual and Developmental Disabilities: A Scoping Review.
Adults with intellectual and developmental disabilities (IDD) are twice as likely as their peers without disabilities to have had a physical exam in the past year; however, as a result of challenging behavior during office visits, they are significantly less likely to have received recommended health screenings. Challenging behaviors in clinical settings have been identified as a barrier to providing adequate care for this population. This scoping review examined the within-session effects of multisensory environments (MSEs) on people with IDD to determine the clinical utility of MSEs for this population. Studies published between January 1, 2000, and August 1, 2018, were identified using Summon and Google Scholar. Studies were included in the review if they systematically collected and reported data on within-session effects of an MSE intervention on people with IDD. Thirteen studies met criteria for this review: 4 with Level I evidence, 2 with Level II evidence, 3 with Level III evidence, and 4 with Level IV evidence. Studies examined the effects of MSEs on maladaptive behaviors, positive behaviors, distress and discomfort, activity and alertness states, and cost of care for people with IDD. Preliminary support was found for the use of MSEs in clinical settings to reduce anxiety and challenging behaviors in patients with IDD during clinical care. Further research is needed to determine the efficacy of MSEs for producing the effects described in this review. The findings support the potential of MSEs as a tool that occupational therapy practitioners can use to support their clients with IDD who have sensory sensitivities in clinical settings. This article also highlights a multidisciplinary approach whereby medical providers and occupational therapy practitioners could work together in nontraditional ways to support this population.


Fish oil and glycemic control in diabetes. A meta-analysis.
Hypertriglyceridemia is associated with cardiovascular disease in diabetes. Fibrates effectively lower, but do not always normalize, serum triglyceride levels. Fish oil supplements may then be added to lower serum triglyceride levels. Doubt remains whether the net effect of fish oil intake on glycemic control is beneficial in diabetes. We therefore performed a meta-analysis from published clinical trials. Data sources were Medline (Cologne, Germany), Excerpta Medica, Current Contents, review articles, and published reference lists. Publications of 26 trials were selected, and all trials included more than five diabetes (IDDM and NIDDM) patients and addressed the effects of fish oil (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) on serum lipids and glucose tolerance. We (C.E.F., M.J.F.M.J.) extracted data independently based on predetermined criteria. Studies were classified according to design. All studies combined showed a decrease in mean triglyceride concentrations in association with fish oil: -0.60 mmol/l (95% CI, -0.84 to -0.33, P < 0.01) and a slight but significant increase in serum LDL cholesterol: 0.18 mmol/l (95% CI, 0.04-0.32, P = 0.01), with both findings most prominent in NIDDM. No significant changes in HbA1c percentages occurred in diabetic subjects treated with fish oil. Fasting blood glucose levels were increased with borderline significance in NIDDM subjects (0.43 mmol/l [95% CI, 0.00-0.87], P = 0.06) and were significantly lower in IDDM subjects (-1.86 mmol/l [95% CI, -3.1 to -0.61], P < 0.05). Significant dose-response effects of EPA (g/day) on HbA1c and triglycerides and of DHA (g/day) on fasting blood glucose levels, HbA1c, and triglycerides were demonstrated only in NIDDM subjects. The use of fish oil has no adverse affects on HbA1c in diabetic subjects and lowers triglyceride levels effectively by almost 30%. However, this may be accompanied by a slight increase in LDL cholesterol concentration. Fish oil may be useful in treating dyslipidemia in diabetes.


Clinical symptoms and signs for the diagnosis of Mycoplasma pneumoniae in children and adolescents with community-acquired pneumonia.
Mycoplasma pneumoniae (M. pneumoniae) is a significant cause of community-acquired pneumonia in children and adolescents. Treatment with macrolide antibiotics is recommended. However, M. pneumoniae is difficult to diagnose based on clinical symptoms and signs. Diagnostic uncertainty can lead to inappropriate antibiotic prescribing, which may worsen clinical prognosis and increase antibiotic resistance. The objectives of this review are (i) to assess the diagnostic accuracy of symptoms and signs in the clinical recognition of M. pneumoniae in children and adolescents with community-acquired pneumonia; and (ii) to assess the influence of potential sources of heterogeneity on the diagnostic accuracy of symptoms and signs in the clinical recognition of M. pneumoniae. We searched MEDLINE (January 1950 to 26 June 2012) and EMBASE (January 1980 to 26 June 2012). We identified additional references by handsearching the reference lists of included articles and snowballing. We searched the reference lists of relevant systematic reviews identified by searching the Medion database, Database of Reviews of Effects 2012, Issue 6 (25 June 2012) and the Cochrane Register of Diagnostic Test Accuracy studies (2 July 2012). Experts in the field reviewed our list of included studies for any obvious omissions. We included peer-reviewed published studies which prospectively and consecutively recruited children with community-acquired pneumonia from any healthcare setting, confirmed the presence of M. pneumoniae using serology with or without other laboratory methods and reported data on clinical symptoms and signs in sufficient detail to construct 2 x 2 tables. One review author scanned titles to exclude obviously irrelevant articles. Two review authors independently scanned the remaining titles and abstracts, reviewed full-text versions of potentially relevant articles, assessed the quality of included articles and extracted data on study characteristics and the following clinical features: cough, wheeze, coryza, crepitations, fever, rhonchi, shortness of breath, chest pain, diarrhea, myalgia and headache.We calculated study-specific values for sensitivity, specificity and positive and negative likelihood ratios with 95% confidence intervals (CIs). We estimated the post-test probability of M. pneumoniae based on the absence or presence of symptoms and signs.We calculated pooled sensitivities, specificities, positive and negative likelihood ratios with 95% CIs for symptoms and signs where data were reported by at least four included studies by fitting a bivariate normal model for the logit transforms of sensitivity and specificity. We explored potential sources of heterogeneity by fitting bivariate models with covariates using multi-level mixed-effects logistic regression. We performed sensitivity analyses excluding data from studies for which we were concerned about the representativeness of the study population and/or the acceptability of the reference standard. Our search identified 8299 articles (excluding duplicates). We examined the titles and abstracts of 1125 articles and the full-text versions of 97 articles. We included seven studies in our review, which reported data from 1491 children; all were conducted in hospital settings. Overall, study quality was moderate. In two studies the presence of chest pain more than doubled the probability of M. pneumoniae. Wheeze was 12% more likely to be absent in children with M. pneumoniae (pooled positive likelihood ratio (LR+) 0.76, 95% CI 0.60 to 0.97; pooled negative likelihood ratio (LR-) 1.12, 95% CI 1.02 to 1.23). Our sensitivity analysis showed that the presence of crepitations was associated with M. pneumoniae, but this finding was of borderline statistical significance (pooled LR+ 1.10, 95% CI 0.99 to 1.23; pooled LR- 0.66, 95% CI 0.46 to 0.96). M. pneumoniae cannot be reliably diagnosed in children and adolescents with community-acquired pneumonia based on clinical symptoms and signs. Although the absence of wheeze is a statistically significant diagnostic indicator, it does not have sufficient diagnostic value to guide empirical macrolide treatment. Data from two studies suggest that the presence of chest pain more than doubles the probability of M. pneumoniae. However, further research is needed to substantiate this finding. More high quality large-scale studies in primary care settings are needed to help develop prediction rules based on epidemiological data as well as clinical and baseline patient characteristics.


Cognitive-behavioral screening reveals prevalent impairment in a large multicenter ALS cohort.
To characterize the prevalence of cognitive and behavioral symptoms using a cognitive/behavioral screening battery in a large prospective multicenter study of amyotrophic lateral sclerosis (ALS). Two hundred seventy-four patients with ALS completed 2 validated cognitive screening tests and 2 validated behavioral interviews with accompanying caregivers. We examined the associations between cognitive and behavioral performance, demographic and clinical data, and C9orf72 mutation data. Based on the ALS Cognitive Behavioral Screen cognitive score, 6.5% of the sample scored below the cutoff score for frontotemporal lobar dementia, 54.2% scored in a range consistent with ALS with mild cognitive impairment, and 39.2% scored in the normal range. The ALS Cognitive Behavioral Screen behavioral subscale identified 16.5% of the sample scoring below the dementia cutoff score, with an additional 14.1% scoring in the ALS behavioral impairment range, and 69.4% scoring in the normal range. This investigation revealed high levels of cognitive and behavioral impairment in patients with ALS within 18 months of symptom onset, comparable to prior investigations. This investigation illustrates the successful use and scientific value of adding a cognitive-behavioral screening tool in studies of motor neuron diseases, to provide neurologists with an efficient method to measure these common deficits and to understand how they relate to key clinical variables, when extensive neuropsychological examinations are unavailable. These tools, developed specifically for patients with motor impairment, may be particularly useful in patient populations with multiple sclerosis and Parkinson disease, who are known to have comorbid cognitive decline.


Maternal recall of birthweight and birth size in Entebbe, Uganda.
To assess the reliability of maternally recalled birthweight and size in Entebbe, Uganda. The study population comprised 404 mothers, who were participants in the Entebbe Mother and Baby Study (EMaBS). Mothers were recruited to EMaBS during antenatal care, maternal characteristics were recorded during pregnancy, and birthweight was recorded at delivery. Four to seven years after delivery, mothers were asked to recall the child's birthweight and size. Their responses were compared with the birthweight recorded in the EMaBS database. Of 404 interviewed mothers, 303 (75%) were able to give an estimate of birthweight and for 265 of these EMaBS data on recorded birthweights were available. Women who were educated and whose children had low birth order were more likely to be able to give an estimate: 37 (14%) recalled the exact recorded birthweight; a further 52 (20%) were accurate to within 0.1 kg of the recorded weight. On average, mothers overestimated birthweight by 0.06 kg (95% CI: 0.00-0.13 kg, P = 0.04). Recalled and recorded birthweights showed moderate agreement with an intraclass correlation coefficient of 0.64. Four hundered mothers gave an estimate of birth size: the sensitivity and specificity of recalled birth size for classifying low birthweight were 76% (95% CI: 50-93%) and 70% (95% CI: 65-75%), respectively. Mothers' recall of birthweight was not precise but in absence of other data, recall of birthweight and size may have some value in epidemiological studies in these settings.


Findings from a simulated disabled submarine survival trial.
Eleven volunteer submariners were exposed to simulated disabled submarine conditions for a maximum of 7 days to determine if the limited clothing and rations provided in escape compartments would compromise survival prospects. Daily rations were 0.568 liters of water (none on Day 1) and 100 g of barley sugar. The subjects wore working rig and the liner from the Mark 10 submarine escape and immersion equipment throughout, and slept in the outer dry suit. Air temperature fell from 22 degrees to 4.4 degrees C over 2 days and then remained at 4.4 degrees C. Although the subjects felt cold they were able to maintain their deep body temperature. The greatest threat to survival in this situation would be dehydration, one subject was withdrawn on Day 4 as his urine production over the previous 24 h was 130 ml and if not withdrawn and rehydrated this may have led to renal failure. Other medical problems suffered by the subjects during the 7 days included diarrhea, vomiting, hypoglycemia, headaches, and back pains, and, following the trial, non-freezing cold injuries to their feet. It is concluded that the rations are not adequate and could compromise the submariners ability to survive for 7 days in these conditions and during a subsequent escape procedure.


Macro-/nanoporous silicon as a support for high-performance protein microarrays.
The present work demonstrates the possibilities of using macroporous silicon as a substrate for highly sensitive protein chip applications. The formation of 3D porous silicon structures was performed by electrochemical dissolution of monocrystalline silicon. The fabricated macroporous silicon network has a rigid spongelike structure showing high uniformity and mechanical stability. The microfluidic properties of the substrates were found to be essential for a good bioassay performance. Small spot area, good spot reproducibility, and homogeneous spot profiles were demonstrated on the substrates for immobilized aRIgG. Water contact angles were measured on the porous surface and compared to that of planar silicon, silanized glass, and ordinary microscope glass slides. The effect of the porous surface on the performance of a model IgG-binding immunoassay is presented. aRIgG was microdispensed onto the chip surface forming a microarray of spots with high affinity for the target analyte. The dispensing was performed using an in-house-developed piezoelectric flow-through dispenser. Each spot was formed by a single droplet (100 pL) at each position. The macroporous silicon allowed a high-density microarraying with spot densities up to 4400 spots/cm2 in human plasma samples without cross-talk and consumption of only 0.6 pmol of antibodies/1-cm2 array. Antigen levels down to 70 pM were detected.


The Aurora kinase inhibitor ZM447439 accelerates first meiosis in mouse oocytes by overriding the spindle assembly checkpoint.
Previous studies have established that when maturing mouse oocytes are continuously incubated with the Aurora inhibitor ZM447439, meiotic maturation is blocked. In this study, we observe that by altering the time of addition of the inhibitor, oocyte maturation can actually be accelerated by 1 h as measured by the timing of polar body extrusion. ZM447439 also had the ability to overcome a spindle assembly checkpoint (SAC) arrest caused by nocodazole and so rescue polar body extrusion. Consistent with the ability of the SAC to inhibit cyclin B1 degradation by blocking activation of the anaphase-promoting complex, we could also observe a rescue in cyclin B1 degradation when ZM447439 was added to nocodazole-treated oocytes. The acceleration of the first meiotic division by ZM447439, which has not been achieved previously, and its effects on the SAC are all consistent with the proposed mitotic role of Aurora B in activating the SAC. We hypothesize that Aurora kinase activity controls the SAC in meiosis I, despite differences to the mitotic cell cycle division in spindle architecture brought about by the meiotic mono-orientation of sister kinetochores.


Fabricating a novel HLC-hBMP2 fusion protein for the treatment of bone defects.
Treating serious bone trauma with an osteo-inductive agent such as bone morphogenetic proteins (BMPs) has been considered as an optimized option when delivered via a collagen sponge (CS). Previous works have shown that the BMP concentration and release rate from approved CS carriers is difficult to control with precision. Here we presented the fabrication of a recombinant fusion protein from recombinant human-like collagen (HLC) and human BMP-2 (hBMP2). The fusion protein preserved the characteristic of HLC allowing the recombinant protein to be expressed in Yeast (such as Pichia pastoris GS115) and purified rapidly and easily with mass production after methanol induction. It also kept the stable properties of HLC and hBMP2 in the body fluid environment with good biocompatibility and no cytotoxicity. Moreover, the recombinant fusion protein fabricated a vertical through-hole structure with improved mechanical properties, and thus facilitated migration of bone marrow mesenchymal stem cells (MSCs) into the fusion materials. Furthermore, the fusion protein degraded and released hBMP-2 in vivo allowing osteoinductive activity and the enhancement of utilization rate and the precise control of the hBMP2 release. This fusion protein when applied to cranial defects in rats was osteoinductively active and improved bone repairing enhancing the repairing rate 3.5- fold and 4.2- fold when compared to the HLC alone and the control, respectively. There were no visible inflammatory reactions, infections or extrusions around the implantation sites observed. Our data strongly suggests that this novel recombinant fusion protein could be more beneficial in the treatment of bone defects than the simple superposition of the hBMP2/collagen sponge.


Ppg1, a PP2A-type protein phosphatase, controls filament extension and virulence in Candida albicans.
Candida albicans, a major human fungal pathogen, is the primary cause of invasive candidiasis in a wide array of immunocompromised patients. C. albicans virulence requires the ability to undergo a reversible morphological transition from yeast to filaments in response to a variety of host environmental cues. These cues are sensed by the pathogen and activate multiple signal transduction pathways to induce filamentation. Reversible phosphorylation events are critical for regulation of many of these pathways. While a variety of protein kinases are known to function as components of C. albicans filamentous growth signal transduction pathways, considerably little is known about the role of phosphatases. Here we demonstrate that PPG1, encoding a putative type 2A-related protein phosphatase, is important for C. albicans filament extension, invasion, and virulence in a mouse model of systemic candidiasis. PPG1 is also important for downregulation of NRG1, a key transcriptional repressor of C. albicans filamentous growth, and is shown to affect the expression of several filament-specific target genes. An epistasis analysis suggests that PPG1 controls C. albicans filamentation via the cyclic AMP-protein kinase A (cAMP-PKA) signaling pathway. We demonstrate that Ppg1 possesses phosphatase activity and that a ppg1 catalytic mutant shows nearly equivalent filamentation, invasion, and virulence defects compared to those of a ppg1Δ/Δ strain. Overall, our results suggest that phosphatases, such as Ppg1, play critical roles in controlling and fine-tuning C. albicans filament extension and virulence as well as signal transduction pathways, transcriptional regulators, and target genes associated with these processes.


The STARD statement for reporting studies of diagnostic accuracy: explanation and elaboration. The Standards for Reporting of Diagnostic Accuracy Group.
The quality of reporting of studies of diagnostic accuracy is less than optimal. Complete and accurate reporting is necessary to enable readers to assess the potential for bias in a study and to evaluate the generalisability of the results. A group of scientists and editors has developed the STARD (Standards for Reporting of Diagnostic Accuracy) statement to improve the quality of reporting of studies of diagnostic accuracy. The statement consists of a checklist of 25 items and flow diagram that authors can use to ensure that all relevant information is present. This explanatory document aims to facilitate the use, understanding and dissemination of the checklist. The document contains a clarification of the meaning, rationale and optimal use of each item on the checklist, as well as a short summary of the available evidence on bias and applicability. The STARD statement, checklist, flowchart, and this explanation and elaboration document should be useful resources to improve the reporting of diagnostic accuracy studies. Complete and informative reporting can only lead to better decisions in health care.


The effects of smoking and abstinence on experience of happiness and sadness in response to positively valenced, negatively valenced, and neutral film clips.
Incentive motivation theories of addiction suggest that behavioural concomitants of compromised mesocorticolimbic reward activity during abstinence might include decreased affective reactions to natural reinforcers. This study tested implications for hedonic reactions in abstinent smokers. It was hypothesised that positively valenced (pleasurable) film clips would elicit lower ratings of happiness in abstinent than satiated smokers. Twenty-nine smokers, randomly assigned to either an 'abstinent' or a 'satiated' condition, and 15 non-smokers took part in a single session in which they rated (i) signs and symptoms of nicotine withdrawal and (ii) affective responses to positively valenced, negatively valenced, and neutral film clips. Compared with satiated smokers, abstinent smokers rated positive clips as eliciting significantly lower levels of happiness, and this was independent of self-reported nicotine withdrawal symptoms; the scores of non-smokers fell between those of abstinent and satiated smokers, more closely approximating those of the latter. By contrast, sadness ratings in response to negative clips were not affected by smoking status, indicating that the effect on happiness was not simply due to general emotional blunting. These results suggest that, for regular smokers, stimuli that are motivationally salient for the general population may elicit reduced positive affective responses during periods of abstinence.


Plant defenses against parasitic plants show similarities to those induced by herbivores and pathogens.
Herbivores and pathogens come quickly to mind when one thinks of the biotic challenges faced by plants. Important but less appreciated enemies are parasitic plants, which can have important consequences for the fitness and survival of their hosts. Our knowledge of plant perception, signaling, and response to herbivores and pathogens has expanded rapidly in recent years, but information is generally lacking for parasitic species. In a recent paper we reported that some of the same defense responses induced by herbivores and pathogens--notably increases in jasmonic acid (JA), salicylic acid (SA), and a hypersensitive-like response (HLR)--also occur in tomato plants upon attack by the parasitic plant Cuscuta pentagona (field dodder). Parasitism induced a distinct pattern of JA and SA accumulation, and growth trials using genetically-altered tomato hosts suggested that both JA and SA govern effective defenses against the parasite, though the extent of the response varied with host plant age. Here we discuss similarities between the induced responses we observed in response to Cuscuta parasitism to those previously described for herbivores and pathogens and present new data showing that trichomes should be added to the list of plant defenses that act against multiple enemies and across Kingdoms.


Geometric structure and information change in phase transitions.
We propose a toy model for a cyclic order-disorder transition and introduce a geometric methodology to understand stochastic processes involved in transitions. Specifically, our model consists of a pair of forward and backward processes (FPs and BPs) for the emergence and disappearance of a structure in a stochastic environment. We calculate time-dependent probability density functions (PDFs) and the information length L, which is the total number of different states that a system undergoes during the transition. Time-dependent PDFs during transient relaxation exhibit strikingly different behavior in FPs and BPs. In particular, FPs driven by instability undergo the broadening of the PDF with a large increase in fluctuations before the transition to the ordered state accompanied by narrowing the PDF width. During this stage, we identify an interesting geodesic solution accompanied by the self-regulation between the growth and nonlinear damping where the time scale τ of information change is constant in time, independent of the strength of the stochastic noise. In comparison, BPs are mainly driven by the macroscopic motion due to the movement of the PDF peak. The total information length L between initial and final states is much larger in BPs than in FPs, increasing linearly with the deviation γ of a control parameter from the critical state in BPs while increasing logarithmically with γ in FPs. L scales as |lnD| and D^{-1/2} in FPs and BPs, respectively, where D measures the strength of the stochastic forcing. These differing scalings with γ and D suggest a great utility of L in capturing different underlying processes, specifically, diffusion vs advection in phase transition by geometry. We discuss physical origins of these scalings and comment on implications of our results for bistable systems undergoing repeated order-disorder transitions (e.g., fitness).


Impact of Disease Complexity on Cardiovascular Events after the Transition to an Adult Congenital Heart Disease Specialized Medical Unit.
The follow-up of patients with adult congenital heart disease (ACHD) at a specialized medical unit is necessary for the patients' appropriate medical care. However, limited information is available about cardiovascular events among ACHD patients. Here we investigated the type and frequency of cardiovascular events in ACHD patients in relation to disease complexity. We retrospectively analyzed the cases of 535 patients (median age 35 years) referred to our ACHD center between 2014 and 2017. We divided the patients into 3 groups based on their disease complexity. To evaluate the relationship between disease complexity and cardiovascular events, we performed univariate and multivariate survival analyses. The Simple, moderate, and complex disease groups accounted for 62%, 19%, and 19% of the patients, respectively. Apart from events related to atrial septal defect (ASD) trans-catheter treatment, the frequency of cardiovascular events was dependent on the disease complexity (event-free survival rates at 3 years were 85%, 65%, and 58%, respectively). The hazard ratios were 4.0 and 5.1 in the moderate and complex groups, respectively. With the exception of scheduled transcatheter intervention, cardiovascular events were strongly related to the disease complexity of original heart disease. However, cardiovascular events were not rare even in the simple ACHD group.


Effect of two selected yogic breathing techniques of heart rate variability.
The heart rate variability (HRV) is an indicator of the cardiac autonomic control. Two spectral components are usually recorded, viz. high frequency (0.15-0.50 Hz), which is due to vagal efferent activity and a low frequency component (0.05-0.15 Hz), due to sympathetic activity. The present study was conducted to study the HRV in two yoga practices which have been previously reported to have opposite effects, viz, sympathetic stimulation (kapalabhati, breathing at high frequency, i.e., 2.0 Hz) and reduced sympathetic activity (nadisuddhi, alternate nostril breathing). Twelve male volunteers (age range, 21 to 33 years) were assessed before and after each practice on separate days. The electrocardiogram (lead I) was digitized on-line and off-line analysis was done. The results showed a significant increase in low frequency (LF) power and LF/HF ratio while high frequency (HF) power was significantly lower following kapalabhati. There were no significant changes following nadisuddhi. The results suggest that kapalabhati modifies the autonomic status by increasing sympathetic activity with reduced vagal activity. The study also suggests that HRV is a more useful psychophysiological measure than heart rate alone.


Special topics in immunotherapy and radiation therapy: reirradiation and palliation.
Immunotherapy has revolutionized the treatment of non-small cell lung cancer (NSCLC). However, thus far, its use has only been established in patients with advanced disease either as first-line therapy in selected patients or following chemotherapy. What is not yet known is how best to incorporate radiation with immunotherapy agents. Many patients with advanced disease can benefit from palliative radiation, but the combination of radiation with immunotherapy has the potential to increase the toxicity of both modalities. Intriguingly, the combination also has the potential to enhance the efficacy of both modalities. For this reason, combining immunotherapy and radiation may help salvage patients with recurrent localized disease who are candidates for re-irradiation. We review the current data evaluating immunotherapy with both palliative radiation as well as definitive re-irradiation in NSCLC.


Outcome of the upper limb in cervical spinal cord injury: Profiles of recovery and insights for clinical studies.
Improved appreciation of recovery profiles of sensory and motor function as well as complex motor functions (prehension) after cervical spinal cord injury (SCI) will be essential to inform clinical studies to consider primary and secondary outcome measures for interventions and the optimization of dosing and timing of therapies in acute and chronic SCI. (1) To define the sensory, motor, and prehension recovery profiles of the upper limb and hand in acute cervical SCI and (2) to confirm the impact of AIS severity and conversion on upper limb sensorimotor recovery. An observational longitudinal cohort study consisting of serial testing of 53 patients with acute cervical SCI was conducted. International Standards of Neurological Classification of Spinal Cord Injury, Graded Redefined Assessment of Strength Sensibility and Prehension (GRASSP), Capabilities of Upper Extremity (CUE-Q) Questionnaire, and Spinal Cord Independence Measure III (SCIM-III) were administered at 0-10 days, 1, 3, 6, and 12 months. Change over time was plotted using mean and standard deviation of the total and subgroups of the sample. Individuals with traumatic tetraplegia show distinct patterns of recovery. Factors that distinguish homogeneous subgroups of the sample are: severity of injury (level of injury, completeness) at baseline and conversion from a complete to an incomplete injury. In cervical SCI, clinical recovery can be assessed using standardized measures that distinguish levels of activity and impairment. Specific recovery profiles of the upper limb over the 1-year timecourse provide new insights and opportunity for combined analysis of recovery profiles for different clinical assessment tools of upper limb function which are meaningful to inform the design of study protocols.


Online market research panel members as controls in case-control studies to investigate gastrointestinal disease outbreaks: early experiences and lessons learnt from the UK.
Established methods of recruiting population controls for case-control studies to investigate gastrointestinal disease outbreaks can be time consuming, resulting in delays in identifying the source or vehicle of infection. After an initial evaluation of using online market research panel members as controls in a case-control study to investigate a Salmonella outbreak in 2013, this method was applied in four further studies in the UK between 2014 and 2016. We used data from all five studies and interviews with members of each outbreak control team and market research panel provider to review operational issues, evaluate risk of bias in this approach and consider methods to reduce confounding and bias. The investigators of each outbreak reported likely time and cost savings from using market research controls. There were systematic differences between case and control groups in some studies but no evidence that conclusions on the likely source or vehicle of infection were incorrect. Potential selection biases introduced by using this sampling frame and the low response rate are unclear. Methods that might reduce confounding and some bias should be balanced with concerns for overmatching. Further evaluation of this approach using comparisons with traditional methods and population-based exposure survey data is recommended.


Long-lasting insecticide-treated net use and malaria infections on the Kenyan coast.
A study was conducted to examine the impact of long-lasting insecticide-treated net (LLIN) use on the prevalence of malaria infections across all ages, 25 y after a trial of insecticide-treated nets was conducted in the same area along the Kenyan coast. The study comprised four community-based infection surveys and a simultaneous 12-month surveillance at six government outpatient health facilities (March 2018-February 2019). Logistic regression was used to examine the effect of LLIN use on malaria infections across all ages. There was a high level of reported LLIN use by the community (72%), notably among children <5 y of age (84%). Across all ages, the adjusted odds ratio of LLIN use against asymptomatic parasitaemia in community surveys was 0.45 (95% confidence interval [CI] 0.36 to 0.57; p<0.001) and against fevers associated with infection presenting to health facilities was 0.63 (95% CI 0.58 to 0.68; p<0.001). There was significant protection of LLIN use against malaria infections across all ages.


A multi-criteria approach to camera motion design for volume data animation.
We present an integrated camera motion design and path generation system for building volume data animations. Creating animations is an essential task in presenting complex scientific visualizations. Existing visualization systems use an established animation function based on keyframes selected by the user. This approach is limited in providing the optimal in-between views of the data. Alternatively, computer graphics and virtual reality camera motion planning is frequently focused on collision free movement in a virtual walkthrough. For semi-transparent, fuzzy, or blobby volume data the collision free objective becomes insufficient. Here, we provide a set of essential criteria focused on computing camera paths to establish effective animations of volume data. Our dynamic multi-criteria solver coupled with a force-directed routing algorithm enables rapid generation of camera paths. Once users review the resulting animation and evaluate the camera motion, they are able to determine how each criterion impacts path generation. In this paper, we demonstrate how incorporating this animation approach with an interactive volume visualization system reduces the effort in creating context-aware and coherent animations. This frees the user to focus on visualization tasks with the objective of gaining additional insight from the volume data.


Spinal cord repair strategies: why do they work?
There are now numerous preclinical reports of various experimental treatments promoting some functional recovery after spinal cord injury. Surprisingly, perhaps, the mechanisms that underlie recovery have rarely been definitively established. Here, we critically evaluate the evidence that regeneration of damaged pathways or compensatory collateral sprouting can promote recovery. We also discuss several more speculative mechanisms that might putatively explain or confound some of the reported outcomes of experimental interventions.


An intact membrane is essential for small extracellular vesicle-induced modulation of α-synuclein fibrillization.
The misfolding and fibrillization of the protein, α-synuclein (αsyn), is associated with neurodegenerative disorders referred to as the synucleinopathies. Understanding the mechanisms of αsyn misfolding is an important area of interest given that αsyn misfolding contributes to disease pathogenesis. While many studies report the ability of synthetic lipid membranes to modulate αsyn folding, there is little data pertaining to the mechanism(s) of this interaction. αSyn has previously been shown to associate with small lipid vesicles released by cells called extracellular vesicles (EVs) and it is postulated these interactions may assist in the spreading of pathological forms of this protein. Together, this presents the need for robust characterisation studies on αsyn fibrillization using biologically-derived vesicles. In this study, we comprehensively characterised the ability of lipid-rich small extracellular vesicles (sEVs) to alter the misfolding of αsyn induced using the Protein Misfolding Cyclic Amplification (PMCA) assay. The biochemical and biophysical properties of misfolded αsyn were examined using a range of techniques including: Thioflavin T fluorescence, transmission electron microscopy, analytical centrifugation and western immunoblot coupled with protease resistance assays and soluble/insoluble fractionation. We show that sEVs cause an acceleration in αsyn fibrillization and provide comprehensive evidence that this results in an increase in the abundance of mature insoluble fibrillar species. In order to elucidate the relevance of the lipid membrane to this interaction, sEV lipid membranes were modified by treatment with methanol, or a combination of methanol and sarkosyl. These treatments altered the ultrastructure of the sEVs without changing the protein cargo. Critically, these modified sEVs had a reduced ability to influence αsyn fibrillization compared to untreated counterparts. This study reports the first comprehensive examination of αsyn:EV interactions and demonstrates that sEVs are powerful modulators of αsyn fibrillization, which is mediated by the sEV membrane. In doing so, this work provides strong evidence for a role of sEVs in contributing directly to αsyn misfolding in the synucleinopathy disorders.