A constrained mixture approach to mechano-sensing and force generation in contractile cells.
Biological tissues are very particular types of materials that have the ability to change their structure, properties and chemistry in response to external cues. Contractile cells, i.e. fibroblasts, are key players of tissue adaptivity as they are capable of reorganizing their surrounding extra-cellular matrix (ECM) by contracting and generating mechanical forces. This contractile behavior is attributed to the development of a stress-fiber (SF) network within the cell's cytoskeleton, a process that is known to be highly dependent of the nature of the mechanical environment (such as ECM stiffness or the presence of stress and strain). To describe these processes in a consistent manner, the present paper introduces a mutiphasic formulation (fluid/solid/solute mixture) that accounts for four major elements of cell contraction: cytoskeleton, cytosol, SF and actin monomers, as well as their interactions. The model represents the cross-talks between mechanics and chemistry through various means: (a) a mechano-sensitive formation and dissociation of an anisotropic SF network described by mass exchange between actin monomer and polymers, (b) a bio-mechanical model for SF contraction that captures the well-known length-tension and velocity-tension relation for muscles cells and (c) a convection/diffusion description for the transport of fluid and monomers within the cell. Numerical investigations show that the multiphasic model is able to capture the dependency of cell contraction on the stiffness of the mechanical environment and accurately describes the development of an oriented SF network observed in contracting fibroblasts.


Rat postnatal prostate development is impaired by in vitro high-glucose environment.
The prostate development has an important postnatal period where cell proliferation begins at the first days after birth and is related to gland growth and ramification. Any metabolic and/or hormonal changes occurring during the postnatal period can interfere with prostate branching. Hyperglycemia is a common condition in low-weight preterm babies at neonatal period and also a disorder found in the offspring of obese mothers. Thus, this study aimed to investigate the in vitro effects of a glucose-rich environment during prostate postnatal development. Wistar rats prostate were removed at birth and cultured for 1, 2 and 3 days in DMEM under normal (5.5 mM) or elevated (7 and 25 mM) glucose concentrations. Samples were processed for morphological analysis, PCNA and smooth muscle α-actin immunohistochemistry, evaluation of active caspase-3, ERK1/2 and Wnt5a gene expression. High glucose concentrations reduced the number of prostatic buds and proliferating cells. The natural increase in smooth muscle cells and collagen deposition observed in control prostates during the first 3 days of development was reduced by elevated glucose concentrations. The amount of active caspase-3 was higher in prostates incubated at 7 mM and TGF-β levels also increased sharply after both glucose concentrations. Additionally, high glucose environment decreased ERK 1/2 activation and increased Wnt5a expression. These data show that high levels of glucose during the first postnatal days affected prostate development by inhibiting cell proliferation which impairs bud branching and this was associated with anti-proliferative signals such as decreased ERK1/2 activation and increased Wnt5a expression.


Antithrombotic effects of magnesium sulfate in in vivo experiments.
In this study, magnesium sulfate was effective in reducing the mortality of adenosine diphosphate-induced acute pulmonary thromboembolism in mice, when it was administered intravenously at doses of 100 and 200 microg/g body weight. In addition, intravenous injections of magnesium sulfate (100 and 200 microg/g) significantly prolonged bleeding time in the severed mesenteric arteries of rats by approximately 1.7- and 1.9-fold, respectively, compared with normal saline. Continuous infusion of magnesium sulfate (20 microg/g per minute) for 10 minutes also significantly increased the bleeding time by approximately 1.7-fold, and the bleeding time returned to baseline within 60 minutes of cessation of magnesium sulfate infusion. On the other hand, platelet thrombi formation was induced by irradiating mesenteric venules with filtered light in mice pretreated with intravenous fluorescein sodium. When magnesium sulfate was administered at 300 microg/g during induction of platelet plug formation with 10 microg/kg fluorescein sodium, occlusion time was not significantly prolonged, but a dose of 600 microg/g did significantly prolong the occlusion time. Furthermore, aspirin (250 microg/g) also showed a similar activity in this experiment in prolonging the occlusion time. In conclusion, these results suggest that magnesium sulfate has an effective antithrombotic activity in vivo, and treatment with magnesium sulfate may lower the risk of thromboembolic-related disorders.


The effect of low-level laser on postoperative pain after tibial fracture surgery: a double-blind controlled randomized clinical trial.
Postoperative pain is a common complication that can lead to serious morbidities and delayed recovery. The aim of this study was to investigate the effect of low-level laser therapy on acute pain after tibial fracture surgery. In this randomized clinical trial, 54 patients who were candidate for tibial fracture surgery were allocated randomly to two groups, namely, control and laser therapy. Both groups had the same type of surgery and technique of spinal anesthesia. Patients in laser group were treated with the combination of two lasers (GaALAs, 808 nm; and GaALInP, 650 nm) at the end of the surgery while control group received laser in turn-off mode with the same duration as laser group. Patients were evaluated for pain intensity according to the visual analogue scale (VAS) and the amount of analgesic use during 24 hours after surgery. Laser group experienced less pain intensity in comparison with control group at second, fourth, eighth, 12(th), and 24(th) hours after surgery (P Value < 0.05). In addition, the amount of consumed opioid in laser group was significantly less than the control group (51.62 ± 29.52 and 89.28 ± 35.54 mg, respectively; P Value, 0.008). Low Level Laser Therapy is a proper method to reduce postoperative pain because it is painless, safe, and noninvasive and is easily accepted by patients.


[Two methods to analyze trends in the incidence of heroin and cocaine use in Barcelona [Spain]].
To describe 2 statistical methods for estimating trends in the incidence of heroin and cocaine use in Barcelona. Admissions for treatment of heroin and cocaine consumption recorded by the Barcelona Drug Information System between 1991 and 2003 were used. We selected 4,367 subjects initiating treatment for the first time for heroin use, and 2,147 for cocaine use. Two statistical techniques were employed: Reporting Delay Adjustment (RDA) and the Log-linear Model (LLM). RDA was used in subjects who initiated drug consumption between 1991 and 2003, and LLM for those who began heroin use between 1967 and 2003 and cocaine use between 1971 and 2003. In addition, for each drug and method the latency period (LP) was determined (years between first consumption and first treatment). Comparison of the distributions of the LP for each drug revealed that heroin users initiated treatment for the first time sooner than cocaine users, regardless of the method employed. In general, the estimated incidence of heroin use in Barcelona fell progressively after 1982. In contrast, the incidence of cocaine use rose rapidly until 1998, and has been irregular since. The incidence of cocaine use began to be substantial in the early 1990s, but took several years to manifest itself as problematic. The estimated incidence was underestimated by RDA compared with LLM, but the incidence of heroin use could be biased before 1991 due to changes in treatment provisions. Although the estimated incidence is relative to individuals who are admitted for treatment at some time in their life, trends in incidence can be used to plan future actions.


Engineering Fusarium head blight resistance in wheat by expression of a fusion protein containing a Fusarium-specific antibody and an antifungal peptide.
Fusarium head blight (FHB) or scab of wheat is a devastating disease in warm and humid regions at wheat-flowering periods worldwide. Natural resistance against FHB pathogens is inadequate and the development of FHB-resistant wheat cultivars has been a challenge. Expression of pathogen-specific antibodies in plants has been proposed as a strategy for crop protection. In this study, an antibody fusion protein comprising a Fusarium-specific recombinant antibody derived from chicken and an antifungal peptide from Aspergillus giganteus was expressed in wheat as a method for protecting plants against FHB pathogens. Plants expressing the antibody fusion displayed a very significantly enhanced resistance in T2 and T3 generations upon single-floret inoculation with the macroconidia of Fusarium asiaticum, the predominant species causing FHB in China, indicating a type II resistance. Spraying inoculation further revealed an enhanced type I resistance in the transgenic wheat plants. Remarkably, more grains were produced in the transgenic plants than the nontransgenic controls. Our results demonstrated that the antibody fusion protein may be used as an effective tool for the protection of crops against FHB pathogens.


Graph theory analysis reveals an assortative pain network vulnerable to attacks.
The neural substrate of pain experience has been described as a dense network of connected brain regions. However, the connectivity pattern of these brain regions remains elusive, precluding a deeper understanding of how pain emerges from the structural connectivity. Here, we use graph theory to systematically characterize the architecture of a comprehensive pain network, including both cortical and subcortical brain areas. This structural brain network consists of 49 nodes denoting pain-related brain areas, linked by edges representing their relative incoming and outgoing axonal projection strengths. Sixty-three percent of brain areas in this structural pain network share reciprocal connections, reflecting a dense network. The clustering coefficient, a measurement of the probability that adjacent nodes are connected, indicates that brain areas in the pain network tend to cluster together. Community detection, the process of discovering cohesive groups in complex networks, successfully reveals two known subnetworks that specifically mediate the sensory and affective components of pain, respectively. Assortativity analysis, which evaluates the tendency of nodes to connect with other nodes with similar features, indicates that the pain network is assortative. Finally, robustness, the resistance of a complex network to failures and perturbations, indicates that the pain network displays a high degree of error tolerance (local failure rarely affects the global information carried by the network) but is vulnerable to attacks (selective removal of hub nodes critically changes network connectivity). Taken together, graph theory analysis unveils an assortative structural pain network in the brain processing nociceptive information, and the vulnerability of this network to attack opens up the possibility of alleviating pain by targeting the most connected brain areas in the network.


The AMOG/beta 2 subunit of Na,K-ATPase is not necessary for long-term survival of telencephalic grafts.
Adhesion molecule on glia (AMOG) represents the beta 2-subunit of murine Na,K-ATPase. Mice carrying a targeted deletion of the AMOG/beta 2 gene exhibit tremor and limb paralysis at postnatal day (P) 15 and die 2 days after the onset of symptoms. The brains of these mice show edema and swelling of astrocytic end feet. However, the cause of death has remained unclear. To identify long-term consequences of AMOG/beta 2 deficiency, we have grafted parts of the embryonic telencephalic anlage of AMOG/beta 2-deficient mice into the caudoputamen of wild-type mice and analyzed the grafts up to 500 days after transplantation. Histological, immunocytochemical, and in situ hybridization techniques were applied to examine histoarchitecture, proliferation, differentiation, and long-term survival of grafts. AMOG/beta 2-deficient telencephalic grafts develop normally and form solid neural tissue that cannot be distinguished from control grafts by morphological features or with immunocytochemical stains for neuronal and glial markers. No signs of degeneration can be found. Expression analysis, however, revealed that no AMOG/beta 2 protein of possible host origin can be detected in AMOG/beta 2-deficient grafts. Graft-borne astrocytes express neither the AMOG/beta 1 nor the AMOG/beta 2 subunit of Na,K-ATPase as examined with immunocytochemistry and in situ hybridization. These findings indicate that AMOG/beta 2 is not necessary for long-term survival of telencephalic graft tissue.


Linkage between the frequency of muscular weakness and loci that regulate immune responsiveness in murine experimental myasthenia gravis.
Mice immunized with acetylcholine receptor (AChR) purified from Torpedo californica form anti-AChR antibodies and often develop muscular weakness and flaccid paralysis closely resembling the human disease myasthenia gravis. This condition, termed experimental myasthenia gravis (EMG), is strain dependent in that the frequency of paralysis is much greater in some strains than in others. Differences in the frequency of EMG might result from differences in the immune system or the neuromuscular junction. In these studies, we have identified two loci, the major histocompatibility complex (H-2) region on chromosome 17 and the region that contains the structural genes for the constant region of immunoglobulin heavy chains (IgCH region) on chromosome 12, which significantly effect the probability with which a mouse immunized with T. californica AChR can be expected to become paralyzed. One genotype (H-2b, Ig-1b) correlated with high susceptibility to EMG in four strains with three dissimilar backgrounds. These studies demonstrate that susceptibility to EMG is a heritable trait determined by at least two distinct loci that are linked to regions of the mouse genome that regulate immune responsiveness.


Kainic acid-induced seizures modulate Akt (SER473) phosphorylation in the hippocampus of dopamine D2 receptor knockout mice.
Dopamine D2 receptor (D2R) signalling has been shown to modulate seizure-induced hippocampal cell death. D2R knockout (D2R-/-) mice are more susceptible to kainic acid (KA)-induced excitotoxicity, displaying cell death in the CA3 subfield of the hippocampus at KA doses not damaging in wild-type (WT) animals. Absence of D2R signalling in the hippocampus leads to activation (dephosphorylation) of glycogen synthase kinase 3β (GSK-3β) after KA (20 mg/kg), which is not associated with a change in the phosphorylation of the GSK-3β regulator Akt at the canonical threonine 308 residue. In the present study, we investigated alternative pathways responsible for the activation of GSK-3β in the hippocampus of the D2R-/- mice 24 h following KA-induced seizures. Here, we show that phosphorylation of Akt occurs at serine 473 (Ser473) in the CA3 region of WT but not D2R-/- mice following KA. Moreover, the CA1 subregion, which does not undergo neurodegeneration in either WT or D2R-/- mice, displays a strong induction of Akt (Ser473) phosphorylation after KA. Additionally, the vulnerability in the CA3 is not associated with changes to p38MAPK and Dishevelled activation, and β-catenin does not appear to be a downstream target of the GSK-3β. Thus, we propose that GSK-3β phosphorylation-mediated hippocampal cell survival may depend on Akt (Ser473) phosphorylation; loss of D2R-mediated signalling in the CA3 region of D2R-/- mice leads to reduced Akt (Ser473) phosphorylation rendering neurons more vulnerable to apoptosis. Further investigation is required to fully elucidate the GSK-3β targets involved in D2R-dependent response to excitotoxicity.


Relationship between hyperbaric oxygen therapy and quality of life in participants with chronic diabetic foot ulcers: data from a randomized controlled trial.
To investigate the effect of hyperbaric oxygen therapy on health-related quality of life (HRQoL) in participants with diabetes and chronic foot ulcers. Using data from a randomized controlled trial, we included 103 participants (49 in hyperbaric oxygen therapy group and 54 in sham group) for analyses. The primary outcome was HRQoL as measured by the EQ-5D-3L instrument, while secondary outcomes included quality of life evaluated by the Short Form 36 (SF-36) and Diabetic Foot Ulcers Scale-Short Form (DFS-SF). We used the analysis of covariance to assess whether the EQ-5D index values in hyperbaric oxygen therapy group differed from the sham group. Logistic regression was used to assess the relationship between hyperbaric oxygen therapy and the responses of 'problems' for the EQ-5D health states. No significant differences in EQ-5D index values were found between the hyperbaric oxygen therapy and sham groups: 0.01 (95% CI -0.25, 0.28; p = 0.93) at week 12; 0.07 (95% CI -0.21, 0.34; p = 0.64) at week 6. Hyperbaric oxygen therapy was found to be associated with fewer participants reporting 'problems' in mobility (OR 0.24, 95% CI 0.07, 0.85 at week 12) and pain or discomfort (OR 0.20, 95% CI 0.07, 0.61 at week 6; OR 0.32, 95% CI 0.11, 0.97 at week 12), compared with the sham group. No significant differences in SF-36 or DFS-SF were observed. No significant effect of hyperbaric oxygen therapy on HRQoL measured by EQ-5D index value was found in this study. Due to the potential insufficient power to assess statistical difference, more large-scale research is needed to further evaluate the effect of hyperbaric oxygen therapy on HRQoL in participants with chronic diabetic foot ulcers.


Discovering anomalous patterns in large digital pathology images.
Advances in medical imaging technology have created opportunities for computer-aided diagnostic tools to assist human practitioners in identifying relevant patterns in massive, multiscale digital pathology slides. This work presents Hierarchical Linear Time Subset Scanning, a novel statistical method for pattern detection. Hierarchical Linear Time Subset Scanning exploits the hierarchical structure inherent in data produced through virtual microscopy in order to accurately and quickly identify regions of interest for pathologists to review. We take a digital image at various resolution levels, identify the most anomalous regions at a coarse level, and continue to analyze the data at increasingly granular resolutions until we accurately identify its most anomalous subregions. We demonstrate the performance of our novel method in identifying cancerous locations on digital slides of prostate biopsy samples and show that our methods detect regions of cancer in minutes with high accuracy, both as measured by the ROC curve (measuring ability to distinguish between benign and cancerous slides) and by the spatial precision-recall curve (measuring ability to pick out the malignant areas on a slide which contains cancer). Existing methods need small scale images (small areas of a slide preselected by the pathologist for analysis, eg, 32 × 32 pixels) and may not work effectively on large, raw digitized images of size 100K × 100K pixels. In this work, we provide a methodology to fill this significant gap by analyzing large digitized images and identifying regions of interest that may be indicative of cancer.


Does Measurement of Esophagogastric Junction Distensibility by EndoFLIP Predict Therapy- responsiveness to Endoluminal Fundoplication in Patients With Gastroesophageal Reflux Disease?
In patients with gastroesophageal reflux disease (GERD), an increased esophagogastric junction (EGJ) distensibility has been described. Assessment of EGJ distensibility with the endoscopic functional luminal imaging probe (EndoFLIP) technique might identify patients responsive to transoral incisionless fundoplication (TIF), whereas postoperative measurement of EGJ distensibility might provide insight into the antireflux mechanism of TIF. Therefore, we investigated the value of the EndoFLIP technique in GERD patients treated by TIF. Forty-two GERD patients underwent EGJ distensibility measurement before TIF using the EndoFLIP technique. In a subgroup of 25 patients, EndoFLIP measurement was repeated both postoperative and at 6 months follow-up. Treatment outcome was assessed according to esophageal acid exposure time (AET; objective outcome) and symptom scores (clinical outcome) 6 months after TIF. Multiple logistic regression analysis showed that preoperative EGJ distensibility (OR, 0.16; 95% CI, 0.03-0.78; P = 0.023) and preoperative AET (OR, 0.62; 95% CI, 0.42-0.90; P = 0.013) were independent predictors for objective treatment outcome but not for clinical outcome after TIF. The best cut-off value for objective outcome was 2.3 mm(2)/mmHg for preoperative EGJ distensibility and 11% for preoperative AET. EGJ distensibility decreased direct postoperative from 2.0 (1.2-3.3) to 1.4 (1.0-2.2) mm(2)/mmHg (P = 0.014), but increased to 2.2 (1.5-3.0) at 6 months follow-up (P = 0.925, compared to preoperative). Preoperative EGJ distensibility and preoperative AET were independent predictors for objective treatment outcome but not for clinical outcome after TIF. According to our data, the EndoFLIP technique has no added value either in the preoperative diagnostic work-up or in the post-procedure evaluation of endoluminal antireflux therapy.


Quantum teleportation between remote atomic-ensemble quantum memories.
Quantum teleportation and quantum memory are two crucial elements for large-scale quantum networks. With the help of prior distributed entanglement as a "quantum channel," quantum teleportation provides an intriguing means to faithfully transfer quantum states among distant locations without actual transmission of the physical carriers [Bennett CH, et al. (1993) Phys Rev Lett 70(13):1895-1899]. Quantum memory enables controlled storage and retrieval of fast-flying photonic quantum bits with stationary matter systems, which is essential to achieve the scalability required for large-scale quantum networks. Combining these two capabilities, here we realize quantum teleportation between two remote atomic-ensemble quantum memory nodes, each composed of ∼10(8) rubidium atoms and connected by a 150-m optical fiber. The spin wave state of one atomic ensemble is mapped to a propagating photon and subjected to Bell state measurements with another single photon that is entangled with the spin wave state of the other ensemble. Two-photon detection events herald the success of teleportation with an average fidelity of 88(7)%. Besides its fundamental interest as a teleportation between two remote macroscopic objects, our technique may be useful for quantum information transfer between different nodes in quantum networks and distributed quantum computing.


Opioid receptor involvement in the adaptation to motion sickness in Suncus murinus.
The aim of the present study was to investigate an opioid receptor involvement in the adaptation response to motion sickness in Suncus murinus. Different groups of animals were treated intraperitoneally with either saline, morphine (0.1 and 1.0 mg/kg), naloxone (1.0, 10.0 and 5.0 mg/kg) or a combination of naloxone plus morphine in the absence or 30 min prior to a horizontal motion stimulus of 1 Hz and 40 mm amplitude. For the study of adaptation, different groups received saline on the first trial, and in subsequent trials (every 2 days) they received either saline, naloxone (1.0 and 10.0 mg/kg, i.p.) or morphine (0.1 mg/kg, i.p.) 30 min prior to the motion stimulus. Pretreatment with morphine caused a dose-related reduction in emesis induced by a single challenge to a motion stimulus. Pretreatment with naloxone alone did not induce emesis in its own right nor did it modify emesis induced by a single challenge to a motion stimulus. However, pretreatment with naloxone (5.0 mg/kg, i.p.) revealed an emetic response to morphine (P<.001) (1.0 mg/kg, i.p.) and antagonised the reduction of motion sickness induced by morphine. In animals that received saline or naloxone (1.0 mg/kg), a motion stimulus inducing emesis decreased the responsiveness of animals to a second and subsequent motion stimulus challenge when applied every 2 days for 11 trials. However, the animals receiving naloxone 10.0 mg/kg prior to the second and subsequent challenges showed no significant reduction in the intensity of emesis compared to the first trial. The data are revealing of an emetic potential of morphine when administered in the presence of a naloxone pretreatment. The administration of naloxone is also revealing of an additional inhibitory opioid system whose activation by endogenous opioid(s) may play a role in the adaptation to motion sickness on repeated challenge in S. murinus.


Multiple vanishing tumours simulating pulmonary neoplasms. A case report.
Vanishing fluid collection (or tumour) in an interlobar fissure associated with congestive cardiac failure is not common. Multiple vanishing tumours are most uncommon and can resemble other multiple opacities, e.g. metastases. The disappearance of these so-called tumours after treatment for cardiac failure provided proof of the diagnosis in the patient reported. This diagnosis is important to consider in order to prevent unnecessary investigation and treatment.


Comparative analysis of the 15.5kD box C/D snoRNP core protein in the primitive eukaryote Giardia lamblia reveals unique structural and functional features.
Box C/D ribonucleoproteins (RNP) guide the 2'-O-methylation of targeted nucleotides in archaeal and eukaryotic rRNAs. The archaeal L7Ae and eukaryotic 15.5kD box C/D RNP core protein homologues initiate RNP assembly by recognizing kink-turn (K-turn) motifs. The crystal structure of the 15.5kD core protein from the primitive eukaryote Giardia lamblia is described here to a resolution of 1.8 Å. The Giardia 15.5kD protein exhibits the typical α-β-α sandwich fold exhibited by both archaeal L7Ae and eukaryotic 15.5kD proteins. Characteristic of eukaryotic homologues, the Giardia 15.5kD protein binds the K-turn motif but not the variant K-loop motif. The highly conserved residues of loop 9, critical for RNA binding, also exhibit conformations similar to those of the human 15.5kD protein when bound to the K-turn motif. However, comparative sequence analysis indicated a distinct evolutionary position between Archaea and Eukarya. Indeed, assessment of the Giardia 15.5kD protein in denaturing experiments demonstrated an intermediate stability in protein structure when compared with that of the eukaryotic mouse 15.5kD and archaeal Methanocaldococcus jannaschii L7Ae proteins. Most notable was the ability of the Giardia 15.5kD protein to assemble in vitro a catalytically active chimeric box C/D RNP utilizing the archaeal M. jannaschii Nop56/58 and fibrillarin core proteins. In contrast, a catalytically competent chimeric RNP could not be assembled using the mouse 15.5kD protein. Collectively, these analyses suggest that the G. lamblia 15.5kD protein occupies a unique position in the evolution of this box C/D RNP core protein retaining structural and functional features characteristic of both archaeal L7Ae and higher eukaryotic 15.5kD homologues.


Note: design and construction of a multi-scale, high-resolution, tube-generated x-ray computed-tomography system for three-dimensional (3D) imaging.
The design and construction of a high resolution modular x-ray computed tomography (XCT) system is described. The approach for meeting a specified set of performance goals tailored toward experimental versatility is highlighted. The instrument is unique in its detector and x-ray source configuration, both of which enable elevated optimization of spatial and temporal resolution. The process for component selection is provided. The selected components are specified, the custom component design discussed, and the integration of both into a fully functional XCT instrument is outlined. The novelty of this design is a new lab-scale detector and imaging optimization through x-ray source and detector modularity.


Design by Immersion: A Transdisciplinary Approach to Problem-Driven Visualizations.
While previous work exists on how to conduct and disseminate insights from problem-driven visualization projects and design studies, the literature does not address how to accomplish these goals in transdisciplinary teams in ways that advance all disciplines involved. In this paper we introduce and define a new methodological paradigm we call design by immersion, which provides an alternative perspective on problem-driven visualization work. Design by immersion embeds transdisciplinary experiences at the center of the visualization process by having visualization researchers participate in the work of the target domain (or domain experts participate in visualization research). Based on our own combined experiences of working on cross-disciplinary, problem-driven visualization projects, we present six case studies that expose the opportunities that design by immersion enables, including (1) exploring new domain-inspired visualization design spaces, (2) enriching domain understanding through personal experiences, and (3) building strong transdisciplinary relationships. Furthermore, we illustrate how the process of design by immersion opens up a diverse set of design activities that can be combined in different ways depending on the type of collaboration, project, and goals. Finally, we discuss the challenges and potential pitfalls of design by immersion.


Accessibility and Historical Change: An Emergent Cluster Led Uncles and Aunts to Become Aunts and Uncles.
There are times when a curiously odd relic of language presents us with a thread, which when pulled, reveals deep and general facts about human language. This paper unspools such a case. Prior to 1930, English speakers uniformly preferred male-before-female word order in conjoined nouns such as uncles and aunts; nephews and nieces; men and women. Since then, at least a half dozen items have systematically reversed their preferred order (e.g., aunts and uncles, nieces and nephews) while others have not (men and women). We review evidence that the unusual reversals began with mother and dad(dy) and spread to semantically and morphologically related binomials over a period of decades. The present work proposes that three aspects of cognitive accessibility combine to quantify the probability of A&B order: (1) the relative accessibility of the A&B terms individually, (2) competition from B&A order, and critically, (3) cluster strength (i.e., similarity to related A'&B' cases). The emergent cluster of female-first binomials highlights the influence of semantic neighborhoods in memory retrieval. We suggest that cognitive accessibility can be used to predict the word order of both familiar and novel binomials generally, as well as the diachronic change focused on here.


Anomalous chord of the left atrium without involvement of the mitral valve.
An anomalous chord from the left side of the atrial septum to the left atrial free wall was incidentally noted on transthoracic echocardiography in a 14-year-old boy with vasovagal syncope. Previously reported cases of anomalous chords in the left atrium were associated with the mitral valve leaflets in all but two cases. This is the first reported case of an echocardiographic diagnosis of anomalous left atrial chord without insertion of the chord into the mitral valve.


Heparan sulfate phage display antibodies recognise epitopes defined by a combination of sugar sequence and cation binding.
Phage display antibodies are widely used to follow heparan sulfate (HS) expression in tissues and cells. We demonstrate by ELISA, that cations alter phage display antibody binding profiles to HS and this is mediated by changes in polysaccharide conformation, demonstrated by circular dichroism spectroscopy. Native HS structures, expressed on the cell surfaces of neuroblastoma and fibroblast cells, also exhibited altered antibody binding profiles following exposure to low mM concentrations of these cations. Phage display antibodies recognise conformationally-defined HS epitopes, rather than sequence alone, as has been assumed, and resemble proteins in being sensitive to changes in both charge distribution and conformation following binding of cations to HS polysaccharides.


Violence against children in Latin America and Caribbean countries: a comprehensive review of national health sector efforts in prevention and response.
Violence against children (VAC) remains a global problem. The health sector has an opportunity and responsibility to be part of the multi-sector collaboration to prevent and respond to VAC. This review aimed to assess the health sector's response to VAC among Latin American & Caribbean (LAC) countries, particularly as it relates to physical violence, sexual violence, and neglect. National protocols for the identification and provision of health care to child survivors of violence, abuse and neglect were solicited in partnership with UNICEF and PAHO/WHO country offices within the LAC region. A parallel systematic review was undertaken in January 2015 to review studies published in the last 10 years that describe the regional health sector response to VAC. We obtained health sectors guidelines/protocols related to VAC from 22 of 43 (51 %) countries and reviewed 97 published articles/reports that met the review inclusion criteria. Country protocols were presented in Spanish (n = 12), Portuguese (n = 1), and English (n = 9). Thematic areas of country protocols included: 1) identifying signs and symptoms of VAC, 2) providing patient-centered care to the victim, and 3) immediate treatment of injuries related to VAC. The systematic review revealed that health professionals are often unaware of national protocols and lack training, resources, and support to respond to cases of VAC. Further, there is limited coordination between health and social protection services. VAC remains an international, public health priority. Health professionals are well-positioned to identify, treat and refer cases of VAC to appropriate institutions and community-based partners. However, poor protocol dissemination and training, limited infrastructure, and inadequate human resources challenge adherence to VAC guidelines.


Attentional effects of nicotinic agonists in rats.
Nicotine can increase stimulus detection, response rate and speed in the five-choice serial reaction time task, a rodent test of attention. In the present experiments, four other nicotinic agonists with different pharmacological profiles were compared in the same procedure. The response profile of epibatidine resembled that previously obtained with nicotine in that response accuracy was enhanced and omission errors and correct response latency decreased. ABT-418 transiently increased accuracy in the first 10 min of test sessions and reduced response latency. Isoarecolone caused a dose-related increase in accuracy, but had no effect on omissions or response latency. This absence of effects on response rate- or speed-related measures may be related to its previously reported reduced ability to release dopamine as compared with nicotine. The alpha7-agonist AR-R17779 was without effect on any measure, indicating that this receptor subtype may not mediate nicotinic effects on attention. Affinity constants of compounds, determined in competition binding assays targeting the alpha4beta2, alpha7, alpha3beta4 and alpha3beta2* nAChR subtypes, could not explain the differential behavioural effects observed. Differences in their functional efficacy at nAChR subtypes may instead be responsible. The finding that attentional performance and response rate and speed can be selectively modulated by nicotinic agonists is encouraging for the development of drugs with therapeutic properties similar to those of nicotine but with reduced unwanted effects.


Postmortem whole-body MRI in traumatic causes of death.
The aim of this study was to determine the sensitivity and specificity of postmortem whole-body MRI for typical injuries resulting from traumatic causes of death. Forty cases of accidental death were evaluated with postmortem whole-body MRI. Imaging was conducted according to a standard protocol, and each examination had an average duration of 90 minutes. The imaging findings were correlated with the autopsy findings, which served as the reference standard. MRI showed the main pathologic process leading to death in 39 of the 40 cases. The sensitivity of postmortem MRI ranged from 100% (pneumothorax) to 40% (fractures of the upper extremities). In general, MRI had a high level of performance for depicting soft-tissue lesions, such as subcutaneous hematoma (e.g., galeal hematoma with a sensitivity 95%). The sensitivity of MRI was remarkably lower for lesions of the upper abdominal organs (liver, 80%; spleen, 50%; pancreas, 60%; kidneys, 66%). Postmortem whole-body MRI had overall good performance for depicting traumatic findings in corpses and therefore may serve an important role as an adjunct to classic autopsy for the forensic examination of cases of traumatic cause of death. However, the reduced sensitivity of postmortem MRI for lacerations of the upper abdominal organs and the observed superimposition of antemortem findings and postmortem findings (e.g., in the pulmonary tissue) in this retrospective study suggest that whole-body postmortem MRI not be recommended as a replacement for classic autopsy.


Musca domestica L D.
Field strains of the house fly (Musca domestica L. Diptera: Muscidae) were collected in April and September 2002 from cow farms (Antalya, Izmir) and garbage dumps (Adana, Ankara, Istanbul, Sanliurfa) in Turkey. The resistance levels of first to fifth generation offspring were evaluated against six insecticides (cypermethrin, cyphenothrin, deltamethrin, permethrin, resmethrin, fenitrothion). Resistance levels for pyrethroid group insecticides ranged from 23.27 (permethrin-Istanbul fall strain) to 633.09 (cypermethrin-Izmir spring strain) and for fenitrothion ranged from 5.78 (Istanbul fall strain) to 51.04 (Antalya spring strain). Our results showed that pyrethroid resistance was high and changed from spring to fall in relation to usage and application frequencies of these compounds at the study sites. Although fenitrothion resistance levels were determined to be lower than pyrethroids, these levels were still high and led to control failure. Flies from cow farms were more resistant than those from garbage dumps, but resistance levels for Sanliurfa and Adana strains were also high in relation to usage of different insecticides for agricultural purposes. Although resistance levels against different pyrethroids decreased from spring to fall, these levels still indicated the presence of a strong selective pressure on the populations.


Biochemistry of the erythrocyte Rh polypeptides: a review.
The clinically important Rh blood group system is complex, consisting of multiple distinct antigens. Despite clinical recognition for over 50 years, the Rh blood group antigens have remained poorly understood on a molecular level until the recent identification and characterization of the "Rh polypeptides," the core structural proteins of the Rh antigens. This group of erythrocyte membrane proteins of molecular weight 30,000-35,000 daltons was first recognized by employing Rh-specific antibodies to immunoprecipitate radiolabeled components of erythrocyte membranes. By using antibodies specific for the Rh D, c, and E antigens, a series of highly related non-identical proteins were immunoprecipitated, indicating that the Rh antigens are composed of multiple related proteins. The Rh polypeptides have been purified and characterized, and they were found to have several unusual biochemical characteristics. The Rh polypeptides penetrate the membrane bilayer; they are linked to the underlying membrane skeleton; they are covalently fatty acid acylated with palmitate. While the Rh antigenic reactivity is unique to human erythrocytes, the Rh polypeptides have been isolated from erythrocytes of diverse species and are thought to be fundamental components of all mammalian erythrocyte membranes. The functional role of the Rh polypeptides remains undefined, but a role in the organization of membrane phospholipid is suspected.


Optimal timing of pediatric heart transplantation.
Despite success in adults, heart transplantation (HT) is still considered by many as only desperation therapy for children with end-stage heart disease. Thus, of 30 pediatric patients undergoing HT at our center, only seven (23%) patients had not developed pulmonary hypertension with increased pulmonary vascular resistance (PH) or hemodynamic decompensation (HD) requiring inotropic support at the time of transplantation. We have retrospectively reviewed the effect of preoperative PH, HD, and seven other potential risk factors on survival of our pediatric heart transplant recipients. All 30 patients, aged 5 days to 18 years, had New York Heart Association class III or IV symptoms. Twenty had idiopathic cardiomyopathy, nine had congenital lesions, and one infant had a large left ventricular tumor. A univariate and multivariate Cox proportional-hazards analysis was performed examining the effects of nine variables on survival after transplantation: PH, HD, age, need for hospitalization, congenital heart disease, need for surgical pulmonary artery reconstruction, prior stroke, history of cardiac arrest(s), and mechanical ventilator dependence. One-year actuarial survival for the entire series was 66% and was 100% for the seven patients with neither PH nor HD. None of the nine potential risk factors was a statistically significant predictor of risk, yet the combined presence of PH and HD represented a highly significant predictor of mortality (relative risk, 4.08: 1; p less than 0.002). One-year actuarial survival of the 10 patients with this combination was 30% versus 84% of those without the combination.(ABSTRACT TRUNCATED AT 250 WORDS)


Marine Oomycetes of the Genus Halophytophthora Harbor Viruses Related to Bunyaviruses.
We investigated the incidence of RNA viruses in a collection of Halophytophthora spp. from estuarine ecosystems in southern Portugal. The first approach to detect the presence of viruses was based on the occurrence of dsRNA, typically considered as a viral molecule in plants and fungi. Two dsRNA-banding patterns (∼7 and 9 kb) were observed in seven of 73 Halophytophthora isolates tested (9.6%). Consequently, two dsRNA-hosting isolates were chosen to perform stranded RNA sequencing for de novo virus sequence assembly. A total of eight putative novel virus species with genomic affinities to members of the order Bunyavirales were detected and their full-length RdRp gene characterized by RACE. Based on the direct partial amplification of their RdRp gene by RT-PCR multiple viral infections occur in both isolates selected. Likewise, the screening of those viruses in the whole collection of Halophytophthora isolates showed that their occurrence is limited to one single Halophytophthora species. To our knowledge, this is the first report demonstrating the presence of negative (-) ssRNA viruses in marine oomycetes.


Laser-treated hydrophobic paper: an inexpensive microfluidic platform.
We report a method for fabricating inexpensive microfluidic platforms on paper using laser treatment. Any paper with a hydrophobic surface coating (e.g., parchment paper, wax paper, palette paper) can be used for this purpose. We were able to selectively modify the surface structure and property (hydrophobic to hydrophilic) of several such papers using a CO(2) laser. We created patterns down to a minimum feature size of 62±1 µm. The modified surface exhibited a highly porous structure which helped to trap/localize chemical and biological aqueous reagents for analysis. The treated surfaces were stable over time and were used to self-assemble arrays of aqueous droplets. Furthermore, we selectively deposited silica microparticles on patterned areas to allow lateral diffusion from one end of a channel to the other. Finally, we demonstrated the applicability of this platform to perform chemical reactions using luminol-based hemoglobin detection.


Human bilirubin UDP-glucuronosyltransferase catalyzes the glucuronidation of ethinylestradiol.
The synthetic estrogen ethinylestradiol is extensively eliminated as glucuronide metabolites in humans, but the UDP-glucuronosyltransferases (UGTs) catalyzing this reaction have not been identified. Therefore, ethinylestradiol was tested as a substrate for cloned human UGTs stably expressed in V79 cell lines. Two cloned expressed human enzymes, a bilirubin UGT and a phenol UGT, were observed to catalyze the glucuronidation of ethinylestradiol. High performance liquid chromatographic analysis of the products formed revealed that the expressed bilirubin UGT specifically produced ethinylestradiol-3-glucuronide. In human liver microsomes the ratio of 3-glucuronide/17-glucuronide was 97:3. Subsequent study of the cloned expressed enzymes and human liver microsomes from Crigler-Najjar patients by kinetic analysis and by substrate inhibition strongly indicated that a human liver bilirubin UGT was largely responsible for glucuronidation of ethinylestradiol. These results may provide an explanation for jaundice caused by ethinylestradiol in certain susceptible individuals.


Electrochemical therapy of pelvic pain: effects of pulsed electromagnetic fields (PEMF) on tissue trauma.
Unusually effective and long-lasting relief of pelvic pain of gynaecological origin has been obtained consistently by short exposures of affected areas to the application of a magnetic induction device producing short, sharp, magnetic-field pulses of a minimal amplitude to initiate the electrochemical phenomenon of electroporation within a 25 cm2 focal area. Treatments are short, fasting-acting, economical and in many instances have obviated surgery. This report describes typical cases such as dysmenorrhoea, endometriosis, ruptured ovarian cyst, acute lower urinary tract infection, post-operative haematoma, and persistent dyspareunia in which pulsed magnetic field treatment has not, in most cases, been supplemented by analgesic medication. Of 17 female patients presenting with a total of 20 episodes of pelvic pain, of which 11 episodes were acute, seven chronic and two acute as well as chronic, 16 patients representing 18 episodes (90%) experienced marked, even dramatic relief, while two patients representing two episodes reported less than complete pain relief.


[National Research Program on the prevention of cardiovascular diseases: plan of study].
The main objectives of the Swiss National Research Program on primary prevention of cardiovascular diseases are: 1) the reduction of known cardiovascular risk factors among the local populations of two intervention Communities compared to two "regular care" communities and 2) the provision of tested cost-effective methods for nation-wide use in the future control of CVD. The main focus during both the screening and the three years intervention phase will be on the total mobilization of community resources to induce behavior change (active participation of the population as well as the local health and social services system both in planning and implementation). A program such as this has to meet the challenge of developing a design that combines the needs for rigorous evaluation with a maximal amount of flexibility regarding the results of local initiative and involvement.


The willingness and attitude of patients towards self-administration of medication in hospital.
Literature suggests a positive impact of self-administration of medication during hospitalization on medication adherence and safety, and on patient satisfaction. However, self-administration is not a common practice in Belgian hospitals. The aim of this study was to describe patients' willingness towards self-administration of medication while in hospital. A cross-sectional observational study was conducted in three Belgian hospitals in November and December 2015. All patients of 14 randomly selected wards were asked to participate. The structured questionnaire comprised patient characteristics, their willingness and attitude towards self-administration of medication, perceived ability to self-administer during hospitalization, and prerequisites and perceived consequences. In total, 124 patients participated (36% of all eligible patients). The main reasons not to participate were the patients' physical and mental condition (30%) and the absence of patients during the time of data collection (23%). The majority of the 124 participating patients had a positive attitude towards the implementation of self-administration; 83.9% were willing to self-administer their medication while in hospital. Most important prerequisites were self-administration at home before and after hospitalization, patients' motivation, and a regular evaluation of the patients' competences. Patients acknowledged benefits such as an increase in autonomy, independence and medication knowledge. Patients did not expect self-administration would cause important safety issues. The majority of patients, capable of participating in the study, would want to self-administer medication during hospitalization. They had a positive attitude towards self-administration of medication. Nevertheless, patients stated important conditions which need to be considered in order to implement self-administration.


The meaning and process of pain acceptance. Perceptions of women living with arthritis and fibromyalgia.
Within the past 10 years, cognitive-behavioural pain management models have moved beyond the traditional focus on coping strategies and perceived control over pain, to incorporate mindfulness- and acceptance-based approaches. Pain acceptance is the process of giving up the struggle with pain and learning to live life despite pain. Acceptance is associated with lower levels of pain, disability and psychological distress. Relatively little is known, however, about how patients arrive at a state of acceptance without the aid of therapy. To explore personal definitions of acceptance and the factors that facilitate or hinder acceptance. Eleven focus groups, involving a total of 45 women with arthritis and fibromyalgia, were conducted. The qualitative analysis revealed that, while the women rejected the word 'acceptance', they did agree with the main components of existing research definitions. The women's responses revealed that acceptance was a process of realizations and acknowledgements, including realizing that the pain was not normal and help was needed, receiving a diagnosis, acknowledging that there was no cure and realizing that they needed to redefine 'normal'. Diagnosis, social support, educating self and others, and self-care were factors that promoted acceptance. Struggling to retain a prepain identity, negative impacts on relationships, others not accepting their pain and the unspoken message that the pain was 'all in their head' were barriers to acceptance. The implications of these findings, distinctions between the diagnostic groups and recommendations regarding how health professionals can facilitate the process of acceptance are discussed.


Role of plant-based diet in late-life cognitive decline: results from the Salus in Apulia Study.
Consistency among population-based studies investigating the relationship between diet and cognition in older inhabitants in the Mediterranean area is poor. The present study investigated whether diet changes over 12 years were associated with cognitive function in older people in Southern-Italy. From the 'Salus in Apulia Study', that includes the MICOL and GreatAGE Studies, 584 participants were selected, firstly enrolled in MICOL3 (M3) and later in the GreatAGE Study (MICOL4, M4). Foods and micronutrients intake were recorded in both studies, and global cognitive function in M4, assessed with the Mini Mental State Examination. Plant-based foods, particularly coffee and vegetables, as well as vitamin A sources, were inversely associated to age-related cognitive impairment. Alcohol consumption showed a detrimental role on cognition, while red meat appeared to be beneficial in the present study, although its role is traditionally considered harmful for cognitive function. Our study confirmed that a traditional Mediterranean dietary pattern based on agricultural products and low alcohol consumption may help to prevent/delay age-related cognitive impairment.


A neonate with contiguous deletion syndrome in XP21.
We report a case of a male infant with the association of pseudohypertriglyceridemia, hypoadrenalism (hyponatremia, hyperpotasemia, dehydration), high creatine phosphokinase level (possible Duchenne's muscular dystrophy, DMD) and diagnosed contiguous gene deletion syndrome in Xp21. A 1-month-old male term infant was referred due to no weight gain. The examination revealed dehydration (decreased skin turgor), scrotal hyperpigmentation and hypotonia. Laboratory findings showed hyponatremia of 124 mmol/L, hyperpotasemia of 6.9 mg/dL, high creatine phosphokinase level of 7019 IU/L, and high blood triglyceride level of 1244 mg/dL. There was no deletion detected in the dystrophin gene with the study investigating selected exons, no dystrophin staining and nonspecific atrophic findings in the muscle biopsy. Further laboratory findings defined high glycerol concentrations both in blood and in urine that were compatible with a glycerol kinase deficiency (GKD). Array CGH study confirmed the existence of a deletion in Xp21 of the genes responsible for DMD, GKD and the congenital adrenal hypoplasia (gene DAX1 or NROB1 gene: Xp21.3-21.2). The infant showed good response to mineralocorticoid therapy, hyponatremia resolved and gained weight. Physicians should consider contiguous gene deletion syndrome in Xp21 in the infants with myopathic compromise, increased levels of creatine phosphokinase and pseudohypertriglyceridaemia to be able to prevent and treat the metabolic complications. Furthermore, geneticists should take into account to design routine deletion studies including the promoter region in this disorder.


An international consensus approach to the management of atypical hemolytic uremic syndrome in children.
Atypical hemolytic uremic syndrome (aHUS) emerged during the last decade as a disease largely of complement dysregulation. This advance facilitated the development of novel, rational treatment options targeting terminal complement activation, e.g., using an anti-C5 antibody (eculizumab). We review treatment and patient management issues related to this therapeutic approach. We present consensus clinical practice recommendations generated by HUS International, an international expert group of clinicians and basic scientists with a focused interest in HUS. We aim to address the following questions of high relevance to daily clinical practice: Which complement investigations should be done and when? What is the importance of anti-factor H antibody detection? Who should be treated with eculizumab? Is plasma exchange therapy still needed? When should eculizumab therapy be initiated? How and when should complement blockade be monitored? Can the approved treatment schedule be modified? What approach should be taken to kidney and/or combined liver-kidney transplantation? How should we limit the risk of meningococcal infection under complement blockade therapy? A pressing question today regards the treatment duration. We discuss the need for prospective studies to establish evidence-based criteria for the continuation or cessation of anticomplement therapy in patients with and without identified complement mutations.


Inhibition of cellular proliferation by the Wilms' tumor suppressor WT1 is associated with suppression of insulin-like growth factor I receptor gene expression.
We have investigated the regulation of the insulin-like growth factor I receptor (IGF-I-R) gene promoter by the Wilms' tumor suppressor WT1 in intact cells. The levels of endogenous IGF-I-R mRNA and the activity of IGF-I-R gene promoter fragments in luciferase reporter constructs were found to be significantly higher in G401 cells (a Wilms' tumor-derived cell line lacking detectable WT1 mRNA) than in 293 cells (a human embryonic kidney cell line which expresses significant levels of WT1 mRNA). To study whether WT1 could suppress the expression of the endogenous IGF-I-R gene, WT1-negative G401 cells were stably transfected with a WT1 expression vector. Expression of WT1 mRNA in G401 cells resulted in a significant decrease in the rate of cellular proliferation, which was associated with a reduction in the levels of IGF-I-R mRNA, promoter activity, and ligand binding and with a reduction in IGF-I-stimulated cellular proliferation, thymidine incorporation, and anchorage-independent growth. These data suggest that a major aspect of the action of the WT1 tumor suppressor is the repression of IGF-I-R gene expression.


Interventions for generalized anxiety disorder in older adults: systematic review and meta-analysis.
Generalized anxiety disorder (GAD) is one of the most common anxiety disorders in later life, with widespread consequences for individuals and society. To perform a systematic review of the efficacy of controlled interventions for GAD in adults aged 55 years and older. Direct search of digital databases and the main publications on aging and iterative searches of the references from retrieved articles. Twenty-seven trials (14 pharmacological, 13 psychotherapeutic) fulfilled the inclusion criteria, reporting results from 2373 baseline participants. There were no differences between trials in their overall quality. Pooled treatment effects for pharmacological (OR=0.32, 95% CI: 0.18, 0.54) and psychotherapeutic (OR=0.33, 95% CI: 0.17, 0.66) trials were similar, with findings in each case favoring active interventions over control conditions. Older adults with GAD benefited from both pharmacological and psychotherapeutic interventions. Future studies should investigate combined treatment with medication and psychotherapy.


Eligibility criteria in heart failure randomized controlled trials: a gap between evidence and clinical practice.
The aim of the present study was to compare the characteristics of patients referred to our heart failure outpatient clinic with those of patients enrolled in clinical trials on heart failure pharmacological treatment. Thus, we estimated the proportion of patients admitted to our heart failure outpatient clinic who would have been included in randomized controlled trials evaluating the effects of medical treatments on heart failure mortality, published over a 10 years period (1993-2003). Sixteen studies (n = 45276) and 299 consecutive outpatients, were included. On average, only 34% of the outpatients would have been included in at least one of the 16 trials (8-71%). The main reasons for exclusion were: NYHA class (70% were in NYHA class II), ejection fraction (29% had EF > 35%), co-morbidity (51% had co-morbidity, mainly renal failure, COPD, and disthyroidism), age (22% were older than 80 years), and occurrence of a recent acute event (50% experienced an ischemic coronary syndrome, revascularization, pulmonary edema, or stroke in the prior 6 months). These results underline the crucial role of patient selection in clinical trials, raising uncertainties about the complete applicability of trial results to clinical practice.


Antigen 85A and mycobacterial DNA-binding protein 1 are targets of immunoglobulin G in individuals with past tuberculosis.
Development of accurate methods for predicting progression of tuberculosis (TB) from the latent state is recognized as vitally important in controlling TB, because a majority of cases develop from latent infections. Past TB that has never been treated has a higher risk of progressing than does latent Mycobacterium tuberculosis infection in patients who have previously received treatment. Antibody responses against 23 kinds of M. tuberculosis proteins in individuals with past TB who had not been medicated were evaluated. These individuals had significantly higher concentrations of antibodies against Antigen 85A and mycobacterial DNA-binding protein 1 (MDP1) than did those with active TB and uninfected controls. In addition, immunohistochemistry revealed colocalization of tubercle bacilli, antigen 85 and MDP1 inside tuberculous granuloma lesions in an asymptomatic subject, showing that M. tuberculosis in lesions expresses both antigen 85 and MDP1. Our study suggests the potential usefulness of measuring antibody responses to antigen 85A and MDP1 for assessing the risk of TB progression.


Neural representations of nouns and verbs in Chinese: an fMRI study.
The neural representation of nouns and verbs has been a focus of many recent neuroimaging and neuropsychological studies. These studies have in general found that in English and other Indo-European languages, verbs are represented in the frontal region (e.g., the left prefrontal cortex) while nouns in the posterior regions (the temporal-occipital regions). There is accumulating evidence, however, that the picture may have been overly simplified. In the present study, we examine the representations of nouns and verbs in Chinese, a language that has unique properties in its grammar and particularly in the structure of nouns and verbs. In an fMRI experiment, subjects viewed a list of disyllabic nouns, verbs, and class-ambiguous words and performed a lexical decision on the target. Results from the experiment indicate that nouns and verbs in Chinese activate a wide range of overlapping brain areas in distributed networks, in both the left and the right hemispheres. The results provide support for the prediction regarding the impact of linguistic typology and language-specific influences on the neural representation of grammatical categories. They are consistent with recent proposals that specific linguistic experience shapes neural systems of reading and speaking and that the language-specific properties of the Chinese grammar affect the representation, processing, and acquisition in this language.


Local and global pyrogeographic evidence that indigenous fire management creates pyrodiversity.
Despite the challenges wildland fire poses to contemporary resource management, many fire-prone ecosystems have adapted over centuries to millennia to intentional landscape burning by people to maintain resources. We combine fieldwork, modeling, and a literature survey to examine the extent and mechanism by which anthropogenic burning alters the spatial grain of habitat mosaics in fire-prone ecosystems. We survey the distribution of Callitris intratropica, a conifer requiring long fire-free intervals for establishment, as an indicator of long-unburned habitat availability under Aboriginal burning in the savannas of Arnhem Land. We then use cellular automata to simulate the effects of burning identical proportions of the landscape under different fire sizes on the emergent patterns of habitat heterogeneity. Finally, we examine the global extent of intentional burning and diversity of objectives using the scientific literature. The current distribution of Callitris across multiple field sites suggested long-unburnt patches are common and occur at fine scales (<0.5 ha), while modeling revealed smaller, patchy disturbances maximize patch age diversity, creating a favorable habitat matrix for Callitris. The literature search provided evidence for intentional landscape burning across multiple ecosystems on six continents, with the number of identified objectives ranging from two to thirteen per study. The fieldwork and modeling results imply that the occurrence of long-unburnt habitat in fire-prone ecosystems may be an emergent property of patch scaling under fire regimes dominated by smaller fires. These findings provide a model for understanding how anthropogenic burning alters spatial and temporal aspects of habitat heterogeneity, which, as the literature survey strongly suggests, warrant consideration across a diversity of geographies and cultures. Our results clarify how traditional fire management shapes fire-prone ecosystems, which despite diverse objectives, has allowed human societies to cope with fire as a recurrent disturbance.


Control Capabilities of Myoelectric Robotic Prostheses by Hand Amputees: A Scientific Research and Market Overview.
Hand amputation can dramatically affect the capabilities of a person. Cortical reorganization occurs in the brain, but the motor and somatosensorial cortex can interact with the remnant muscles of the missing hand even many years after the amputation, leading to the possibility to restore the capabilities of hand amputees through myoelectric prostheses. Myoelectric hand prostheses with many degrees of freedom are commercially available and recent advances in rehabilitation robotics suggest that their natural control can be performed in real life. The first commercial products exploiting pattern recognition to recognize the movements have recently been released, however the most common control systems are still usually unnatural and must be learned through long training. Dexterous and naturally controlled robotic prostheses can become reality in the everyday life of amputees but the path still requires many steps. This mini-review aims to improve the situation by giving an overview of the advancements in the commercial and scientific domains in order to outline the current and future chances in this field and to foster the integration between market and scientific research.


Lactate Regulates Metabolic and Pro-inflammatory Circuits in Control of T Cell Migration and Effector Functions.
Lactate has long been considered a "waste" by-product of cell metabolism, and it accumulates at sites of inflammation. Recent findings have identified lactate as an active metabolite in cell signalling, although its effects on immune cells during inflammation are largely unexplored. Here we ask whether lactate is responsible for T cells remaining entrapped in inflammatory sites, where they perpetuate the chronic inflammatory process. We show that lactate accumulates in the synovia of rheumatoid arthritis patients. Extracellular sodium lactate and lactic acid inhibit the motility of CD4+ and CD8+ T cells, respectively. This selective control of T cell motility is mediated via subtype-specific transporters (Slc5a12 and Slc16a1) that we find selectively expressed by CD4+ and CD8+ subsets, respectively. We further show both in vitro and in vivo that the sodium lactate-mediated inhibition of CD4+ T cell motility is due to an interference with glycolysis activated upon engagement of the chemokine receptor CXCR3 with the chemokine CXCL10. In contrast, we find the lactic acid effect on CD8+ T cell motility to be independent of glycolysis control. In CD4+ T helper cells, sodium lactate also induces a switch towards the Th17 subset that produces large amounts of the proinflammatory cytokine IL-17, whereas in CD8+ T cells, lactic acid causes the loss of their cytolytic function. We further show that the expression of lactate transporters correlates with the clinical T cell score in the synovia of rheumatoid arthritis patients. Finally, pharmacological or antibody-mediated blockade of subtype-specific lactate transporters on T cells results in their release from the inflammatory site in an in vivo model of peritonitis. By establishing a novel role of lactate in control of proinflammatory T cell motility and effector functions, our findings provide a potential molecular mechanism for T cell entrapment and functional changes in inflammatory sites that drive chronic inflammation and offer targeted therapeutic interventions for the treatment of chronic inflammatory disorders.


The importance and limits of harm in identifying mental disorder.
The In Review articles in this issue on normality and disorder by Dr Rachel Cooper and Dr Derek Bolton explore the importance of a value component of harm in the concept of mental disorder. They focus on the Diagnostic and Statistical Manual of Mental Disorder's clinical significance criterion, requiring that symptoms cause significant distress or role impairment, as the expression of the harm component. As Dr Bolton argues, harm in the form of distress or role impairment has always been intimately tied to the concept of disorder and treatment decisions; as Dr Cooper argues, without the harm requirement, any disliked anomaly may be labelled a disorder. Moreover, as Cooper argues, a harm requirement is not incompatible with a natural kinds approach to distinguishing among disorders or to a categorical approach to disorder; the lack of zones of rarity on the harm continuum does not preclude categorical underlying causal processes. However, neither paper systematically develops arguments regarding the other component of disorder, the requirement that the harm must be caused by underlying dysfunction. The dysfunction component distinguishes disorders from the many other negative conditions in life. Cooper's identification of dysfunction with symptom severity ignores the fact that normal suffering can be severe, and Bolton's attempt to encompass risk of harm within harm yields an implausibly expansive conception of disorder. While the harm component is essential, clarification of the dysfunction component of the concept of disorder, pursued in part 2 of this In Review in the December 2013 issue, is also essential to establishing a coherent and plausibly limited domain of psychiatric disorder within the broader arena of harmful conditions.


A global attentional scope setting prioritizes faces for conscious detection.
The scope of visual attention is known to affect conscious object perception, with recent studies showing that a global attentional scope boosts holistic face processing, relative to a local scope. Here we show that attentional scope settings can also modulate the availability of information for conscious visual awareness. In an initial experiment, we show that adopting a global attentional scope accelerates conscious detection of initially invisible faces, presented under continuous flash suppression (CFS). Furthermore, face detection time was not modulated by attentional scope in a nonrivalrous control condition, which emulated the experience of CFS without inducing binocular rivalry. In a follow-up experiment, we report an exact replication of the original effect, as well as data suggesting that this effect is specific to upright faces, and is abolished when using both inverted faces and images of houses in an otherwise identical task. Thus, attentional scope settings can modulate the availability of information to conscious awareness, fundamentally altering the contents of our subjective visual experience.


Comparative analysis of syndromic and PCR-based diagnostic assay reveals misdiagnosis/ overtreatment for trichomoniasis based on subjective judgment in symptomatic patients.
Trichomoniasis, a sexually transmitted disease (STD), is caused by Trichomonas vaginalis in both men and women. Screening of trichomoniasis is problematic in resource challenged settings as currently available, inexpensive diagnostic methods are of low sensitivity and/or specificity. In India, National AIDS Control organization (NACO) recommended syndromic case management (SCM) for treatment. The objective of the present study was to compare the utility of the NACO-NACP III Algorithms for STI/RTI treatment used by clinicians with PCR based diagnosis. Patients visiting Department of Obstetrics & Gynecology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi from January 2011 to June 2014 were enrolled in the study to compare the diagnostic efficiency of PCR-based assays against SCM. Based on SCM, patients (n = 820) were treated with antibiotics using pre-packed STI/RTI kits (sexually transmitted infection/reproductive tract infection; procured by National AIDS Control/State AIDS Control Society (NACO/SACS), Ministry of Health and Family Welfare, Govt of India.) under National AIDS Control Programme (NACP III) for syndromic case management (SCM). Ectocervical dry swab samples were also obtained from these patients and out of that 634 samples were tested by PCR. Total genomic DNA was extracted from these samples and used as template for PCR amplification using pfoB, gyrA and orf1 gene specific primers for diagnosis of T. vaginalis (TV), Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) respectively. Out of 6000 patients who visited OPD, 820 (14 %) female patients reported vaginal discharge and were recommended antibiotic treatment for one or more pathogens namely, TV, CT, NG and Candida or for co-infection. On the basis of signs & symptoms and NACO guidelines, the following distribution of various infections was observed: TV (46 %), CT (20 %), coinfection with TV and CT (12 %), coinfection with CT and NG (11 %), coinfection with TV, CT and Candida (7 %) and coinfection with TV and NG (2 %). Others were infected with NG alone (1 %), coinfected with TV and Candida (0.4 %) and 0.3 % were coinfected with CT, NG and Candida. Based on PCR method, 110 (17 %) women tested positive for one or more of these three pathogens while 524 (83 %) women were negative for any of these three pathogens but could be positive for other STIs not tested in this study. Since all the patients (634) were given antibiotics, we estimate that the over-treatment was 85 % while 524 (83 %) patients were also misdiagnosed by SCM. The over-treatment and inaccurate diagnosis of pathogens due to subjective judgment based on syndromic approach in symptomatic women is a large economic wastage and may also contribute towards increased resistance. The misdiagnosed patients will also serve as a reservoir for transmission of pathogens to their sexual partner.


Lyophilization of lepidopteran midguts: a preserving method for Bacillus thuringiensis toxin binding studies.
Binding assays with brush border membrane vesicles (BBMV) from insect midguts are commonly used in the study of the interactions between Bacillus thuringiensis Cry toxins and their receptors. Collaboration between laboratories often require that frozen insect samples are sent in dry ice. Because of customs restrictions and delays, sample thawing is always a risk and often the biological material becomes ruined during shipping. We have tested lyophilization as an alternative method for preserving insect midguts for binding studies with B. thuringiensis Cry toxins. For this purpose, BBMV were prepared from both frozen and lyophilized midguts from three lepidopteran species: Spodoptera exigua, Manduca sexta, and Helicoverpa armigera. Higher membrane protein recovery was always obtained from lyophilized midguts compared to frozen midguts, and similar membrane marker enzyme activities were found in BBMV from either treatment. Comparable equilibrium dissociation constants and binding site concentrations, calculated from binding experiments with labeled (125)I-Cry1Ab toxin, were found using BBMV from either method. In the light of these results, lyophilization is a good preserving method of lepidopteran midguts to study binding of B. thuringiensis Cry toxins.


Effect of melatonin administration and long day-length on endocrine cycles in the hedgehog Erinaceus europaeus.
The effects of exogenous melatonin (subcutaneous implants containing 0.031 +/- 0.006 mg/gm body mass melatonin) or long photoperiod (18L:6D) on wild-caught adult male hedgehogs were studied. Hedgehogs were implanted with melatonin-filled or empty capsules in May, August, or September, or maintained under long photoperiod from August. Blood samples collected at monthly intervals were assayed for testosterone, melatonin, and thyroxin. Melatonin-filled capsules elevated plasma melatonin concentrations for 4-6 months. Although melatonin administration in May depressed plasma testosterone levels, testicular reactivation was advanced by 1 month the following year, and the characteristic prehibernal gain in body mass was abolished. Melatonin administration in August had no effect on plasma testosterone concentrations but reduced body mass fluctuations before and during hibernation. Hedgehogs receiving melatonin in September recovered early from hibernal body mass loss and showed a 2 month advance in testicular reactivation the following year. Maintaining hedgehogs at 18L:6D photoperiod, however, elevated plasma melatonin concentrations. Testicular reactivation the following spring was delayed by 1 month, ended 3 months early, and testosterone concentrations were depressed. All treatments depressed plasma thyroxin levels. These results suggest that elevated melatonin levels during winter are important in the regulation of endogenous endocrine cycles in the hedgehog. Hedgehogs do not respond positively to melatonin at the end of the breeding season, but are again responsive to melatonin as early as September.


Immediate neurophysiological effects of transcranial electrical stimulation.
Noninvasive brain stimulation techniques are used in experimental and clinical fields for their potential effects on brain network dynamics and behavior. Transcranial electrical stimulation (TES), including transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), has gained popularity because of its convenience and potential as a chronic therapy. However, a mechanistic understanding of TES has lagged behind its widespread adoption. Here, we review data and modelling on the immediate neurophysiological effects of TES in vitro as well as in vivo in both humans and other animals. While it remains unclear how typical TES protocols affect neural activity, we propose that validated models of current flow should inform study design and artifacts should be carefully excluded during signal recording and analysis. Potential indirect effects of TES (e.g., peripheral stimulation) should be investigated in more detail and further explored in experimental designs. We also consider how novel technologies may stimulate the next generation of TES experiments and devices, thus enhancing validity, specificity, and reproducibility.


Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial.
VEGF and VEGF receptor 2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether the addition of ramucirumab, a VEGFR-2 antagonist monoclonal antibody, to first-line chemotherapy improves outcomes in patients with metastatic gastric or gastro-oesophageal junction adenocarcinoma. For this double-blind, randomised, placebo-controlled, phase 3 trial done at 126 centres in 20 countries, we recruited patients aged 18 years or older with metastatic, HER2-negative gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function. Eligible patients were randomly assigned (1:1) with an interactive web response system to receive cisplatin (80 mg/m2, on the first day) plus capecitabine (1000 mg/m2, twice daily for 14 days), every 21 days, and either ramucirumab (8 mg/kg) or placebo on days 1 and 8, every 21 days. 5-Fluorouracil (800 mg/m2 intravenous infusion on days 1-5) was permitted in patients unable to take capecitabine. The primary endpoint was investigator-assessed progression-free survival, analysed by intention to treat in the first 508 patients. We did a sensitivity analysis of the primary endpoint, including a central review of CT scans. Overall survival was a key secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT02314117. Between Jan 28, 2015, and Sept 16, 2016, 645 patients were randomly assigned to receive ramucirumab plus fluoropyrimidine and cisplatin (n=326) or placebo plus fluoropyrimidine and cisplatin (n=319). Investigator-assessed progression-free survival was significantly longer in the ramucirumab group than the placebo group (hazard ratio [HR] 0·753, 95% CI 0·607-0·935, p=0·0106; median progression-free survival 5·7 months [5·5-6·5] vs 5·4 months [4·5-5·7]). A sensitivity analysis based on central independent review of the radiological images did not corroborate the investigator-assessed difference in progression-free survival (HR 0·961, 95% CI 0·768-1·203, p=0·74). There was no difference in overall survival between groups (0·962, 0·801-1·156, p=0·6757; median overall survival 11·2 months [9·9-11·9] in the ramucirumab group vs 10·7 months [9·5-11·9] in the placebo group). The most common grade 3-4 adverse events were neutropenia (85 [26%] of 323 patients in the ramucirumab group vs 85 [27%] of 315 in the placebo group), anaemia (39 [12%] vs 44 [14%]), and hypertension (32 [10%] vs 5 [2%]). The incidence of any-grade serious adverse events was 160 (50%) of 323 patients in the ramucirumab group and 149 (47%) of 315 patients in the placebo group. The most common serious adverse events were vomiting (14 [4%] in the ramucirumab group vs 21 [7%] in the placebo group) and diarrhoea (11 [3%] vs 19 [6%]). There were seven deaths in each group, either during study treatment or within 30 days of discontinuing study treatment, which were the result of treatment-related adverse events. In the ramucirumab group, these adverse events were acute kidney injury, cardiac arrest, gastric haemorrhage, peritonitis, pneumothorax, septic shock, and sudden death (n=1 of each). In the placebo group, these adverse events were cerebrovascular accident (n=1), multiple organ dysfunction syndrome (n=2), pulmonary embolism (n=2), sepsis (n=1), and small intestine perforation (n=1). Although the primary analysis for progression-free survival was statistically significant, this outcome was not confirmed in a sensitivity analysis of progression-free survival by central independent review, and did not improve overall survival. Therefore, the addition of ramucirumab to cisplatin plus fluoropyrimidine chemotherapy is not recommended as first-line treatment for this patient population. Eli Lilly and Company.


Phylogenetic analysis of Ciona intestinalis gene superfamilies supports the hypothesis of successive gene expansions.
Understanding the formation of metazoan multigene families is a good approach to reconstitute the evolution of the chordate genome. In this attempt, the analysis of the genome of selected species provides valuable information. Ciona intestinalis belongs to the urochordates, whose lineage separated from the chordate lineage that later gave birth to vertebrates. We have searched available sequences from the small marine ascidian C. intestinalis for orthologs of members of five vertebrate superfamilies, including tyrosine kinase receptors, ETS, FOX and SOX transcription factors, and WNT secreted regulatory factors, and conducted phylogenetic analyses. We have found that most vertebrate subfamilies have a single C. intestinalis ortholog. Our results support the hypothesis of a gene expansion prior the base of chordate ancestry followed by another gene expansion during vertebrate evolution. They also indicate that Ciona intestinalis genome will be a very valuable tool for evolutionary analyses.


Insights on HPV vaccination in the United States from mothers' comments on Facebook posts in a randomized trial.
In the United States, parents' health beliefs affect HPV vaccination decisions for children. Our team acquired insights into mothers' health beliefs from their reactions and comments to posts on HPV vaccination in a social media adolescent health campaign in a randomized trial (n = 881 mothers; 63.1% reported daughters had 1+ doses of the HPV vaccine) evaluating communication intended to reduce daughters' indoor tanning. A total of 10 HPV vaccination messages in didactic (n = 7) and narrative (n = 3) formats were posted on vaccination need, uptake, and effectiveness and stories of young women who died from cervical cancer and a mother's decision to vaccinate her daughters. These posts received 28 reactions (like, love, and sad buttons; mean = 2.8 per post) and 80 comments (mean = 8.0 per post). More comments were favorable (n = 43) than unfavorable (n = 34). Data was not collected on views for posts. The most common favorable comment reported that daughters were vaccinated (n = 31). Unfavorable comments cited safety concerns, lack of physician support, distrust of pro-vaccine sources, and increased sexual activity of daughters. Mothers posting unfavorable (18.2%) as opposed to favorable (78.6%) comments or not commenting (64.0%) were less likely to have had their daughters vaccinated (chi-square = 22.27, p < 0.001). Favorable comments often did not state reasons for vaccinating. Concerns about lack of vaccine safety remain a barrier. Mothers may express distrust in pro-vaccine sources to reduce discomfort with not vaccinating daughters to reduce their risk for HPV infection. Many mothers who remained silent had vaccinated daughters, which suggests they did not resisit HPV vaccination.


Simultaneous assessment of aneuploidy, polymorphisms, and mitochondrial DNA content in human polar bodies and embryos with the use of a novel microarray platform.
To develop a microarray platform that allows simultaneous assessment of aneuploidy and quantification of mitochondrial DNA (mtDNA) in human polar bodies and embryos. Optimization and validation applied to cell lines and clinical samples (polar bodies, blastomeres, and trophectoderm biopsies). University research laboratory and a preimplantation genetic diagnosis (PGD) reference laboratory. Samples from 65 couples who underwent PGD for aneuploidy and/or a single-gene disorder. None. 1) Comparison of aneuploidy screening results obtained with the use of the new microarray with those derived from two well established cytogenetic techniques. 2) mtDNA quantification. 3) Analysis of single-nucleotide polymorphisms. The fully optimized microarray was estimated to have an accuracy of ≥97% for the detection of individual aneuploidies and to detect 99% of chromosomally abnormal embryos. The microarray was shown to accurately determine relative quantities of mtDNA. Information provided from polymorphic loci was sufficient to allow confirmation that an embryo was derived from specific parents. It is hoped that methods such as those reported here, which provide information on several aspects of oocyte/embryo genetics, could lead to improved strategies for identifying viable embryos, thereby increasing the likelihood of successful implantation. Additionally, the provision of genotyping information has the potential to reveal DNA contaminants and confirm parental origin of embryos.


Asymptomatic tubular duplication of the transverse colon in an adult.
Colonic duplication is a rare congenital anomaly of the alimentary tract. In most cases, symptomatic duplications of the colon are recognized and treated by childhood. It is uncommon for these lesions to be detected in the adulthood since they present with vague symptoms if at all. We experienced a case of asymptomatic tubular duplication of the transverse colon in a 40-year-old female. Barium enema revealed a tubular duplication of the transverse colon. The duplicated segment arose from the mid ascending colon and incorporated just proximal to the splenic flexure, running parallel to the transverse colon and communicating with it at both ends. Colonoscopy demonstrated a normal colonic mucosa in the duplicated segment. The diameter of its lumen gradually narrowed proximally and the colonoscope could not be passed through the proximal opening of the segment. The patient did not need any treatment. Duplications of the alimentary tract can be found at any age. The possibility of congenital lesions in the adult population should not be overlooked.


Riboflavin Metabolism Variation among Clinical Isolates of Streptococcus pneumoniae Results in Differential Activation of Mucosal-associated Invariant T Cells.
Streptococcus pneumoniae is an important bacterial pathogen that causes a range of noninvasive and invasive diseases. The mechanisms underlying variability in the ability of S. pneumoniae to transition from nasopharyngeal colonization to disease-causing pathogen are not well defined. Mucosal-associated invariant T (MAIT) cells are prevalent in mucosal tissues such as the airways and are believed to play an important role in the early response to infection with bacterial pathogens. The ability of MAIT cells to recognize and contain infection with S. pneumoniae is not known. In the present study, we analyzed MAIT-cell responses to infection with clinical isolates of S. pneumoniae serotype 19A, a serotype linked to invasive pneumococcal disease. We found that although MAIT cells were capable of responding to human dendritic and airway epithelial cells infected with S. pneumoniae, the magnitude of response to different serotype 19A isolates was determined by genetic differences in the expression of the riboflavin biosynthesis pathway. MAIT-cell release of cytokines correlated with differences in the ability of MAIT cells to respond to and control S. pneumoniae in vitro and in vivo in a mouse challenge model. Together, these results demonstrate first that there are genetic differences in riboflavin metabolism among clinical isolates of the same serotype and second that these likely determine MAIT-cell function in response to infection with S. pneumoniae. These differences are critical when considering the role that MAIT cells play in early responses to pneumococcal infection and determining whether invasive disease will develop.


Advanced practice nurses: Improving access to fertility preservation for oncology patients.
Cancer therapies such as chemotherapy, radiation therapy and surgery may place the future fertility of both children and young adults at risk. Oncofertility is a rapidly evolving area that involves increasing access to fertility preservation (FP) information and services. This manuscript aims to: a) highlight the fertility risks associated with cancer therapy and its psychosocial impact, b) describe FP options, c) discuss the unique challenges of FP in distinct cancer populations, and d) illustrate the pivotal role of APNs in oncofertility counselling and education.


Comparison of Maternal and Neonatal Antibody Levels After COVID-19 Vaccination vs SARS-CoV-2 Infection.
Pregnant persons are at an increased risk of severe COVID-19 from SARS-CoV-2 infection, and COVID-19 vaccination is currently recommended during pregnancy. To ascertain the association of vaccine type, time from vaccination, gestational age at delivery, and pregnancy complications with placental transfer of antibodies to SARS-CoV-2. This cohort study was conducted in Pennsylvania Hospital in Philadelphia, Pennsylvania, and included births at the study site between August 9, 2020, and April 25, 2021. Maternal and cord blood serum samples were available for antibody level measurements for maternal-neonatal dyads. SARS-CoV-2 infection vs COVID-19 vaccination. IgG antibodies to the receptor-binding domain of the SARS-CoV-2 spike protein were measured by quantitative enzyme-linked immunosorbent assay. Antibody concentrations and transplacental transfer ratios were measured after SARS-CoV-2 infection or receipt of COVID-19 vaccines. A total of 585 maternal-newborn dyads (median [IQR] maternal age, 31 [26-35] years; median [IQR] gestational age, 39 [38-40] weeks) with maternal IgG antibodies to SARS-CoV-2 detected at the time of delivery were included. IgG was detected in cord blood from 557 of 585 newborns (95.2%). Among 169 vaccinated persons without SARS-CoV-2 infection, the interval from first dose of vaccine to delivery ranged from 12 to 122 days. The geometric mean IgG level among 169 vaccine recipients was significantly higher than that measured in 408 persons after infection (33.88 [95% CI, 27.64-41.53] arbitrary U/mL vs 2.80 [95% CI, 2.50-3.13] arbitrary U/mL). Geometric mean IgG levels were higher after vaccination with the mRNA-1273 (Moderna) vaccine compared with the BNT162b2 (Pfizer/BioNTech) vaccine (53.74 [95% CI, 40.49-71.33] arbitrary U/mL vs 25.45 [95% CI, 19.17-33.79] arbitrary U/mL; P < .001). Placental transfer ratios were lower after vaccination compared with after infection (0.80 [95% CI, 0.68-0.93] vs 1.06 [95% CI, 0.98-1.14]; P < .001) but were similar between the mRNA vaccines (mRNA-1273: 0.70 [95% CI, 0.55-0.90]; BNT162b2: 0.85 [95% CI, 0.69-1.06]; P = .25). Time from infection or vaccination to delivery was associated with transfer ratio in models that included gestational age at delivery and maternal hypertensive disorders, diabetes, and obesity. Placental antibody transfer was detectable as early as 26 weeks' gestation. Transfer ratio that was higher than 1.0 was present for 48 of 51 (94.1%) births at 36 weeks' gestation or later by 8 weeks after vaccination. This study found that maternal and cord blood IgG antibody levels were higher after COVID-19 vaccination compared with after SARS-CoV-2 infection, with slightly lower placental transfer ratios after vaccination than after infection. The findings suggest that time from infection or vaccination to delivery was the most important factor in transfer efficiency.


The Green Box: An Electronically Versatile Perylene Diimide Macrocyclic Host for Fullerenes.
The powerful electron accepting ability of fullerenes makes them ubiquitous components in biomimetic donor-acceptor systems that model the intermolecular electron transfer processes of Nature's photosynthetic center. Exploiting perylene diimides (PDIs) as components in cyclic host systems for the noncovalent recognition of fullerenes is unprecedented, in part because archetypal PDIs are also electron deficient, making dyad assembly formation electronically unfavorable. To address this, we report the strategic design and synthesis of a novel large, macrocyclic receptor composed of two covalently strapped electron-rich bis-pyrrolidine PDI panels, nicknamed the "Green Box" due to its color. Through the principle of electronic complementarity, the Green Box exhibits strong recognition of pristine fullerenes (C60/70), with the noncovalent ground and excited state interactions that occur upon fullerene guest encapsulation characterized by a range of techniques including electronic absorption, fluorescence emission, NMR and time-resolved EPR spectroscopies, cyclic voltammetry, mass spectrometry, and DFT calculations. While relatively low polarity solvents result in partial charge transfer in the host donor-guest acceptor complex, increasing the polarity of the solvent medium facilitates rare, thermally allowed full electron transfer from the Green Box to fullerene in the ground state. The ensuing charge separated radical ion paired complex is spectroscopically characterized, with thermodynamic reversibility and kinetic stability also demonstrated. Importantly, the Green Box represents a seminal type of C60/70 host where electron-rich PDI motifs are utilized as recognition motifs for fullerenes, facilitating novel intermolecular, solvent tunable ground state electronic communication with these guests. The ability to switch between extremes of the charge transfer energy continuum is without precedent in synthetic fullerene-based dyads.


Clinical Integration in a Dental School Clinic Through an Enhanced Patient Intake Process.
Dental care in the U.S. is based on a general practice model of care delivery that can be enhanced by the integration of the dentists and allied dental professionals. There are 25 U.S. dental schools with associated dental hygiene programs, presenting distinctive opportunities for educating the dental health care team. Integrated educational clinical experiences are believed to positively influence teamwork and quality of care that parallels the authentic general practice environment. Lean management, developed by Toyota and used in a variety of types of organizations including health care, provides a distinctive blend of engineering principles and operations management to enhance business and operations processes. A fundamental principle of Lean management is the elimination of waste and preservation of only those value-added components of a process. The faculty and staff of The Ohio State University College of Dentistry, trained in Lean process improvement, applied techniques to enhance and integrate an inefficient patient intake (admissions) process. The aim of this initiative was to improve patient throughput in the patient intake process and to provide dental and dental hygiene students with enhanced educational experiences from improved clinical integration. These goals were achieved through streamlining patient flow and relocating major phases of the process. Although new patient retention and cancellation/no-show rates remained mostly unchanged, this enhancement project resulted in improved access to care, improved continuity of care, expanded scope of dental services offered, improved patient satisfaction, and enhanced dental and dental hygiene student collaboration and teamwork. These outcomes suggest that process improvement initiatives can serve as valuable opportunities for integration of the dental health care team.


Towards the optical cochlear implant: optogenetic approaches for hearing restoration.
Cochlear implants (CIs) are considered the most successful neuroprosthesis as they enable speech comprehension in the majority of half a million CI users suffering from sensorineural hearing loss. By electrically stimulating the auditory nerve, CIs constitute an interface re-connecting the brain and the auditory scene, providing the patient with information regarding the latter. However, since electric current is hard to focus in conductive environments such as the cochlea, the precision of electrical sound encoding-and thus quality of artificial hearing-is limited. Recently, optogenetic stimulation of the cochlea has been suggested as an alternative approach for hearing restoration. Cochlear optogenetics promises increased spectral selectivity of artificial sound encoding, hence improved hearing, as light can conveniently be confined in space to activate the auditory nerve within smaller tonotopic ranges. In this review, we discuss the latest experimental and technological developments of cochlear optogenetics and outline the remaining challenges on the way to clinical translation.