Crisis-Critical Intellectual Property: Findings From the COVID-19 Pandemic.
A pandemic calls for large-scale action across national and international innovation systems in order to mobilize resources for developing and manufacturing crisis-critical products efficiently and in the huge quantities needed. Nowadays, these products also include a wide range of digital innovations. Given that many responses to the pandemic are technology driven, stakeholders involved in the development and manufacturing of crisis-critical products are likely to face intellectual property (IP)-related challenges. To (governmental) decision makers, IP challenges might not appear to be of paramount urgency compared to the many undoubtedly huge operational challenges to deploy critical resources. However, if IP challenges are considered too late, they may cause delays to urgently mobilize resources effectively. Innovation stakeholders could then be reluctant to fully engage in the development and manufacturing of crisis-critical products. This article adopts an IP and innovation perspective to learn from the currently unfolding COVID-19 pandemic using secondary data, including patent data, synthesized with an IP roadmap. We focus on technical aspects related to research, development, and upscaling of capacity to manufacture crisis-critical products in the huge volumes suddenly in demand. In this article, we offer a set of contributions. We provide a structure, framework, and language for those concerned with steering clear of IP challenges to avoid delays in fighting a pandemic. We provide a reasoning why IP needs to be considered earlier rather than too late in a global health crisis. Major stakeholders we identify include 1) governments; 2) manufacturing firms owning existing crisis-critical IP (incumbents in crisis-critical sectors); 3) manufacturing firms normally not producing crisis-critical products suddenly rushing into crisis-critical sectors to support the manufacturing of crisis-critical products in the quantities that far exceed incumbents' production capacities; and 4) voluntary grassroot initiatives that form during a pandemic, often by highly skilled engineers and scientists in order to contribute to the development and dissemination of crisis-critical products. For these major stakeholders, we draw up three scenarios, from which we identify associated IP challenges they face related to the development and manufacturing of technologies and products for 1) prevention (of spread); 2) diagnosis of infected patients; and 3) the development of treatments. This article provides a terminology to help policy and other decision makers to discuss IP considerations during pandemics. We propose a framework that visualizes changing industrial organizations and IP-associated challenges during a pandemic and derive initial principles to guide innovation and IP policy making during a pandemic. Obviously, our findings result only from observations of one ongoing pandemic and thus need to be verified further and interpreted with care.


The critical Barkhausen avalanches in thin random-field ferromagnets with an open boundary.
The interplay between the critical fluctuations and the sample geometry is investigated numerically using thin random-field ferromagnets exhibiting the field-driven magnetisation reversal on the hysteresis loop. The system is studied along the theoretical critical line in the plane of random-field disorder and thickness. The thickness is varied to consider samples of various geometry between a two-dimensional plane and a complete three-dimensional lattice with an open boundary in the direction of the growing thickness. We perform a multi-fractal analysis of the Barkhausen noise signals and scaling of the critical avalanches of the domain wall motion. Our results reveal that, for sufficiently small thickness, the sample geometry profoundly affects the dynamics by modifying the spectral segments that represent small fluctuations and promoting the time-scale dependent multi-fractality. Meanwhile, the avalanche distributions display two distinct power-law regions, in contrast to those in the two-dimensional limit, and the average avalanche shapes are asymmetric. With increasing thickness, the scaling characteristics and the multi-fractal spectrum in thicker samples gradually approach the hysteresis loop criticality in three-dimensional systems. Thin ferromagnetic films are growing in importance technologically, and our results illustrate some new features of the domain wall dynamics induced by magnetisation reversal in these systems.


Brain structure evolution in a basal vertebrate clade: evidence from phylogenetic comparative analysis of cichlid fishes.
The vertebrate brain is composed of several interconnected, functionally distinct structures and much debate has surrounded the basic question of how these structures evolve. On the one hand, according to the 'mosaic evolution hypothesis', because of the elevated metabolic cost of brain tissue, selection is expected to target specific structures mediating the cognitive abilities which are being favored. On the other hand, the 'concerted evolution hypothesis' argues that developmental constraints limit such mosaic evolution and instead the size of the entire brain varies in response to selection on any of its constituent parts. To date, analyses of these hypotheses of brain evolution have been limited to mammals and birds; excluding Actinopterygii, the basal and most diverse class of vertebrates. Using a combination of recently developed phylogenetic multivariate allometry analyses and comparative methods that can identify distinct rates of evolution, even in highly correlated traits, we studied brain structure evolution in a highly variable clade of ray-finned fishes; the Tanganyikan cichlids. Total brain size explained 86% of the variance in brain structure volume in cichlids, a lower proportion than what has previously been reported for mammals. Brain structures showed variation in pair-wise allometry suggesting some degree of independence in evolutionary changes in size. This result is supported by variation among structures on the strength of their loadings on the principal size axis of the allometric analysis. The rate of evolution analyses generally supported the results of the multivariate allometry analyses, showing variation among several structures in their evolutionary patterns. The olfactory bulbs and hypothalamus were found to evolve faster than other structures while the dorsal medulla presented the slowest evolutionary rate. Our results favor a mosaic model of brain evolution, as certain structures are evolving in a modular fashion, with a small but non-negligible influence of concerted evolution in cichlid fishes. Interestingly, one of the structures presenting distinct evolutionary patterns within cichlids, the olfactory bulbs, has also been shown to evolve differently from other structures in mammals. Hence, our results for a basal vertebrate clade also point towards a conserved developmental plan for all vertebrates.


Spectrum of illness in international migrants seen at GeoSentinel clinics in 1997-2009, part 2: migrants resettled internationally and evaluated for specific health concerns.
Increasing international migration may challenge healthcare providers unfamiliar with acute and long latency infections and diseases common in this population. This study defines health conditions encountered in a large heterogenous group of migrants. Migrants seen at GeoSentinel clinics for any reason, other than those seen at clinics only providing comprehensive protocol-based health screening soon after arrival, were included. Proportionate morbidity for syndromes and diagnoses by country or region of origin were determined and compared. A total of 7629 migrants from 153 countries were seen at 41 GeoSentinel clinics in 19 countries. Most (59%) were adults aged 19-39 years; 11% were children. Most (58%) were seen >1 year after arrival; 27% were seen after >5 years. The most common diagnoses were latent tuberculosis (22%), viral hepatitis (17%), active tuberculosis (10%), human immunodeficiency virus (HIV)/AIDS (7%), malaria (7%), schistosomiasis (6%), and strongyloidiasis (5%); 5% were reported healthy. Twenty percent were hospitalized (24% for active tuberculosis and 21% for febrile illness [83% due to malaria]), and 13 died. Tuberculosis diagnoses and HIV/AIDS were reported from all regions, strongyloidiasis from most regions, and chronic hepatitis B virus (HBV) particularly in Asian immigrants. Regional diagnoses included schistosomiasis (Africa) and Chagas disease (Americas). Eliciting a migration history is important at every encounter; migrant patients may have acute illness or chronic conditions related to exposure in their country of origin. Early detection and treatment, particularly for diagnoses related to tuberculosis, HBV, Strongyloides, and schistosomiasis, may improve outcomes. Policy makers should consider expansion of refugee screening programs to include all migrants.


Do older patients' perceptions of safety highlight barriers that could make their care safer during organisational care transfers?
Healthcare is a series of complex, interwoven systems in which any discontinuities of care may affect the safety of patients, who have been reported to perceive safety differently to clinicians. This study aimed to explore patient perceptions of safety and identify how they can be used to construct additional barriers to reduce safety incidents within organisational care transfers, which are known to be high in risk. Appreciative Inquiry (AI) methodology was used to develop semi-structured interviews, using the Discover and Dream processes of AI. Fourteen patients (four men, 10 women; average age 76.2 years) were purposively recruited from NHS community care teams, social care homes and private nursing homes based on their experience of going through organisational care transfers. Thematic analysis was used to highlight key themes, which participants verified. Communication, responsiveness and avoidance of traditional safety risks were identified as being important for patients to feel safe. Communication and responsiveness were mapped onto the Swiss-Cheese model of safety, presenting two new barriers to safety incidents. Traditional risks and the role of trust are discussed in relation to patients feeling safe. Perceptions of safety such as communication and responsiveness were similar to those found in previous studies. Mapping these perceptions onto the Swiss-Cheese model of safety identifies how further defences, barriers and safeguards can be constructed to make people feel safer by reinforcing communication and responsiveness. Traditional risks are widely published, but the identification by patients reinforces the role they can play in identifying and reporting these risks.


Earthworms and humans in vitro: characterizing evolutionarily conserved stress and immune responses to silver nanoparticles.
Little is known about the potential threats of silver nanoparticles (AgNPs) to ecosystem health, with no detailed report existing on the stress and immune responses of soil invertebrates. Here we use earthworm primary cells, cross-referencing to human cell cultures with a particular emphasis on the conserved biological processes, and provide the first in vitro analysis of molecular and cellular toxicity mechanisms in the earthworm Eisenia fetida exposed to AgNPs (83 ± 22 nm). While we observed a clear difference in cytotoxicity of dissolved silver salt on earthworm coelomocytes and human cells (THP-1 cells, differentiated THP-1 cells and peripheral blood mononuclear cells), the coelomocytes and differentiated (macrophage-like) THP-1 cells showed a similar response to AgNPs. Intracellular accumulation of AgNPs in the coelomocytes, predominantly in a phagocytic population, was evident by several methods including transmission electron microscopy. Molecular signatures of oxidative stress and selected biomarker genes probed in a time-resolved manner suggest early regulation of oxidative stress genes and subsequent alteration of immune signaling processes following the onset of AgNP exposure in the coelomocytes and THP-1 cells. Our findings provide mechanistic clues on cellular innate immunity toward AgNPs that is likely to be evolutionarily conserved across the animal kingdom.


Investigation of the role of ANKH in ankylosing spondylitis.
The ank/ank mouse develops a phenotype similar to ankylosing spondylitis (AS) in humans. ANKH, the human homolog of the mutated gene in the ank/ank mouse, has been implicated in familial autosomal-dominant chondrocalcinosis and autosomal-dominant craniometaphyseal dysplasia. This study was undertaken to investigate the role of ANKH in susceptibility to and clinical manifestations of AS. Sequence variants were identified by genomic sequencing of the 12 ANKH exons and their flanking splice sites in 48 AS patients; variants were then screened in 233 patients and 478 controls. Linkage to the ANKH locus was assessed in 185 affected-sibling-pair families. Five single-nucleotide polymorphisms were identified within the coding region and flanking splice sites. No association between either susceptibility to AS or its clinical manifestations and these novel polymorphisms, or between disease susceptibility and 3 known promoter variants, was seen. No linkage between the ANKH locus and AS was observed. Multipoint exclusion mapping rejected the hypothesis of a locus of a magnitude lambda>/=1.4 (logarithm of odds score <-2) (equivalent to a genetic contribution of >10% to the AS sibling recurrence risk ratio) within this area contributing to AS. These findings indicate that ANKH is not significantly involved in susceptibility to or clinical manifestations of AS.


The farnesoid X receptor agonist obeticholic acid upregulates biliary excretion of asymmetric dimethylarginine via MATE-1 during hepatic ischemia/reperfusion injury.
We previously showed that increased asymmetric dimethylarginine (ADMA) biliary excretion occurs during hepatic ischemia/reperfusion (I/R), prompting us to study the effects of the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) on bile, serum and tissue levels of ADMA after I/R. Male Wistar rats were orally administered 10mg/kg/day of OCA or vehicle for 5 days and were subjected to 60 min partial hepatic ischemia or sham-operated. After a 60 min reperfusion, serum, tissue and bile ADMA levels, liver mRNA and protein expression of ADMA transporters (CAT-1, CAT-2A, CAT-2B, OCT-1, MATE-1), and enzymes involved in ADMA synthesis (protein-arginine-N-methyltransferase-1, PRMT-1) and metabolism (dimethylarginine-dimethylaminohydrolase-1, DDAH-1) were measured. OCA administration induced a further increase in biliary ADMA levels both in sham and I/R groups, with no significant changes in hepatic ADMA content. A reduction in CAT-1, CAT-2A or CAT-2B transcripts was found in OCA-treated sham-operated rats compared with vehicle. Conversely, OCA administration did not change CAT-1, CAT-2A or CAT-2B expression, already reduced by I/R. However, a marked decrease in OCT-1 and increase in MATE-1 expression was observed. A similar trend occurred with protein expression. The reduced mRNA expression of hepatic CAT transporters suggests that the increase in serum ADMA levels is probably due to decreased liver uptake of ADMA from the systemic circulation. Conversely, the mechanism involved in further increasing biliary ADMA levels in sham and I/R groups treated with OCA appears to be MATE-1-dependent.


Dietary glutathione intake and the risk of oral and pharyngeal cancer.
Glutathione, a tripeptide found in a variety of foods, may function as an anticarcinogen by acting as an antioxidant and by binding with cellular mutagens. The association between dietary glutathione intake and risk of oral and pharyngeal cancer was investigated using data from 1,830 white participants (855 cases and 975 controls) in a population-based case-control study conducted in New Jersey; metropolitan Atlanta, Georgia; Los Angeles County, California; and Santa Clara and San Mateo counties, south of San Francisco-Oakland, California, during 1984-1985. The estimated relative risk of cancer among people with the highest quartile of glutathione intake from all sources was 0.5 (95% confidence interval 0.3-0.7). When analyzed by dietary source, however, glutathione intakes derived from all vegetables and from meat were not related to risk of cancer. Only glutathione derived from fruit and from vegetables commonly consumed raw was associated with reduced oral cancer risk. Relative to the lowest level of combined intake of fruit and of fruit-derived glutathione, risk of cancer decreased slightly with increasing intake of fruit glutathione. This analysis was limited, however, by the small numbers of subjects with extreme combinations of intakes. Further studies are needed to distinguish the potential effect of glutathione from that of fruit and raw vegetables per se or from the influence of other constituents in these foods.


Present and future schistosomiasis control activities with support from the Schistosomiasis Control Initiative in West Africa.
Since 2004 the West African countries of Burkina Faso, Mali and Niger have implemented national schistosomiasis and soil-transmitted helminthiasis control programmes with financial and technical support from the Schistosomiasis Control Initiative (SCI). In the first three years of the control programmes, nearly 13.5 million doses of praziquantel and albendazole have been administered against schistosomiasis and soil-transmitted helminthiasis with coverage rates varying between 67.0% and 93.9%. These treatments have resulted in a reduction of the prevalence and intensity of Schistosoma infection in the sentinel cohorts that were set up to monitor and evaluate the national control programmes. The challenges currently faced by these national control programmes are the ability to maintain the reduction in morbidity achieved thus far due to the mass treatment campaigns and ensuring sustainability. For reinforcement of surveillance, the establishment of a geographical information system is suggested in order to contribute towards enhanced sustainability of these programmes. Our new working hypothesis is that targeted control accompanied by periodic mass treatment campaigns (every two to three years) can contribute to maintaining the low levels of morbidity achieved thus far. The implementation of integrated neglected tropical disease control programmes in these countries will provide means to ensure the financial sustainability of control activities for the years to come.


Renal infection by a new coccidian genus in big brown bats (Eptesicus fuscus).
A novel coccidian parasite from the kidney of big brown bats (Eptesicus fuscus) is described. This coccidian (Nephroisospora eptesici nov. gen., n. sp.) was associated with a generally mild, focal or multifocal, well-demarcated cortical renal lesion less than 1 mm in diameter. The lesion represented cystic, dilated tubules with hypertrophied tubular epithelial cells and was present in the kidneys of 29 of 590 bats. Numerous coccidian parasites in various stages of development were present within the tubular epithelial cells and within the cyst lumina. Oocysts were collected from cystic dilated tubules. Thin-walled, sporulated ellipsoidal oocysts measuring an average of 18.9 x 20.8 microm were present in kidney tissue. The oocysts contained 2 sporocysts with 4 sporozoites. A polar body and a prominent oocyst residuum were present in the oocysts, but no micropyle, sporocyst residuum, or Stieda bodies were detected. Analysis of the 18S rRNA gene sequence put the parasite in the Sarcocystidae. The parasite is closely related to Besnoitia, Hammondia, Neospora, and Toxoplasma. Ultrastructural features, such as the presence of an apical complex in merozoites, support the identification of a coccidian. A new genus and species, Nephroisospora eptesicii, is proposed for this unusual coccidian in which the entire cycle is completed in the kidney of a single host; it has a membrane-like oocyst wall, sporogony occurs in the host rather than in the abiotic environment, and the positioning of the parasite by nucleic acid sequence indicates it to be closely allied to Sarcocystis and Besnoitia.


Acupuncture for the relief of cancer-related pain--a systematic review.
This systematic review summarises the existing evidence on acupuncture for cancer-related pain. Literature searches were conducted in seven databases. All clinical studies of acupuncture, electroacupuncture and ear acupuncture in cancer patients with the main outcome measure of pain were included. Data were extracted according to pre-defined criteria by two independent reviewers and methodological quality was assessed using the Jadad scale. Of the seven studies included, one high quality randomised clinical trial of ear acupuncture showed statistically significant pain relief in comparison with placebo ear acupuncture. All the other studies were either non-blinded (n=2) or uncontrolled clinical trials (n=4). Most investigations suffered from methodological flaws such as inadequate study design, poor reporting of results, small sample size and overestimation of the results. The notion that acupuncture may be an effective analgesic adjunctive method for cancer patients is not supported by the data currently available from the majority of rigorous clinical trials. Because of its widespread acceptance, appropriately powered RCTs are needed.


One-pot phase transfer and surface modification of CdSe-ZnS quantum dots using a synthetic functional copolymer.
We present a facile, one-pot procedure for the organic-to-water phase transfer and biofunctionalization of semiconductor nanocrystals (quantum dots, or QDs) which employs a synthetic functional copolymer, namely poly(DMA-NAS-MAPS), consisting of three components: a surface interacting monomer, N,N-dimethylacrylamide (DMA), a chemically reactive monomer, N-acryloyloxysuccinimide (NAS), and a silane monomer, [3-(methacryloyloxy)-propyl]-trimethoxysilane (MAPS). The nanocrystals were transferred to water by exploiting the amphiphilic character of the copolymer backbone. Hydrolyzed MAPS units contributed to improve the solubility of QDs in water, whereas NAS exhibited reactivity toward biomolecules. A solution of streptavidin in phosphate buffer exhibited good dispersion ability leading to a clear and transparent colloidal suspension, indicative of good QD dispersion during phase transfer and purification. Unlike most of the published methods, the proposed functionalization approach does not require coupling agents and multistep reactions.


Effect of intravenous nitrates on mortality in acute myocardial infarction: an overview of the randomised trials.
About 2000 patients have been randomised in ten trials of intravenous nitroglycerin or nitroprusside in acute myocardial infarction. Taken separately, the individual trials have all been too small to provide a reliable estimate of the effects of treatment on mortality, but collectively they provide strong evidence of benefit. In total there have been 136 nitrate and 193 control deaths, and an appropriate overview of the separate trial results indicated a "typical" reduction of 35% (SD 10) in the odds of death (2p less than 0.001, with 95% confidence limits of about one-sixth to one-half). Both nitroglycerin and nitroprusside reduced mortality, the reduction being non-significantly greater with nitroglycerin than with nitroprusside. The greatest reduction in mortality occurred during the first week or so of follow-up, with a non-significant further reduction after this early period. This suggests that the early benefit is not rapidly lost.


Comparison of Frequency- and Time-Domain Autoregulation and Vasoreactivity Indices in a Piglet Model of Hypoxia-Ischemia and Hypothermia.
The optimal method to detect impairments in cerebrovascular pressure autoregulation in neonates with hypoxic-ischemic encephalopathy (HIE) is unclear. Improving autoregulation monitoring methods would significantly advance neonatal neurocritical care. We tested several mathematical algorithms from the frequency and time domains in a piglet model of HIE, hypothermia, and hypotension. We used laser Doppler flowmetry and induced hypotension to delineate the gold standard lower limit of autoregulation (LLA). Receiver operating characteristics curve analyses were used to determine which indices could distinguish blood pressure above the LLA from that below the LLA in each piglet. Phase calculation in the frequency band with maximum coherence, as well as the correlation between mean arterial pressure (MAP) and near-infrared spectroscopy relative total tissue hemoglobin (HbT) or regional oxygen saturation (rSO2), accurately discriminated functional from dysfunctional autoregulation. Neither hypoxia-ischemia nor hypothermia affected the accuracy of these indices. Coherence alone and gain had low diagnostic value relative to phase and correlation. Our findings indicate that phase shift is the most accurate component of autoregulation monitoring in the developing brain, and it can be measured using correlation or by calculating phase when coherence is maximal. Phase and correlation autoregulation indices from MAP and rSO2 and vasoreactivity indices from MAP and HbT are accurate metrics that are suitable for clinical HIE studies.


BOLD response to spatial phase congruency in human brain.
Human psychophysical observations, computational models, and the selectivity of neurons in primary visual cortex all suggest that an early step in visual processing is the detection of features such as lines and edges. However, previous fMRI experiments investigating the responses of early visual areas to phase coherence have led to apparently discordant results. We studied the human brain BOLD responses to structured periodic band-pass images of matched amplitude spectrum but of different phase spectra, arranged to create three distinct types of stimuli: pure edges; pure lines (matched global and local energy to the edges, but different phase); and random noise (random phase spectrum, hence no salient features, and a different spatial distribution of local energy from the lines and edges stimuli). Alternation of lines against edges did not activate primary visual cortex, but did activate two higher order visual areas. Alternation of these lines or edges against the random stimulus produced a strong activity in many visual areas, including primary visual cortex. Interestingly, the BOLD activity was higher for the edges and lines than for the random stimuli for a wide range of stimulus contrasts, indicating the presence of non-linear gain modulation in the cell response. These results show that phase congruency is coded at the level of primary visual cortex. We show that a stage of response gain modulation can explain our present and previous fMRI discordant results.


Cicatricial (scarring) alopecias: an overview of pathogenesis, classification, diagnosis, and treatment.
Cicatricial (scarring) alopecia forms a group of disorders in which the common final pathway is the destruction of the hair follicle unit that is replaced by fibrous tissue. Hair loss may occur as a primary event when the follicle is the main target of the disease process (primary cicatricial alopecias) or as a secondary event when the follicle act as an 'innocent bystander' in the course of a disease occurring outside of the follicular unit (secondary cicatricial alopecias). Permanent hair loss may also occur in the late phases of some nonscarring alopecias that are called 'biphasic alopecias.' Primary cicatricial alopecia accounts for 5% of all trichologic consultations at the Section of Dermatology, University of Genoa, Genoa, Italy. Considering that hair loss has a strong impact on patients' psychology and quality of life, and that cicatricial alopecias can be associated with underlying systemic implications, it is extremely important that every clinician is familiar with the diagnosis and treatment of the different types of cicatricial alopecia. An accurate clinical assessment integrated with (video) dermatoscopy and histopathologic studies permits a high standard performance of correct diagnoses. A brief review of our current knowledge of disease pathogenesis and the hypothetical disease mechanisms is presented. Some practical considerations for improving the 2001 North American Hair Research Society working classification of the primary cicatricial alopecias are suggested. The aim of treatment is to slow or stop the progression of the inflammatory waves and the scarring process at the earliest phase of involvement. Recommendations for therapy are based upon a literature review, personal experience, expected adverse effects, and some pragmatic considerations such as the cost and patient compliance.


Structure-activity relationships of diverse xanthones against multidrug resistant human tumor cells.
Thirteen xanthones were isolated naturally from the stem of Securidaca inappendiculata Hassk, and structure-activity relationships (SARs) of these compounds were comparatively predicted for their cytotoxic activity against three human multidrug resistant (MDR) cell lines MCF-7/ADR, SMMC-7721/Taxol, and A549/Taxol cells. The results showed that the selected xanthones exhibited different potent cytotoxic activity against the growth of different human tumor cell lines, and most of the xanthones exhibited selective cytotoxicity against SMMC-7721/Taxol cells. Furthermore, some tested xanthones showed stronger cytotoxicity than Cisplatin, which has been used in clinical application extensively. The SARs analysis revealed that the cytotoxic activities of diverse xanthones were affected mostly by the number and position of methoxyl and hydroxyl groups. Xanthones with more free hydroxyl and methoxyl groups increased the cytotoxic activity significantly, especially for those with the presence of C-3 hydroxyl and C-4 methoxyl groups.


Regulation of cytoplasmic dynein ATPase by Lis1.
Mutations in Lis1 cause classical lissencephaly, a developmental brain abnormality characterized by defects in neuronal positioning. Over the last decade, a clear link has been forged between Lis1 and the microtubule motor cytoplasmic dynein. Substantial evidence indicates that Lis1 functions in a highly conserved pathway with dynein to regulate neuronal migration and other motile events. Yeast two-hybrid studies predict that Lis1 binds directly to dynein heavy chains (Sasaki et al., 2000; Tai et al., 2002), but the mechanistic significance of this interaction is not well understood. We now report that recombinant Lis1 binds to native brain dynein and significantly increases the microtubule-stimulated enzymatic activity of dynein in vitro. Lis1 does this without increasing the proportion of dynein that binds to microtubules, indicating that Lis1 influences enzymatic activity rather than microtubule association. Dynein stimulation in vitro is not a generic feature of microtubule-associated proteins, because tau did not stimulate dynein. To our knowledge, this is the first indication that Lis1 or any other factor directly modulates the enzymatic activity of cytoplasmic dynein. Lis1 must be able to homodimerize to stimulate dynein, because a C-terminal fragment (containing the dynein interaction site but missing the self-association domain) was unable to stimulate dynein. Binding and colocalization studies indicate that Lis1 does not interact with all dynein complexes found in the brain. We propose a model in which Lis1 stimulates the activity of a subset of motors, which could be particularly important during neuronal migration and long-distance axonal transport.


[Assessment of guideline adherence and quality of care with routine outcome monitoring data].
Treatment guidelines are widely used nowadays but it is not really clear whether or to what extent patients in routine care benefit from these guidelines.
 AIM: To achieve a twofold objective: to measure in a routine clinical setting, the overall level of adherence to clinical guidelines by using a set of process indicators that are independent of the disorder under study, and to measure the clinical and psychosocial correlates of adherence among outpatients suffering from mood, anxiety and somatoform disorders.
 METHOD: We developed a set of quality indicators and tested the set over a period of three years in a randomly selected sample of 300 outpatients who were about to receive treatment for a mood, anxiety and somatoform disorder. We used routine outcome monitoring (ROM) data to determine risk factors for non-adherence and to identify patients whose treatment outcomes were likely poor.
 RESULTS: A high percentage of indicators were positive, indicating that many elements of treatment in this routine clinical practice had been carried out according to the guidelines. We observed that the combined treatment group showed significantly lower adherence than the two other treatment groups. Low-adherence was predicted independently by a low score on the vitality subscale of the SF-36. No significant differences relating to the degree of adherence were found in socio-demographic variables, comorbidity and the scores on the BSI subscales. Predictor indicators for poor treatment outcome included higher age, a comorbid axis I diagnosis, a number of dysfunctional personality traits and a (reported) poor general health status.
 CONCLUSION: It is possible to assess guideline adherence by means of our set of process indicators that were independent of all type of disorder involved. Most factors hampering adherence could be identified. An understanding of the factors that affect treatment adherence to treatment guidelines may help to prevent non-adherence and can contribute to both the quality and the cost-effectiveness of care.


Carprofen-induced depletion of proton motive force reverses TetK-mediated doxycycline resistance in methicillin-resistant Staphylococcus pseudintermedius.
We previously showed that doxycycline (DOX) and carprofen (CPF), a veterinary non-steroidal anti-inflammatory drug, have synergistic antimicrobial activity against methicillin-resistant Staphylococcus pseudintermedius (MRSP) carrying the tetracycline resistance determinant TetK. To elucidate the molecular mechanism of this synergy, we investigated the effects of the two drugs, individually and in combination, using a comprehensive approach including RNA sequencing, two-dimensional differential in-gel electrophoresis, macromolecule biosynthesis assays and fluorescence spectroscopy. Exposure of TetK-positive MRSP to CPF alone resulted in upregulation of pathways that generate ATP and NADH, and promote the proton gradient. We showed that CPF is a proton carrier that dissipates the electrochemical potential of the membrane. In the presence of both CPF and DOX, the energy compensation strategy was attenuated by downregulation of all the processes involved, such as citric acid cycle, oxidative phosphorylation and ATP-providing arginine deiminase pathway. Furthermore, protein biosynthesis inhibition increased from 20% under DOX exposure alone to 75% upon simultaneous exposure to CPF. We conclude that synergistic interaction of the drugs restores DOX susceptibility in MRSP by compromising proton-motive-force-dependent TetK-mediated efflux of the antibiotic. MRSP is unable to counterbalance CPF-mediated PMF depletion by cellular metabolic adaptations, resulting in intracellular accumulation of DOX and inhibition of protein biosynthesis.


Regulatory Effect of SlyA on rcsB Expression in Salmonella enterica Serovar Typhimurium.
The Salmonella enterica serovar Typhimurium RcsCDB system regulates the synthesis of colanic acid and the flagellum as well as the expression of virulence genes. We previously demonstrated that the rcsC11 mutant, which constitutively activates the RcsB regulator, attenuates Salmonella virulence in an animal model. This attenuated phenotype was also produced by deletion of the slyA gene. In this work, we investigated if this antagonistic behavior is produced by modulating the expression of both regulator-encoding genes. We demonstrated that SlyA overproduction negatively regulates rcsB transcription. A bioinformatics analysis enabled us to identify putative SlyA binding sites on both promoters, P rcsDB and P rcsB , which control rcsB transcriptional levels. We also determined that SlyA is able to recognize and bind to these predicted sites to modulate the activity of both rcsB promoters. According to these results, SlyA represses rcsB transcription by direct binding to specific sites located on the rcsB promoters, thus accounting for the attenuated/virulence antagonistic behaviors. Moreover, we showed that the opposite effect between both regulators also physiologically affects the Salmonella motility phenotype. In this sense, we observed that under SlyA overproduction, P rcsB is repressed, and consequently, bacterial motility is increased. On the basis of these results, we suggest that during infection, the different RcsB levels produced act as a switch between the virulent and attenuated forms of Salmonella Thereby, we propose that higher concentrations of RcsB tilt the balance toward the attenuated form, while absence or low concentrations resulting from SlyA overproduction tilt the balance toward the virulent form.IMPORTANCE The antagonistic behavior of RcsB and SlyA on virulence gene expression led us to hypothesize that there is interplay between both regulators in a regulatory network and these could be considered coordinators of this process. Here, we report that the SlyA virulence factor influences motility behavior by controlling rcsB transcription from the P rcsB promoter. We also demonstrate that SlyA negatively affects the expression of the rcsB gene by direct binding to P rcsDB and P rcsB promoters. We suggest that different levels of RcsB act as a switch between the virulent and attenuated forms of Salmonella, where high concentrations of the regulator tend to tilt the balance toward the attenuated form and low concentrations or its absence tilt it toward the virulent form.


Experimental Robot Model Adjustments Based on Force-Torque Sensor Information.
The computational complexity of humanoid robot balance control is reduced through the application of simplified kinematics and dynamics models. However, these simplifications lead to the introduction of errors that add to other inherent electro-mechanic inaccuracies and affect the robotic system. Linear control systems deal with these inaccuracies if they operate around a specific working point but are less precise if they do not. This work presents a model improvement based on the Linear Inverted Pendulum Model (LIPM) to be applied in a non-linear control system. The aim is to minimize the control error and reduce robot oscillations for multiple working points. The new model, named the Dynamic LIPM (DLIPM), is used to plan the robot behavior with respect to changes in the balance status denoted by the zero moment point (ZMP). Thanks to the use of information from force-torque sensors, an experimental procedure has been applied to characterize the inaccuracies and introduce them into the new model. The experiments consist of balance perturbations similar to those of push-recovery trials, in which step-shaped ZMP variations are produced. The results show that the responses of the robot with respect to balance perturbations are more precise and the mechanical oscillations are reduced without comprising robot dynamics.


Mechanistic analysis of resistance to REIC/Dkk-3-induced apoptosis in human bladder cancer cells.
We have recently shown that a new therapeutic modality using the REIC/Dkk-3 gene (Ad-REIC) is effective against various human cancers, including those of prostate, testis and breast origins. The aim of the present study was to examine the sensitivity of bladder cancers to Ad-REIC and to clarify the molecular mechanisms that determine sensitivity/resistance. We found that 2 human bladder cancer cell lines, T24 and J82, are resistant to Ad-REIC. In T24 and J82 cells, the ER stress response and activation of JNK were observed in a manner similar to that in the sensitive PC3 cells. Translocation of Bax to mitochondria occurred in PC3 cells but not in T24 and J82 cells. Bcl-2 was remarkably overexpressed in T24 and J82 compared with the expression levels in sensitive cell lines. Treatment of T24 and J82 cells with a Bcl-2 inhibitor sensitized the cells to Ad-REIC-induced apoptosis. The results indicate that some human bladder cancers are resistant to apoptosis induced by overexpression of REIC/Dkk-3, which is at least in part due to up-regulation of Bcl-2. These results provide a basis for possible use of Bcl-2 as a marker of sensitive cancers and to try to sensitize resistant cancers to Ad-REIC by down-regulation of Bcl-2.


How women are treated during facility-based childbirth in four countries: a cross-sectional study with labour observations and community-based surveys.
Women across the world are mistreated during childbirth. We aimed to develop and implement evidence-informed, validated tools to measure mistreatment during childbirth, and report results from a cross-sectional study in four low-income and middle-income countries. We prospectively recruited women aged at least 15 years in twelve health facilities (three per country) in Ghana, Guinea, Myanmar, and Nigeria between Sept 19, 2016, and Jan 18, 2018. Continuous observations of labour and childbirth were done from admission up to 2 h post partum. Surveys were administered by interviewers in the community to women up to 8 weeks post partum. Labour observations were not done in Myanmar. Data were collected on sociodemographics, obstetric history, and experiences of mistreatment. 2016 labour observations and 2672 surveys were done. 838 (41·6%) of 2016 observed women and 945 (35·4%) of 2672 surveyed women experienced physical or verbal abuse, or stigma or discrimination. Physical and verbal abuse peaked 30 min before birth until 15 min after birth (observation). Many women did not consent for episiotomy (observation: 190 [75·1%] of 253; survey: 295 [56·1%] of 526) or caesarean section (observation: 35 [13·4%] of 261; survey: 52 [10·8%] of 483), despite receiving these procedures. 133 (5·0%) of 2672 women or their babies were detained in the facility because they were unable to pay the bill (survey). Younger age (15-19 years) and lack of education were the primary determinants of mistreatment (survey). For example, younger women with no education (odds ratio [OR] 3·6, 95% CI 1·6-8·0) and younger women with some education (OR 1·6, 1·1-2·3) were more likely to experience verbal abuse, compared with older women (≥30 years), adjusting for marital status and parity. More than a third of women experienced mistreatment and were particularly vulnerable around the time of birth. Women who were younger and less educated were most at risk, suggesting inequalities in how women are treated during childbirth. Understanding drivers and structural dimensions of mistreatment, including gender and social inequalities, is essential to ensure that interventions adequately account for the broader context. United States Agency for International Development and the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, Department of Reproductive Health and Research, WHO.


Implicit meaning in 18-month-old toddlers.
A substantial body of evidence demonstrates that infants understand the meaning of spoken words from as early as 6 months. Yet little is known about their ability to do so in the absence of any visual referent, which would offer diagnostic evidence for an adult-like, symbolic interpretation of words and their use in language mediated thought. We used the head-turn preference procedure to examine whether infants can generate implicit meanings from word forms alone as early as 18 months of age, and whether they are sensitive to meaningful relationships between words. In one condition, toddlers were presented with lists of words taken from the same taxonomic category (e.g. animals or body parts). In a second condition, words taken from two other categories (e.g. clothes and food items) were interleaved within the same list. Listening times were found to be longer in the related-category condition than in the mixed-category condition, suggesting that infants extract the meaning of spoken words and are sensitive to the semantic relatedness between these words. Our results show that infants have begun to construct the rudiments of a semantic system based on taxonomic relations even before they enter a period of accelerated vocabulary growth.


The Link between Microdevelopment and Long-Term Learning Trajectories in Science Learning.
Long-term learning trajectories evolve through microdevelopmental sequences (i.e., short-term processes of change during learning tasks) and depend on variability during and across learning tasks. The aim of this study is to examine the coupling between short-term teacher-student dynamics and students' long-term learning trajectories, thereby providing empirical support for the link between the short- and long-term time scale in cognitive development. For 31 students (ages 3-5 years) from regular and special education, five teacher-student interactions during science tasks were filmed and coded in real time with regard to the student's level of understanding and the teacher's support throughout the task. A hierarchical cluster analysis resulted in four different learning trajectories over the course of 1.5 years, labeled as a high-scoring, mid-scoring, fluctuating, and low-scoring group of students. When connecting these trajectories to microdevelopmental data, the interactions of the high-scoring students were characterized by more moment-to-moment variations in the teacher's support and student's level of understanding, while the low-scoring group had the least variability compared to the other groups. Students with emotional and behavioral disabilities were represented across all learning trajectories, despite frequent accounts in the literature on their significant academic delays.


Evaluation of Antiplasmodial activity of extracts and constituents from Ampelozizyphus amazonicus.
Ampelozizyphus amazonicus Ducke, a plant that is widely used by the population of the Amazonian region to prevent and treat malaria, was investigated in this work, which describes, for the first time, the antiplasmodial activity of its extracts and associates this activity with its isolated constituents. Different extracts with solvents of increasing polarity (hexane, chloroform, ethanol, and water) were obtained of the root bark. This procedure resulted in extracts that were characterized for their constituents. The cytotoxicity and activity of the extracts against Plasmodium berghei (schizontocidal activity, liver stage) and Plasmodium falciparum (3D7 and Dd2 strains, erythrocyte stage) were assessed in vitro. Of the four extracts assayed against P. berghei, the chloroform extract showed the greatest activity, with an inhibitory concentration 50% (IC50) value of 30.1 µg/mL, followed by the aqueous extract (IC50 = 39.9 µg/mL). The chloroform extract exhibited the highest antiplasmodial activity in the erythrocyte stage of P. falciparum, with an IC50 value lower than 15 µg/mL. Fractionation of this more active extract led to the isolation and elucidation of pentacyclic triterpenes, lupeol, betulin and betulinic acid, which showed antiplasmodial activities with IC50 values ranging from 5.6 to 80.30 µM. The most active of these, betulinic acid, was further quantified in the extracts by high-performance liquid chromatography-photodiode array detector analyzes. The higher amount was found in the chloroform extract, which was the most active one against P. falciparum. The results obtained in this work may partly explain the popular intake of A. amazonicusas an antimalarial remedy in the Amazon region.


The giant titin: how to evaluate its role in cardiomyopathies.
Titin, the largest protein known, has attracted a lot of interest in the cardiovascular field in recent years, since the discovery that truncating variants in titin are commonly found in patients with dilated cardiomyopathy. This review will discuss the contribution of variants in titin to inherited cardiac conditions (cardiomyopathies) and how model systems, such as animals and cellular systems, can help to provide insights into underlying disease mechanisms. It will also give an outlook onto exciting technological developments, such as in the field of CRISPR, which may facilitate future research on titin variants and their contributions to cardiomyopathies.


Quantitative chemical imaging with background-free multiplex coherent anti-Stokes Raman scattering by dual-soliton Stokes pulses.
Coherent anti-Stokes Raman microscopy (CARS) is a quantitative, chemically specific, and label-free optical imaging technique for studying inhomogeneous systems. However, the complicating influence of the nonresonant response on the CARS signal severely limits its sensitivity and specificity and especially limits the extent to which CARS microscopy has been used as a fully quantitative imaging technique. On the basis of spectral focusing mechanism, we establish a dual-soliton Stokes based CARS microspectroscopy and microscopy scheme capable of quantifying the spatial information of densities and chemical composition within inhomogeneous samples, using a single fiber laser. Dual-soliton Stokes scheme not only removes the nonresonant background but also allows robust acquisition of multiple characteristic vibrational frequencies. This all-fiber based laser source can cover the entire fingerprint (800-2200 cm-1) region with a spectral resolution of 15 cm-1. We demonstrate that quantitative degree determination of lipid-chain unsaturation in the fatty acids mixture can be achieved by the characterization of C = C stretching and CH2 deformation vibrations. For microscopy purposes, we show that the spatially inhomogeneous distribution of lipid droplets can be further quantitatively visualized using this quantified degree of lipid unsaturation in the acyl chain for contrast in the hyperspectral CARS images. The combination of compact excitation source and background-free capability to facilitate extraction of quantitative composition information with multiplex spectral peaks will enable wider applications of quantitative chemical imaging in studying biological and material systems.


Factors associated with self-reported STDs: data from a national survey.
STD prevention programs need to identify population subgroups and risk behaviors that are associated with higher rates of disease. To see what levels of STD experience were reported by respondents to a national survey and what factors were associated with self-reported STDs. The survey data are from Cycle IV (1988) of the National Survey of Family Growth (NSFG), a nationally representative household-based sample of 8450 women ages 15 to 44 years. We examined characteristics of survey respondents who reported STD experience, characteristics of STD cases reported to the national STD surveillance system, and factors related to self-reported STDs using multiple logistic regression. The self-reported survey data indicate that the majority of respondents who ever had gonorrhea (55%) were white, but white women account for only 19% of the annual cases in the surveillance system. Logistic regression analysis of survey data indicates factors associated with reported gonorrhea experience, sexual behavior, race/ethnicity, socioeconomic background, perceived risk of AIDS, receiving birth control education, and region of residence. Reporting of chlamydia appears to be strongly related to knowledge of this infection. Because of basic differences in the statistics being compared, we cannot rule out other explanations. Our results suggest that the surveillance data may reflect underreporting of higher socioeconomic groups making use of private health care. Survey data, on the other hand, are probably affected by underreporting of STD experience. Questions to measure STD experience, treatment, and source of care on surveys of this type would greatly increase the understanding of STDs in the national population.


Visualizing the Neurobiology of Trauma: Design and evaluation of an eLearning module for continuing professional development of family physicians in the Online Psychiatric Education Network.
Traumatic experiences can change brain structures and compromise emotional, cognitive, and bodily functions, thereby debilitating patients. Yet, trauma is not well understood by physicians and few educational resources are available, despite its prevalence. The goal of this design research project is to develop and evaluate 2D animations in a case-based eLearning module. Complexities of post-traumatic stress disorder, including physical, emotional, and sexual abuse, are difficult to teach, talk about, and visually portray. Results of this study elucidate effective design dimensions of graphic narratives, keywords, and animations.


Comparison of orthogonal NLP methods for clinical phenotyping and assessment of bone scan utilization among prostate cancer patients.
Clinical care guidelines recommend that newly diagnosed prostate cancer patients at high risk for metastatic spread receive a bone scan prior to treatment and that low risk patients not receive it. The objective was to develop an automated pipeline to interrogate heterogeneous data to evaluate the use of bone scans using a two different Natural Language Processing (NLP) approaches. Our cohort was divided into risk groups based on Electronic Health Records (EHR). Information on bone scan utilization was identified in both structured data and free text from clinical notes. Our pipeline annotated sentences with a combination of a rule-based method using the ConText algorithm (a generalization of NegEx) and a Convolutional Neural Network (CNN) method using word2vec to produce word embeddings. A total of 5500 patients and 369,764 notes were included in the study. A total of 39% of patients were high-risk and 73% of these received a bone scan; of the 18% low risk patients, 10% received one. The accuracy of CNN model outperformed the rule-based model one (F-measure = 0.918 and 0.897 respectively). We demonstrate a combination of both models could maximize precision or recall, based on the study question. Using structured data, we accurately classified patients' cancer risk group, identified bone scan documentation with two NLP methods, and evaluated guideline adherence. Our pipeline can be used to provide concrete feedback to clinicians and guide treatment decisions.


Melanoma stem cells in experimental melanoma are killed by radioimmunotherapy.
In spite of recently approved B-RAF inhibitors and immunomodulating antibodies, metastatic melanoma has poor prognosis and novel treatments are needed. Melanoma stem cells (MSC) have been implicated in the resistance of this tumor to chemotherapy. Recently we demonstrated in a Phase I clinical trial in patients with metastatic melanoma that radioimmunotherapy (RIT) with 188-Rhenium((188)Re)-6D2 antibody to melanin was a safe and effective modality. Here we investigated the interaction of MSC with RIT as a possible mechanism for RIT efficacy. Mice bearing A2058 melanoma xenografts were treated with either 1.5 mCi (188)Re-6D2 antibody, saline, unlabeled 6D2 antibody or (188)Re-labeled non-specific IgM. On Day 28 post-treatment the tumor size in the RIT group was 4-times less than in controls (P<0.001). The tumors were analyzed by immunohistochemistry and FACS for two MSC markers--chemoresistance mediator ABCB5 and H3K4 demethylase JARID1B. There were no significant differences between RIT and control groups in percentage of ABCB5 or JARID1B-positive cells in the tumor population. Our results demonstrate that unlike chemotherapy, which kills tumor cells but leaves behind MSC leading to recurrence, RIT kills MSC at the same rate as the rest of tumor cells. These results have two main implications for melanoma treatment and possibly other cancers. First, the susceptibility of ABCB5+ and JARID1B+cells to RIT in melanoma might be indicative of their susceptibility to antibody-targeted radiation in other cancers where they are present as well. Second, specifically targeting cancer stem cells with radiolabeled antibodies to ABCB5 or JARID1B might help to completely eradicate cancer stem cells in various cancers.


A recommended scale for cognitive screening in clinical trials of Parkinson's disease.
Cognitive impairment is common in Parkinson's disease (PD). There is a critical need for a brief, standard cognitive screening measure for use in PD trials whose primary focus is not on cognition. The Parkinson Study Group (PSG) Cognitive/Psychiatric Working Group formed a Task Force to make recommendations for a cognitive scale that could screen for dementia and mild cognitive impairment in clinical trials of PD where cognition is not the primary outcome. This Task Force conducted a systematic literature search for cognitive assessments previously used in a PD population. Scales were then evaluated for their appropriateness to screen for cognitive deficits in clinical trials, including brief administration time (<15 minutes), assessment of the major cognitive domains, and potential to detect subtle cognitive impairment in PD. Five scales of global cognition met the predetermined screening criteria and were considered for review. Based on the Task Force's evaluation criteria the Montreal Cognitive Assessment (MoCA), appeared to be the most suitable measure. This Task Force recommends consideration of the MoCA as a minimum cognitive screening measure in clinical trials of PD where cognitive performance is not the primary outcome measure. The MoCA still requires further study of its diagnostic utility in PD populations but appears to be the most appropriate measure among the currently available brief cognitive assessments. Widespread adoption of a single instrument such as the MoCA in clinical trials can improve comparability between research studies on PD.


Immunization Against Oxidized Elastin Exacerbates Structural and Functional Damage in Mouse Model of Smoke-Induced Ocular Injury.
Age-related macular degeneration (AMD) is the leading cause of blindness in Western populations. While an overactive complement system has been linked to pathogenesis, mechanisms contributing to its activation are largely unknown. In aged and AMD eyes, loss of the elastin layer (EL) of Bruch's membrane (BrM) has been reported. Elastin antibodies are elevated in patients with AMD, the pathogenic significance of which is unclear. Here we assess the role of elastin antibodies using a mouse model of smoke-induced ocular pathology (SIOP), which similarly demonstrates EL loss. C57BL/6J mice were immunized with elastin or elastin peptide oxidatively modified by cigarette smoke (ox-elastin). Mice were then exposed to cigarette smoke or air for 6 months. Visual function was assessed by optokinetic response, retinal morphology by spectral-domain optical coherence tomography and electron microscopy, and complement activation and antibody deposition by Western blot. Ox-elastin IgG and IgM antibodies were elevated in ox-elastin immunized mice following 6 months of smoke, whereas elastin immunization had a smaller effect. Ox-elastin immunization exacerbated smoke-induced vision loss, with thicker BrM and more damaged retinal pigment epithelium (RPE) mitochondria compared with mice immunized with elastin or nonimmunized controls. These changes were correlated with increased levels of IgM, IgG2, IgG3, and complement activation products in RPE/choroid. These data demonstrate that SIOP mice generate elastin-specific antibodies and that immunization with ox-elastin exacerbates ocular pathology. Elastin antibodies represented complement fixing isotypes that, together with the increased presence of complement activation seen in immunized mice, suggest that elastin antibodies exert pathogenic effects through mediating complement activation.


Serological Tests Do Not Predict Residual Fibrosis in Hepatitis C Cirrhotics with a Sustained Virological Response to Interferon.
Liver biopsy (LB) has lost popularity to stage liver fibrosis in the era of highly effective anti-hepatitis C virus (HCV) therapy, yet diagnosis of persistent cirrhosis may have important implications following HCV eradication. As performance of serological non-invasive tests (NITs) to predict residual fibrosis in non-viremic HCV patients is unknown, we investigated accuracy of NITs to predict residual fibrosis in cirrhotics after a sustained virological response (SVR) to interferon (IFN). Thirty-eight patients with a pre-treatment histological diagnosis of cirrhosis and a 48-104 months post-SVR LB were tested with APRI, CDS, FIB-4, FibroQ, Forns Score, GUCI Index, King Score, Lok Index, PLF, ELF. In 23 (61%) patients, cirrhosis had histologically regressed. All NITs values declined after SVR without any significant difference between regressors and non-regressors (AUROC 0.52-0.75). Using viremic cut-offs, PPV ranged from 34% to 100%, with lower NPV (63% - 68%). NITs performance did not improve using derived cut-offs (PPV: 40% - 80%; NPV: 66% - 100%). PLF, which combines several NITs with transient elastography, had the best diagnostic performance (AUROC 0.75, Sn 61%, Sp 90%, PPV 80%, NPV 78%). After treatment, none of the NITs resulted significantly associated with any of the histological features (activity grade, fibrosis stage, area of fibrosis). The diagnostic estimates obtained using both viremic and derived cut-off values of NITs were suboptimal, indicating that none of these tests helps predicting residual fibrosis and that LB remains the gold standard for this purpose.


Elderly people's interaction with advanced technology.
Aging of population is an inevitable process by which the number of elderly people is increasing. Rapid development of information and communication technology (ICT) is changing basic needs of elderly people; therefore society should ensure opportunities for elderly to learn and use ICT in a way to manage their daily life activities and in this way enable them participation in the information and knowledge society. The purpose of the study was to find out whether elderly are acquainted with the advanced technology and to what extent they use it or they desire to use it. Within the single point study we interviewed 100 randomly selected elderly people from different geographical regions in Slovenia. Results showed the differences in the use of advanced technology by Slovenian regions; therefore in the future activities should be focused on organizing promotional and demonstrational activities including ICT courses to increase elderly's motivation for ICT interaction.


Divergent lineage of a novel hantavirus in the banana pipistrelle (Neoromicia nanus) in Côte d'Ivoire.
Recently identified hantaviruses harbored by shrews and moles (order Soricomorpha) suggest that other mammals having shared ancestry may serve as reservoirs. To investigate this possibility, archival tissues from 213 insectivorous bats (order Chiroptera) were analyzed for hantavirus RNA by RT-PCR. Following numerous failed attempts, hantavirus RNA was detected in ethanol-fixed liver tissue from two banana pipistrelles (Neoromicia nanus), captured near Mouyassué village in Côte d'Ivoire, West Africa, in June 2011. Phylogenetic analysis of partial L-segment sequences using maximum-likelihood and Bayesian methods revealed that the newfound hantavirus, designated Mouyassué virus (MOUV), was highly divergent and basal to all other rodent- and soricomorph-borne hantaviruses, except for Nova virus in the European common mole (Talpa europaea). Full genome sequencing of MOUV and further surveys of other bat species for hantaviruses, now underway, will provide critical insights into the evolution and diversification of hantaviruses.


Biomonitoring with Gammarus pulex at the Meuse (NL), Aller (GER) and Rhine (F) rivers with the online Multispecies Freshwater Biomonitor.
Biological early warning systems represent a set of tools that may be able to respond to certain chemical monitoring requirements of recent European legislation, the Water Framework Directive (WFD2000/60/EC), that aims to improve and protect water quality across Europe. In situ biomonitoring was performed along the rivers Meuse (NL), Aller (GER) and Rhine (F) within the frame of the European Union-funded Project SWIFT-WFD. Gammarus pulex was used as a test organism during the evaluation of the Multispecies Freshwater Biomonitor(R) (MFB), an online biomonitor to quantitatively record different behaviour patterns of animals. At the river Meuse G. pulex reacted to pulse exposure of either a mixture of trace metals or of several organic xenobiotics, by showing up to 20% decreased locomotory activity (already at the 1st pulse) and increased mortality (at 2nd or 3rd pulse only). G. pulex deployed within the MFB system were observed to survive well at the monitoring station on the Aller (100%) and monitoring did not result in the measurement of chemical irregularities. In contrast, deployment at the monitoring station on the Rhine river demonstrated that the test organism was able to detect chemical irregularities by up to 20% decreased locomotory activity in the animals. The MFB proved to be an alert system for water quality monitoring at sensitive sites and sites with accidental pollution.


Counseling about and use of emergency contraception in the United States.
Few nationally representative studies have examined the prevalence and predictors of emergency contraception use or of receipt of counseling about the method. The impact of the U.S. Food and Drug Administration's 2006 approval of behind-the-counter sales of the method to women aged 18 and older remains to be seen; therefore, understanding patterns of use and counseling before the 2006 policy change is necessary to assess its impact. Data collected from 7,643 women aged 15-44 participating in the 2002 National Survey of Family Growth were analyzed using multivariable logistic regression to assess predictors of receipt of counseling and use of emergency contraception. Overall, 3% of women reported that a clinician had discussed emergency contraception with them in the past year, and 4% of those who had ever had sex with a man reported having used the method. Only 4% of those who had seen a gynecologist in the past year reported having received counseling. Women's likelihood of having received counseling was reduced if they were 30 or older (odds ratio, 0.2), and was elevated if they were Hispanic (4.1), black (2.6) or ever-married (2.4). Receipt of counseling in the last 12 months was the strongest predictor of ever-use (11.7). Clinicians can play a pivotal role in ensuring that women have accurate information about how to access and use emergency contraception. However, efforts are needed to explore other ways to deliver this counseling.


Improving the quality and quantity of life among patients with cancer: a review of the effectiveness of group psychotherapy.
Cancer patients suffer from a number of psychosocial problems related to the progression of their disease as well as standard medical interventions. Fortunately, there is empirical evidence suggesting that group psychotherapy is effective at ameliorating psychological distress and in some cases improving survival. For this literature review we examined the psychological morbidity, particularly anxiety and depression, among cancer patients. Further, we conducted a critical examination of the current evidence regarding the effectiveness of group psychotherapy for improving the quality as well as the quantity of life in cancer patients. Finally, we explored the specific components of effective group psychotherapy, which has been associated with enhanced survival. We conclude that there is compelling evidence indicating that group psychotherapy improves the quality of life of cancer patients. Furthermore, there is a growing body of evidence suggesting that group psychotherapy improves survival of cancer patients.


Biological effects and mechanisms of action of mesenchymal stem cell therapy in chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is the most frequent chronic respiratory disease and a leading cause of morbidity and mortality, worldwide. Given that the foremost risk factor leading to the development of COPD is cigarette smoke, the initial treatment for COPD is smoking cessation. Even after smoking cessation, inflammation, apoptosis and oxidative stress can persist and continue to contribute to COPD. Although current therapies for COPD (which are primarily based on anti-inflammatory drugs such as corticosteroids, theophylline and bronchodilators) reduce airway obstruction, limit COPD exacerbation and improve the patient's health-related quality-of-life, none can prevent disease progression or reduce mortality. Recent advances in stem cell research have provided novel insight into the potential of bone marrow mesenchymal stem cells (MSCs) in the treatment of several pulmonary diseases. This review article discusses the biological effects and mechanisms of action of MSC transplantation in COPD, and highlights the foundation that MSCs provide for novel therapeutic approaches in COPD.


The blackfly vectors and transmission of Onchocerca volvulus in Mahenge, south eastern Tanzania.
The Mahenge Mountains onchocerciasis focus in south eastern Tanzania was historically one of the most heavily infected areas in the country. The vectors of Onchocerca volvulus are mainly Simulium damnosum complex blackflies, but a species of the Simulium neavei group may also contribute to transmission in some areas. The only detailed studies of parasite transmission in Mahenge were conducted in the late 1960s. The taxonomy of the S. damnosum complex has since been revised and onchocerciasis control through annual community directed treatment with ivermectin (CDTI) commenced in 1997. This study aimed to provide a cytogenetic and molecular update of the S. damnosum complex cytoforms present in Mahenge, and to evaluate the current status of O. volvulus transmission by blackflies following 19 years of annual CDTI. Rivers were surveyed to identify sites of S. damnosum s.l. breeding among the eastern slopes of the mountains, and human landing collections of adult female blackflies were made close to breeding sites. Identification of S. damnosum complex cytoforms was by cytotaxonomy of late-instar larvae and ITS1 amplicon size polymorphisms of larvae and adults. Adult blackflies were pool screened for O. volvulus infection using a triplex real-time PCR. The cytoforms 'Nkusi', Simulium kilibanum and 'Turiani' were found breeding in perennial rivers. 'Nkusi' and S. kilibanum were collected on human bait at 7/7 catch sites and possessed ITS1 profiles most closely resembling the molecular forms 'Nkusi J' and S. kilibanum 'T'. Whereas 'Turiani' was present in rivers, it was not collected on human bait and appears to be zoophilic. Simulium nyasalandicum was collected in low numbers on human bait at 3/7 catch sites. In total, 12,452 S. damnosum s.l. were pool screened and O. volvulus infection was detected in 97/104 pools of bodies and 51/104 pools of heads. The estimated percentage of S. damnosum s.l. carrying infective L3 stage parasites was 0.57% (95% CI 0.43%-0.74%). Onchocerca volvulus transmission by S. damnosum s.l. is continuing in the Mahenge Mountains after 19 years of annual CDTI. Infection rates appear similar to those reported in the 1960s, but a more detailed study is required to fully understand the epidemiological significance of the ongoing transmission. These results provide further evidence that annual CDTI may be insufficient to eliminate the parasite in formerly hyperendemic foci.


Effects of environmental enrichment on extinction and reinstatement of amphetamine self-administration and sucrose-maintained responding.
The current experiments aimed to determine whether differential rearing alters extinction and/or reinstatement of amphetamine self-administration or sucrose-maintained responding. Male Sprague-Dawley rats were raised in either an enriched condition or an isolated condition. Rats were then trained to lever press on a continuous reinforcement schedule across either 15 daily amphetamine self-administration sessions or 15 sucrose-reinforced sessions, followed by 10 sessions of extinction. After the extinction sessions, priming doses of amphetamine (0, 0.25 or 1.0 mg/kg) were administered 15 min before the session, or sucrose (one or 10 pellets) was delivered non-contingently at the beginning of the session. Enriched condition rats showed greater extinction for amphetamine and sucrose-maintained responding than isolated condition rats. When primed with amphetamine, isolated condition rats reinstated responding following 0.25 mg/kg of amphetamine, whereas enriched condition rats only reinstated responding after 1.0 mg/kg of amphetamine. Isolated condition rats failed to reinstate responding following sucrose delivery, while enriched condition rats reinstated responding following the delivery of 10 sucrose pellets. These results indicate that environmental enrichment enhanced the extinction of both amphetamine and sucrose-maintained responding. Environmental enrichment also raised the reinstatement threshold specific to the amphetamine prime, suggesting a reduction in the incentive motivational effect of amphetamine.


Receptive sign vocabulary tests: tests of single-word vocabulary or iconicity?
First-, fourth-, and ninth-grade hearing students were administered randomly selected items from the Carolina Picture Vocabulary Test (CPVT; Layton & Holmes, 1985) to determine the degree to which signs used in the CPVT are iconic (see note) and can actually convey a sign's meaning at the moment of testing, thus providing an inflated vocabulary score. Hearing students were tested because they had no prior sign knowledge or experience. Results indicate that the signs used in the CPVT are sufficiently iconic to enable students unfamiliar with signs to identify a test picture; 73% of their responses were correct when chance selection was 25%. Such findings signal potential problems with existing receptive sign vocabulary tests; consequently, test results should be interpreted cautiously. Note: Not all signs are iconic. Iconic signs have semantic features nested in their formation, location, and movement that visually convey enough information to manifest word meaning. Formation, location, and movement are also called cheremic features of sign.


The experience of "medicine companions" to support adherence to antiretroviral therapy: quantitative and qualitative data from a trial population in Uganda.
Good adherence is critical for antiretroviral therapy (ART) in sub-Saharan Africa. We report on the characteristics of medicine companions (MCs) chosen by Ugandan patients enrolling on ART, and on how MCs were chosen, and what roles they played. Baseline data on MCs of 1453 participants in a randomized controlled trial comparing facility and home-based delivery of ART in Jinja, Uganda were analyzed. Textual data on experience with MCs were collected through in-depth interviews among a subsample of 40 trial participants equally divided by sex and trial arm. Significantly more women (71%) than men (29%) were recruited. The majority (75%) of women participants were either widowed (51%) or separated or divorced (24%), whereas most of the men (66%) were married. Women were most likely to choose a child as their MC while men were most likely to choose their spouse; 41% of women chose an MC under 21 compared with only 14% of men. Only 31% of married women chose their husband, compared with 66% of married men who chose their wife. Qualitative interviews suggested MCs proved useful for reminding and other supportive tasks in the first three months but were generally less essential by six months and beyond. Convenience, reliability, and trust were key considerations in choosing an MC. Children provided the only alternative for many unmarried women, but even some married women felt children made more reliable MCs than husbands. Participants who had disclosed their serostatus usually received drug-taking reminders from multiple household members. One participant in the qualitative sample with poor family relations delayed starting treatment due to unwillingness to identify an MC. MCs were generally welcome and useful in supporting early adherence. However, disclosure to an MC should not be a condition of obtaining treatment.


Development of a growth medium suitable for exopolysaccharide production and structural characterisation by Bifidobacterium animalis ssp. lactis AD011.
Exopolysaccharides (EPSs) produced by Bifidobacteria have received considerable attention due to their ability to modify the rheological and physicochemical properties of dairy products. However, the quantification and characterisation of Bifidobacterial EPS are hampered by the presence of EPS-equivalent (EPS-E) substances in complex media such as Reinforced Clostridial Medium (RCM). This study has developed a medium based on RCM which both supports the growth of Bifidobacterium animalis ssp. lactis AD011 and does not interfere with the quantification and characterisation of the EPS generated. Medium development involved the identification of EPE-E containing components via NMR analysis followed by their removal, substitution or pre-treatment. Both beef extract and casein acid hydrolysate required chemical pre-treatment to remove polysaccharide components before the medium was free of EPS-E materials. Once EPS-E free components had been identified, lactose, glucose and galactose were evaluated as potential carbon sources. Glucose was found to be the optimum carbon source. The final medium composition supported growth to the same extent as RCM providing significant EPS yields and no interferences during analysis.


Macromolecular crowding induces polypeptide compaction and decreases folding cooperativity.
A cell's interior is comprised of macromolecules that can occupy up to 40% of its available volume. Such crowded environments can influence the stability of proteins and their rates of reaction. Using discrete molecular dynamics simulations, we investigate how both the size and number of neighboring crowding reagents affect the thermodynamic and folding properties of structurally diverse proteins. We find that crowding induces higher compaction of proteins. We also find that folding becomes less cooperative with the introduction of crowders into the system. The crowders may induce alternative non-native protein conformations, thus creating barriers for protein folding in highly crowded media.


Body size dissatisfaction and avoidance behavior: how gender, age, ethnicity, and relative clothing size predict what some won't try.
Sixty-eight percent of U.S. adults are overweight/obese, and this epidemic has physical, psychosocial, and behavioral consequences. An internet sample of adults (N=2997) perceiving themselves as larger than ideal in clothing size reported their body mass index (BMI), relative clothing size (RS; discrepancy between current and ideal size), and avoidance behaviors. Exploratory factor analysis of 10 avoidance items produced social avoidance and body display avoidance factors. A relative importance analysis revealed RS as a better predictor than BMI for avoidance. A hierarchical multivariate analysis of covariance found RS to predict both avoidance constructs. The relationship between RS and both avoidance constructs was stronger for women than men, and for younger as compared to older participants. Caucasians reported more body display avoidance than African Americans. This suggests that personal dissatisfaction with body size may deter involvement in varied life events and that women are especially avoidant of activities that entail displaying their bodies.


Effect of Individual Environmental Heat-Stress Variables on Training and Recovery in Professional Team Sport.
Exercise in hot environments increases body temperature and thermoregulatory strain. However, little is known regarding the magnitude of effect that ambient temperature (Ta), relative humidity (RH), and solar radiation individually have on team-sport athletes. To determine the effect of these individual heat-stress variables on team-sport training performance and recovery. Professional Australian Rules Football players (N = 45) undertook 8-wk preseason training producing a total of 579 outdoor field-based observations with Ta, RH, and solar radiation recorded at every training session. External load (distance covered, in m/min; percentage high-speed running [%HSR] >14.4 km/h) was collected via a global positioning system. Internal load (ratings of perceived exertion and heart rate) and recovery (subjective ratings of well-being and heart-rate variability [root mean square of the successive differences]) were monitored throughout the training period. Mixed-effects linear models analyzed relationships between variables using standardized regression coefficients. Increased solar-radiation exposure was associated with reduced distance covered (-19.7 m/min, P < .001), %HSR (-10%, P < .001) during training and rMSSD 48 h posttraining (-16.9 ms, P = .019). Greater RH was associated with decreased %HSR (-3.4%, P = .010) but increased percentage duration >85% HRmax (3.9%, P < .001), ratings of perceived exertion (1.8 AU, P < .001), and self-reported stress 24 h posttraining (-0.11 AU, P = .002). In contrast, higher Ta was associated with increased distance covered (19.7 m/min, P < .001) and %HSR (3.5%, P = .005). The authors show the importance of considering the individual factors contributing to thermal load in isolation for team-sport athletes and that solar radiation and RH reduce work capacity during team-sport training and have the potential to slow recovery between sessions.


Oral Administration of Cannabis and Δ-9-tetrahydrocannabinol (THC) Preparations: A Systematic Review.
Changes in cannabis legalization regimes in several countries have influenced the diversification of cannabis use. There is an ever-increasing number of cannabis forms available, which are gaining popularity for both recreational and therapeutic use. From a therapeutic perspective, oral cannabis containing Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is a promising route of administration but there is still little information about its pharmacokinetics (PK) effects in humans. The purpose of this systematic review is to provide a general overview of the available PK data on cannabis and THC after oral administration. A search of the published literature was conducted using the PubMed database to collect available articles describing the PK data of THC after oral administration in humans. The literature search yielded 363 results, 26 of which met our inclusion criteria. The PK of oral THC has been studied using capsules (including oil content), tablets, baked goods (brownies and cookies), and oil and tea (decoctions). Capsules and tablets, which mainly correspond to pharmaceutical forms, were found to be the oral formulations most commonly studied. Overall, the results reflect the high variability in the THC absorption of oral formulations, with delayed peak plasma concentrations compared to other routes of administration. Oral THC has a highly variable PK profile that differs between formulations, with seemingly higher variability in baked goods and oil forms. Overall, there is limited information available in this field. Therefore, further investigations are required to unravel the unpredictability of oral THC administration to increase the effectiveness and safety of oral formulations in medicinal use.


Soil responses to management, increased precipitation, and added nitrogen in ponderosa pine forests.
Forest management, climatic change, and atmospheric N deposition can affect soil biogeochemistry, but their combined effects are not well understood. We examined the effects of water and N amendments and forest thinning and burning on soil N pools and fluxes in ponderosa pine forests near Flagstaff, Arizona (USA). Using a 15N-depleted fertilizer, we also documented the distribution of added N into soil N pools. Because thinning and burning can increase soil water content and N availability, we hypothesized that these changes would alleviate water and N limitation of soil processes, causing smaller responses to added N and water in the restored stand. We found little support for this hypothesis. Responses of fine root biomass, potential net N mineralization, and the soil microbial N to water and N amendments were mostly unaffected by stand management. Most of the soil processes we examined were limited by N and water, and the increased N and soil water availability caused by forest restoration was insufficient to alleviate these limitations. For example, N addition caused a larger increase in potential net nitrification in the restored stand, and at a given level of soil N availability, N addition had a larger effect on soil microbial N in the restored stand. Possibly, forest restoration increased the availability of some other limiting resource, amplifying responses to added N and water. Tracer N recoveries in roots and in the forest floor were lower in the restored stand. Natural abundance delta15N of labile soil N pools were higher in the restored stand, consistent with a more open N cycle. We conclude that thinning and burning open up the N cycle, at least in the short-term, and that these changes are amplified by enhanced precipitation and N additions. Our results suggest that thinning and burning in ponderosa pine forests will not increase their resistance to changes in soil N dynamics resulting from increased atmospheric N deposition or increased precipitation due to climatic change. Restoration plans should consider the potential impact on long-term forest productivity of greater N losses from a more open N cycle, especially during the period immediately after thinning and burning.


Differential Diagnosis and Management Issues of Idiopathic Angiooedema and their Resolution.
Angiooedema is a local and self-limiting swelling of the subcutaneous and sub mucosal tissues, produced by vasoactive peptides that temporary increase the vascular permeability. It is recognized that recurrent angiooedema exposes patients to the risk of fatalities and reduced quality of life, being in some circumstances associated with a critical condition. Angiooedema can occur with or without wheals. The first symptom is urticaria, the second is a distinct nosologic entity. In absence of an identifiable cause, recurrent angiooedema without wheals can be defined as idiopathic and marked"idiopathic histaminergic angiooedema" when it is responsive to anti histamine treatment, and "idiopathic non-histaminergic angiooedema" when it is not. Furthermore, idiopathic non-histaminergic angiooedema can be diagnosed as hereditary or sporadic by family history. In this review, we summarize the approaches to diagnose and treat different forms of idiopathic angiooedema.


The Effectiveness of Assertiveness Training on the Levels of Stress, Anxiety, and Depression of High School Students.
Adolescence is a transition period from childhood to early adulthood. Because of the immense pressure imposed on adolescents due to the complications and ambiguities of this transition, their level of excitement increases and sometimes it appears in the form of sensitivity and intense excitement. This study aimed at determining the effectiveness of assertiveness training on the levels of stress, anxiety, and depression of high school students. This quasi-experimental study was conducted on high school students of Isfahan in academic year 2012 - 13. A total of 126 second grade high school students were collected according to simple random sampling method and divided into two groups: experimental with 63 participants and control with the same number. Data gathering instruments included a demographic questionnaire, Gambill-Richey assertiveness scale, and depression anxiety stress scales (DASS-21). Assertiveness training was carried out on the experimental group in 8 sessions; after 8 weeks, posttest was carried out on both groups. Statistical tests such as independent t test, repeated measures ANOVA, Chi-square test, and the Mann-Whitney test were used to interpret and analyze the data. The Chi-square and Mann-Whitney tests did not show significant statistical differences between the two groups in terms of demographic variables (P ≥ 0.05). Repeated measures ANOVA showed no significant difference between the mean scores for assertiveness before (100.23 ± 7.37), immediately after (101.57 ± 16.06), and 2 months after (100.77 ± 12.50) the intervention in the control group. However, the same test found a significant difference between the mean score for assertiveness in the experimental group before (101.6 ± 9.1), immediately after (96.47 ± 10.84), and 2 months after (95.41 ± 8.37) implementing the training program (P = 0.002). The independent t test showed no significant difference in the mean score for anxiety and stress between two groups before the assertiveness training program; however, 2 months after the intervention, the mean score for anxiety in the experimental group was found significantly lower than the control group. As for the mean score for depression, the independent t test showed no significant difference between two groups before training; however, despite the decrease in the mean scores for depression in the experimental group following the intervention, the difference was not significant (P = 0.09). The results of the current study show that conducting assertive training in high school students decreases their anxiety, stress, and depression. Given that high school years are among the most sensitive stages of one's life plus the fact that conducting such training programs besides their safe and low cost nature are effective and practical, it is highly recommended that such programs be carried out among high school adolescents.


Gastrointestinal complications in liver transplant recipients: MITOS study.
Liver transplant recipients frequently suffer gastrointestinal (GI) complications but their prevalence and their influence on quality of life remain unknown. The objective of this study was to asses the prevalence, impact on quality of life, and management of GI complications in liver transplant recipients. This was an epidemiologic, cross-sectional, multicenter study. Four hundred seventeen liver recipients were recruited in 14 centers. A questionnaire was filled for every patient. The median age of the patients was 55 years. The median time since transplantation was 4.1 +/- 4 years. Whereas 19.2% presented some GI disease before transplantation, 49.4% showed this type of complication after transplantation. Diarrhea was the most prevalent GI complication, and anorexia was the GI disorder that affected patients daily activities the most frequently. GI complications were more frequent among female patients, subjects with pretransplantation hiatal hernia, and those readmitted after transplantation. Of the patients with GI complications, 70.9% received pharmacological treatment (89.7% with gastric protectors). Immunosuppressive therapy was also modified because of GI complications. Immunosuppressive drug dose was reduced in 18.1%, transiently stopped in 3.4%, and definitively stopped in 3.4% of cases. The drug most frequently changed was mycophenolate mofetil: dose reduction, 23.6%; transient withdrawal, 5.7%; and definitive withdrawal, 6.6%. The prevalence of GI complications in the liver transplant population was approximately 50%. GI complications showed a significant impact on the quality of life of the patients. They were related to female gender, to pretransplantation GI pathology, and posttransplantation hospital admission. These complications were frequently managed with pharmacological therapy or with changes in immunosuppressive therapy.


Stromal infiltration of CD8 T cells is associated with improved clinical outcome in HPV-positive oropharyngeal squamous carcinoma.
Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) have a better prognosis than those with HPV-negative tumours. There is interest in de-escalating their treatment but strategies are needed for risk stratification to identify subsets with a poor prognosis. This study investigated tumour-infiltrating lymphocytes (TILs) in relation to HPV tumour status and patient survival. Biopsies from 218 patients diagnosed with OPSCC between 2002 and 2011, who underwent chemo/radiotherapy were analysed for HPV by PCR, in-situ hybridisation and p16 immunohistochemistry (IHC). One hundred and thirty-nine samples with concordant HPV detection were analysed for CD3, CD4, CD8 and FoxP3 expression in tumour and stromal regions using multiplexIHC and multispectral image analysis. Labelling of smooth muscle actin (SMA) identified activated stroma. Human papillomavirus-positive compared with HPV-negative OPSCC had higher infiltration in both tumour and stromal areas of CD4 and CD8 T cells but not FoxP3 T regulatory cells. Only CD3+CD8+ stromal and not tumour area infiltration was associated with increased survival (P=0.02). There was significantly higher SMA expression in HPV-positive compared with -negative tumours, which did not correlate with survival. Studies of TILs for risk stratification in OPSCC should assess stromal infiltration.


Comorbidity, use of common medications, and risk of early death in patients with localized or locally advanced prostate cancer.
In this paper, we analyze predictive factors for early death from comorbidity (defined as death within 3 years from diagnosis and unrelated to prostate cancer) in patients with localized or locally advanced prostate cancer. Such information may guide individually tailored treatment or observation strategies, and help to avoid overtreatment. We retrospectively analyzed baseline parameters including information on comorbidity and medication use among 177 patients (median age at diagnosis 70 years). Actuarial survival analyses were performed. During the first 3 years, two patients (1.1%) died from progressive prostate cancer after they had developed distant metastases. The risk of dying from other causes (3.4%) was numerically higher, although not to a statistically significant degree. Six patients who died from other causes had age-adjusted Charlson comorbidity index (CCI) scores ≥5 (CCI is a sum score where each comorbid condition is assigned with a score depending on the risk of dying associated with this condition). The main comorbidity was cardiovascular disease. The two statistically significant predictive factors were medication use and age-adjusted CCI score ≥5 (univariate analysis). However, medication use was not an independent factor as all patients with age-adjusted CCI score ≥5 also used at least one class of medication. Median survival was 30 months in patients with age-adjusted CCI score ≥5. Prediction of non-prostate cancer death may be important to prevent overtreatment in patients who are more threatened by comorbidity. Our data suggest that simple parameters such as use of medications vs. none, or presence of serious cardiac disease vs. none, are not sufficient, and that age-adjusted CCI scores outperform the other factors included in our analysis.


Preterm Preeclampsia Risk Modelling: Examining Hemodynamic, Biochemical, and Biophysical Markers Prior to Pregnancy.
Preeclampsia (PE) is a leading cause of maternal and perinatal death globally and can lead to unplanned preterm birth. Predicting risk for preterm or early-onset PE, has been investigated primarily after conception, and particularly in the early and mid-gestational periods. However, there is a distinct clinical advantage in identifying individuals at risk for PE prior to conception, when a wider array of preventive interventions are available. In this work, we leverage machine learning techniques to identify potential pre-pregnancy biomarkers of PE in a sample of 80 women, 10 of whom were diagnosed with preterm preeclampsia during their subsequent pregnancy. We explore biomarkers derived from hemodynamic, biophysical, and biochemical measurements and several modeling approaches. A support vector machine (SVM) optimized with stochastic gradient descent yields the highest overall performance with ROC AUC and detection rates up to .88 and .70, respectively on subject-wise cross validation. The best performing models leverage biophysical and hemodynamic biomarkers. While preliminary, these results indicate the promise of a machine learning based approach for detecting individuals who are at risk for developing preterm PE before they become pregnant. These efforts may inform gestational planning and care, reducing risk for adverse PE-related outcomes.