Systemic DPP4 activity is reduced during primary HIV-1 infection and is associated with intestinal RORC+ CD4+ cell levels: a surrogate marker candidate of HIV-induced intestinal damage.
Combined anti-retroviral therapy (cART) transformed HIV-1 from a deadly disease into a chronic infection, but does not cure HIV infection. It also does not fully restore HIV-induced gut damage unless administered extremely early after infection. Additional biomarkers are needed to evaluate the capacity of therapies aimed at HIV remission/cure to restore HIV-induced intestinal immune damage and limit chronic inflammation. Herein, we aimed to identify a systemic surrogate marker whose levels would reflect gut immune damage such as intestinal Th17 cell loss starting from primary HIV-1 infection. Biomarker discovery approaches were performed in four independent cohorts, covering HIV-1 primary and chronic infection in 496 naïve or cART-treated patients (Amsterdam cohort (ACS), ANRS PRIMO, COPANA and CODEX cohorts). The concentration and activity of soluble Dipeptidylpeptidase 4 (sDPP4) were quantified in the blood from these patients, including pre- and post-infection samples in the ACS cohort. For quantification of DPP4 in the gut, we utilized two non-human primate models, representing pathogenic (macaque) and non-pathogenic (African green monkey) SIV infection. Four gut compartments were analysed in each animal model (ileum, jejunum, colon and rectum) for quantification of DPP4, RORC and TBX21 gene expression in sorted CD4+ cells. To analyse if sDPP4 levels increase when Th17 cells were restored, we quantified sDPP4 in plasma from SIV-infected macaques treated with IL-21. We showed that sDPP4 levels were strongly decreased in primary HIV-1 infection. Strikingly, sDPP4 levels in primary HIV-1 infection predicted time to AIDS. They were not increased by cART in chronic HIV-1 infection (median 36 months on cART). In the gut of SIV-infected non-human primates, DPP4 mRNA was higher in CD4+ than CD4- leucocytes. DPP4 specifically correlated with RORC expression, a Th17 marker, in CD4+ cells from the intestine. We further demonstrated that sDPP4 activity levels were increased in animals treated with IL-21 and that this increase was associated with restoration of the Th17 compartment and reduced inflammation. Furthermore, DPP4 mRNA levels in small intestine CD4+ cells positively correlated with circulating DPP4 activity. These data provide evidence that blood sDPP4 levels could be useful as a correlate for HIV-induced intestinal damage.


A systematic review of assessment of skill acquisition and operative competency in vascular surgical training.
The aim of this systematic review is to describe the literature and assessment tools evaluating vascular surgical operative performance that could potentially be used for the assessment of educational outcomes applicable to the Milestone Project and the Next Accreditation System. A systematic review of PubMed/MEDLINE, EMBASE, PsycINFO, and key journals from 1985 to 2013 was performed to identify English-language articles describing assessment of vascular surgical skills and competence. Qualifying studies were abstracted for data concerning study aims, study and assessment setting, skills measured, and metrics used to determine competency. Strengths, weaknesses, and psychometric robustness of the assessment tools were determined. The literature search identified 617 citations. After title and abstract review, 65 articles were retrieved for full-text assessment and 48 articles were included in the final review. Twenty-nine articles assessed open vascular skills; 19, endovascular skills; six, nontechnical skills; and one, teamwork skills. The majority (84%) of studies were performed in a simulated environment, four (8%) were performed in the operating room, and the remaining three were performed in both a simulated environment and an operating room. Strengths and weaknesses of assessment tools were study and assessor dependent, with none applicable to all study scenarios or procedures. The literature describing assessment tools pertinent to vascular surgery is diverse. Existing assessment tools may be relevant to individual technical skill acquisition assessment; however, an operative assessment tool relevant to vascular/endovascular surgery and generalizable to the wide spectrum of technical and nontechnical skills pertinent to vascular surgery needs to be developed, validated, and implemented to allow the practical assessment of resident readiness to operate in an unsupervised setting.


On-Surface Synthesis of Highly Oriented Thin Metal-Organic Framework Films through Vapor-Assisted Conversion.
Controlled on-surface film growth of porous and crystalline frameworks is a central prerequisite for incorporating these materials into functional platforms and operational devices. Here, we present the synthesis of thin zirconium-based metal-organic framework (MOF) films by vapor-assisted conversion (VAC). We established protocols adequate for the growth of UiO-66, UiO-66(NH2), UiO-67, and UiO-68(NH2) as well as the porous interpenetrated Zr-organic framework, PPPP-PIZOF-1, as highly oriented thin films. Through the VAC approach, precursors in a cast solution layer on a bare gold surface are reacting to form a porous continuous MOF film, oriented along the [111] crystal axis, by exposure to a solvent vapor at elevated temperature of 100 °C and 3 h reaction time. It was found that the concentration of dicarboxylic acid, the modulator, the droplet volume, and the reaction time are vital parameters to be controlled for obtaining oriented MOF films. Using VAC for the MOF film growth on gold surfaces modified with thiol SAMs and on a bare silicon surface yielded oriented MOF films, rendering the VAC process robust toward chemical surface variations. Ethanol sorption experiments show that a substantial part of the material pores is accessible. Thereby, the practical VAC method is an important addition to the toolbox of synthesis methods for thin MOF films. We expect that the VAC approach will open new horizons in the formation of highly defined functional thin MOF films for numerous applications.


Reliability of electromyographic methods used for assessing hip and knee neuromuscular activity in females diagnosed with patellofemoral pain syndrome.
Patellofemoral pain syndrome (PFPS) is one of the most common, yet misunderstood, knee pathologies. PFPS is thought to result from abnormal patella tracking caused from altered neuromuscular control. Researchers have investigated neuromuscular influences from the gluteus medius (GM), vastus medialis (VM), and vastus lateralis (VL) but with inconsistent findings. A reason for these discrepancies may be from varying methodology. The purpose of this study was to determine the reliability of electromyographic (EMG) methods used to assess amplitudes and timing differences of the GM, VM, and VL in subjects with PFPS. Seven females with PFPS participated. GM, VM, and VL activity was assessed during the stance phase of a stair descent task on two separate occasions. Amplitudes during the different intervals of stance were recorded and expressed as a percent of each muscle's maximum voluntary isometric contraction. Muscle onsets at the beginning of stair descent were also determined. VM-GM, VL-GM, and VL-VM onset timing differences were quantified. Intraclass correlation coefficients (ICCs) and standard errors of measurement (SEMs) were calculated to assess between-day reliability. Most EMG measures had acceptable reliability (ICC(3,5)>or=0.70). Although some measures had moderate reliability (ICC<0.70), they had low SEMs, which suggested high measurement precision. These findings support using these methods for examining neuromuscular activity in subjects with PFPS.


TRIAGE-STROKE: Treatment strategy In Acute larGE vessel occlusion: Prioritize IV or endovascular treatment-A randomized trial.
For patients with acute ischemic stroke and large vessel occlusions, intravenous thrombolysis and endovascular therapy are standard of care, but the effect of endovascular therapy is superior to intravenous thrombolysis. If a severe stroke with symptoms indicating large vessel occlusions occurs in the catchment area of a primary stroke center, there is equipoise regarding optimal transport strategy. For patients presenting with suspected large vessel occlusions (PASS ≥ 2) and a final diagnosis of acute ischemic stroke, we hypothesize that bypassing the primary stroke center will result in an improved 90-day functional outcome. We aim to randomize 600 patients, 1:1. A national investigator-driven, multi-center, randomized assessor-blinded clinical trial. The Prehospital Acute Stroke Severity Scale has been developed. It identifies most patients with large vessel occlusions in the pre-hospital setting. Patients without a contraindication for intravenous thrombolysis are randomized to either transport directly to a comprehensive stroke centers for intravenous thrombolysis and of endovascular therapy or to a primary stroke center for intravenous thrombolysis and subsequent transport to a comprehensive stroke centers for of endovascular therapy, if needed. The primary outcome will be the 90-day modified Rankin Scale score (mRS) for all patients with acute ischemic stroke. Secondary outcomes include 90-day mRS for all randomized patients, all patients with ischemic stroke but without large vessel occlusions, and patients with hemorrhagic stroke. The safety outcomes include severe dependency or death and time to intravenous thrombolysis for ischemic stroke patients. Study results will influence decision making regarding transport strategy for patients with suspected large vessel occlusions.


Rasch-Transformed Total Neuropathy Score clinical version (RT-TNSc(©) ) in patients with chemotherapy-induced peripheral neuropathy.
Composite scales such as the Total Neuropathy Score clinical version (TNSc(©) ) have been widely used to measure neurological impairment in a standardized manner but they have been criticized due to their ordinal setting having no fixed unit. This study aims to improve impairment assessment in patients with chemotherapy-induced peripheral neuropathy (CIPN) by subjecting TNSc(©) records to Rasch analyses. In particular, we wanted to investigate the influence of factors affecting the use of the TNSc(©) in clinical practice. TNSc(©) has 7 domains (sensory, motor, autonomic, pin-prick, vibration, strength, and deep tendon reflexes [DTR]) each being scored 0-4. Data obtained in 281 patients with stable CIPN were subjected to Rasch analyses to determine the fit to the model. The TNSc(©) did not meet Rasch model's expectations primarily because of misfit statistics in autonomic and DTR domains. Removing these two, acceptable model fit and uni-dimensionality were obtained. However, disordered thresholds (vibration and strength) and item bias (mainly cultural) were still seen, but these findings were kept to balance the assessment range of the Rasch-Transformed TNSc(©) (RT-TNSc(©) ). Acceptable reliability findings were also obtained. A 5-domains RT-TNSc(©) may be a more proper assessment tool in patients with CIPN. Future studies are needed to examine its responsive properties.


Coherent backscattering by polydisperse discrete random media: exact T-matrix results.
The numerically exact superposition T-matrix method is used to compute, for the first time to our knowledge, electromagnetic scattering by finite spherical volumes composed of polydisperse mixtures of spherical particles with different size parameters or different refractive indices. The backscattering patterns calculated in the far-field zone of the polydisperse multiparticle volumes reveal unequivocally the classical manifestations of the effect of weak localization of electromagnetic waves in discrete random media, thereby corroborating the universal interference nature of coherent backscattering. The polarization opposition effect is shown to be the least robust manifestation of weak localization fading away with increasing particle size parameter.


Optical delineation of human malignant melanoma using second harmonic imaging of collagen.
Skin cancer incidence has increased exponentially over the last three decades. In 2008 skin cancer caused 2280 deaths in the UK, with 2067 due to malignant melanoma. Early diagnosis can prevent mortality, however, conventional treatment requires multiple procedures and increasing treatment times. Second harmonic generation (SHG) imaging could offer diagnosis and demarcation of melanoma borders non-invasively at presentation thereby short-cutting the excision biopsy stage. To test the efficacy and accuracy of SHG imaging of collagen in skin and to delineate the borders of skin cancers, unstained human melanoma biopsy sections were imaged using SHG microscopy. Comparisons with sister sections, stained with H&E or Melan-A were made for correlation of invasion borders. Fresh ex vivo normal human and rat skin was imaged through its whole thickness using SHG to demonstrate this technique is transferable to in vivo tissues. SHG imaging demonstrated detailed collagen distribution in normal skin, with total absence of SHG signal (fibrillar collagen) within the melanoma-invaded tissue. The presence or absence of signal changes dramatically at the borders of the melanoma, accurately demarcating the edges that strongly correlated with H&E and Melan-A defined borders (p<0.002). SHG imaging of ex vivo human and rat skin demonstrated collagen architecture could be imaged through the full thickness of the skin. We propose that SHG imaging could be used for diagnosis and accurate demarcation of melanoma borders on presentation and therefore potentially reduce mortality rates.


Optimal allocation of PCR tests to minimise disease transmission through contact tracing and quarantine.
PCR testing is a crucial capability for managing disease outbreaks, but it is also a limited resource and must be used carefully to ensure the information gain from testing is valuable. Testing has two broad uses for informing public health policy, namely to track epidemic dynamics and to reduce transmission by identifying and managing cases. In this work we develop a modelling framework to examine the effects of test allocation in an epidemic, with a focus on using testing to minimise transmission. Using the COVID-19 pandemic as an example, we examine how the number of tests conducted per day relates to reduction in disease transmission, in the context of logistical constraints on the testing system. We show that if daily testing is above the routine capacity of a testing system, which can cause delays, then those delays can undermine efforts to reduce transmission through contact tracing and quarantine. This work highlights that the two goals of aiming to reduce transmission and aiming to identify all cases are different, and it is possible that focusing on one may undermine achieving the other. To develop an effective strategy, the goals must be clear and performance metrics must match the goals of the testing strategy. If metrics do not match the objectives of the strategy, then those metrics may incentivise actions that undermine achieving the objectives.


A database of marine phytoplankton abundance, biomass and species composition in Australian waters.
There have been many individual phytoplankton datasets collected across Australia since the mid 1900s, but most are unavailable to the research community. We have searched archives, contacted researchers, and scanned the primary and grey literature to collate 3,621,847 records of marine phytoplankton species from Australian waters from 1844 to the present. Many of these are small datasets collected for local questions, but combined they provide over 170 years of data on phytoplankton communities in Australian waters. Units and taxonomy have been standardised, obviously erroneous data removed, and all metadata included. We have lodged this dataset with the Australian Ocean Data Network (http://portal.aodn.org.au/) allowing public access. The Australian Phytoplankton Database will be invaluable for global change studies, as it allows analysis of ecological indicators of climate change and eutrophication (e.g., changes in distribution; diatom:dinoflagellate ratios). In addition, the standardised conversion of abundance records to biomass provides modellers with quantifiable data to initialise and validate ecosystem models of lower marine trophic levels.


Detection and typing of human papillomavirus DNA in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis.
To clarify the role of human papillomavirus (HPV) in penile cancer we evaluated the prevalence of HPV DNA in different histological subtypes of penile carcinoma, dysplasia, and condyloma using a novel, sensitive SPF10 HPV polymerase chain reaction assay and a novel genotyping line probe assay, allowing simultaneous identification of 25 different HPV types. Formalin-fixed, paraffin-embedded tissue samples were collected from the United States and Paraguay. HPV DNA was detected in 42% cases of penile carcinoma, 90% cases of dysplasia, and 100% cases of condyloma. There were significant differences in HPV prevalence in different histological cancer subtypes. Although keratinizing squamous cell carcinoma and verrucous carcinoma were positive for HPV DNA in only 34.9 and 33.3% of cases, respectively, HPV DNA was detected in 80% of basaloid and 100% of warty tumor subtypes. There was no significant difference in HPV prevalence between cases from Paraguay and the United States. In conclusion, the overall prevalence of HPV DNA in penile carcinoma (42%) is lower than that in cervical carcinoma (approximately 100%) and similar to vulvar carcinoma (approximately 50%). In addition, specific histological subtypes of penile cancer--basaloid and warty--are consistently associated with HPV, however, only a subset of keratinizing and verrucous penile carcinomas is positive for HPV DNA, and thus these two tumor groups seem to develop along different pathogenetic pathways.


Condition-dependent natal dispersal in a large herbivore: heavier animals show a greater propensity to disperse and travel further.
Natal dispersal is defined as the movement between the natal range and the site of first breeding and is one of the most important processes in population dynamics. The choice an individual makes between dispersal and philopatry may be condition dependent, influenced by either phenotypic attributes and/or environmental factors. Interindividual variability in dispersal tactics has profound consequences for population dynamics, particularly with respect to metapopulation maintenance. A better understanding of the mechanisms underlying this variability is thus of primary interest. We investigated the ranging behaviour of 60 juvenile European roe deer, Capreolus capreolus, monitored with GPS collars for 1 year prior to their first reproduction, from 2003 to 2010 in South-West France. Dispersal occurs across a spatial continuum so that dividing individuals into two categories (dispersers vs. philopatric) may lead to information loss. Therefore, to investigate condition-dependent dispersal more accurately, we developed an individual-based measure of dispersal distance, which took into account interindividual variation in ranging behaviour. We assessed the influence of body mass, the degree of habitat heterogeneity and sex on dispersal initiation date, dispersal propensity and distance. The overall population dispersal rate was 0·34, with a mean ± SD linear distance between natal and post-dispersal home ranges of 12·3 ± 10·5 km. Dispersal distances followed a classical leptokurtic distribution. We found no sex bias in either dispersal rate or distance. Forest animals dispersed less than those living in more heterogeneous habitats. Heavier individuals dispersed with a higher probability, earlier and further than lighter individuals. Our individual-based standardised dispersal distance increased linearly with body mass, with some suggestion of a body mass threshold of 14 kg under which no individual dispersed. Natal dispersal in roe deer was thus dependent on both phenotypic attributes and environmental context. Our results suggest that population connectivity can be altered by a change in average body condition and is likely higher in the rich and heterogeneous habitats typical of modern day agricultural landscapes.


Macrophage migration inhibitory factor promotes cyst growth in polycystic kidney disease.
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by renal cyst formation, inflammation, and fibrosis. Macrophages infiltrate cystic kidneys, but the role of these and other inflammatory factors in disease progression are poorly understood. Here, we identified macrophage migration inhibitory factor (MIF) as an important regulator of cyst growth in ADPKD. MIF was upregulated in cyst-lining epithelial cells in polycystin-1-deficient murine kidneys and accumulated in cyst fluid of human ADPKD kidneys. MIF promoted cystic epithelial cell proliferation by activating ERK, mTOR, and Rb/E2F pathways and by increasing glucose uptake and ATP production, which inhibited AMP-activated protein kinase signaling. MIF also regulated cystic renal epithelial cell apoptosis through p53-dependent signaling. In polycystin-1-deficient mice, MIF was required for recruitment and retention of renal macrophages, which promoted cyst expansion, and Mif deletion or pharmacologic inhibition delayed cyst growth in multiple murine ADPKD models. MIF-dependent macrophage recruitment was associated with upregulation of monocyte chemotactic protein 1 (MCP-1) and inflammatory cytokine TNF-α. TNF-α induced MIF expression, and MIF subsequently exacerbated TNF-α expression in renal epithelial cells, suggesting a positive feedback loop between TNF-α and MIF during cyst development. Our study indicates MIF is a central and upstream regulator of ADPKD pathogenesis and provides a rationale for further exploration of MIF as a therapeutic target for ADPKD.


The cassava mealybug (Phenacoccus manihoti) in Asia: first records, potential distribution, and an identification key.
Phenacoccus manihoti Matile-Ferrero (Hemiptera: Pseudococcidae), one of the most serious pests of cassava worldwide, has recently reached Asia, raising significant concern over its potential spread throughout the region. To support management decisions, this article reports recent distribution records, and estimates the climatic suitability for its regional spread using a CLIMEX distribution model. The article also presents a taxonomic key that separates P. manihoti from all other mealybug species associated with the genus Manihot. Model predictions suggest P. manihoti imposes an important, yet differential, threat to cassava production in Asia. Predicted risk is most acute in the southern end of Karnataka in India, the eastern end of the Ninh Thuan province in Vietnam, and in most of West Timor in Indonesia. The model also suggests P. manihoti is likely to be limited by cold stress across Vietnam's northern regions and in the entire Guangxi province in China, and by high rainfall across the wet tropics in Indonesia and the Philippines. Predictions should be particularly important to guide management decisions for high risk areas where P. manihoti is absent (e.g., India), or where it has established but populations remain small and localized (e.g., South Vietnam). Results from this article should help decision-makers assess site-specific risk of invasion, and develop proportional prevention and surveillance programs for early detection and rapid response.


Neuronal underpinnings of cognitive impairment in bipolar disorder: A large data-driven functional magnetic resonance imaging study.
Cognitive impairment occurs in approximately 50% of remitted patients with bipolar disorder (BD). However, there exists no treatment with replicated and robust efficacy on cognition in BD. This is partially due to limited insight into the neuronal underpinnings of cognitive impairment in these patients. This is the first study to investigate neuronal underpinnings of cognitive impairment in a large functional magnetic resonance imaging (fMRI) dataset comparing neural activity patterns between distinct neurocognitive subgroups of partially or fully remitted patients with BD. Patients (n = 153) and healthy controls (HC) (n = 52) underwent neuropsychological assessment and fMRI, during which they performed a verbal N-back working memory (WM) task. Based on hierarchical cluster analysis of neuropsychological test performance, patients were grouped into one of two neurocognitive subgroups (cognitively impaired, n = 91; cognitively normal compared to HC, n = 62) that were compared on WM-related neural activity. Cognitively impaired patients displayed WM-related hypo-activity in left dorsolateral prefrontal cortex and frontal and parietal regions within a cognitive control network (CCN) as well as hyper-activity in the default mode network (DMN) compared to cognitively normal patients. In contrast, cognitively normal patients only exhibited hypo-activity within a small cluster in the superior frontal gyrus relative to HC. Cognitive impairment in BD seems to originate from a failure to recruit key regions in the CCN and to suppress task-irrelevant DMN activity during cognitive performance. These results highlight modulation of aberrant dorsal prefrontal and DMN activity as a putative target for pro-cognitive treatment in BD.


Management of Penetrating Cerebrovascular Injuries in Pediatric Trauma: A Retrospective Multicenter Study.
Blunt cerebrovascular injury is uncommon in the pediatric population; penetrating cerebrovascular injuries are even rarer and are thus poorly understood. To describe the diagnosis and management of penetrating cerebrovascular injuries and describe outcomes of available treatment modalities. Clinical and radiographic data were collected retrospectively from a multicenter trauma registry for children screened for cerebrovascular injury during 2003 to 2013 at 4 academic pediatric trauma centers. Among 645 pediatric patients evaluated with computed tomography angiography with blunt cerebrovascular injury, 130 also had a penetrating trauma indication. Seven penetrating cerebrovascular injuries were diagnosed in 7 male patients (mean age 12.4 years, range 12-18 years). Focal neurological deficit and concomitant intracranial injury were each seen in 2 patients. There were 2 intracranial carotid artery injuries, 4 extracranial carotid artery injuries, and 1 vertebral artery injury. The majority of injuries were higher than grade I (5/7; 71%): 2 were grade I, 1 grade II, 2 grade III, and 2 grade IV. The 2 patients with grade III injuries required open surgery, and 1 patient with a grade IV injury underwent endovascular treatment. Two patients suffered immediate stroke secondary to the penetrating cerebrovascular injury. There were no delayed neurological deficits from the penetrating injuries, and no patients died as a result of the injuries. This is the largest series of penetrating cerebrovascular trauma in the pediatric literature. Although rare, penetrating cerebrovascular injuries can be high-grade injuries that require urgent recognition and may require aggressive endovascular and/or open surgery for treatment.


Microscale solid-state thermal diodes enabling ambient temperature thermal circuits for energy applications.
Thermal diodes, or devices that transport thermal energy asymmetrically, analogous to electrical diodes, hold promise for thermal energy harvesting and conservation, as well as for phononics or information processing. The junction of a phase change material and phase invariant material can form a thermal diode; however, there are limited constituent materials available for a given target temperature, particularly near ambient. In this work, we demonstrate that a micro and nanoporous polystyrene foam can house a paraffin-based phase change material, fused to PMMA, to produce mechanically robust, solid-state thermal diodes capable of ambient operation with Young's moduli larger than 11.5 MPa and 55.2 MPa above and below the melting transition point, respectively. Moreover, the composites show significant changes in thermal conductivity above and below the melting point of the constituent paraffin and rectification that is well-described by our previous theory and the Maxwell-Eucken model. Maximum thermal rectifications range from 1.18 to 1.34. We show that such devices perform reliably enough to operate in thermal diode bridges, dynamic thermal circuits capable of transforming oscillating temperature inputs into single polarity temperature differences - analogous to an electrical diode bridge with widespread implications for transient thermal energy harvesting and conservation. Overall, our approach yields mechanically robust, solid-state thermal diodes capable of engineering design from a mathematical model of phase change and thermal transport, with implications for energy harvesting.


Benign smooth muscle tumors of the gastrointestinal tract. A 24-year experience.
Between 1963 and 1987, 131 patients with benign gastrointestinal stromal tumors, primarily leiomyomas, were treated at the Massachusetts General Hospital. Eighty per cent of tumors were located in stomach or small intestine. Two thirds of the tumors were discovered in symptomatic patients before operation by a variety of diagnostic studies. A mitotic index (MI) was determined for each tumor, defined as the number of mitoses per 50 high-power microscopic fields. Only gastric and small intestine tumors had MIs more than 2. Tumors were treated by conservative excision in 67% and radical excision in 33%. At a median follow-up of 6 years there were no local recurrences. No patient with a tumor discovered incidentally has recurred. Three symptomatic patients have died of metastatic liver disease. Each patient with recurrence had a tumor with MI of 2 or more, which represents a recurrence rate of 16% in this group. We conclude that symptomatic gastric and small intestine tumors having two or more mitoses per 50 high-power fields carry a significant risk for recurrence, and that routine pathologic assessment of MI may identify a subset of patients who would potentially benefit from close follow-up and consideration for further therapy.


Relationship between depression and frailty in older adults: A systematic review and meta-analysis.
Depression and frailty are prevalent and burdensome in older age. However, the relationships between these entities are unclear and no quantitative meta- analysis exists. We conducted a systematic review and meta-analysis to investigate the associations between depression and frailty. Two authors searched major electronic databases from inception until November-2016 for cross-sectional/longitudinal studies investigating depression and frailty. The strength of the reciprocal associations between frailty and depression was assessed through odds ratios (ORs) adjusted for potential confounders. From 2306 non duplicated hits, 24 studies were included. The overall prevalence of depression in 8023 people with frailty was 38.60% (95% CI 30.07-47.10, I2=94%). Those with frailty were at increased odds of having depression (OR adjusted for publication bias 4.42, 95%CI 2.66-7.35, k=11), also after adjusting for potential confounders (OR=2.64; 95%CI: 1.59-4.37, I2=55%, k=4). The prevalence of frailty in 2167 people with depression was 40.40% (95%CI 27.00-55.30, I2=97%). People with depression were at increased odds of having frailty (OR=4.07, 95%CI 1.93-8.55, k=8). The pooled OR for incident frailty, adjusted for a median of 7 confounders, was 3.72 (95%CI 1.95-7.08, I2=98%, k=4), whilst in two studies frailty increased the risk of incident depression with an OR=1.90 (95%CI 1.55-2.32, I2=0%). This meta-analysis points to a reciprocal interaction between depression and frailty in older adults. Specifically, each condition is associated with an increased prevalence and incidence of the other, and may be a risk factor for the development of the other. However, further prospective investigations are warranted.


Massively parallel sequencing of enriched target amplicons for high-resolution genotyping of Salmonella serovars.
With next generation sequencing (NGS) technology, it is now possible to carry out in-depth, large-scale sequencing projects, such as whole genome sequencing, in a fast and inexpensive manner. However, often it is more practical and convenient to sequence and analyze multiple, smaller regions of the bacterial genome to gain valuable information about an organism. One such application is genotyping of bacterial strains by multilocus sequence typing (MLST) that involves PCR and sequencing analysis of typically 7 housekeeping genes. Recently, we described a novel MLST method, called MLST-seq that combines a PCR-based target enrichment method and NGS technology to simultaneously analyze numerous target gene sequences, thereby improving the resolution and high-throughput capacity of current MLST approaches. However, the performance of the MLST-seq method was hampered from a substantial bias in target enrichment step. In this study, we used an improved target enrichment method using hairpin selectors to amplify 21 target genes simultaneously from each of 41 Salmonella strains. The resulting amplicons tagged with strain-specific barcodes were pooled and sequenced en masse by 454 pyrosequencing. Analysis of sequence data from 38 Salmonella strains using combinations of 3, 7 and 14 target genes resulted in 23, 32 and 37 distinct allelic profiles, respectively. These results demonstrated that MLST-seq with an increased number of target genes is an efficient way to improve discrimination among closely-related strains of Salmonella. With the rapidly increasing sequencing capacity of NGS technologies combined with further improvements in target capturing methods, MLST-seq could become a promising approach to perform high-resolution strain typing of a large collection of Salmonella, and likely other genera in a labor- and cost-efficient manner in the future.


A global perspective on feeding assessment in the neonatal intensive care unit.
A comprehensive assessment of feeding performance of infants in the neonatal intensive care unit (NICU) includes not only the traditional approaches of evaluating oral motor control and sensory responses but also evaluation of other factors. Infant feeding is a highly complex and integrated process involving numerous body systems. A global assessment would determine the infant's feeding function in the key areas of state and behavior, tactile responses, motoric control, oral motor function, physiologic control, and coordination of sucking, swallowing, and breathing. Information is obtained through skilled clinical observation as well as from technological monitors or medical tests and procedures. This article provides an overview of a comprehensive assessment that occupational therapists may use when providing service to infants in the NICU.


Electronic Absorption Spectra from MM and ab initio QM/MM Molecular Dynamics: Environmental Effects on the Absorption Spectrum of Photoactive Yellow Protein.
We describe a new interface of the GPU parallelized TeraChem electronic structure package and the Amber molecular dynamics package for quantum mechanical (QM) and mixed QM and molecular mechanical (MM) molecular dynamics simulations. This QM/MM interface is used for computation of the absorption spectra of the photoactive yellow protein (PYP) chromophore in vacuum, aqueous solution, and protein environments. The computed excitation energies of PYP require a very large QM region (hundreds of atoms) covalently bonded to the chromophore in order to achieve agreement with calculations that treat the entire protein quantum mechanically. We also show that 40 or more surrounding water molecules must be included in the QM region in order to obtain converged excitation energies of the solvated PYP chromophore. These results indicate that large QM regions (with hundreds of atoms) are a necessity in QM/MM calculations.


Reliability of multi-site UK Biobank MRI brain phenotypes for the assessment of neuropsychiatric complications of SARS-CoV-2 infection: The COVID-CNS travelling heads study.
Magnetic resonance imaging (MRI) of the brain could be a key diagnostic and research tool for understanding the neuropsychiatric complications of COVID-19. For maximum impact, multi-modal MRI protocols will be needed to measure the effects of SARS-CoV-2 infection on the brain by diverse potentially pathogenic mechanisms, and with high reliability across multiple sites and scanner manufacturers. Here we describe the development of such a protocol, based upon the UK Biobank, and its validation with a travelling heads study. A multi-modal brain MRI protocol comprising sequences for T1-weighted MRI, T2-FLAIR, diffusion MRI (dMRI), resting-state functional MRI (fMRI), susceptibility-weighted imaging (swMRI), and arterial spin labelling (ASL), was defined in close approximation to prior UK Biobank (UKB) and C-MORE protocols for Siemens 3T systems. We iteratively defined a comparable set of sequences for General Electric (GE) 3T systems. To assess multi-site feasibility and between-site variability of this protocol, N = 8 healthy participants were each scanned at 4 UK sites: 3 using Siemens PRISMA scanners (Cambridge, Liverpool, Oxford) and 1 using a GE scanner (King's College London). Over 2,000 Imaging Derived Phenotypes (IDPs), measuring both data quality and regional image properties of interest, were automatically estimated by customised UKB image processing pipelines (S2 File). Components of variance and intra-class correlations (ICCs) were estimated for each IDP by linear mixed effects models and benchmarked by comparison to repeated measurements of the same IDPs from UKB participants. Intra-class correlations for many IDPs indicated good-to-excellent between-site reliability. Considering only data from the Siemens sites, between-site reliability generally matched the high levels of test-retest reliability of the same IDPs estimated in repeated, within-site, within-subject scans from UK Biobank. Inclusion of the GE site resulted in good-to-excellent reliability for many IDPs, although there were significant between-site differences in mean and scaling, and reduced ICCs, for some classes of IDP, especially T1 contrast and some dMRI-derived measures. We also identified high reliability of quantitative susceptibility mapping (QSM) IDPs derived from swMRI images, multi-network ICA-based IDPs from resting-state fMRI, and olfactory bulb structure IDPs from T1, T2-FLAIR and dMRI data. These results give confidence that large, multi-site MRI datasets can be collected reliably at different sites across the diverse range of MRI modalities and IDPs that could be mechanistically informative in COVID brain research. We discuss limitations of the study and strategies for further harmonisation of data collected from sites using scanners supplied by different manufacturers. These acquisition and analysis protocols are now in use for MRI assessments of post-COVID patients (N = 700) as part of the ongoing COVID-CNS study.


Environmental contaminants activate human and polar bear (Ursus maritimus) pregnane X receptors (PXR, NR1I2) differently.
Many persistent organic pollutants (POPs) accumulate readily in polar bears because of their position as apex predators in Arctic food webs. The pregnane X receptor (PXR, formally NR1I2, here proposed to be named promiscuous xenobiotic receptor) is a xenobiotic sensor that is directly involved in metabolizing pathways of a wide range of environmental contaminants. In the present study, we comparably assess the ability of 51 selected pharmaceuticals, pesticides and emerging contaminants to activate PXRs from polar bears and humans using an in vitro luciferase reporter gene assay. We found that polar bear PXR is activated by a wide range of our test compounds (68%) but has a slightly more narrow ligand specificity than human PXR that was activated by 86% of the 51 test compounds. The majority of the agonists identified (70%) produces a stronger induction of the reporter gene via human PXR than via polar bear PXR, however with some notable and environmentally relevant exceptions. Due to the observed differences in activation of polar bear and human PXRs, exposure of each species to environmental agents is likely to induce biotransformation differently in the two species. Bioinformatics analyses and structural modeling studies suggest that amino acids that are not part of the ligand-binding domain and do not interact with the ligand can modulate receptor activation.


EGFR-targeted hybrid plasmonic magnetic nanoparticles synergistically induce autophagy and apoptosis in non-small cell lung cancer cells.
The epidermal growth factor receptor (EGFR) is overexpressed in 80% of non-small cell lung cancer (NSCLC) and is associated with poor survival. In recent years, EGFR-targeted inhibitors have been tested in the clinic for NSCLC. Despite the emergence of novel therapeutics and their application in cancer therapy, the overall survival rate of lung cancer patients remains 15%. To develop more effective therapies for lung cancer we have combined the anti-EGFR antibody (Clone 225) as a molecular therapeutic with hybrid plasmonic magnetic nanoparticles (NP) and tested on non-small cell lung cancer (NSCLC) cells. Cell viability was determined by trypan-blue assay. Cellular protein expression was determined by Western blotting. C225-NPs were detected by electron microscopy and confocal microscopy, and EGFR expression using immunocytochemistry. C225-NP exhibited a strong and selective antitumor effect on EGFR-expressing NSCLC cells by inhibiting EGFR-mediated signal transduction and induced autophagy and apoptosis in tumor cells. Optical images showed specificity of interactions between C225-NP and EGFR-expressing NSCLC cells. No binding of C225-NP was observed for EGFR-null NSCLC cells. C225-NP exhibited higher efficiency in induction of cell killing in comparison with the same amount of free C225 antibody in tumor cells with different levels of EGFR expression. Furthermore, in contrast to C225-NP, free C225 antibody did not induce autophagy in cells. However, the therapeutic efficacy of C225-NP gradually approached the level of free antibodies as the amount of C225 antibody conjugated per nanoparticle was decreased. Finally, attaching C225 to NP was important for producing the enhanced tumor cell killing as addition of mixture of free C225 and NP did not demonstrate the same degree of cell killing activity. We demonstrated for the first time the molecular mechanism of C225-NP induced cytotoxic effects in lung cancer cells that are not characteristic for free molecular therapeutics thus increasing efficacy of therapy against NSCLC.


TAp63 prevents premature aging by promoting adult stem cell maintenance.
The cellular mechanisms that regulate the maintenance of adult tissue stem cells are still largely unknown. We show here that the p53 family member, TAp63, is essential for maintenance of epidermal and dermal precursors and that, in its absence, these precursors senesce and skin ages prematurely. Specifically, we have developed a TAp63 conditional knockout mouse and used it to ablate TAp63 in the germline (TAp63(-/-)) or in K14-expressing cells in the basal layer of the epidermis (TAp63(fl/fl);K14cre+). TAp63(-/-) mice age prematurely and develop blisters, skin ulcerations, senescence of hair follicle-associated dermal and epidermal cells, and decreased hair morphogenesis. These phenotypes are likely due to loss of TAp63 in dermal and epidermal precursors since both cell types show defective proliferation, early senescence, and genomic instability. These data indicate that TAp63 serves to maintain adult skin stem cells by regulating cellular senescence and genomic stability, thereby preventing premature tissue aging.


Synthesis and self-assembly of a DNA molecular brush.
We report herein on the polymer-crystallization-assisted thiol-ene photosynthesis of an amphiphilic comb/graft DNA copolymer, or molecular brush, composed of a hydrophobic poly(2-oxazoline) backbone and hydrophilic short single-stranded nucleic acid grafts. Coupling efficiencies are above 60% and thus higher as compared with the straight solid-phase-supported synthesis of amphiphilic DNA block copolymers. The DNA molecular brushes self-assemble into sub-micron-sized spherical structures in water as evidenced by light scattering as well as atomic force and electron microscopy imaging. The nucleotide sequences remain functional, as assessed by UV and fluorescence spectroscopy subsequent to isoindol synthesis at the surface of the structures. The determination of a vesicular morphology is supported by encapsulation and subsequent spectroscopy monitoring of the release of a water-soluble dye and spectroscopic quantification of the hybridization efficiency (30% in average) of the functional nucleic acid strands engaged in structure formation: about one-half of the nucleotide sequences are available for hybridization, whereas the other half are hindered within the self-assembled structure. Because speciation between complementary and non complementary sequences in the medium could be ascertained by confocal laser scanning microscopy, the stable self-assembled molecular brushes demonstrate the potential for sensing applications.


Exploring the impact of digital stories on empathic learning in neonatal nurse education.
Within neonatal nurse education, learning to understand the compelling emotional experiences of parents following the birth of their premature baby is essential to give person-centred empathic care. A collection of digital stories informed by parents' experiences was created to use as a pedagogical tool for students and staff within the neonatal speciality. This study reports on an exploration of the value of these digital stories for the enhancement of empathic learning. Using the principles of narrative inquiry, a mixed-methods design comprising 'point-of-view', reflective exercises, interviews and a questionnaire distributed to nursing students and practice staff ascertained views of three digital stories. The participants evaluated the digital stories positively overall and it was clear they were an effective and innovative way to learn about emotional experiences of parents. Powerful emotional messages from parents enhanced awareness, understanding and insight into their affective experience. Within the context of narrative-based neonatal education, there is a place for digital storytelling as a pedagogical strategy informed by parent narratives, to teach students and staff about the emotional impact of the neonatal care experience. In turn, this can potentially lead to more empathic, person-centred care relating to the families of sick, vulnerable babies.


The Impact of External Loads Carried by Police Officers on Vertical Jump Performance.
The purpose of this study was to examine the impact that external loads have on vertical jump height and peak anaerobic power output (PAPw) of police officers during a vertical jump (VJ) test. Retrospective data of 47 (mean age 38.79 ± 7.97 years) police officers from a US Law Enforcement Agency (LEA) were used for analysis. VJ heights and body mass were used in the Sayers Peak Power Equation to calculate PAPw. Power-to-weight (P:W) ratios were then calculated by dividing PAPw by the officer's body mass. VJ height significantly (p < .001) decreased with load (unloaded = 49.49 ± 8.46 cm: loaded = 43.62 ± 7.68 cm). A Pearson's correlation showed a significant (p < .01) low-moderate (r = .387) relationship between absolute load (9.57 ± .94 kg) and change in PAPw, and a significant (p < .01) strong (r = .794) correlation between relative load and changes in P:W. This study supports previous research that suggests that occupational load carriage has a negative impact on VJ performance in police officers and may influence job performance, and that training programs may mitigate these negative effects.


Using high spatial resolution remote sensing for risk mapping of malaria occurrence in the Nouna district, Burkina Faso.
Malaria control measures such as early diagnosis and treatment, intermittent treatment of pregnant women, impregnated bed nets, indoor spraying and larval control measures are difficult to target specifically because of imprecise estimates of risk at a small-scale level. Ways of estimating local risks for malaria are therefore important. A high-resolution satellite view from the SPOT 5 satellite during 2008 was used to generate a land cover classification in the malaria endemic lowland of North-Western Burkina Faso. For the area of a complete satellite view of 60 x 60 km, a supervised land cover classification was carried out. Ten classes were built and correlated to land cover types known for acting as Anopheles mosquito breeding sites. According to known correlations of Anopheles larvae presence and surface water-related land cover, cultivated areas in the riverine vicinity of Kossi River were shown to be one of the most favourable sites for Anopheles production. Similar conditions prevail in the South of the study region, where clayey soils and higher precipitations benefit the occurrence of surface water. Besides pools, which are often directly detectable, rice fields and occasionally flooded crops represent most appropriate habitats. On the other hand, forests, elevated regions on porous soils, grasslands and the dryer, sandy soils in the north-western part turned out to deliver fewer mosquito breeding opportunities. Potential high and low risks for malaria at the village level can be differentiated from satellite data. While much remains to be done in terms of establishing correlations between remotely sensed risks and malaria disease patterns, this is a potentially useful approach which could lead to more focused disease control programmes.


School-aged Children Who Are Not Progressing Academically: Considerations for Pediatricians.
Pediatricians and other pediatric primary care providers may be consulted when families have concerns that their child is not making expected progress in school. Pediatricians care not only for an increasingly diverse population of children who may have behavioral, psychological, and learning difficulties but also for increasing numbers of children with complex and chronic medical problems that can affect the development of the central nervous system and can present with learning and academic concerns. In many instances, pediatric providers require additional information about the nature of cognitive, psychosocial, and educational difficulties that affect their school-aged patients. Our purpose for this report is to describe the current state of the science regarding educational achievement to inform pediatricians' decisions regarding further evaluation of a child's challenges. In this report, we review commonly available options for psychological evaluation and/or treatment, medical referrals, and/or recommendations for referral for eligibility determinations at school and review strategies for collaborating with families, schools, and specialists to best serve children and families.


Successful use of long-acting octreotide for intractable chronic gastrointestinal bleeding in children.
Octreotide reduces splanchnic blood flow and is effective in controlling gastrointestinal bleeding (GIB) caused by portal hypertension. Monthly long-acting octreotide (OCT-LAR) with an efficacy and safety profile similar to subcutaneous daily administration presents an attractive option for long-term therapy. We report our experience with OCT-LAR for severe/recurrent GIB in children with portal hypertension secondary to chronic liver disease or portal vein thrombosis who were unresponsive to standard interventions. A total of 9 patients, 7 boys, who received OCT-LAR between 2000 and 2009 were studied retrospectively (median age at first bleeding 21 months, range 1 month-14.5 years). The dose (2.5-20 mg intramuscularly monthly) was extrapolated from that used in adult acromegaly and neuroendocrine tumours (10-60 mg/mo). Response to treatment was assessed by comparing the number of bleeding events, hospital admissions for acute bleeding, and number of blood units required during the year before and year after starting OCT-LAR. OCT-LAR led to a reduction in the number of bleeding episodes in all of the children and to cessation of bleeding in 7. Two children listed for transplantation because of severe GIB were removed from the list. No serious adverse effects immediately attributable to OCT-LAR were observed. One child developed growth hormone deficiency and hypothyroidism during a prolonged period of treatment with subcutaneous octreotide before commencing OCT-LAR. OCT-LAR can control severe intractable recurrent GIB in children with portal hypertension. Prospective randomised controlled trials and pharmacokinetic studies are indicated to establish the optimum dose and length of treatment of OCT-LAR and confirm its efficacy and long-term safety in children.


PAPER--accelerating parallel evaluations of ROCS.
Modern graphics processing units (GPUs) are flexibly programmable and have peak computational throughput significantly faster than conventional CPUs. Herein, we describe the design and implementation of PAPER, an open-source implementation of Gaussian molecular shape overlay for NVIDIA GPUs. We demonstrate one to two order-of-magnitude speedups on high-end commodity GPU hardware relative to a reference CPU implementation of the shape overlay algorithm and speedups of over one order of magnitude relative to the commercial OpenEye ROCS package. In addition, we describe errors incurred by approximations used in common implementations of the algorithm.


Outcomes and Resource Use of Sepsis-associated Stays by Presence on Admission, Severity, and Hospital Type.
To establish a baseline for the incidence of sepsis by severity and presence on admission in acute care hospital settings before implementation of a broad sepsis screening and response initiative. A retrospective cohort study using hospital discharge abstracts of 5672 patients, aged 18 years and above, with sepsis-associated stays between February 2012 and January 2013 at an academic medical center and 5 community hospitals in Texas. Sepsis was present on admission in almost 85% of cases and acquired in-hospital in the remainder. The overall inpatient death rate was 17.2%, but was higher in hospital-acquired sepsis (38.6%, medical; 29.2%, surgical) and Stages 2 (17.6%) and 3 (36.4%) compared with Stage 1 (5.9%). Patients treated at the academic medical center had a higher death rate (22.5% vs. 15.1%, P<0.001) and were more costly ($68,050±184,541 vs. $19,498±31,506, P<0.001) versus community hospitals. Greater emphasis is needed on public awareness of sepsis and the detection of sepsis in the prehospitalization and early hospitalization period. Hospital characteristics and case mix should be accounted for in cross-hospital comparisons of sepsis outcomes and costs.


Dermal xenobiotic metabolism: a comparison between native human skin, four in vitro skin test systems and a liver system.
The xenobiotic metabolism of 4 in vitro human skin test systems (2D and 3D) was compared with that of the native human skin samples from which the skin test systems had been produced. In total 3 skin samples were investigated, each from a different donor to exclude variability due to gender, donor or tissue supplier. In addition, the skin cultures were compared with a surrogate of the liver. Basal and induced phase I and phase II enzymes were analyzed regarding gene/protein expression as well as enzyme activity. The distinctions between the different test systems and the two dermal compartments (epidermis and dermis) were more noticeable than any donor variability. The 3D models of skin and liver mirrored the in vivo situation more realistically than did the monolayer cultures. Phase I metabolism was more pronounced in the hepatic model, whereas phase II metabolism was more prominent in the reconstructed skin. These results show that reconstructed skin models are a valuable tool for organ-specific safety assessment with regard to xenobiotic metabolism.


The causes and effects of socio-demographic exclusions from clinical trials.
To investigate the exclusion from trials of women, older people and minority ethnic groups, focusing on two drug exemplars, statins and non-steroidal anti-inflammatory drugs (NSAIDs). Medical and ethical databases. Workshops with stakeholders. Literature was reviewed on exclusions in healthcare research and three workshops were held with stakeholders. Twenty-seven randomised controlled trials (RCTs) of statins use for secondary prevention of coronary heart disease (CHD) and 25 NSAIDs trials for pain in osteoarthritis (OA) were analysed. Using a Scottish cohort with record-linkage, profiling was carried out for 3188 people needing secondary prevention for CHD (1993-1996), ascertaining the independent effects of statins, and 131,410 people dispensed NSAIDs (1989-1996), examining adverse effects. Routine data sources were accessed to profile the need for secondary prevention of CHD in England and usage was estimated by consulting published surveys. The Somerset and Avon Survey of Health (SASH) 1996-97 and published data were accessed for information on potential need and usage of NSAIDs in OA. For both drugs, the socio-demographic profiles of trial samples, the population in potential need and those on treatment were compared. An evidence synthesis was produced to clarify the effects of statins on women and older people and the relationship of absolute effectiveness outcomes with underlying risk levels of disease events was modelled, examining the likely effects of trial exclusions. The average age of statins trial participants was 58.5 years; only 16.3% were women. Statins reduced cardiovascular disease (CVD) incidence by about 25% in both men and women. Older people up to 75 years of age also benefited. Meta-analysis and two landmark trials confirmed these results. The average age of NSAIDs trial participants was 61.9 years and women were well represented (68.5%). Gastrointestinal (GI) adverse events were commonly reported, but renal side-effects were not. Outcomes were seldom reported according to socio-demographic group. For both drugs, USA trials were more inclusive than UK/European trials. Ethnicity was not well reported for either drug. Some 23% of the cohort were treated with statins. Users were younger than non-statins users (but no more likely to be male) and had superior outcomes. High current exposure to NSAIDs elevated the risk of GI side-effects by about 50% versus no current exposure and renal impairment risk by nearly 140%. Side-effect risk increased with age; being female diminished risk. Approximately 537,000 incident cases of CVD would qualify for statins use in England each year. Women constitute 45% of this population with need, two-thirds of whom are aged 65 years or over. Need varies by ethnic group. No sex bias in prescribing statins was detected, but use was commoner in younger people. For NSAIDs, 6.3% of adults aged 35+ years reported hip and/or knee pain associated with OA; 3.9% of adults used prescribed analgesics for this and they were more likely to be women and to be >65 years old. For statins, women formed almost half of the 'with need' and 'on treatment' populations, but were markedly under-represented in trials. Those aged 65+ years formed nearly two-thirds of the 'with need' population, but only one-fifth of trial samples, and were less likely to be treated than younger subjects. For NSAIDs, women formed similar proportions. Associations of side-effects with socio-demographic factors was revealed in cohort data but not in trials. The issue of exclusion from trials of women, older people and ethnic minorities has been relatively neglected in the UK research community, and there is confusion about diversity issues. Under-representation occurs, but in drug trials at least this may not always affect the external validity of relative effect estimates. However, measures of absolute effectiveness, absolute harm and cost-effectiveness are associated with underlying risk levels in different socio-demographic groups. Under-representation will therefore bias absolute effect estimates. The following areas are suggested for future research: multi-disciplinary assessment of realistic options for trialists to address the issue of exclusions; clarification of the use of ethnic categories in health research and of the implications of the different dimensions of ageing and sex/gender; identification of barriers and facilitators to the involvement of different population groups in research, further investigation of the susceptibility of older men to NSAID adverse events, and the development of a 'register of registries and databases' and exploration of how linked health information systems in the UK could be improved.


Inhibition of lipase and inflammatory mediators by Chlorella lipid extracts for antiacne treatment.
Acne vulgaris is a chronic inflammatory disease, and its treatment is challenging due to the multifactorial etiology and emergence of antibiotic-resistant Propionibacterium acnes strains. This study was focused to reduce antibiotics usage and find an alternate therapeutic source for treating acne. Lipid extracts of six Chlorella species were tested for inhibition of lipase, reactive oxygen species (ROS) production, cytokine production using P. acnes (Microbial Type Culture Collection 1951). Lipase inhibitory assay was determined by dimercaprol Tributyrate - 5, 5'- dithiobis 2-nitrobenzoic acid method and ROS production assay was performed using nitro-blue tetrazolium test. The anti-inflammatory activity of algal lipid extracts was determined by in vitro screening method based on inhibition of pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) produced by human peripheral blood mononuclear cells. Minimum inhibitory concentration (MIC) values of lipid extracts were determined by microdilution method, and the fatty acid methyl esters (FAME) were analyzed by gas chromatography-mass spectroscopy. Chlorella ellipsoidea has the highest lipase inhibitory activity with 61.73% inhibition, followed by Chlorella vulgaris (60.31%) and Chlorella protothecoides (58.9%). Lipid extracts from C. protothecoides and C. ellipsoidea has significantly reduced the ROS production by 61.27% and 58.34% respectively. Inhibition of pro-inflammatory cytokines TNF-α showed the inhibition ranging from 58.39% to 78.67%. C. vulgaris has exhibited the MICvalue of 10 μg/ml followed by C. ellipsoidea, C. protothecoides and Chlorella pyrenoidosa (20 μg/ml). FAME analysis detected 19 fatty acids of which 5 were saturated fatty acids, and 14 were unsaturated fatty acids ranging from C14 to C24. The results suggest that lipid extracts of Chlorella species has significant inhibitory activity on P. acnes by inhibiting lipase activity. Further, anti-inflammatory reaction caused by the pathogen could be reduced by the inhibiting the production of ROS and inflammatory mediators TNF-α and exposes new frontiers on the antiacne activities of Chlorella lipid extracts.


Ethnomedicinal plants used for snakebite treatments in Ethiopia: a comprehensive overview.
Traditional medicine plays an important role in the daily lives of people living in rural parts of Ethiopia. Despite the fact that Ethiopia has a long history of using traditional medicinal plants as an alternative medicine source, there is no checklist compiling these plants used for snakebite treatment. This review collected and compiled available knowledge on and practical usage of such plants in the country. A literature review on medicinal plants used to treat snakebites was conducted from 67 journal articles, PhD dissertation and MSc theses available online. Data that summarize scientific and folk names, administration methods, plant portion used for treatment and method of preparation of recipes were organized and analyzed based on citation frequency. The summarized results revealed the presence of 184 plant species distributed among 67 families that were cited for treating snakebite in Ethiopia. In this literature search, no single study was entirely dedicated to the study of traditional medicinal plants used for the treatment of snakebite in Ethiopia. Most of the species listed as a snakebite remedy were shrubs and climbers (44%) followed by herbs (33%) and trees (23%). Fabaceae was the most predominant family with the greatest number of species, followed by Solanaceae and Vitaceae. Remedies are mainly prepared from roots and leaves, through decoctions, infusions, powders and juices. Most remedies were administered orally (69%). The six most frequently mentioned therapeutically important plants were Nicotiana tabacum, Solanum incanum, Carissa spinanrum, Calpurnia aurea, Croton macrostachyus and Cynodon dactylon. Authors reviewed the vegetal substances involved in snakebite management and their action mode. In addition to screening the biologically active ingredients and pharmacological activities of these plant materials, future studies are needed to emphasize the conservation and cultivation of important medicinal plants of the country.


Screening for thoracic aortic pathology: Clinical practice in a single tertiary center.
The aim is to present current clinical practice of thoracic aorta screening in a tertiary referral center. We identified how often imaging techniques were used for screening and established the value of transthoracic echocardiography (TTE) in comparison with computed tomography (CT) to detect aortic dilation. We also investigated which additional abnormalities of the heart, aorta or smaller arteries were discovered. All patients ≥15 years who visited our tertiary center in 2012-2016 for first thoracic aortic screening were retrospectively included. Diameters of the sinus of Valsalva (SoV) and maximum ascending aorta (AA) were compared between TTE and CT. The sensitivity and specificity of TTE to detect aortic dilation (≥40 mm) was assessed with CT as reference standard. Intracardiac abnormalities found with TTE and arterial abnormalities found with CT were identified. In total 349 patients (155 men, age 41 ± 15 years, 10% genetic mutation) were included. Screening was performed with TTE only in 35% and with TTE and CT in 65%. Patients who underwent TTE only were younger, had less often hypertension and less often a family history of aortic pathology. Although there was a good correlation between TTE and CT, the diameters measured with TTE were typically lower (SoV -1.0, 95%CI -6.6 to 4.7 and AA -0.4, 95%CI -6.5 to 5.8). Sensitivity of TTE for detecting aortic dilation was 61% (SoV) and 57% (AA) and specificity was 96% (SoV) and 100% (AA). Valve abnormalities, ventricular dilation or reduced ventricular function was found with TTE in 26 patients (7%). In 47 patients (13%) ascending aortic dilation was diagnosed and in 10 patients (4%) relevant peripheral arterial abnormalities were identified using CT. Most often patients received both TTE and CT (65%). Since TTE showed a low sensitivity to detect aortic dilation, CT imaging is advised at least once in patients referred for thoracic aortic screening.


Diabetes mellitus is associated with increased mortality in patients receiving curative therapy for hepatocellular carcinoma.
Diabetes mellitus (DM) is closely associated with hepatocarcinogenesis. This study explores the prognostic impact of DM in patients who received curative therapy for localized hepatocellular carcinoma (HCC). Patients who had been diagnosed with stage I or II HCC in 2003 and 2004 and received surgical resection or local ablation therapy were identified from the population-based Taiwan National Cancer Registry. Data pertaining to DM and other comorbidities were retrieved from the Taiwan National Health Insurance database. Liver cancer-specific survival (LCS), liver disease-related survival (LDS) and overall survival (OS) rates were compared between patients with and without DM. The presence of other comorbidities and tumor status were adjusted using multivariate analysis. A total of 931 patients who fulfilled the study criteria were analyzed; 185 (20%) of them had DM (type 1 or type 2). The LCS, LDS, and OS rates were significantly worse for patients with DM than patients without DM (all p < .001). After adjusting for age, sex, tumor stage, treatment, and the presence of other comorbidities, DM remained an independent predictor of poorer LCS (hazard ratio [HR] = 1.57; p < .001), LDS (HR = 1.70; p < .001), and OS (HR = 1.69; p < .001). The associations between DM and mortality were consistent among subgroups, irrespective of tumor size, stage, treatment modality, and liver cirrhosis. DM is an independent factor for poorer prognosis in patients who received curative therapy for localized HCC.


Graphene double-layer capacitor with ac line-filtering performance.
Electric double-layer capacitors (DLCs) can have high storage capacity, but their porous electrodes cause them to perform like resistors in filter circuits that remove ripple from rectified direct current. We have demonstrated efficient filtering of 120-hertz current with DLCs with electrodes made from vertically oriented graphene nanosheets grown directly on metal current collectors. This design minimized electronic and ionic resistances and produced capacitors with RC time constants of less than 200 microseconds, in contrast with ~1 second for typical DLCs. Graphene nanosheets have a preponderance of exposed edge planes that greatly increases charge storage as compared with that of designs that rely on basal plane surfaces. Capacitors constructed with these electrodes could be smaller than the low-voltage aluminum electrolyte capacitors that are typically used in electronic devices.


Optically Transparent Wood Substrate for Perovskite Solar Cells.
Transparent wood is a candidate for use as an energy-saving building material due to its low density (ca. 1.2 g/cm3), high optical transmittance (over 85% at 1 mm thickness), low thermal conductivity (0.23 W m-1 K-1), and good load-bearing performance with tough failure behavior (no shattering). High optical transmittance also makes transparent wood a candidate for optoelectronic devices. In this work, for the first time, perovskite solar cells processed at low temperature (<150 °C) were successfully assembled directly on transparent wood substrates. A power conversion efficiency up to 16.8% was obtained. The technologies demonstrated may pave the way for integration of solar cells with light transmitting wood building structures for energy-saving purposes.


Structural requirements for optimized delivery, inhibition of oxidative stress, and antiapoptotic activity of targeted nitroxides.
Suppression of mitochondrial production of reactive oxygen species is a promising strategy against intrinsic apoptosis typical of degenerative diseases. Stable nitroxide radicals such as 4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl (TEMPOL) and its analogs combine several important features, including recycleability, electron acceptance from respiratory complexes, superoxide dismutase mimicry, and radical scavenging. Although successful in antioxidant protection, their effective concentrations are too high for successful in vivo applications. Recently (J Am Chem Soc 127:12460, 2005), we reported that 4-amino 2,2,6,6-tetramethyl-1-piperidinyloxy, covalently conjugated to a five-residue segment of gramicidin S (GS), was integrated into mitochondria and blocked actinomycin D (ActD)-induced superoxide generation and apoptosis. Using a model of ActD-induced apoptosis in mouse embryonic cells, we screened a library of nitroxides to explore structure-activity relationships between their antioxidant/antiapoptotic properties and chemical composition and three-dimensional (3D) structure. High hydrophobicity and effective mitochondrial integration are necessary but not sufficient for high antiapoptotic/antioxidant activity of a nitroxide conjugate. By designing conformationally preorganized peptidyl nitroxide conjugates and characterizing their 3D structure experimentally (circular dichroism and NMR) and theoretically (molecular dynamics), we established that the presence of the beta-turn/beta-sheet secondary structure is essential for the desired activity. Monte Carlo simulations in model lipid membranes confirmed that the conservation of the d-Phe-Pro reverse turn in hemi-GS analogs ensures the specific positioning of the nitroxide moiety at the mitochondrial membrane interface and maximizes their protective effects. These new insights into the structure-activity relationships of nitroxide-peptide and -peptide isostere conjugates are instrumental for development of new mechanism-based therapeutically effective agents.


Valence shell charge concentration (VSCC) evolution: a tool to investigate the transformations within a VSCC throughout a chemical reaction.
Theoretical studies about reaction mechanisms are usually limited to the determination of the energetic paths that connect reactants, transition states, and products. Recently, our group proposed the structural evolution, which has provided insights about the molecular structure changes occurring along a reaction path. Structural evolution may be defined as the development of a chemical reaction system across the partitioning of the nuclear configuration space into a finite number of structural regions defined on account of the topology of a scalar field, e.g., the electron density. In this paper, we present a tool to investigate within the framework of the Quantum Theory of Atoms in Molecules the evolvement of the Valence Shell Charge Concentration, the VSCC evolution, which is the description of the changes of electron density concentrations and depletions around the bonding area of an atom. The VSCC evolution provides supplementary information to the structural evolution because it allows the analysis of valence shells within a structural region, i.e., a subset of R(Q) with the same connectivity among the atoms forming a molecule. This new approach constitutes also a complement to the Valence-Shell Electron Pair Repulsion (VSEPR) model because it gives an account of the adjustments of electron pairs in the valence shell of an atom across a chemical reaction. The insertion reaction in the hydroformylation reaction of ethylene, the reduction of cyclohexanone with lithium aluminum hydride, the oxidation of methanol with chlorochromate, and the bimolecular nucleophilic substitution of CH(3)F with F(-) are used as representatives examples of the application of the VSCC evolution. Overall, this paper shows how the VSCC evolution through an analysis of the modifications of local charge concentrations and depletions in individual steps of a chemical reaction gives new insights about these processes.


Network based elucidation of drug response: from modulators to targets.
: Network-based drug discovery aims at harnessing the power of networks to investigate the mechanism of action of existing drugs, or new molecules, in order to identify innovative therapeutic treatments. In this review, we describe some of the most recent advances in the field of network pharmacology, starting with approaches relying on computational models of transcriptional networks, then moving to protein and signaling network models and concluding with "drug networks". These networks are derived from different sources of experimental data, or literature-based analysis, and provide a complementary view of drug mode of action. Molecular and drug networks are powerful integrated computational and experimental approaches that will likely speed up and improve the drug discovery process, once fully integrated into the academic and industrial drug discovery pipeline.


Effects of amino acid substitutions at positions 33 and 37 on UDP-glucuronosyltransferase 1A9 (UGT1A9) activity and substrate selectivity.
UGT1A9 contributes to the glucuronidation of numerous drugs and xenobiotics. There is evidence to suggest that the Met33Thr substitution, as occurs in the polymorphic variant UGT1A9*3, variably affects xenobiotic glucuronidation. The equivalent position in UGT1A4 is also known to influence enzyme activity, whilst an N-terminal domain histidine (His37 in UGT1A9) is believed to function as the catalytic base in most UGT enzymes. To elucidate the roles of key amino acids and characterise structure-function relationships, we determined the effects of amino acid substitutions at positions 33 and 37 of UGT1A9 on the kinetics of 4-methylumbelliferone (4-MU), mycophenolic acid (MPA), propofol (PRO), sulfinpyrazone (SFZ), frusemide (FSM), (S)-naproxen (NAP) and retigabine (RTB) glucuronidation, compounds that undergo glucuronidation at either a phenolic (4-MU, MPA, PRO), carboxylate (FSM, NAP), acidic carbon (SFZ) or amine (RTB) function. Substitution of Met33 with Val, Ile, Thr, and Gln, as occur in UGT1A1, UGT1A3, UGT1A4 and UGT1A6 respectively, variably affected kinetics and catalytic efficiency. Whilst K(m) values were generally higher and V(max) and CL(int) values were generally lower than for wild-type UGT1A9 with most substrate-mutant pairs, the pattern and the magnitude of the changes in each parameter differed substantially. Moreover, exceptions occurred; CL(int) values for MPA and FSM glucuronidation by the position-33 mutants were the same as or higher than that of UGT1A9. Mutation of His37 abolished activity towards all substrates, except RTB N-glucuronidation. The data confirm the importance of single amino acids for UGT enzyme activity and substrate selectivity, and support a pivotal role for residue-33 in facilitating substrate binding to UGT1A9.


Mechanism of the large polarization rotation effect in the all-dielectric artificially chiral nanogratings.
The physical mechanism of the large polarization rotation effect in direct transmission of the all-dielectric artificially chiral nanogratings is explored by experiment and numerical analysis. It is shown that the different coupling of right- and left-circularly polarized components of the normally incident light to the leaky guided modes or Fabry-Pérot resonance modes lead to the enhanced circular dichroism, resulting in the giant polarization rotation effect. The mode profile and local field calculations demonstrate intuitive images of the different coupling performance at resonances.


Reconstitution of T cell receptor zeta-mediated calcium mobilization in nonlymphoid cells.
T cell antigen receptor (TCR) activation involves interactions between receptor subunits and nonreceptor protein tyrosine kinases (PTKs). Early steps in signaling through the zeta chain of the TCR were examined in transfected COS-1 cells. Coexpression of the PTK p59fynT, but not p56lck, with zeta or with a homodimeric TCR beta-zeta fusion protein produced tyrosine phosphorylation of both zeta and phospholipase C (PLC)-gamma 1, as well as calcium ion mobilization in response to receptor cross-linking. CD45 coexpression enhanced these effects. No requirement for the PTKZAP-70 was observed. Thus, p59fynT may link zeta directly to the PLC-gamma 1 activation pathway.


Tuning Pharmacokinetics to Improve Tumor Accumulation of a Prostate-Specific Membrane Antigen-Targeted Phototheranostic Agent.
We describe a simple and effective bioconjugation strategy to extend the plasma circulation of a low molecular weight targeted phototheranostic agent, which achieves high tumor accumulation (9.74 ± 2.26%ID/g) and high tumor-to-background ratio (10:1). Long-circulating pyropheophorbide (LC-Pyro) was synthesized with three functional building blocks: (1) a porphyrin photosensitizer for positron-emission tomography (PET)/fluorescence imaging and photodynamic therapy (PDT), (2) a urea-based prostate-specific membrane antigen (PSMA) targeting ligand, and (3) a peptide linker to prolong the plasma circulation time. With porphyrin's copper-64 chelating and optical properties, LC-Pyro demonstrated its dual-modality (fluorescence/PET) imaging potential for selective and quantitative tumor detection in subcutaneous, orthotopic, and metastatic murine models. The peptide linker in LC-Pyro prolonged its plasma circulation time about 8.5 times compared to its truncated analog. High tumor accumulation of LC-Pyro enabled potent PDT, which resulted in significantly delayed tumor growth in a subcutaneous xenograft model. This approach can be applied to improve the pharmacokinetics of existing and future targeted PDT agents for enhanced tumor accumulation and treatment efficacy.


The role of phenolic compounds on olive oil aroma release.
In this study, atmospheric pressure chemical ionisation-mass spectrometry (APCI-MS) was successfully applied to understand the effect of phenolic compounds on the release of olive oil aroma compounds. Eight aroma compounds were monitored under in-vivo and in-vitro dynamic conditions in olive oil with and without the addition of virgin olive oil (VOO) biophenols. Three model olive oils (MOOs) were set up with identical volatile compounds concentrations using a refined olive oil (ROO). Phenolics were extracted from VOOs and were added to two MOOs in order to obtain two different concentrations of phenolic compounds (P+ = 354 mg kg-1; P++ = 593 mg kg-1). Another MOO was without VOO biophenols (P-). Phenolic compounds impacted both the intensity and time of aroma release. In the in-vivo study, 1-penten-3-one, trans-2-hexenal and esters had lower release in the presence of higher levels of biophenols after swallowing. In contrast, linalool and 1-hexanol had a greater release. The more hydrophobic compounds had a longer persistence in the breath than the hydrophilic compounds. VOO phenolics-proline-rich proteins complexes could explain the binding of aroma compounds and consequently their decrease during analysis and during organoleptic assessment of olive oil.


Bile acid sequestration reduces plasma glucose levels in db/db mice by increasing its metabolic clearance rate.
Bile acid sequestrants (BAS) reduce plasma glucose levels in type II diabetics and in murine models of diabetes but the mechanism herein is unknown. We hypothesized that sequestrant-induced changes in hepatic glucose metabolism would underlie reduced plasma glucose levels. Therefore, in vivo glucose metabolism was assessed in db/db mice on and off BAS using tracer methodology. Lean and diabetic db/db mice were treated with 2% (wt/wt in diet) Colesevelam HCl (BAS) for 2 weeks. Parameters of in vivo glucose metabolism were assessed by infusing [U-(13)C]-glucose, [2-(13)C]-glycerol, [1-(2)H]-galactose and paracetamol for 6 hours, followed by mass isotopologue distribution analysis, and related to metabolic parameters as well as gene expression patterns. Compared to lean mice, db/db mice displayed an almost 3-fold lower metabolic clearance rate of glucose (p = 0.0001), a ∼300% increased glucokinase flux (p = 0.001) and a ∼200% increased total hepatic glucose production rate (p = 0.0002). BAS treatment increased glucose metabolic clearance rate by ∼37% but had no effects on glucokinase flux nor total hepatic or endogenous glucose production. Strikingly, BAS-treated db/db mice displayed reduced long-chain acylcarnitine content in skeletal muscle (p = 0.0317) but not in liver (p = 0.189). Unexpectedly, BAS treatment increased hepatic FGF21 mRNA expression 2-fold in lean mice (p = 0.030) and 3-fold in db/db mice (p = 0.002). BAS induced plasma glucose lowering in db/db mice by increasing metabolic clearance rate of glucose in peripheral tissues, which coincided with decreased skeletal muscle long-chain acylcarnitine content.


Abrupt transition to complete congestion on complex networks and control.
Previous works on traffic-flow dynamics on complex networks have mostly focused on continuous phase transition from a free-flow state to a locally congested state as a parameter, such as the packet-generating rate, is increased through a critical value. Above the transition point congestion occurs on a small subset of nodes. Utilizing a conventional traffic-flow model based on the packet birth-death process and more importantly, taking into account the fact that in realistic networks nodes have only finite buffers, we find an abrupt transition from free flow to complete congestion. Slightly below the transition point, the network can support the maximum amount of traffic for some optimal value of the routing parameter. We develop a mean-field theory to explain the surprising transition phenomenon and provide numerical support. Furthermore, we propose a control strategy based on the idea of random packet dropping to prevent/break complete congestion. Our finding provides insights into realistic communication networks where complete congestion can occur directly from a free-flow state without any apparent precursor, and our control strategy can be effective to restore traffic flow once complete congestion has occurred.


Involvement of hydrogenases in the formation of highly catalytic Pd(0) nanoparticles by bioreduction of Pd(II) using Escherichia coli mutant strains.
Escherichia coli produces at least three [NiFe] hydrogenases (Hyd-1, Hyd-2 and Hyd-3). Hyd-1 and Hyd-2 are membrane-bound respiratory isoenzymes with their catalytic subunits exposed to the periplasmic side of the membrane. Hyd-3 is part of the cytoplasmically oriented formate hydrogenlyase complex. In this work the involvement of each of these hydrogenases in Pd(II) reduction under acidic (pH 2.4) conditions was studied. While all three hydrogenases could contribute to Pd(II) reduction, the presence of either periplasmic hydrogenase (Hyd-1 or Hyd-2) was required to observe Pd(II) reduction rates comparable to the parent strain. An E. coli mutant strain genetically deprived of all hydrogenase activity showed negligible Pd(II) reduction. Electron microscopy suggested that the location of the resulting Pd(0) deposits was as expected from the subcellular localization of the particular hydrogenase involved in the reduction process. Membrane separation experiments established that Pd(II) reductase activity is membrane-bound and that hydrogenases are required to initiate Pd(II) reduction. The catalytic activity of the resulting Pd(0) nanoparticles in the reduction of Cr(VI) to Cr(III) varied according to the E. coli mutant strain used for the initial bioreduction of Pd(II). Optimum Cr(VI) reduction, comparable to that observed with a commercial Pd catalyst, was observed when the bio-Pd(0) catalytic particles were prepared from a strain containing an active Hyd-1. The results are discussed in the context of economic production of novel nanometallic catalysts.


Survey of cuff management practices in intensive care units in Australia and New Zealand.
Cuff management varies widely in Europe and North America. Little is known about current practice in Australia and New Zealand. To characterize important aspects of cuff management in intensive care units in Australia and New Zealand to compare with international reports. A questionnaire was sent to all nurse managers of adult intensive care units in Australia and New Zealand. Survey response was 53% (92/175). After intubation, most units (50/92, 54%) used both minimal occlusive volume technique and cuff pressure measurement; 5 (5.5%) used these methods along with pilot balloon palpation. Twenty units (22%) used cuff pressure measurement exclusively and 16 units (17.5%) used the minimal occlusive volume technique exclusively. Only 1 unit (1%) used the minimal leak technique after intubation. For ongoing management, cuff pressure measurement was the preferred method, used exclusively in 42 units (46%), with the minimal occlusive volume technique used in 40 units (43%; sole method in 6 units [7%]) and palpation in 4 units (4%). In most units (65/92, 71%), cuffs were monitored once per nursing shift. In units using the minimal occlusive volume technique, oropharyngeal suctioning (74%) and semirecumbent positioning (58%) were routinely incorporated; sigh breaths (6%), discontinuation of enteral feeding (10%), and nasogastric tube aspiration (26%) were uncommon. Cuff management protocols (37%) and subglottic suctioning (12%) were used infrequently. Cuff pressure measurement was the preferred method, used exclusively or in combination with other methods. The minimal occlusive volume technique was used more often after intubation than for ongoing management.


Host factors abolish the need for polysaccharides and extracellular matrix-binding protein in Staphylococcus epidermidis biofilm formation.
Introduction. Staphylococcus epidermidis is predominant in implant-associated infections due to its capability to form biofilms. It can deploy several strategies for biofilm development using either polysaccharide intercellular adhesin (PIA), extracellular DNA (eDNA) and/or proteins, such as the extracellular matrix-binding protein (Embp).Hypothesis/Gap Statement. We hypothesize that the dichotomic regulation of S. epidermidis adhesins is linked to whether it is inside a host or not, and that in vitro biofilm investigations in laboratory media may not reflect actual biofilms in vivo.Aim. We address the importance of PIA and Embp in biofilm grown in 'humanized' media to understand if these components play different roles in biofilm formation under conditions where bacteria can incorporate host proteins in the biofilm matrix.Methodology. S. epidermidis 1585 WT (deficient in icaADBC), and derivative strains that either lack embp, express embp from an inducible promotor, or express icaADBC from a plasmid, were cultivated in standard laboratory media, or in media with human plasma or serum. The amount, structure, elasticity and antimicrobial penetration of biofilms was quantified to describe structural differences caused by the different matrix components and growth conditions. Finally, we quantified the initiation of biofilms as suspended aggregates in response to host factors to determine how quickly the cells aggregate in response to the host environment and reach a size that protects them from phagocytosis.Results. S. epidermidis 1585 required polysaccharides to form biofilm in laboratory media. However, these observations were not representative of the biofilm phenotype in the presence of human plasma. If human plasma were present, polysaccharides and Embp were redundant for biofilm formation. Biofilms formed in human plasma were loosely attached and existed mostly as suspended aggregates. Aggregation occurred after 2 h of exposing cells to plasma or serum. Despite stark differences in the amount and composition of biofilms formed by polysaccharide-producing and Embp-producing strains in different media, there were no differences in vancomycin penetration or susceptibility.Conclusion. We suggest that the assumed importance of polysaccharides for biofilm formation is an artefact from studying biofilms in laboratory media void of human matrix components. The cell-cell aggregation of S. epidermidis can be activated by host factors without relying on either of the major adhesins, PIA and Embp, indicating a need to revisit the basic question of how S. epidermidis deploys self-produced and host-derived matrix components to form antibiotic-tolerant biofilms in vivo.


Concurrent malignant melanoma and cutaneous involvement by classical Hodgkin lymphoma (CHL) in a 63 year-old man.
Classical Hodgkin lymphoma (CHL) is a lymphoproliferative disorder that has a bimodal age distribution, affecting young and elderly individuals, and is curable in more than 90% of patients. Here we report the coexistence of cutaneous CHL and malignant melanoma as the presentation of papules and a plaque, in an individual with remote history of systemic CHL. One of the biopsies showed a mononuclear cell infiltrate with Reed-Sternberg (RS) like cells that were positive for CD30 and CD15, but negative for CD45. A second concurrent biopsy showed an atypical melanocytic proliferation with significant pagetoid spreading and diffuse Melan-A staining. Based on morphology alone, it is almost impossible to distinguish CHL from other primary cutaneous lymphoproliferative disorders, such as CD30+ lymphoproliferative disorder (lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large-cell lymphoma), or even tumor stage mycosis fungoides when the epidermotropism is minimal. Additionally, bizarre melanocytic cells can also appear similar to RS cells. Our case illustrates the first case report of malignant melanoma and CHL in a patient presenting simultaneously. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8979757349937225.


CDK1-Mediated SIRT3 Activation Enhances Mitochondrial Function and Tumor Radioresistance.
Tumor adaptive resistance to therapeutic radiation remains a barrier for further improvement of local cancer control. SIRT3, a member of the sirtuin family of NAD(+)-dependent protein deacetylases in mitochondria, promotes metabolic homeostasis through regulation of mitochondrial protein deacetylation and plays a key role in prevention of cell aging. Here, we demonstrate that SIRT3 expression is induced in an array of radiation-treated human tumor cells and their corresponding xenograft tumors, including colon cancer HCT-116, glioblastoma U87, and breast cancer MDA-MB231 cells. SIRT3 transcriptional activation is due to SIRT3 promoter activation controlled by the stress transcription factor NF-κB. Posttranscriptionally, SIRT3 enzymatic activity is further enhanced via Thr150/Ser159 phosphorylation by cyclin B1-CDK1, which is also induced by radiation and relocated to mitochondria together with SIRT3. Cells expressing Thr150Ala/Ser159Ala-mutant SIRT3 show a reduction in mitochondrial protein lysine deacetylation, Δψm, MnSOD activity, and mitochondrial ATP generation. The clonogenicity of Thr150Ala/Ser159Ala-mutant transfectants is lower and significantly decreased under radiation. Tumors harboring Thr150Ala/Ser159Ala-mutant SIRT3 show inhibited growth and increased sensitivity to in vivo local irradiation. These results demonstrate that enhanced SIRT3 transcription and posttranslational modifications in mitochondria contribute to adaptive radioresistance in tumor cells. CDK1-mediated SIRT3 phosphorylation is a potential effective target to sensitize tumor cells to radiotherapy.


An examination of periodontal treatment, dental care, and pregnancy outcomes in an insured population in the United States.
We examined whether periodontal treatment or other dental care is associated with adverse birth outcomes within a medical and dental insurance database. In a retrospective cohort study, we examined the records of 23,441 women enrolled in a national insurance plan who delivered live births from singleton pregnancies in the United States between January 1, 2003, and September 30, 2006, for adverse birth outcomes on the basis of dental treatment received. We compared rates of low birthweight and preterm birth among 5 groups, specifying the relative timing and type of dental treatment received. We used logistic regression analysis to compare outcome rates across treatment groups while adjusting for duration of continuous dental coverage, maternal age, pregnancy complications, neighborhood-level income, and race/ethnicity. Analyses showed that women who received preventive dental care had better birth outcomes than did those who received no treatment (P < .001). We observed no evidence of increased odds of adverse birth outcomes from dental or periodontal treatment. For women with medical and dental insurance, preventive care is associated with a lower incidence of adverse birth outcomes.


Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature.
The management of women with prosthetic heart valves during pregnancy poses a particular challenge as there are no available controlled clinical trials to provide guidelines for effective antithrombotic therapy. Oral anticoagulants such as warfarin sodium cause fetal embryopathy; subcutaneous administration of heparin sodium has been reported to be ineffective in preventing thromboembolic complications. To identify the risks of maternal and fetal complications in women with mechanical heart valves treated with different anticoagulation regimens during pregnancy. We performed a systematic review of the literature to determine pooled estimates of maternal and fetal risks associated with the 3 commonly used approaches: (1) oral anticoagulants (OA) throughout pregnancy, (2) replacing OA with heparin in the first trimester (from 6-12 weeks' gestation), and (3) heparin use throughout pregnancy. Fetal outcomes included spontaneous abortions and fetopathic effects, and maternal outcomes were major bleeding, thromboembolic complications, and death. The use of OA throughout pregnancy is associated with warfarin embryopathy in 6.4% (95% confidence interval [CI], 4.6%-8.9%) of livebirths. The substitution of heparin at or prior to 6 weeks, and continued until 12 weeks, eliminated this risk. Overall risks for fetal wastage (spontaneous abortion, stillbirths, and neonatal deaths) were similar in women treated with OA throughout, compared with women treated with heparin in the first trimester. Maternal mortality was 2.9% (95% CI, 1.9%-4.2%). Maj or bleeding events occurred in 2.5% (95% CI, 1.7%-3.5%) of all pregnancies, most at the time of delivery. The regimen associated with the lowest risk of valve thrombosis (3.9%; 95% CI, 2.9-5.9%) was the use of OA throughout; using heparin only between 6 and 12 weeks' gestation was associated with an increased risk of valve thrombosis (9.2%; 95% CI, 5.9%-13.9%). Thromboembolic prophylaxis of women with mechanical heart valves during pregnancy is best achieved with OA; however, this increases the risk of fetal embryopathy. Substituting OA with heparin between 6 and 12 weeks reduces the risk of fetopathic effects, but with an increased risk of thromboembolic complications. The use of low-dose heparin is definitely inadequate; the use of adjusted-dose heparin warrants aggressive monitoring and appropriate dose adjustment. Large prospective trials to determine the best regimen for these women are needed.