PADS Arsenal: a database of prokaryotic defense systems related genes.
Defense systems are vital weapons for prokaryotes to resist heterologous DNA and survive from the constant invasion of viruses, and they are widely used in biochemistry investigation and antimicrobial drug research. So far, numerous types of defense systems have been discovered, but there is no comprehensive defense systems database to organize prokaryotic defense gene datasets. To fill this gap, we unveil the prokaryotic antiviral defense system (PADS) Arsenal (https://bigd.big.ac.cn/padsarsenal), a public database dedicated to gathering, storing, analyzing and visualizing prokaryotic defense gene datasets. The initial version of PADS Arsenal integrates 18 distinctive categories of defense system with the annotation of 6 600 264 genes retrieved from 63,701 genomes across 33 390 species of archaea and bacteria. PADS Arsenal provides various ways to retrieve defense systems related genes information and visualize them with multifarious function modes. Moreover, an online analysis pipeline is integrated into PADS Arsenal to facilitate annotation and evolutionary analysis of defense genes. PADS Arsenal can also visualize the dynamic variation information of defense genes from pan-genome analysis. Overall, PADS Arsenal is a state-of-the-art open comprehensive resource to accelerate the research of prokaryotic defense systems.


Biosensors and rapid diagnostic tests on the frontier between analytical and clinical chemistry for biomolecular diagnosis of dengue disease: a review.
The past decades have witnessed enormous technological improvements towards the development of simple, cost-effective and accurate rapid diagnostic tests for detection and identification of infectious pathogens. Among them is dengue virus, the etiologic agent of the mosquito-borne dengue disease, one of the most important emerging infectious pathologies of nowadays. Dengue fever may cause potentially deadly hemorrhagic symptoms and is endemic in the tropical and sub-tropical world, being also a serious threat to temperate countries in the developed world. Effective diagnostics for dengue should be able to discriminate among the four antigenically related dengue serotypes and fulfill the requirements for successful decentralized (point-of-care) testing in the harsh environmental conditions found in most tropical regions. The accurate identification of circulating serotypes is crucial for the successful implementation of vector control programs based on reliable epidemiological predictions. This paper briefly summarizes the limitations of the main conventional techniques for biomolecular diagnosis of dengue disease and critically reviews some of the most relevant biosensors and rapid diagnostic tests developed, implemented and reported so far for point-of-care testing of dengue infections. The invaluable contributions of microfluidics and nanotechnology encompass the whole paper, while evaluation concerns of rapid diagnostic tests and foreseen technological improvements in this field are also overviewed for the diagnosis of dengue and other infectious and tropical diseases as well.


Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics.
In December 2016, a panel of experts in microbiology, nutrition and clinical research was convened by the International Scientific Association for Probiotics and Prebiotics to review the definition and scope of prebiotics. Consistent with the original embodiment of prebiotics, but aware of the latest scientific and clinical developments, the panel updated the definition of a prebiotic: a substrate that is selectively utilized by host microorganisms conferring a health benefit. This definition expands the concept of prebiotics to possibly include non-carbohydrate substances, applications to body sites other than the gastrointestinal tract, and diverse categories other than food. The requirement for selective microbiota-mediated mechanisms was retained. Beneficial health effects must be documented for a substance to be considered a prebiotic. The consensus definition applies also to prebiotics for use by animals, in which microbiota-focused strategies to maintain health and prevent disease is as relevant as for humans. Ultimately, the goal of this Consensus Statement is to engender appropriate use of the term 'prebiotic' by relevant stakeholders so that consistency and clarity can be achieved in research reports, product marketing and regulatory oversight of the category. To this end, we have reviewed several aspects of prebiotic science including its development, health benefits and legislation.


Solving the obesity epidemic: voices from the community.
"Science and Community: Ending Obesity Improving Health" (S&C) aimed to reduce obesity in Houston by developing community partnerships to identify research priorities and develop a sustainable obesity reduction program. Partnership members were recruited from S&C events and invited to participate in in-depth interviews to gain insight into obesity prevalence, causes, and solutions. Members (n = 22) completed a 60-90-min in-depth interview. The interview guide consisted of 30 questions about pressing health problems in the community, potential solutions to health problems and obesity and how the environment has impacted obesity and health behaviors in the community. Interviewees (n = 12 women and 10 men) were mostly Hispanic/Latino (n = 9) and African American (n = 7). Common problems identified were childhood obesity, balancing a healthy diet and physical inactivity. Interviewees identified obesity as a major problem in their communities and cited access to quality food and physical activity resources as both a problem and a solution. Additional emergent themes focused on solutions, including increasing awareness and education, coordinated efforts among organizations and using an ecologic approach to combat obesity. Community insight gleaned from this study may be used to enhance relevance and sustainability of programs developed to reduce obesity and suggests possible avenues for participatory research and intervention.


Comparison of zotarolimus-eluting and everolimus-eluting coronary stents.
New-generation coronary stents that release zotarolimus or everolimus have been shown to reduce the risk of restenosis. However, it is unclear whether there are differences in efficacy and safety between the two types of stents on the basis of prospectively adjudicated end points endorsed by the Food and Drug Administration. In this multicenter, noninferiority trial with minimal exclusion criteria, we randomly assigned 2292 patients to undergo treatment with coronary stents releasing either zotarolimus or everolimus. Twenty percent of patients were randomly selected for repeat angiography at 13 months. The primary end point was target-lesion failure, defined as a composite of death from cardiac causes, any myocardial infarction (not clearly attributable to a nontarget vessel), or clinically indicated target-lesion revascularization within 12 months. The secondary angiographic end point was the extent of in-stent stenosis at 13 months. At least one off-label criterion for stent placement was present in 66% of patients. The zotarolimus-eluting stent was noninferior to the everolimus-eluting stent with respect to the primary end point, which occurred in 8.2% and 8.3% of patients, respectively (P<0.001 for noninferiority). There were no significant between-group differences in the rate of death from cardiac causes, any myocardial infarction, or revascularization. The rate of stent thrombosis was 2.3% in the zotarolimus-stent group and 1.5% in the everolimus-stent group (P=0.17). The zotarolimus-eluting stent was also noninferior regarding the degree (+/-SD) of in-stent stenosis (21.65+/-14.42% for zotarolimus vs. 19.76+/-14.64% for everolimus, P=0.04 for noninferiority). In-stent late lumen loss was 0.27+/-0.43 mm in the zotarolimus-stent group versus 0.19+/-0.40 mm in the everolimus-stent group (P=0.08). There were no significant between-group differences in the rate of adverse events. At 13 months, the new-generation zotarolimus-eluting stent was found to be noninferior to the everolimus-eluting stent in a population of patients who had minimal exclusion criteria. (ClinicalTrials.gov number, NCT00617084.)


Tolerance in TCR/cognate antigen double-transgenic mice mediated by incomplete thymic deletion and peripheral receptor downregulation.
Influenza nucleoprotein (NP)-specific T-cell receptor transgenic mice (F5) were crossed with transgenic mice expressing the cognate antigenic protein under the control of the H-2Kb promoter. Double-transgenic mice show negative selection of thymocytes at the CD4+8+TCRlo to CD4+8+TCRhi transition stage. A few CD8+ T cells, however, escape clonal deletion, and in the peripheral lymphoid organs of these mice, they exhibit low levels of the transgenic receptor and upregulated levels of the CD44 memory marker. Such cells do not proliferate upon exposure to antigen stimulation in vivo or ex vivo, however, they can develop low but detectable levels of antigen-specific cytotoxic function after stimulation in vitro in the presence of IL-2.


Epidemiology of bitter crab disease (Hematodinium sp.) in snow crabs Chionoecetes opilio from Newfoundland, Canada.
The parasitic dinoflagellate Hematodinium sp. causes a condition known as bitter crab disease (BCD) in snow crabs Chionoecetes opilio and Tanner crabs C. bairdi. As the name of the condition implies, crabs infected with BCD are unmarketable due to their bitter flavor. We surveyed the distribution of BCD in 3 regions within the snow crab fishery of Newfoundland from 1997 to 2003. Over time, the disease has become firmly established in Conception and Bonavista Bays and persists at low levels on the Avalon fishing grounds. An epizootic occurred within Bonavista and Conception Bays in 1999 and persisted in Conception Bay in 2000, reaching prevalences of over 2% to 9% in trapped and trawled male crabs and from 19 to 26% in trawled and trapped female crabs, respectively. Infections were highest in females and small males, i.e. the unfished and pre-recruit portions of the fishery. In a mortality study, all of the naturally infected crabs died and 50% of the experimentally inoculated crabs died. Patterns in the molting cycle and prevalence of infection indicate that transmission occurs during the post-molt condition, and that overt infections probably develop 2 to 4 mo later with mortalities occurring at least 3 to 4 mo thereafter. The hydrography of this bay may have contributed to the epizootic as infections were centered within the deeper confines of the bay. Analysis of various abiotic factors uncovered a significant positive association between prevalence, depth and mud/sand substrates; the nature of this relationship was not apparent but may be related to diet or alternate hosts. Lastly, given the increase in BCD in snow crabs in Newfoundland, we recommend that fishery management programs for Chionoecetes fisheries employ non-selective gear to monitor for Hematodinium infections in female and juvenile crabs because these under-sampled members of the population may forewarn of impending recruitment declines that might otherwise remain unexplained.


Introduction of macromolecules into bovine adrenal medullary chromaffin cells and rat pheochromocytoma cells (PC12) by permeabilization with streptolysin O: inhibitory effect of tetanus toxin on catecholamine secretion.
Conditions are described for controlled plasma membrane permeabilization of rat pheochromocytoma cells (PC12) and cultured bovine adrenal chromaffin cells by streptolysin O (SLO). The transmembrane pores created by SLO invoke rapid efflux of intracellular 86Rb+ and ATP, and also permit passive diffusion of proteins, including immunoglobulins, into the cells. SLO-permeabilized PC12 cells release [3H]dopamine in response to micromolar concentrations of free Ca2+. Permeabilized adrenal chromaffin cells present a similar exocytotic response to Ca2+ in the presence of Mg2+/ATP. Permeabilized PC12 cells accumulate antibodies against synaptophysin and calmodulin, but neither antibody reduces the Ca2+-dependent secretory response. Reduced tetanus toxin, although ineffective when applied to intact chromaffin cells, inhibits Ca2+-induced exocytosis by both types of permeabilized cells studied. Omission of dithiothreitol, toxin inactivation by boiling, or preincubation with neutralizing antibodies abolishes the inhibitory effect. The data indicate that plasma membrane permeabilization by streptolysin O is a useful tool to probe and define cellular components that are involved in the final steps of exocytosis.


Attenuation of alcohol consumption by MDMA (ecstasy) in two strains of alcohol-preferring rats.
Alcohol preference and manifestation of alcoholism are thought by many to be associated with serotonin (5-HT) dysfunction in the brain. Thus, experiments were performed to determine the effect of acute and subchronic administration of (+/-) 3,4-methylenedioxymethamphetamine (MDMA), an amphetamine analog that stimulates 5-HT release, on alcohol preference in two strains of alcohol-preferring rats, the Fawn-Hooded (FH) and alcohol-preferring (P) rats. Rats were individually housed and provided free access to a solution of 10% ethanol, food, and water. Ethanol, food, and water intakes were measured daily. After establishing a stable baseline for ethanol and water intake, each rat was injected SC with a dose of 5.0 mg/kg MDMA or an equal volume of saline for 1 or 3 consecutive days. Body temperature was recorded immediately before and 120, 240, and 360 min after MDMA treatment. Ethanol, food, and water intake were measured for the preceding 24 h. Further, to determine the effect of MDMA on alcohol metabolism rats were injected with 5.0 mg/kg MDMA or saline and 15 min later with 2.5 g/kg alcohol. Then, blood alcohol levels were determined at 1, 3, and 5 h after alcohol administration. Our results show that a single administration of 5.0 mg/kg MDMA significantly decreased ethanol intake in both FH and P rats and increased water intake. Subchronic administration of 5.0 mg/kg MDMA for 3 consecutive days significantly attenuated alcohol intake in both strains but only increased water intake in P rats. Administration of MDMA induced hyper- and hypothermia in FH and P rats, respectively. This drug failed to exert any significant effect on the pharmacokinetics of alcohol, indicating a central effect.(ABSTRACT TRUNCATED AT 250 WORDS)


Single gold-bridged nanoprobes for identification of single point DNA mutations.
Consensus ranking of protein affinity to identify point mutations has not been established. Therefore, analytical techniques that can detect subtle variations without interfering with native biomolecular interactions are required. Here we report a rapid method to identify point mutations by a single nanoparticle sensing system. DNA-directed gold crystallization forms rod-like nanoparticles with bridges based on structural design. The nanoparticles enhance Rayleigh light scattering, achieving high refractive-index sensitivity, and enable the system to monitor even a small number of protein-DNA binding events without interference. Analysis of the binding affinity can compile an atlas to distinguish the potential of various point mutations recognized by MutS protein. We use the atlas to analyze the presence and type of single point mutations in BRCA1 from samples of human breast and ovarian cancer cell lines. The strategy of synthesis-by-design of plasmonic nanoparticles for sensors enables direct identification of subtle biomolecular binding distortions and genetic alterations.


FGF14 localization and organization of the axon initial segment.
The axon initial segment (AIS) is highly enriched in the structural proteins ankyrin G and βIV-spectrin, the pore-forming (α) subunits of voltage-gated sodium (Nav) channels, and functional Nav channels, and is critical for the initiation of action potentials. We previously reported that FGF14, a member of the intracellular FGF (iFGF) sub-family, is expressed in cerebellar Purkinje neurons and that the targeted inactivation of Fgf14 in mice (Fgf14(-/-)) results in markedly reduced Purkinje neuron excitability. Here, we demonstrate that FGF14 immunoreactivity is high in the AIS of Purkinje neurons and is distributed in a decreasing, proximal to distal, gradient. This pattern is evident early in the postnatal development of Purkinje neurons and is also observed in many other types of central neurons. In (Scn8a(med)) mice, which are deficient in expression of the Nav1.6 α subunit, FGF14 immunoreactivity is markedly increased and expanded in the Purkinje neuron AIS, in parallel with increased expression of the Nav1.1 (Scn1a) α subunit and expanded expression of βIV-spectrin. Although Nav1.1, FGF14, and βIV-spectrin are affected, ankyrin G immunoreactivity at the AIS of Scn8a(med) and wild type (WT) Purkinje neurons was not significantly different. In Fgf14(-/-) Purkinje neurons, βIV-spectrin and ankyrin G immunoreactivity at the AIS were also similar to WT Purkinje neurons, although both the Nav1.1 and Nav1.6 α subunits are modestly, but significantly (p<0.005), reduced within sub-domains of the AIS, changes that may contribute to the reduced excitability of Fgf14(-/-) Purkinje neurons.


No relevant impact of ambient temperature on disability measurements in a large cohort of patients with multiple sclerosis.
Many patients with multiple sclerosis (MS) report a worsening of symptoms due to high ambient temperatures, but objective data about this association are rare and contradictory. The aim of this study was to investigate the influence of ambient temperature on standard clinical tests. We extracted the Symbol Digit Modality Test, Nine Hole Peg Test, Timed 25 Foot Walk (T25FW), Timed Tandem Walk, Expanded Disability Status Scale (EDSS) and quality-of-life items on cognition, fatigue and depression from our clinical database and matched them to historical temperatures. We used linear mixed-effect models to investigate the association between temperature and outcomes. A total of 1254 patients with MS (mean age, 42.7 years; 69.9% females; 52.1% relapsing-remitting MS, mean EDSS, 3.8) had 5751 assessments between 1996 and 2012. We observed a worsening in the T25FW with higher ambient temperatures in moderately disabled patients (EDSS ≥ 4) but not in less disabled patients. However, an increase of 10°C prolonged the T25FW by just 0.4 s. Other outcomes were not associated with ambient temperatures. Higher ambient temperature might compromise walking capabilities in patients with MS with a manifest walking impairment. However, effects are small and not detectable in mildly disabled patients. Hand function, cognition, mood and fatigue do not appear to be correlated with ambient temperature.


Food safety self-reported behaviors and cognitions of young adults: results of a national study.
With limited opportunities to learn safe food handling via observation, many young adults lack the knowledge needed to keep them safe from foodborne disease. It is important to reach young adults with food safety education because of their current and future roles as caregivers. With a nationwide online survey, the demographic characteristics, self-reported food handling and consumption behaviors, food safety beliefs, locus of control, self-efficacy, stage of change, and knowledge of young adults with education beyond high school (n = 4,343) were assessed. Young adults (mean age, 19.92 +/- 1.67 SD) who participated were mainly female, white, never married, and freshmen or sophomores. Participants correctly answered 60% of the knowledge questions and were most knowledgeable about groups at greatest risk for foodborne disease and least knowledgeable about common food sources of foodborne disease pathogens. They reported less than optimal levels of safe food handling practices. Young adults generally had a limited intake of foods that increase the risk of foodborne disease, positive food safety beliefs, an internal food safety locus of control, and confidence in their ability to handle food safely, and they were contemplating an improvement in, or preparing to improve, their food handling practices. Females significantly outperformed males on nearly all study measures. Future food safety educational efforts should focus on increasing knowledge and propelling young adults into the action stage of safe food handling, especially males. Efforts to improve knowledge and, ultimately, food safety behaviors are essential to safeguard the health of these young adults and enable them to fulfill the role of protecting the health of their future families.


Achieving affective human-virtual agent communication by enabling virtual agents to imitate positive expressions.
Affective communication, communicating with emotion, during face-to-face communication is critical for social interaction. Advances in artificial intelligence have made it essential to develop affective human-virtual agent communication. A person's belief during human-virtual agent interaction that the agent is a computer program affects social-cognitive processes. Whether this belief interferes with affective communication is an open question. We hypothesized that the imitation of a positive emotional expression by a virtual agent induces a positive emotion, regardless of the belief. To test this hypothesis, we conducted an fMRI study with 39 healthy volunteers, who were made to believe that a virtual agent was either a person or a computer. They were instructed to smile, and immediately afterwards, the virtual agent displayed a positive, negative, or neutral expression. The participants reported a positive emotion only when their smile was imitated by the agent's positive expression regardless of their belief. This imitation activated the participants' medial prefrontal cortex and precuneus, which are involved in anthropomorphism and contingency, respectively. These results suggest that a positive congruent response by a virtual agent can overcome the effect of believing that the agent is a computer program and thus contribute to achieving affective human-virtual agent communication.


The association between insulin use and volumetric bone mineral density, bone micro-architecture and bone strength of the distal radius in patients with type 2 diabetes - The Maastricht study.
Type 2 diabetes mellitus (T2DM) has been associated with an increased risk of fractures, despite normal to increased bone mineral density (BMD). Insulin use is one of the factors linked to this increased fracture risk. However, direct negative effects of insulin on bone quality are not expected since insulin is thought to be anabolic to bone. In this cross-sectional study the association between insulin use and volumetric BMD (vBMD), bone micro-architecture and bone strength of the distal radius, as measured with HR-pQCT, was examined. Data from 50 participants with T2DM of The Maastricht Study (mean age 62±7.5years, 44% women) was used. Participants were classified as insulin user (n=13) or non-insulin user (n=37) based on prescription data. Linear regression analysis was used to estimate the association between current insulin use and HR-pQCT derived parameters. After adjustment for age, sex, body mass index, glycated hemoglobin A1c and T2DM duration, insulin use was associated with lower total vBMD (standardized beta (β):-0.56 (95% CI:-0.89 to -0.24)), trabecular vBMD (β:-0.58 (95% CI:-0.87 to -0.30)), trabecular thickness (β:-0.55 (95% CI:-0.87 to -0.23)), cortical thickness (β:-0.41 (95% CI:-0.74 to -0.08)), log cortical pore volume (β:-0.43 (95% CI:-0.73 to -0.13)), bone stiffness (β:-0.39 (95% CI:-0.62 to -0.17)) and failure load (β:-0.39 (95% CI:-0.60 to -0.17)) when compared to the non-insulin users. Insulin use was not associated with cortical vBMD, trabecular number, trabecular separation, cortical porosity and cortical pore diameter. This study indicates that insulin use is negatively associated with bone density, bone micro-architectural and bone strength parameters. These findings may partly explain the previously observed increased fracture risk in insulin users, although there may be residual confounding by other factors related to disease severity in insulin users.


Bone Morphogenetic Protein-9 Enhances Osteogenic Differentiation of Human Periodontal Ligament Stem Cells via the JNK Pathway.
Bone morphogenetic protein-9 (BMP9) shows great osteoinductive potential in bone regeneration. Periodontal ligament stem cells (PDLSCs) with multi-differentiation capability and low immunogenicity are increasingly used as seed cells for periodontal regenerative therapies. In the present study, we investigated the potent osteogenic activity of BMP9 on human PDLSCs (hPDLSCs), in which the c-Jun N-terminal kinase (JNK) pathway is possibly involved. Our results showed that JNK inhibition by the specific inhibitor SP600125 or adenovirus expressing small interfering RNA (siRNA) targeting JNK (AdR-si-JNK) significantly decreased BMP9-induced gene and protein expression of early and late osteogenic markers, such as runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), osteopontin (OPN), and osteocalcin (OCN), in hPDLSCs. We also confirmed the in-vivo positive effect of JNKs on ectopic bone formation induced by hPDLSCs injected into the musculature of athymic nude mice and BMP9 ex vivo gene delivery. For the cellular mechanism, we found that BMP9 activated the phosphorylation of JNKs and Smad2/3, and that JNKs may engage in cross-talk with the Smad2/3 pathway in BMP9-mediated osteogenesis.


Solution structure of r(gaggacug):d(CAGTCCTC) hybrid: implications for the initiation of HIV-1 (+)-strand synthesis.
The three-dimensional solution structure of the hybrid duplex r(gaggacug):d(CAGTCCTC) has been determined by two-dimensional NMR, distance geometry (DG), restrained molecular dynamics (rMD) and NOE back-calculation methods. This hybrid, consisting of a purine-rich RNA strand and a pyrimidine-rich DNA strand, is related to the polypurine (+)-strand primer formed after (-)-strand DNA synthesis and RNase H degradation of the viral RNA strand and contains the site of a specific cleavage by reverse transcription (RT) RNase H at the end of the HIV-1 polypurine tract. This polypurine primer is an important intermediate in the formation of virally encoded double-stranded DNA prior to HIV-1 retrovirus integration. The correct processing of this primer is vital in the life cycle of the human immunodeficiency virus type (HIV-1) retrovirus. The structure of the r(gaggacug):d(CAGTCCTC) hybrid, as determined in solution by NMR, is intermediate between canonical A-type and B-type double helices, and has mixed structural characteristics. It is quantitatively different from the previously determined solution structures of other RNA-DNA hybrids, particularly in the width and shape of the major groove, which is wider than the major groove of other hybrids and is close to the dimension of the major groove of B-type DNA duplexes. The structure of this hybrid duplex contains a prominent bend in the double helix with a magnitude and direction similar to the bend in Okazaki fragments. The structural features of the present duplex may explain the unique interactions of this sequence with HIV-1 RT during both (-)-strand and (+)-strand DNA synthesis.


Antitumor activity of recombinant Bacille Calmette-Guérin secreting interleukin-15-Ag85B fusion protein against bladder cancer.
Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is used for the treatment of bladder cancer. The recruitment of neutrophlis to the bladder after BCG instillation exerts anti-tumor activity against bladder tumor. We have recently demonstrated that interleukin (IL)-17A produced by γδ T cells played a role in the recruitment of neutrophlis to the bladder after BCG instillation. IL-15 is known to play an important role in neutrophil migration during inflammation. We previously constructed a recombinant BCG strain expressing the fusion protein of IL-15 and Ag85B (BCG-IL-15) for prevention of Mycobacterium tuberculosis infection. Here we compared the efficacy of the BCG-IL-15 in protection against bladder cancer with that of rBCG-Ag85B (BCG). Six-week-old female C57BL/6 mice were inoculated with MB49 bladder tumor cells in the bladder and subsequently intravesically inoculated with BCG or BCG-IL-15. BCG-IL-15 treatment significantly prolonged survival of mice inoculated with bladder cancer cells compared with BCG treatment. Infiltration of neutrophils was significantly elevated in BCGB-IL-15 treated mice accompanied by increased chemokines (MIP-2 and MIP-1α) in the bladder. Thus, BCG-IL-15 exerted additive effect on Infiltration of neutrophils in the bladder. BCG-IL-15 may be a promising drug for non-muscle invasive bladder cancer.


Synergistic action of dietary phyto-antioxidants on survival and proliferation of ovarian cancer cells.
A number of herbal dietary antioxidant supplements containing Indole-3 Carbinol (I3C) and Resveratrol (RE) have been established as anti-proliferative agents in cancer. These compounds have both similar as well as unique molecular targeting profiles. The purpose of this study is to analyze their mechanism of action when used individually and in combination in ovarian cancer. SK-OV-3 ovarian cancer cells were treated with various doses of I3C, RE or I3C+RE. AlamarBlue dye assay was used to examine cell growth and proliferation. Cell cycle and apoptosis were analyzed by flow cytometry. Western blot was performed to determine the expression of the genes associated with cell cycle and apoptosis. CA-125, a functional marker of ovarian cancer, and nitric oxide, were analyzed by ELISA. I3C or RE inhibited cell proliferation, and caused cell contraction and apoptosis. Analysis of apoptosis-associated genes revealed an inhibition of Retinoblastoma protein (Rb) and Survivin (SVV) gene expression. This was accompanied by elevation of p21, a tumor suppressor. Cell cycle was inhibited at both G1 and G2/M by individual treatments, and accentuated by a combination. AlamarBlue assay revealed a clear synergistic action of I3C+RE. CA125 was inhibited by either I3C or RE treatments. In contrast, basal nitric oxide production was inhibited by I3C and I3C+RE but not RE alone. This is the first evidence demonstrating the effects of I3C on ovarian cancer cells and its synergism with RE. Based on this model, our data indicate that combinations of compounds with different targeting properties will be more effective in chemoprevention and/or chemotherapy of ovarian and possibly other cancers.


Defining Patient Centric Pharmaceutical Drug Product Design.
The term "patient centered," "patient centric," or "patient centricity" is increasingly used in the scientific literature in a wide variety of contexts. Generally, patient centric medicines are recognized as an essential contributor to healthy aging and the overall patient's quality of life and life expectancy. Besides the selection of the appropriate type of drug substance and strength for a particular indication in a particular patient, due attention must be paid that the pharmaceutical drug product design is also adequately addressing the particular patient's needs, i.e., assuring adequate patient adherence and the anticipate drug safety and effectiveness. Relevant pharmaceutical design aspects may e.g., involve the selection of the route of administration, the tablet size and shape, the ease of opening the package, the ability to read the user instruction, or the ability to follow the recommended (in-use) storage conditions. Currently, a harmonized definition on patient centric drug development/design has not yet been established. To stimulate scientific research and discussions and the consistent interpretation of test results, it is essential that such a definition is established. We have developed a first draft definition through various rounds of discussions within an interdisciplinary AAPS focus group of experts. This publication summarizes the outcomes and is intended to stimulate further discussions with all stakeholders towards a common definition of patient centric pharmaceutical drug product design that is useable across all disciplines involved.


A Novel Platinum-based Compound with Preferential Cytotoxic Activity against a Panel of Cancer Cell Lines
Cisplatin as a platinum (Pt)-based chemotherapeutic compound is commonly applied for the treatment of several types of cancer. Nonetheless, drug resistance and severe adverse effects have been observed upon using cisplatin. Here, we have explored the cytotoxicity of novel Pt-based compounds on several cancer cell lines. Five synthetic Pt compounds as well as cisplatin were investigated by XTT assay to determine their cytotoxicity against cell lines originated from prostate, ovary, and breast cancers at different time periods at various concentrations. Additionally, the apoptosis rate in cell lines was determined using flow cytometry. Binding to DNA was investigated through spectrophotometric and viscometric studies. With the exception of one compound, all of the Pt-complexes effectively killed the prostate cancer cell lines (i.e. PC-3 and DU 145). One compound, [Pt(2,2'- dipyridylamine)Cl4].DMF, was chosen as the most potent compound due to its high selective cytotoxic activity and its cytotoxicity was further tested and compared with that of cisplatin on SKOV-3, Caov-4, MDA-MB-231, and MCF7 cell lines. [Pt(2,2'-dipyridylamine)Cl4].DMF had a higher selective cytotoxic capacity in comparison with cisplatin at higher concentrations and longer culture periods. Furthermore, as related to apoptosis induction, treatment with [Pt(2,2'-dipyridylamine)Cl4 ].DMF was significantly more effective than that of cisplatin in five out of six examined cell lines. [Pt(2,2'-dipyridylamine)Cl4].DMF was shown to intercalate into DNA. The current study introduced a novel Pt-based complex with highly selective and potent in vitro anti-tumor impacts superior to those of cisplatin, a conventional chemotherapeutic agent. [Pt (2,2'-dipyridylamine)Cl4].DMF could be regarded as a promising anti-tumor agent in future investigations.


A new computational method for detection of chimeric 16S rRNA artifacts generated by PCR amplification from mixed bacterial populations.
A new computational method (chimeric alignment) has been developed to detect chimeric 16S rRNA artifacts generated during PCR amplification from mixed bacterial populations. In contrast to other nearest-neighbor methods (e.g., CHECK_CHIMERA) that define sequence similarity by k-tuple matching, the chimeric alignment method uses the score from dynamic programming alignments. Further, the chimeric alignments are displayed to the user to assist in sequence classification. The distribution of improvement scores for 500 authentic, nonchimeric sequences and 300 artificial chimeras (constructed from authentic sequences) was used to study the sensitivity and accuracy of both chimeric alignment and CHECK_CHIMERA. At a constant rate of authentic sequence misclassification (5%), chimeric alignment incorrectly classified 13% of the artificial chimeras versus 14% for CHECK_CHIMERA. Interestingly, only 1% of nonchimeras and 10% of chimeras were misclassified by both programs, suggesting that optimum performance is obtained by using the two methods to assign sequences to three classes: high-probability nonchimeras, high-probability chimeras, and sequences that need further study by other means. This study suggests that k-tuple-based matching methods are more sensitive than alignment-based methods when there is significant parental sequence similarity, while the opposite becomes true as the sequences become more distantly related. The software and a World Wide Web-based server are available at http://www-hto.usc.edu/software/mglobal CHI.


Impact of Cancer Therapy-Related Cardiac Dysfunction on Risk of Heart Failure in Pregnancy.
Cancer treatment can lead to left ventricular (LV) dysfunction in female cancer survivors of reproductive age, and pregnancy-related hemodynamic stress may result in LV dysfunction or heart failure (HF). We performed a systematic review and meta-analysis to determine the incidence of LV systolic dysfunction or HF during or soon after pregnancy in cancer survivors and evaluated the impact of history of cancer therapeutics-related cardiac dysfunction (CTRCD). We systematically searched electronic databases (MEDLINE and EMBASE) from inception to January 2020 to identify cohort studies that examined cardiac disease in pregnant cancer survivors. Meta-analysis was performed using the inverse-variance fixed effects method. Potential sources of heterogeneity were explored using subgroup analyses and meta-regression. Of 13,782 identified articles, 6 studies consisting of 2,016 pregnancies, predominantly in childhood cancer survivors, were included. Overall, there were 33 cardiac events. The total weighted incidence of LV dysfunction or HF with pregnancy was 1.7% (95% confidence interval [CI]: 0.9% to 2.7%) overall; 28.4% (95% CI: 14.6% to 43.9%) in those with a history of CTRCD and 0.24% (95% CI: 0% to 0.81%) in those without, translating into an odds ratio of 47.4 (95% CI: 17.9 to 125.8). Interstudy heterogeneity was low (I2 = 17.5%). Metaregression did not reveal significant sources of heterogeneity. The incidence of LV dysfunction or HF during pregnancy in cancer survivors was low. Although risk estimates are limited by the small number of events, women with a history of CTRCD compared to those without had a 47.4-fold higher odds of experiencing pregnancy-related LV dysfunction or HF.


Cancer stem cells generated by alcohol, diabetes, and hepatitis C virus.
Cancer stem cells (tumor-initiating stem-like cells: TISCs) are resistant to chemotherapy and are associated with metastatic hepatocellular carcinoma (HCC), which is commonly observed in hepatitis C virus (HCV)-infected patients with obesity or alcohol abuse. However, it is unknown whether the TLR4-NANOG pathway serves as a universal oncogenic signaling in the genesis of TISCs and HCC. We aimed to determine whether Tlr4 is a putative proto-oncogene for TISCs in liver oncogenesis due to different etiologies and how Tlr4 is regulated at the transcriptional and epigenetic levels. CD133+/CD49f+ TISCs were isolated using FACS from HCC developed in HCV Core Tg mice fed alcohol, diethylnitrosamine-treated mice, and alcoholic patients with or without HCV infection. CD133+/CD49f+ cells isolated from the animal models and patients are tumorigenic both in vitro and in a xenograft model, and Tlr4 or Nanog silencing with shRNA attenuates their tumor initiating property. Functional oncogene screening of a cDNA library identified the organ size control pathway targets Yap1 and AKT activator Igf2bp3 as NANOG-dependent genes that inhibit transforming growth factor-β signaling in TISCs. Tlr4 expression is higher in TISCs compared with CD133-/CD49f+ cells. Taken together, Tlr4 may be a universal proto-oncogene responsible for the genesis of TLR4-NANOG dependent TISCs, and this pathway serves as a novel therapeutic target for HCC.


Vertical ridge augmentation by expanded-polytetrafluoroethylene membrane and a combination of intraoral autogenous bone graft and deproteinized anorganic bovine bone (Bio Oss).
To evaluate, from a histological and histomorphometrical perspective, the efficacy of a 1 : 1 mixture of deproteinized bovine bone mineral (DBBM) and autogenous bone graft associated with an expanded-polytetrafluoroethylene (e-PTFE) membrane for vertical ridge augmentation in the human. Seven patients with 10 surgical sites requiring vertical ridge augmentation of partially edentulous lower jaws were included in the study. The vertical augmentation procedure was performed combining a titanium-reinforced e-PTFE Gore-Tex membrane with a composite graft consisting of a 1 : 1 ratio of DBBM (Bio-Oss) and autogenous bone. Twenty-seven Branemark implants have been inserted. Eleven biopsies from the regenerated area were analyzed histologically and histomorphometrically. The healing period was uneventful in nine surgical sites. In one site the membrane showed an exposure after 3 months. At the abutment connection, all implants appeared stable and submerged by a hard regenerated tissue clinically similar to bone. The histological analysis showed new bone formation and ongoing remodelling of the autogenous bone and the DBBM particles. The findings from the present clinical and histological study support the use of a 1 : 1 combination of DBBM and autogenous bone chips for vertical ridge augmentation by means of guided bone regeneration techniques. The regenerated bone may lead to proper osseointegration of a dental implant inserted at the time of the regenerative procedure or after a healing period of at least 6 months. DBBM undergoes very slow resorption and substitution with new bone. Furthermore, long-term clinical studies are needed to confirm the positive effect of DBBM in enhancing the lasting stability of the vertically augmented bone.


Transmission of Leishmania metacyclic promastigotes by phlebotomine sand flies.
A thorough understanding of the transmission mechanism of any infectious agent is crucial to implementing an effective intervention strategy. Here, our current understanding of the mechanisms that Leishmania parasites use to ensure their transmission from sand fly vectors by bite is reviewed. The most important mechanism is the creation of a "blocked fly" resulting from the secretion of promastigote secretory gel (PSG) by the parasites in the anterior midgut. This forces the sand fly to regurgitate PSG before it can bloodfeed, thereby depositing both PSG and infective metacyclic promastigotes in the skin of a mammalian host. Other possible factors in transmission are considered: damage to the stomodeal valve; occurrence of parasites in the salivary glands; and excretion of parasites from the anus of infected sand flies. Differences in the transmission mechanisms employed by parasites in the three subgenera, Leishmania, Viannia and Sauroleishmania are also addressed.


[Translated article] Immunotherapy and Targeted Therapy in Patients With Advanced Melanoma and the V600 BRAF Mutation: Which One First?
Systemic treatment with immunotherapy or targeted therapy can significantly improve survival in patients with advanced (metastatic or high-risk) melanoma. Fifty percent of patients with melanoma have a BRAF mutation. Decisions on optimal sequencing of systemic treatments should take into account drug- and tumor-related factors and patient characteristics. Although the combination of ipilimumab and nivolumab is associated with the best survival outcomes, it is associated with significant toxicity. Targeted therapy may be a more favorable option in certain clinical situations. We review the literature on immunotherapy and targeted therapy in melanoma and present an algorithm for guiding decision-making on their use as first-line systemic treatments for advanced BRAF-mutated melanoma.


Evaluation of the Strengths and Difficulties Questionnaire-Dysregulation Profile (SDQ-DP).
The Dysregulation Profile (DP) has emerged as a measure of concurrent affective, behavioral and cognitive dysregulation, associated with severe psychopathology, and poor adjustment. While originally developed with the Child Behavior Checklist, more recently the DP has also been defined on the Strengths and Difficulties Questionnaire (SDQ), mostly with a 5-item, but also a 15-item, SDQ-DP measure. This study evaluated the SDQ-DP by examining its factor structure, measurement invariance, and construct validity. Different SDQ-DP operationalizations were compared. In a United States longitudinal community sample (N = 768), a bifactor model consisting of a general Dysregulation factor and three specific factors of Emotional Symptoms, Conduct Problems, and Hyperactivity-Inattention fitted best, across three different developmental periods (early childhood, middle childhood, and adolescence) and across three different reporters (parents, teachers, and youth). Measurement invariance across reporter, gender, and developmental period was demonstrated. These findings indicate that the SDQ-DP, like the CBCL-DP, reflects a broad syndrome of dysregulation that exists in addition to specific syndromes of emotional symptoms, conduct problems, and hyperactivity-inattention. SDQ-DP bifactor scores were strongly related with scores on the 5- and 15-item SDQ-DP measures and similarly concurrently associated with two markers of self-regulation, ego-resiliency and effortful control, and longitudinally with antisocial behavior and disciplinary measures. As reliability, validity, and stability was weaker for the SDQ-DP 5-item measure, use of all 15 items is recommended. Advantages of using a bifactor approach are discussed as well as the potential of the SDQ-DP as an easy screening measure of children at risk for developing serious psychopathology. (PsycINFO Database Record


Primary Souter-Strathclyde total elbow prosthesis in rheumatoid arthritis. Surgical technique.
Total elbow arthroplasty is a well-established treatment for the painful elbow joint in patients with rheumatoid arthritis. We present the results of what we believe to be the first prospective study of the Souter-Strathclyde total elbow prosthesis. Between June 1982 and December 2000, 204 primary total elbow prostheses were inserted in 166 patients who had rheumatoid arthritis. No patient was lost to follow-up. The mean duration of follow-up was 6.4 years. All patients were examined preoperatively, at one and two years postoperatively, and at regular intervals thereafter. Six of the 204 elbows had pain at rest at the time of the latest follow-up. Ten patients (ten elbows) without previous neurological symptoms had development of paresthesias in the distribution of the ulnar nerve postoperatively. Patients who had pain at rest or at night and those who had ulnar nerve symptoms preoperatively were found to have a significant chance of having the same complaints postoperatively. Pain at rest or at night and a decrease in function during the follow-up period were associated with humeral loosening. Twenty-four elbows had revision of the total elbow prosthesis because of loosening of the humeral component (ten), loosening after fracture (six), dislocation (four), infection (two), restricted range of motion (one), or fracture of the middle part of the humeral shaft, proximal to the prosthesis (one). One prosthesis was removed because of humeral loosening, and eight were removed because of deep infection. Another five prostheses were radiographically loose at the time of the latest follow-up. The rate of implant survival, according to the method of Kaplan-Meier, was 77.4% after ten years and 65.2% after eighteen years. Total elbow replacement is associated with a high complication rate and therefore may be warranted only for seriously disabled patients. Currently, the results associated with the Souter-Strathclyde total elbow prosthesis are comparable with the results associated with other prostheses, but loosening of the humeral component remains a concern.


Transposable Element Genomic Fissuring in Pyrenophora teres Is Associated With Genome Expansion and Dynamics of Host-Pathogen Genetic Interactions.
Pyrenophora teres, P. teres f. teres (PTT) and P. teres f. maculata (PTM) cause significant diseases in barley, but little is known about the large-scale genomic differences that may distinguish the two forms. Comprehensive genome assemblies were constructed from long DNA reads, optical and genetic maps. As repeat masking in fungal genomes influences the final gene annotations, an accurate and reproducible pipeline was developed to ensure comparability between isolates. The genomes of the two forms are highly collinear, each composed of 12 chromosomes. Genome evolution in P. teres is characterized by genome fissuring through the insertion and expansion of transposable elements (TEs), a process that isolates blocks of genic sequence. The phenomenon is particularly pronounced in PTT, which has a larger, more repetitive genome than PTM and more recent transposon activity measured by the frequency and size of genome fissures. PTT has a longer cultivated host association and, notably, a greater range of host-pathogen genetic interactions compared to other Pyrenophora spp., a property which associates better with genome size than pathogen lifestyle. The two forms possess similar complements of TE families with Tc1/Mariner and LINE-like Tad-1 elements more abundant in PTT. Tad-1 was only detectable as vestigial fragments in PTM and, within the forms, differences in genome sizes and the presence and absence of several TE families indicated recent lineage invasions. Gene differences between P. teres forms are mainly associated with gene-sparse regions near or within TE-rich regions, with many genes possessing characteristics of fungal effectors. Instances of gene interruption by transposons resulting in pseudogenization were detected in PTT. In addition, both forms have a large complement of secondary metabolite gene clusters indicating significant capacity to produce an array of different molecules. This study provides genomic resources for functional genetics to help dissect factors underlying the host-pathogen interactions.


Improving Communication and Response to Clinical Deterioration to Increase Patient Safety in the Intensive Care Unit.
In the critical care setting, early recognition of clinical decompensation is imperative to trigger prompt intervention and optimize patient outcomes. In a 20-bed surgical intensive care unit of an urban academic medical center, cases of clinical deterioration that highlighted opportunities to improve the communication process prompted a reassessment of health care provider roles and responsibilities. A quality improvement initiative was implemented to enhance communication among intensive care unit clinical staff members, improve the timeliness of reporting clinical deterioration, and ensure implementation of timely, appropriate interventions to eliminate adverse outcomes. Nurses were surveyed to determine their perceptions of communication and collaboration among providers. Education was provided that focused on familiarizing nurses with clinical conditions necessitating direct notification of the attending surgical intensivist and included review of a case in which escalation of care did not occur. Multidisciplinary rounds were expanded to engage night-shift nurses in clinical discussions and decision-making. A template was created to document episodes of escalation in the electronic health record. Since implementation of the quality improvement interventions, no incidents of patient harm or death related to failure to escalate have occurred to date. A total of 16 episodes of escalation for clinical deterioration were documented in the electronic health record. Most nurses reported an increased level of confidence in understanding when to escalate concerns about clinical deterioration. Implementing a multimodal program to empower nurses to escalate clinical concerns directly to the attending physician eliminated adverse events related to failure to escalate.


Impact of baseline BMI and weight change in CCTG adjuvant breast cancer trials.
We hypothesized that increased baseline BMI and BMI change would negatively impact clinical outcomes with adjuvant breast cancer systemic therapy. Data from chemotherapy trials MA.5 and MA.21; endocrine therapy MA.12, MA.14 and MA.27; and trastuzumab HERA/MA.24 were analyzed. The primary objective was to examine the effect of BMI change on breast cancer-free interval (BCFI) landmarked at 5 years; secondary objectives included BMI changes at 1 and 3 years; BMI changes on disease-specific survival (DSS) and overall survival (OS); and effects of baseline BMI. Stratified analyses included trial therapy and composite trial stratification factors. In pre-/peri-/early post-menopausal chemotherapy trials (N = 2793), baseline BMI did not impact any endpoint and increased BMI from baseline did not significantly affect BCFI (P = 0.85) after 5 years although it was associated with worse BCFI (P = 0.03) and DSS (P = 0.07) after 1 year. BMI increase by 3 and 5 years was associated with better DSS (P = 0.01; 0.01) and OS (P = 0.003; 0.05). In pre-menopausal endocrine therapy trial MA.12 (N = 672), patients with higher baseline BMI had worse BCFI (P = 0.02) after 1 year, worse DSS (P = 0.05; 0.004) after 1 and 5 years and worse OS (P = 0.01) after 5 years. Increased BMI did not impact BCFI (P = 0.90) after 5 years, although it was associated with worse BCFI (P = 0.01) after 1 year. In post-menopausal endocrine therapy trials MA.14 and MA.27 (N = 8236), baseline BMI did not significantly impact outcome for any endpoint. BMI change did not impact BCFI or DSS after 1 or 3 years, although a mean increased BMI of 0.3 was associated with better OS (P = 0.02) after 1 year. With the administration of trastuzumab (N = 1395) baseline BMI and BMI change did not significantly impact outcomes. Higher baseline BMI and BMI increases negatively affected outcomes only in pre-/peri-/early post-menopausal trial patients. Otherwise, BMI increases similar to those expected in healthy women either did not impact outcome or were associated with better outcomes. CAN-NCIC-MA5; National Cancer Institute (NCI)-V90-0027; MA.12-NCT00002542; MA.14-NCT00002864; MA.21-NCT00014222; HERA, NCT00045032;CAN-NCIC-MA24; MA-27-NCT00066573.


Incorporation of oxygen atoms as a mechanism for photoluminescence enhancement of chemically treated MoS2.
Chemical treatments to enhance photoluminescence (PL) in MoS2 have been explored extensively by experimental means in recent years. However, satisfactory theoretical explanations of the underlying mechanisms remain elusive. In this work, the surface reactions of the superacid bis(trifluoromethane)-sulfonimide (TFSI), hydrogen peroxide (H2O2), molecular oxygen (O2), and sulfuric acid (H2SO4) on a defective MoS2 monolayer have been studied using first principles calculations. An oxygen transfer reaction into a sulfur vacancy with a low activation barrier and thus significant reaction rates already at room temperature has been found. Band structure unfolding techniques show that the incorporation of oxygen atoms into sulfur vacancies restores the band structure of pristine MoS2, which is predicted to have a high PL quantum yield. PL spectroscopy is used to examine the effect of chemical treatment on PL intensity. Our experimental findings support our theoretical predictions, as PL in MoS2 is enhanced by up to a factor 20 after treatment with H2O2 or H2SO4, while the spectral shape is only slightly altered.


An automated method for comparing motion artifacts in cine four-dimensional computed tomography images.
The aim of this study is to develop an automated method to objectively compare motion artifacts in two four-dimensional computed tomography (4D CT) image sets, and identify the one that would appear to human observers with fewer or smaller artifacts. Our proposed method is based on the difference of the normalized correlation coefficients between edge slices at couch transitions, which we hypothesize may be a suitable metric to identify motion artifacts. We evaluated our method using ten pairs of 4D CT image sets that showed subtle differences in artifacts between images in a pair, which were identifiable by human observers. One set of 4D CT images was sorted using breathing traces in which our clinically implemented 4D CT sorting software miscalculated the respiratory phase, which expectedly led to artifacts in the images. The other set of images consisted of the same images; however, these were sorted using the same breathing traces but with corrected phases. Next we calculated the normalized correlation coefficients between edge slices at all couch transitions for all respiratory phases in both image sets to evaluate for motion artifacts. For nine image set pairs, our method identified the 4D CT sets sorted using the breathing traces with the corrected respiratory phase to result in images with fewer or smaller artifacts, whereas for one image pair, no difference was noted. Two observers independently assessed the accuracy of our method. Both observers identified 9 image sets that were sorted using the breathing traces with corrected respiratory phase as having fewer or smaller artifacts. In summary, using the 4D CT data of ten pairs of 4D CT image sets, we have demonstrated proof of principle that our method is able to replicate the results of two human observers in identifying the image set with fewer or smaller artifacts.


Oxy-functionalization of Group 9 and 10 transition metal methyl ligands: use of pyridine-based hemi-labile ligands.
Hemi-labile ligands (HLLs) are intriguing candidates for catalysts since they may facilitate bond activation and bond formation through facile ligand dissociation/association. DFT studies are reported of hemi-labile ligands in conjunction with Group 9 and 10 metals for oxygen atom insertion into metal-methyl bonds. Analysis of the reaction of pyridine-N-oxide with d(8)-[LnM (Me)(THF)](q+) (M = Co, Rh, Ir, Ni, Pd, Pt; Ln = 2-(CH3OCH2)Py; q = 0 and +1 for Group 9 and 10 metals, respectively; Py = pyridine; THF = tetrahydrofuran) indicates that oxy-insertion for Group 9 complexes occurs with lower free energy barriers than their Group 10 congeners. Analysis of structural changes along the reaction coordinate suggests that the initial oxygen atom transfer and subsequent methyl migration steps are favored by a reduction and increase, respectively, in coordination number. This emphasizes that HLLs could be uniquely positioned to assist both transformations within a single complex. Additionally, such ligands are worthy of experimental study due to their ability to meet the disparate coordination demands for two-step, redox-based oxy-insertion.


Chicory Extracts and Sesquiterpene Lactones Show Potent Activity against Bacterial and Fungal Pathogens.
Chicory (Cichorium intybus L.) is an important industrial crop cultivated mainly to extract the dietary fiber inulin. However, chicory also contains bioactive compounds such as sesquiterpene lactones and certain polyphenols, which are currently discarded as waste. Plants are an important source of active pharmaceutical ingredients, including novel antimicrobials that are urgently needed due to the global spread of drug-resistant bacteria and fungi. Here, we tested different extracts of chicory for a range of bioactivities, including antimicrobial, antifungal and cytotoxicity assays. Antibacterial and antifungal activities were generally more potent in ethyl acetate extracts compared to water extracts, whereas supercritical fluid extracts showed the broadest range of bioactivities in our assays. Remarkably, the chicory supercritical fluid extract and a purified fraction thereof inhibited both methicillin-resistant Staphylococcus aureus (MRSA) and ampicillin-resistant Pseudomonas aeruginosa IBRS P001. Chicory extracts also showed higher antibiofilm activity against the yeast Candida albicans than standard sesquiterpene lactone compounds. The cytotoxicity of the extracts was generally low. Our results may thus lead to the development of novel antibacterial and antifungal preparations that are both effective and safe for human use.


Online EM with weight-based forgetting.
In the online version of the EM algorithm introduced by Sato and Ishii ( 2000 ), a time-dependent discount factor is introduced for forgetting the effect of the old estimated values obtained with an earlier, inaccurate estimator. In their approach, forgetting is uniformly applied to the estimators of each mixture component depending exclusively on time, irrespective of the weight attributed to each unit for the observed sample. This causes an excessive forgetting in the less frequently sampled regions. To address this problem, we propose a modification of the algorithm that involves a weight-dependent forgetting, different for each mixture component, in which old observations are forgotten according to the actual weight of the new samples used to replace older values. A comparison of the time-dependent versus the weight-dependent approach shows that the latter improves the accuracy of the approximation and exhibits much greater stability.


The Consequences of Foster Care Versus Institutional Care in Early Childhood on Adolescent Cardiometabolic and Immune Markers: Results From a Randomized Controlled Trial.
Children exposed to institutional rearing often exhibit problems across a broad array of developmental domains. We compared the consequences of long-term, high-quality foster care versus standard institution-based care, which began in early childhood on cardiometabolic and immune markers assessed at the time of adolescence. The Bucharest Early Intervention Project is a longitudinal investigation of children institutionalized during early childhood (ages 6 to 30 months at baseline) who were subsequently randomized to either high-quality foster care or continued institutional care. At the age of 16 years, 127 respondents participated in a biomarker collection protocol, including 44 institutionalized children randomly assigned to receive care as usual, 41 institutionalized children randomized to be removed from institutional care and placed in high-quality foster care in infancy, and a control group of 42 demographically matched children raised in biological families. Outcomes included body mass index (BMI), systolic and diastolic blood pressure, C-reactive protein, interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor α, glycosylated hemoglobin A1c, and Epstein-Barr virus antibody titers. Early institutional rearing was not associated with differences in cardiometabolic or immune markers. Randomization to foster care and age of placement into foster care were also unrelated to these markers, with the exception of BMI z-score, where children assigned to care as usual had lower BMI z-scores relative to children assigned to foster care (-0.23 versus 0.08, p = .06), and older age at placement was associated with lower BMI (β = -0.07, p = .03). The impact of institutional rearing on measures of cardiometabolic health and immune system functioning is either absent or not evident until later in development. These findings provide new insights into the biological embedding of adversity and how it varies developmentally and across regulatory systems and adversity type. NCT00747396.


Society for Maternal-Fetal Medicine Special Statement: Checklist for initial management of amniotic fluid embolism.
Amniotic fluid embolism is a rare syndrome characterized by sudden cardiorespiratory collapse during labor or soon after delivery. Because of its rarity, many obstetrical providers have no experience in managing amniotic fluid embolism and may therefore benefit from a cognitive aid such as a checklist. We present a sample checklist for the initial management of amniotic fluid embolism based on standard management guidelines. We also suggest steps that each facility can take to implement the checklist effectively.


Neural networks for short-term memory for order differentiate high and low proficiency bilinguals.
Short-term memory (STM) for order information, as compared to STM for item information, has been shown to be a critical determinant of language learning capacity. The present fMRI study asked whether the neural substrates of order STM can serve as markers for bilingual language achievement. Two groups of German-French bilinguals differing in second language proficiency were presented STM tasks probing serial order or item information. During order STM but not item STM tasks, the high proficiency group showed increased activation in the lateral orbito-frontal and the superior frontal gyri associated with updating and grouped rehearsal of serial order information. Functional connectivity analyses for order encoding showed a functional network involving the left IPS, the right IPS and the right superior cerebellum in the high proficiency group while the low proficiency group showed enhanced connectivity between the left IPS and bilateral superior temporal and temporo-parietal areas involved in item processing. The present data suggest that low proficiency bilinguals activate STM networks for order in a less efficient and differentiated way, and this may explain their poorer storage and learning capacity for verbal sequences.


Prevalent glucocorticoid and androgen activity in US water sources.
Contamination of the environment with endocrine disrupting chemicals (EDCs) is a major health concern. The presence of estrogenic compounds in water and their deleterious effect are well documented. However, detection and monitoring of other classes of EDCs is limited. Here we utilize a high-throughput live cell assay based on sub-cellular relocalization of GFP-tagged glucocorticoid and androgen receptors (GFP-GR and GFP-AR), in combination with gene transcription analysis, to screen for glucocorticoid and androgen activity in water samples. We report previously unrecognized glucocorticoid activity in 27%, and androgen activity in 35% of tested water sources from 14 states in the US. Steroids of both classes impact body development, metabolism, and interfere with reproductive, endocrine, and immune systems. This prevalent contamination could negatively affect wildlife and human populations.


Data of characterization and adsorption of fluoride from aqueous solution by using modified Azadirachta indica bark.
This data was decisive on the adsorption of fluoride by microwave assisted carbonized Azadirachta indica bark (MACAIB) adsorbent material from aqueous solution. Azadirachta indica bark is a plant-based effortlessly available item which is transformed into a carbonaceous adsorbent material and utilized for the removal fluoride from aqueous solution. Characterization of the MACAIB adsorbent material demonstrated that it was porous and extremely effective in the removal of fluoride. The operating parameters such as pH, adsorbent dose, agitation speed, initial fluoride concentration, contact time and temperature were efficient on the adsorption ability of fluoride. The maximum removal efficiency of fluoride with an initial fluoride concentration 2 mg/L was found to be 83.50%. Experimental adsorption isotherm equilibrium data furnished was the best with Langmuir adsorption isotherm model, showing monolayer adsorption on a homogenous surface (most extreme monolayer adsorption capacity was 0.923 mg/g at 303 K). The adsorption kinetics experiment was followed by pseudo second-order kinetic model that indicated chemisorptions process. Intra-particle diffusion mechanism was not the sole rate-controlling factor. Thermodynamic analysis proposes that removal of fluoride from aqueous solution by MACAIB material was an exothermic and spontaneous process. Characterization of the MACAIB carbon material before and after adsorption through FTIR, SEM, EDX and XRD techniques confirmed the fluoride adsorption on the adsorbent surface. It could be accomplished that MACAIB is an effective adsorbent material for successful removal of fluoride from aqueous solution.


Modeling of inter-neuronal coupling medium and its impact on neuronal synchronization.
In this paper, modeling of the coupling medium between two neurons, the effects of the model parameters on the synchronization of those neurons, and compensation of coupling strength deficiency in synchronization are studied. Our study exploits the inter-neuronal coupling medium and investigates its intrinsic properties in order to get insight into neuronal-information transmittance and, there from, brain-information processing. A novel electrical model of the coupling medium that represents a well-known RLC circuit attributable to the coupling medium's intrinsic resistive, inductive, and capacitive properties is derived. Surprisingly, the integration of such properties reveals the existence of a natural three-term control strategy, referred to in the literature as the proportional integral derivative (PID) controller, which can be responsible for synchronization between two neurons. Consequently, brain-information processing can rely on a large number of PID controllers based on the coupling medium properties responsible for the coherent behavior of neurons in a neural network. Herein, the effects of the coupling model (or natural PID controller) parameters are studied and, further, a supervisory mechanism is proposed that follows a learning and adaptation policy based on the particle swarm optimization algorithm for compensation of the coupling strength deficiency.


Exploiting few mode-fibers for optical time-stretch confocal microscopy in the short near-infrared window.
Dispersive fiber is well-regarded as the most viable candidate for realizing efficient optical time-stretch process--an ultrafast spectroscopic measurement technique based on the wavelength-to-time mapping via group velocity dispersion (GVD). Despite optical time-stretch has been anticipated to benefit a wide range of high-throughput biomedical diagnoses, the lack of commercially-available dispersive fibers which can operate in the "biomedically-favorable" short near-infrared (~800 nm - 1100 nm) range hinders practical time-stretch-based biomedical spectroscopy and microscopy. We here explore and demonstrate the feasibility of using the standard telecommunication single-mode fibers (e.g. SMF28 and dispersion compensation fiber (DCF)) as few-mode fibers (FMFs) for optical time-stretch confocal microscopy in the 1 μm range. By evaluating GVD of different FMF modes and thus the corresponding time-stretch performances, we show that the fundamental modes (LP(01)) of SMF28 and DCF, having sufficiently high dispersion-to-loss ratios, are particularly useful for practical time-stretch spectroscopy and microscopy at 1 μm, without the need for the specialty 1 μm SMF. More intriguingly, we also show that the higher-order FMF modes (e.g. LP(11)) could be excited and utilized for time-stretch imaging. Such additional degree of freedom creates a new avenue for optimizing and designing the time-stretch operations, such as by tailored engineering of the modal-dispersion as well as the GVD of the individual FMF modes.


Sleep/wake behaviour of endurance cyclists before and during competition.
Good sleep is critical for optimising recovery and athletic performance. Yet, few studies have investigated how athletes sleep before and during competition. The aim of this study was to determine whether such sleep is poorer than that before a usual training day. Twenty-one male endurance cyclists' (age: 19.9 ± 1.7 years) sleep/wake behaviour was assessed using wrist activity monitors for 11 nights, including a six-night baseline training phase, three nights before competition and two nights during competition. Cyclists had less sleep on the night before competition (6.5 ± 0.9 h) and during the first night of competition (6.8 ± 0.8 h) than at baseline (7.4 ± 0.6 h). Cyclists also went to bed and woke up earlier during competition than at baseline. Competition schedules and competition itself can disrupt the sleep/wake behaviour of athletes during competition. Future investigations should examine sleep during three stages of competition (i.e. before, during and after competition). This will help coaches develop a greater understanding of how sleep changes during different phases of competition and enable them to plan post-competition training programmes to ensure appropriate rest and recovery is obtained.


AED and text message responders density in residential areas for rapid response in out-of-hospital cardiac arrest.
For out-of-hospital cardiac arrest (OHCA) in residential areas, a dispatcher driven alert-system using text messages (TM-system) directing local rescuers (TM-responders) to OHCA patients was implemented and the desired density of automated external defibrillators (AEDs) or TM-responders investigated. We included OHCA cases with the TM-system activated in residential areas between 2010-2017. For each case, densities/km2 of activated AEDs and TM-responders within a 1000 m circle were calculated. Time intervals between 112-call and first defibrillation were calculated. In total, 813 patients (45%) had a shockable initial rhythm. In 17% a TM-system AED delivered the first shock. With increasing AED density, the median time to shock decreased from 10:59 to 08:17 min. (p < 0.001) and shocks <6 min increased from 6% to 12% (p = 0.024). Increasing density of TM-responders was associated with a decrease in median time to shock from 10:59 to 08:20 min. (p < 0.001) and increase of shocks <6 min from 6% to 13% (p = 0.005). Increasing density of AEDs and TM-responders resulted in a decline of ambulance first defibrillation by 19% (p = 0.016) and 22% (p = 0.001), respectively. First responder AED defibrillation did not change significantly. Densities of >2 AEDs/km2 did not result in further decrease of time to first shock but >10 TM-responders/km2 resulted in more defibrillations <6 min. With increasing AED and TM-responder density within a TM-system, time to defibrillation in residential areas decreased. AED and TM-responders only competed with ambulances, not with first responders. The recommended density of AEDs and TM-responders for earliest defibrillation is 2 AEDs/km2 and >10 TM-responders/km2.


Single-nucleotide polymorphisms inside microRNA target sites influence tumor susceptibility.
Single-nucleotide polymorphisms (SNP) associated with polygenetic disorders, such as breast cancer (BC), can create, destroy, or modify microRNA (miRNA) binding sites; however, the extent to which SNPs interfere with miRNA gene regulation and affect cancer susceptibility remains largely unknown. We hypothesize that disruption of miRNA target binding by SNPs is a widespread mechanism relevant to cancer susceptibility. To test this, we analyzed SNPs known to be associated with BC risk, in silico and in vitro, for their ability to modify miRNA binding sites and miRNA gene regulation and referred to these as target SNPs. We identified rs1982073-TGFB1 and rs1799782-XRCC1 as target SNPs, whose alleles could modulate gene expression by differential interaction with miR-187 and miR-138, respectively. Genome-wide bioinformatics analysis predicted approximately 64% of transcribed SNPs as target SNPs that can modify (increase/decrease) the binding energy of putative miRNA::mRNA duplexes by >90%. To assess whether target SNPs are implicated in BC susceptibility, we conducted a case-control population study and observed that germline occurrence of rs799917-BRCA1 and rs334348-TGFR1 significantly varies among populations with different risks of developing BC. Luciferase activity of target SNPs, allelic variants, and protein levels in cancer cell lines with different genotypes showed differential regulation of target genes following overexpression of the two interacting miRNAs (miR-638 and miR-628-5p). Therefore, we propose that transcribed target SNPs alter miRNA gene regulation and, consequently, protein expression, contributing to the likelihood of cancer susceptibility, by a novel mechanism of subtle gene regulation.


First Report of Kalanchoe Leaf Scorch Caused by Stemphylium xanthosomatis in Korea.
Kalanchoe (Kalanchoe blossfeldiana Poelln.) is widely cultivated in Korea as an ornamental houseplant and succulent garden plant because of its ease of propagation, low water requirements, and wide variety of flower colors. In August 2010, suspected nursery-stage kalanchoe leaf scorch was found at a grower's greenhouses located in Gimhae, Korea. In some greenhouses, 20 to 30%, and occasionally as much as 50%, of the plants were affected. Symptoms on kalanchoe include browning of the leaf margins and yellowing or darkening of tissues between the main leaf veins. As the disease progresses, affected leaves dried up, turned brown, and became brittle. A velvety, blackish olive mold formed on the surface of the dead tissue, followed by plant defoliation. Fresh leaf specimens were collected from infected plants and the causal pathogen was purified with a single-spore isolation technique and transferred onto potato dextrose agar (PDA). Colonies on PDA developed a gray or grayish brown, hairy, velvety mycelium that was mostly immersed and also formed conidia. Conidia were pale to mid brown, oblong, smooth or verruculose, with three to five transverse and one to two longitudinal septa in two to three transverse divisions, and 32 to 55 × 11 to 18 μm. Conidiophores were pale to mid brown, solitary or in fascicles, unbranched or occasionally branched, straight or flexuous, more or less cylindrical but enlarged slightly at one to three apical percurrent proliferations, septate, and 80 to 300 × 2 to 5 μm. A representative isolate of the pathogen was inoculated on kalanchoe leaves for pathogenicity testing. Cultures grown on PDA were flooded with sterile distilled water and after rubbing with an artist's paintbrush with hair bristles, the resulting suspensions were filtered through sterile cheesecloth. Conidial suspensions were adjusted to 2.5 × 104 conidia/ml with sterile distilled water. The leaves of five 1-month-old potted plants were wounded by applying pressure with forceps having serrated teeth, bruising the tissue. Wounded plants were sprayed with a conidial suspension until runoff. Five plants sprayed with sterile distilled water served as controls. The plants were maintained for 48 h at 25°C in a humidity chamber with 100% relative humidity and were then moved to a greenhouse. Symptoms similar to those observed in the farmer's greenhouse developed on wounded leaves within 9 days. The causal pathogen was reisolated from the lesions to prove Koch's postulates. To confirm the identity of the fungus, the complete internal transcribed spacer (ITS) rDNA and glyceraldehyde 3-phosphate dehydrogenase (gpd) gene were amplified and sequenced (1). Amplification of the ITS region generated a 579-bp sequence (GenBank Accession No. HQ840713) and gpd was 558 bp (GenBank Accession No. JF776462). The ITS and gpd sequences were 100% similar to the sequences of Stemphylium xanthosomatis (GenBank Accession Nos. AF442804 and AF443903, respectively). On the basis of symptoms, mycological characteristics, pathogenicity, and molecular data, this fungus was identified as S. xanthosomatis. The type culture of the fungus is stored at the Korean Agricultural Culture Collection (KACC 45812), National Academy of Agricultural Science, Korea. To our knowledge, this is the first report of leaf scorch caused by S. xanthosomatis on kalanchoe in Korea. Reference: (1) M. P. S. Câmara et al. Mycologia 94:660, 2002.


Potential Therapeutic Effects of Curcumin on Glycemic and Lipid Profile in Uncomplicated Type 2 Diabetes-A Meta-Analysis of Randomized Controlled Trial.
Diabetes mellitus is an important issue for public health, and it is growing in the world. In recent years, there has been a growing research interest on efficacy evidence of the curcumin use in the regulation of glycemia and lipidaemia. The molecular structure of curcumins allows to intercept reactive oxygen species (ROI) that are particularly harmful in chronic inflammation and tumorigenesis models. The aim of our study performed a systematic review and meta-analysis to evaluate the effect of curcumin on glycemic and lipid profile in subjects with uncomplicated type 2 diabetes. The papers included in the meta-analysis were sought in the MEDLINE, EMBASE, Scopus, Clinicaltrials.gov, Web of Science, and Cochrane Library databases as of October 2020. The sizes were pooled across studies in order to obtain an overall effect size. A random effects model was used to account for different sources of variation among studies. Cohen's d, with 95% confidence interval (CI) was used as a measure of the effect size. Heterogeneity was assessed while using Q statistics. The ANOVA-Q test was used to value the differences among groups. Publication bias was analyzed and represented by a funnel plot. Curcumin treatment does not show a statistically significant reduction between treated and untreated patients. On the other hand, glycosylated hemoglobin, homeostasis model assessment (HOMA), and low-density lipoprotein (LDL) showed a statistically significant reduction in subjects that were treated with curcumin, respectively (p = 0.008, p < 0.001, p = 0.021). When considering HBA1c, the meta-regressions only showed statistical significance for gender (p = 0.034). Our meta-analysis seems to confirm the benefits on glucose metabolism, with results that appear to be more solid than those of lipid metabolism. However, further studies are needed in order to test the efficacy and safety of curcumin in uncomplicated type 2 diabetes.


TU-E-BRB-07: An EPID Based Dosimetric Verification Tool for SBRT with High Dose Rate FFF Beams.
The increasing use of unflattened high dose rate and/or small sized fields in stereotactic body radiosurgery (SBRT) presents a significant challenge and calls for new tools for dosimetric measurements and quality assurance (QA). The purpose of this work is to investigate a high spatial resolution (0.2mm) and high frame rate (50Hz) amorphous silicon flat-panel electronic portal imaging device (EPID) from Perkin Elmer for SBRT. A Monte Carlo N-Particle eXtended (MCNPX) simulation and convolution based calibration procedure has been developed to derive a voxel-based response function specific to the EPID construct and beam characteristics. Both standard photon beams and flattening filter free (FFF) beams of all energies from Varian TrueBeam STX were studied and the linearity and dose rate dependence were tested. EPID with detailed materials composition was simulated using the MCNPX to generate a scatter kernel composed of dose deposition in the EPID phosphor, and optical photon spreading and to deconvolve the EPID images to high spatial resolution photon fluence map. The fluence map was convolved with MCNPX generated kernels to the 3D dose distribution in the phantom and compared with pinpoint ion chamber and film measurements. EPID response showed excellent linearity (R2>0.9998) and dose rate dependence less than 1.8% for up to 2400MU/min. Output factors for field sizes ranging from 1×1 to 20×20cm2 were measured and used to fit the optical photon glare kernel. Fluence profiles deconvolved using MCNPX scattering kernel agrees with the measurements to within 2%. Results of typical pre-treatment QA test exhibit excellent spatial resolution required for SBRT. The high spatial resolution and high frame rate EPID proved to be an accurate and efficient tool for SBRT QA. Through convolution with MCNPX scattering core and comprehensive EPID calibration, accurate 3D dose maps can be generated for independent dosimetric verification of SBRT treatments.


Giant liposarcoma of the mesentery. Report of a case.
Liposarcomas represent the single most common type of soft tissue sarcoma. Its abdominal localization is rare, occurring in only 5% of cases. A 55 year old male was found to have a case of primary giant liposarcoma of the mesenterium with a maximum diameter of 40 cm and weight of 9 kg. Computed tomography revealed the presence of a large mass presenting a dishomogeneous density with an adipose component, probably of mesenteric origin. A xifopubic laparotomy confirmed the presence of a pedunculated growth originating from the mesentery. The mass was removed and the histopathological report noted a well differentiated sclerosing liposarcoma with the peritoneal liquid positive for malignant cells. Surgery currently represents the only possibly curative therapy for this type of tumour but close long-term follow up and accurate evaluation of the clinicopathologic parameters are needed.


Comparative genomics and genome biology of Campylobacter showae.
Campylobacter showae a bacterium historically linked to gingivitis and periodontitis, has recently been associated with inflammatory bowel disease and colorectal cancer. Our aim was to generate genome sequences for new clinical C. showae strains and identify functional properties explaining their pathogenic potential. Eight C. showae genomes were assessed, four strains isolated from inflamed gut tissues from paediatric Crohn's disease patients, three strains from colonic adenomas, and one from a gastroenteritis patient stool. Genome assemblies were analyzed alongside the only 3 deposited C. showae genomes. The pangenome from these 11 strains consisted of 4686 unique protein families, and the core genome size was estimated at 1050 ± 15 genes with each new genome contributing an additional 206 ± 16 genes. Functional assays indicated that colonic strains segregated into 2 groups: adherent/invasive vs. non-adherent/non-invasive strains. The former possessed Type IV secretion machinery and S-layer proteins, while the latter contained Cas genes and other CRISPR associated proteins. Comparison of gene profiles with strains in Human Microbiome Project metagenomes showed that gut-derived isolates share genes specific to tongue dorsum and supragingival plaque counterparts. Our findings indicate that C. showae strains are phenotypically and genetically diverse and suggest that secretion systems may play an important role in virulence potential.


Habitat split and the global decline of amphibians.
The worldwide decline in amphibians has been attributed to several causes, especially habitat loss and disease. We identified a further factor, namely "habitat split"-defined as human-induced disconnection between habitats used by different life history stages of a species-which forces forest-associated amphibians with aquatic larvae to make risky breeding migrations between suitable aquatic and terrestrial habitats. In the Brazilian Atlantic Forest, we found that habitat split negatively affects the richness of species with aquatic larvae but not the richness of species with terrestrial development (the latter can complete their life cycle inside forest remnants). This mechanism helps to explain why species with aquatic larvae have the highest incidence of population decline. These findings reinforce the need for the conservation and restoration of riparian vegetation.


Clinical utility of diagnostic tests for constipation in adults: a systematic review.
Because symptoms alone do not identify pathophysiology or differentiate subgroups of constipation, diagnostic tests are generally recommended. However, their utility is not known. We performed a systematic review of diagnostic tests commonly used in constipation. We searched the English literature using MEDLINE and PUBMED databases from 1966 to 2004 for studies in adults published as full manuscripts whose methodological quality was above a minimum score. No studies assessed the routine use of blood tests or abdominal x-ray. One retrospective endoscopic study showed that cancer and polyp detection rate was comparable to historical controls. Two studies of barium enema were unhelpful in diagnosis of constipation. Physiological studies showed differences in study population, methodology, and interpretation, and there was no gold standard. Ten colonic transit studies showed prevalence of 38-80% in support of slow transit constipation. Nine anorectal manometry studies showed prevalence of 20-75% for detecting dyssynergia. Nine studies of balloon expulsion showed impaired expulsion of 23-67%. Among 10 defecography studies, abnormalities were reported in 25-90% and dyssynergia in 13-37%. Evidence to support the use of blood tests, radiography, or endoscopy in the routine work up of patients with constipation without alarm features is lacking. Colonic transit, anorectal manometry, and balloon expulsion tests reveal physiologic abnormalities in many selected patients with constipation, but no single test adequately defines pathophysiology. Large, well-designed, prospective studies are required to examine the utility of these tests.


Sensitivity of the ViroSeq HIV-1 genotyping system for detection of the K103N resistance mutation in HIV-1 subtypes A, C, and D.
The US Food and Drug Administration-cleared ViroSeq HIV-1 Genotyping System (ViroSeq) and other population sequencing-based human immunodeficiency virus type 1 (HIV-1) genotyping methods detect antiretroviral drug resistance mutations present in the major viral population of a test sample. These assays also detect some mutations in viral variants that are present as mixtures. We compared detection of the K103N nevirapine resistance mutation using ViroSeq and a sensitive, quantitative point mutation assay, LigAmp. The LigAmp assay measured the percentage of K103N-containing variants in the viral population (percentage of K103N). We analyzed 305 samples with HIV-1 subtypes A, C, and D collected from African women after nevirapine administration. ViroSeq detected K103N in 100% of samples with >20% K103N, 77.8% of samples with 10 to 20% K103N, 71.4% of samples with 5 to 10% K103N, and 16.9% of samples with 1 to 5% K103N. The sensitivity of ViroSeq for detection of K103N was similar for subtypes A, C, and D. These data indicate that the ViroSeq system reliably detects the K103N mutation at levels above 20% and frequently detects the mutation at lower levels. Further studies are needed to compare the sensitivity of different assays for detection of HIV-1 drug resistance mutations and to determine the clinical relevance of HIV-1 minority variants.


Digital Ageism: Challenges and Opportunities in Artificial Intelligence for Older Adults.
Artificial intelligence (AI) and machine learning are changing our world through their impact on sectors including health care, education, employment, finance, and law. AI systems are developed using data that reflect the implicit and explicit biases of society, and there are significant concerns about how the predictive models in AI systems amplify inequity, privilege, and power in society. The widespread applications of AI have led to mainstream discourse about how AI systems are perpetuating racism, sexism, and classism; yet, concerns about ageism have been largely absent in the AI bias literature. Given the globally aging population and proliferation of AI, there is a need to critically examine the presence of age-related bias in AI systems. This forum article discusses ageism in AI systems and introduces a conceptual model that outlines intersecting pathways of technology development that can produce and reinforce digital ageism in AI systems. We also describe the broader ethical and legal implications and considerations for future directions in digital ageism research to advance knowledge in the field and deepen our understanding of how ageism in AI is fostered by broader cycles of injustice.


Predicting fetal neurodevelopmental age from ultrasound images.
We propose an automated framework for predicting age and neurodevelopmental maturation of a fetus based on 3D ultrasound (US) brain image appearance. A topology-preserving manifold representation of the fetal skull enabled design of bespoke scale-invariant image features. Our regression forest model used these features to learn a mapping from age-related sonographic image patterns to fetal age and development. The Sylvian Fissure was identified as a critical region for accurate age estimation, and restricting the search space to this anatomy improved prediction accuracy on a set of 130 healthy fetuses (error ± 3.8 days; r = 0.98 performing the best current clinical method. Our framework remained robust when applied to a routine clinical population.


Pathogenicity of H5 influenza viruses for ducks.
Four H5N1 highly pathogenic avian influenza (HPAI) viruses and an avirulent reassortant H5N1 virus were tested for their pathogenicity in domestic ducks. A/chicken/Yamaguchi/7/04 (H5N1) (Ck/Yamaguchi/04) isolated from a dead bird during the HPAI outbreak in Japan and A/duck/Yokohama/aq-10/03 (H5N1) (Dk/Yokohama/03) isolated from duck meat at a quarantine inspection for importation from China replicated in multiple organs including the brain of ducks. The ducks infected with Ck/Yamaguchi/04 did not show any clinical signs, while those infected with Dk/Yokohama/03 showed neurological signs. The ducks infected either with A/Hong Kong/483/97 (H5N1) or A/tern/South Africa/61 (H5N3), or with an avirulent H5N1 reassortant, did not show any clinical signs. Virus-specific antibodies were detected in the sera of the ducks infected with each of the five strains tested, indicating that all of the viral strains infected and replicated in the birds. Dk/Yokohama/03 grew in multiple organs more rapidly than did Ck/Yamaguchi/04. Considerable titers of virus were detected in the brain of the ducks infected with Dk/Yokohama/03 and these birds showed neurological signs. The present results demonstrate that the pathogenicity of influenza viruses for ducks does not correlate with that for chickens and that replication of the virus in the brain is critical for ducks to show neurological signs.


Calcific aortic stenosis: a complication of chronic uraemia.
The incidence of aortic stenosis was studied in 174 consecutive patients aged less than 55 years at initiation of maintenance haemodialysis. Severe, calcific aortic stenosis developed in 6 patients a mean 9.7 years after starting haemodialysis (p = 0.0004 compared to population incidence). In 5 patients stenosis was due to severe premature calcification of a tricuspid aortic valve. Necropsy proven aortic valve calcification (with or without stenosis) was associated with an increased duration of haemodialysis, age greater than 35 years at starting dialysis and mitral annular calcification. There is an increased incidence of aortic stenosis in patients with chronic renal failure due to premature valvular calcification, which may be related to abnormal calcium and phosphate metabolism in uraemia.


Clinicopathological spectrum of colorectal cancer among the population of the KwaZulu-Natal Province in South Africa.
the burden of colorectal carcinoma (CRC), once considered rare in Africa, may be changing with the disease being increasingly diagnosed and there is a suggestion that age and race influence tumour behaviour. We sought to describe the clinicopathological spectrum of CRC among the different race and age groups in a South African setting. analysis of prospectively collected data from an on-going colorectal cancer database, including demographics, clinical presentation, site, staging and grading on all patients enrolled over an 18-year period. a total of 2232 patients with CRC were accrued over the study period (Africans, 798; Indians, 890; Coloureds, 104; and Whites, 440). Mean age was 57.7 (SD 14.4) but varied considerably by race (p < 0.001) with Africans being significantly younger. Young adults (aged < 40 years) totalled 305 and older patients (aged > 40 years) totalled 1927. The proportion of young patients (< 40 years old) was 28%, 7%, 9% and 3% among Africans, Indian, Coloured and White patients respectively. There were minimal variations in anatomical sub-site distribution. There was no difference in tumour stage between the various races and between older and young adults. Mucinous differentiation was more common in Africans and in young patients and poor differentiation was more common in African patients. Africans had a significantly lower resection rate compared to the other race groups (p < 0.001). Younger patients had a significantly lower resection rate compared to the older age group (p < 0.001). African patients were the youngest compared to the other race groups. Mucinous differentiation predominated in Africans and young adults. Poor differentiation predominated in Africans. Resection rate was lower for African patients and in young patients.


Hormonal, Metabolic and Hemodynamic Adaptations to Glycosuria in Type 2 Diabetes Patients Treated with Sodium-Glucose Co-Transporter Inhibitors.
The advent of the sodium-glucose cotransporter-2 inhibitors [SGLT-2i] provides an additional tool to combat diabetes and complications. The use of SGLT-2i leads to effective and durable glycemic control with important reductions in body weight/fat and blood pressure. These agents may delay beta-cell deterioration and improve tissue insulin sensitivity, which might slow the progression of the disease. In response to glycosuria, a compensatory rise in endogenous glucose production, sustained by a decrease in plasma insulin with an increase in glucagon has been described. Other possible mediators have been implicated and preliminary findings suggest that a sympathoadrenal discharge and/or rapid elevation in circulating substrates (i.e., fatty acids) or some yet unidentified humoral factors may have a role in a renal-hepatic inter-organ relationship. A possible contribution of enhanced renal gluconeogenesis to glucose entry into the systemic circulation has not yet been ruled out. Additionally, tissue glucose utilization decreases, whereas adipose tissue lipolysis is stimulated and, there is a switch to lipid oxidation with the formation of ketone bodies; the risk for keto-acidosis may limit the use of SGLT-2i. These metabolic adaptations are part of a counter-regulatory response to avoid hypoglycemia and, as a result, limit the SGLT-2i therapeutic efficacy. Recent trials revealed important cardiovascular [CV] beneficial effects of SGLT-2i drugs when used in T2DM patients with CV disease. Although the underlying mechanisms are not fully understood, there appears to be "class effect". Changes in hemodynamics and electrolyte/body fluid distribution are likely involved, but there is no evidence for anti-atherosclerotic effects. It is anticipated that, by providing durable diabetes control and reducing CV morbidity and mortality, the SGLT-2i class of drugs is destined to become a priority choice in diabetes management.