[Antagonistic action of Pseudomonas aeruginosa against Staphylococci, coliform bacilli and various types of Proteus].
Antagonistic activity of 2 fresh isolates and 3 collection strains of Pseudomonas aeruginosa against 177 microbial strains was determined with the method of late antagonism. Among the microbial strains there were 56 staphylococcal strains isolated from patents and carriers. 38 nontypable colon bacilli isolated from healthy persons, 59 enteropathogenic colon bacilli of various serogroups, 12 strains of Proteus and 12 colon bacilli, carriers of multiple drug resistance factors (R factors). All the cultures were sensitive to the antagonistic action of 5 or at least 3 strains of Pseudomonas used in the study. The most active antagonists were the fresh isolates of Pseudomonas as compared to the collection strains. Among the staphylococci S. aureus proved to be the most resistant to the antagonistic action of Pseudomonas as compared to S. epidermidis, the same as the strains isolated from carriers as compared to the strains isolated from patients. As for the enteric bacilli the most resistant were the strains of Proteus. Acquiring of transmissive R factors by the colon bacilli markedly increased their sensitivity to the antagonistic action of Pseudomonas.


The effect of highly active antiretroviral therapy on liver function in human immunodeficiency virus-infected pediatric patients with or without hepatitis virus co-infection.
Co-infection of hepatitis virus is common in human immunodeficiency virus (HIV) infected adults in China. But little is known about hepatitis virus co-infection in pediatric HIV-infected subjects. The study aimed to investigate the impact of hepatitis B virus (HBV) and/or hepatitis C virus (HCV) co-infection and highly active antiretroviral therapy (HAART) on liver function of pediatric HIV-infected subjects. A cohort study including 101 pediatric HIV-infected subjects with HBV/HCV co-infection and 44 pediatric comparators with HIV mono-infection was carried out in Henan Province of China from September 2011 to September 2012. All patients received HAART for 1-year. HBV and HCV infection was determined by antibody tests. HIV RNA load, CD4(+) T-cell counts and liver function were determined before and after HAART. The Student's t-test or a one-way ANOVA was used for normally distributed values and A Mann-Whitney U-test was performed for values without normal distribution using SPSS statistical package 18.0 (SPSS Inc.). After HAART for 1-year, the median levels of viral load were decreased to lower limit of detection in 90.34% pediatric HIV-infected subjects with/without HBV/HCV co-infection (P < 0.001), and CD4(+) T-cell counts increased significantly (P < 0.001). Compared with the pre-HAART, mean level of alanine aminotransferase (ALT) in each group had a significant increase after HAART (P < 0.01). The mean levels of ALT and aspartate aminotransferase (AST) in nevirapine (NVP) based HAART group increased significantly after HAART (P < 0.01). Mean change values of ALT and AST were significantly higher in the NVP based regimen group than in the efavirenz (EFV) based regimen group (P < 0.01). For HIV/HBV/HCV co-infected patients, mean change values of ALT and AST in NVP-based HAART group was significantly higher than that in EFV-based HAART group (P < 0.01). Highly active antiretroviral therapy can damage liver function in pediatric HIV-infected subjects, especially in those with HBV/HCV co-infection. NVP was more harmful to liver function of pediatric HIV-infected subjects than EFV.


Abscisic acid in the thermoinhibition of lettuce seed germination and enhancement of its catabolism by gibberellin.
Germination of lettuce (Lactuca sativa L. cv. 'Grand Rapids') seeds was inhibited at high temperatures (thermoinhibition). Thermoinhibition at 28 degrees C was prevented by the application of fluridone, an inhibitor of abscisic acid (ABA) biosynthesis. At 33 degrees C, the sensitivity of the seeds to ABA increased, and fluridone on its own was no longer effective. However, a combined application of fluridone and gibberellic acid (GA3) was able to restore the germination. Exogenous GA3 lowered endogenous ABA content in the seeds, enhancing catabolism of ABA and export of the catabolites from the intact seeds. The fluridone application also decreased the ABA content. Consequently, the combined application of fluridone and GA3 decreased the ABA content to a sufficiently low level to allow germination at 33 degrees C. There was no significant temperature-dependent change in endogenous GA1 contents. It is concluded that ABA is an important factor in the regulation of thermoinhibition of lettuce seed germination, and that GA affects the temperature responsiveness of the seeds through ABA metabolism.


Molecular cloning of Ehrlichia risticii and development of a gene probe for the diagnosis of Potomac horse fever.
A gene bank of Ehrlichia risticii was constructed in plasmid vector pUC13. Five clones representing discrete regions of the E. risticii genome were tested for their ability to hybridize specifically to E. risticii DNA. None of the clones cross-hybridized with Ehrlichia equi DNA, whereas four of these clones cross-hybridized with Ehrlichia canis and Ehrlichia sennetsu DNAs. However, one clone carrying a 1-kilobase HindIII fragment of E. risticii DNA failed to cross-react with the genomes of E. sennetsu, E. canis, and E. equi in dot blot hybridization assays. The sensitivity of this probe for the detection of E. risticii DNA was approximately 0.5 pg. By using this probe, the E. risticii DNA was detected in the peripheral blood mononuclear cells of 30 experimentally infected horses by 7 days postinfection (p.i.); the detection of E. risticii DNA peaked between 14 and 17 days p.i., a period immediately after the peak of the second rise in body temperature, during leukopenia and at the onset of diarrhea. E. risticii DNA was not detectable by 25 to 30 days p.i. E. risticii DNA was not detected in noninfected control horses.


Blockage of the light-sensitive conductance in hyperpolarizing photoreceptors of the scallop. Effects of tetraethylammonium and 4-aminopyridine.
The tight-seal whole-cell recording technique was used to examine the effect of tetraethylammonium (TEA) and 4-aminopyridine (4-AP) on the photocurrent of hyperpolarizing ciliary photoreceptors isolated from the distal retina of the bay scallop (Pecten irradians). In these cells, light causes an increase in a conductance that is highly selective to potassium ions. Extracellular application of TEA at a concentration of 50 mM produced a modest, reversible block (approximately 35% at -20 mV holding potential). The blockage was weakly voltage dependent, increasing by approximately 20% for a 20-mV hyperpolarization, suggestive of a site of interaction superficially located within the electric field of the membrane. Treatment with TEA produced no significant changes either in the light sensitivity of the photocurrent or in its kinetics. The effects of superfusion with 4-AP were more dramatic: the light-evoked current was nearly abolished (> 95%) at submillimolar concentrations, with a half-maximal dose of approximately 0.6 microns. The blockage had a rapid onset and was slowly reversible. No significant use or voltage dependency were observed. A number of control experiments indicated that the phototransduction cascade remained functional during treatment with 4-AP: the early receptor current, the prolonged after current and its suppression, the photoresponse kinetics and the light sensitivity of the cell were little affected by 4-AP, suggesting that the suppression of the photocurrent is due to blockage of the light-sensitive channels, rather than impairment of some of the activation steps. The results are discussed in the light of a possible kinship between the light-activated potassium channels of invertebrate hyperpolarizing photoreceptors and the family of rapidly-inactivating voltage-dependent potassium channels, which typically exhibit high susceptibility to blockage by this drug.


Predictors for treatment success and expression of glucocorticoid receptor in giant cell arteritis and polymyalgia rheumatica.
Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) generally respond well to treatment with glucocorticoids (GC). We sought to determine the value of clinical, histopathologic, immunohistochemical, and genetic findings and the expression of the glucocorticoid receptor (GR) for discriminating between patients who achieve complete remission, or partial remission, or who do not improve with glucocorticoid treatment. We examined biopsies of the temporal artery from 60 patients, of whom 27 had GCA, 13 PMR, and 20 arteriosclerosis. Of the clinical variables evaluated, jaw claudication was correlated with the histologic classification of the biopsies (p < 0.0001). Erythrocyte sedimentation rate was significantly higher in patients with PMR and GCA than in patients with arteriosclerosis (p < 0.0001). There were significant differences between patients with GCA versus PMR in the numbers of CD3-, CD8-, and CD4-positive T cells, in CD68-positive monocytes (p < 0.0001), and antigen-presenting cells (p < 0.0001). CD138-positive and CD20-positive cells were absent in patients with PMR but present in patients with GCA (p < 0.0001). In GCA and chronic inflammation most monocytes and lymphocytes expressed GR (88.9%). The number of CD68-positive cells and the extent of GR-staining in chronic inflammation reflected the success of treatment in logistic regression analysis (p < 0.05). GR polymorphism showed that more than 90% of patients had the wild-type (homozygote) of the R23K or N363S polymorphism. There was no evidence that this polymorphism influenced response to treatment with GC (Fisher's exact test 1.0). Expression of GR and the presence of CD20-, CD3-, CD4-, CD8-, CD68-, CD138-positive cells and antigen-presenting cells differ between GCA and PMR. The presence of CD68-positive cells and the extent of GR-staining in chronic inflammation are suitable to predict complete remission in GCA.


Three-year performance of in-situ solidified/stabilised soil using novel MgO-bearing binders.
A new group of MgO-bearing binders has been developed recently which showed improved sustainability and technical performance compared to Portland cement (PC). However, the application of these MgO-bearing binders in the Solidification/Stabilisation (S/S) techniques is very limited. This study investigates the three-year performance of a highly contaminated soil treated by in-situ S/S using MgO-bearing binders and PC. The core quality, strength, permeability and the leaching properties of the S/S materials were evaluated. The effects of binder composition, addition of inorgano-organo-clay (IOC) and the grout content on the properties of the 3-y S/S materials are discussed. It is found that although MgO alone provided negligible strength to the soil, it is superior in immobilising both inorganic and organic contaminants. Replacing MgO by ground granulated blast-furnace slag (GGBS) significantly enhanced the strength while also performed well in immobilising the contaminants. The improved pH buffering capacity was attributed to the low solubilities of brucite and hydrotalcite-like phases formed in the MgO-bearing binders, and was also the reason for the improved performance in stabilising contaminants. The addition of IOC slightly decreased the strength and the permeability of the S/S materials but inconsistent effect on the contaminant immobilisation was found depending on the binder composition. This study showed no degradation of the S/S materials after 3 y exposure to field conditions and has proved the applicability and the advantages of MgO-bearing binders over PC in S/S.


Influence of lignocellulose and low or high levels of sugar beet pulp on nutrient digestibility and the fecal microbiota in dogs.
Lignocellulose is an alternative fiber source for dogs; however, it has not yet been studied as a feed ingredient for the nutrition of dogs. Eight adult Beagles were involved in the study, which consisted of 3 feeding periods of 8 to 12 wk each. All dogs received 3 different diets, which either had the same concentration of fiber sources (2.7% sugar beet pulp or lignocellulose) or were formulated for a similar concentration of approximately 3% crude fiber: 12% sugar beet pulp (highSBP; 3.1% crude fiber), 2.7% sugar beet pulp (lowSBP; 0.96% crude fiber), or 2.7% lignocellulose (LC; 2.4% crude fiber). Feces samples were collected at the end of each feeding period, and the apparent nutrient digestibility, daily amount, and DM content of feces and fecal cell numbers of relevant bacteria were analyzed. The daily feces amount was lower and the feces DM was higher when dogs were fed the LC diet and the lowSBP diet compared with the highSBP diet ( < 0.001). Apparent digestibility of CP, Na, and K was highest with the lowSBP diet followed by the LC and highSBP diets ( < 0.001). After feeding LC, the bacterial cell counts of spp., spp., and the cluster were reduced compared with feeding highSBP and even more reduced after feeding lowSBP ( < 0.001). The bacterial cell count of the cluster was lower in LC and lowSBP compared with highSBP ( < 0.001). The feces of dogs fed LC and lowSBP had lower concentrations of acetate ( < 0.001), propionate ( < 0.001), -butyrate ( = 0.015), total fatty acids ( < 0.001), and lactate ( < 0.001) compared with dogs fed highSBP. The concentration of -butyrate was higher in the feces of dogs fed with LC compared with dogs fed high and low sugar beet pulp (SBP; < 0.001). The pH of the feces of the LC-fed dogs was highest followed by lowSBP- and highSBP-fed dogs ( < 0.001). Depending on the concentration, the use of LC and SBP as fiber sources in dog feed has different impacts on the fecal microbiota and the apparent digestibility of nutrients. Therefore, different areas of application should be considered.


Novel Management of Hypersensitive Dentin Using Propolis-based Herbal Desensitizing Agents: An In Vitro Scanning Electron Microscopic Study.
The objective of this in vitro study was to assess the efficacy of novel propolis-based varnish against the two conventional varnishes on quantitative and qualitative assessments of occlusion of dentin tubules and resistance to erosive and abrasive wears employing scanning electron microscope (SEM). Thirty human premolars free from caries extracted due to orthodontic reasons were included in the study. Experimental group was done based on treatment received and divided into three groups. Group A: ClinProXT Varnish (n = 10), Group B: MI Varnish (n = 10), and Group C: Propolis Varnish (n = 10) were applied. Teeth were cleaned and decoronation of crown was done with dentin disks. Dentin specimens of dimension 4 × 4 × 2 mm were prepared and subjected to finishing and polishing. The sample specimens were submersed in EDTA solution for a period of five minutes to open up the dentinal tubules. This was followed by treatment with varnishes and subjection to acidic-abrasive challenge. The specimens were analyzed with an image analyzer connected to SEM for the verification of the number of opened dentin tubules. The parameter assessed in SEM includes size, topography and surface characteristics of dentinal tubule were assessed. The obliteration potential of dentinal tubules was assessed with SEM images. Additionally, the dentin surface loss and resistance to acidic and abrasive wear were also evaluated with SEM. Data were analyzed with two-way analysis of variance (ANOVA) with post hoc Tukey's test. MI Varnish caused higher obliteration of dentin tubules followed by ClinproXT Varnish. Propolis Varnish showed the least obliteration of dentinal tubules among tested experimental groups. After acidic-abrasive challenge, Propolis Varnish was found to be more efficient with less material loss among the experimental groups tested. There was an insignificant difference among the MI Varnish and ClinProXT Varnish groups. Simulation of hypersensitive lesions mimicking the clinical scenario was a challenging task in this in vitro study. All varnishes tested in the study had good efficacy in the management of dentin hypersensitivity (DH). Propolis-based varnish had good resistance to material loss after subjection to acidic-abrasive challenge among the tested materials. The casein phosphopeptide (CPP)-amorphous calcium phosphate (ACP)-based MI Varnish had good efficacy to obliterate the dentinal tubules among the tested materials. It was prudent to select the varnishes with good long-term efficacy to survive in the clinical scenario which still remains a challenging task for the clinicians. The stability of the varnish plays a vital role in maintenance of its long-term efficacy. The chemical nature along with the ability of the material to interact with the substrate plays a major role in management of DH.


Interleukin-6: an angiogenic target in solid tumours.
During the past decade, incorporating anti-angiogenic agents into the therapeutic management of a myriad of malignancies has in certain cases made a significant impact on survival. However, the development of resistance to these drugs is inevitable and swift disease progression on their cessation often ensues. Hence, there is a drive to devise strategies that aim to enhance response to anti-angiogenic therapies by combining them with other targeted agents that facilitate evasion from resistance. The pleiotropic cytokine, interleukin-6 (IL-6), exerts pro-angiogenic effects in the tumour microenvironment of several solid malignancies and there is emerging evidence that reveals significant relationships between IL-6 signalling and treatment failure with antibodies directed against vascular endothelial growth factor (VEGF). This review summarises the role of IL-6 in pivotal angiogenic processes and preclinical/clinical research to support the future introduction of anti-IL-6 therapies to be utilised either in combination with other anti-angiogenic drugs or as a salvage therapy for patients with diseases that become refractory to these approaches.


Examining the effects of mindfulness-based yoga instruction on positive embodiment and affective responses.
Empirical evidence provides support for the inclusion of yoga as part of eating disorder prevention efforts through its positive impact on positive embodiment and experience of positive core affect. However, there is a need to identify the specific instructional strategies that will more consistently support positive embodiment and positive affect. We examined the effect of teaching a single yoga class using mindfulness-based instruction compared to appearance-based and neutral instruction alternatives on embodiment (i.e., state body surveillance, state body appreciation, pleasure during yoga) and changes in affect from before to after class. Female participants (N = 62; M age = 23.89, SD = 6.86) were randomly assigned to a yoga class that emphasized: being mindfully present in one's body, changing one's appearance, or just getting into yoga poses. ANOVAs revealed significantly higher body surveillance (ηp 2 =.10) and lower forecasted pleasure (ηp 2 =.21) in the appearance class compared to the other two classes. Participants in the mindfulness class experienced greater improvement in affect (ηp 2 =.08) from before to after class and higher remembered pleasure during the yoga class (ηp 2 =.19) compared to those in the appearance class. Emphasizing changes to appearance in yoga instruction may place participants at risk for less positive affect and less positive experiences of embodiment compared to mindfulness-based or even neutral yoga instruction.


Retrieving the ground state of spin glasses using thermal noise: Performance of quantum annealing at finite temperatures.
We study the problem to infer the ground state of a spin-glass Hamiltonian using data from another Hamiltonian with interactions disturbed by noise from the original Hamiltonian, motivated by the ground-state inference in quantum annealing on a noisy device. It is shown that the average Hamming distance between the inferred spin configuration and the true ground state is minimized when the temperature of the noisy system is kept at a finite value, and not at zero temperature. We present a spin-glass generalization of a well-established result that the ground state of a purely ferromagnetic Hamiltonian is best inferred at a finite temperature in the sense of smallest Hamming distance when the original ferromagnetic interactions are disturbed by noise. We use the numerical transfer-matrix method to establish the existence of an optimal finite temperature in one- and two-dimensional systems. Our numerical results are supported by mean-field calculations, which give an explicit expression of the optimal temperature to infer the spin-glass ground state as a function of variances of the distributions of the original interactions and the noise. The mean-field prediction is in qualitative agreement with numerical data. Implications on postprocessing of quantum annealing on a noisy device are discussed.


Baseball bats and chocolate chip cookies: the judicial treatment of DNA in the myriad genetics litigation.
In June 2013, the U.S. Supreme Court rendered a controversial ruling that naturally occurring DNA segments are "products of nature" and therefore not patentable subject matter. At this intersection between science and law, in litigation of crucial importance to patients, science, and multibillion-dollar biotech enterprises, the appellate judges sidestepped genetics and engaged in a war of metaphors from diamonds to chocolate chip cookies. This case is not an outlier. Apprehensive judges and juries in both Canada and the United States find many convenient excuses to avoid coming to grips with the underlying science in patent cases. But this is simply not acceptable. Legal rulings must be, and must seem to be, well grounded, as a matter of both law and science. The legitimacy of court decisions in the eyes of the stakeholders and the broader public depends on it.


Mutant Fibulin-3 Causes Proteoglycan Accumulation and Impaired Diffusion Across Bruch's Membrane.
The mutation R345W in EFEMP1 (fibulin-3) causes macular degeneration. This study sought to determine whether proteoglycan content and diffusion across Bruch's membrane are altered in Efemp1ki/ki mice carrying this mutation or in Efemp1-/- mice. Proteoglycans in mouse Bruch's membranes were stained with Cupromeronic Blue (CB). Heparan sulfated proteoglycan (HSPG) and chondroitin/dermatan sulfate proteoglycan (C/DSPG) distributions were visualized following treatments with chondroitinase ABC (C-ABC) or nitrous acid. Total sulfated glycosaminoglycans (sGAGs) in Bruch's membrane/choroid (BrM/Ch) were measured with dimethylmethylene blue (DMMB). Matrix metalloprotease (MMP)-2, MMP-9, and tissue inhibitor of metalloproteinase (TIMP)-3 were examined by immunofluorescence and quantified using Image J. Molecules with different Stokes radius (Rs) were allowed simultaneously to diffuse through mouse BrM/Ch mounted in a modified Ussing chamber. Samples were quantified using gel exclusion chromatography. HSPGs and C/DSPGs were markedly increased in Efemp1ki/ki Bruch's membrane, and MMP-2 and MMP-9 were decreased, but TIMP-3 was increased. Diffusion across Efemp1ki/ki Bruch's membrane was impaired. In contrast, the proteoglycan amount in Efemp1-/- Bruch's membrane was not significantly different, but the size of proteoglycans was much larger. MMP-2, MMP-3, and TIMP-3 levels were similar to that of Efemp1+/+ mice, but they were localized diffusely in retinal pigment epithelium (RPE) cells instead of Bruch's membrane. Diffusion across Efemp1-/- Bruch's membrane was enhanced. Mutant fibulin-3 causes proteoglycan accumulation, reduction of MMP-2 and MMP-9, but increase of TIMP-3, and impairs diffusion across Bruch's membrane. Fibulin-3 ablation results in altered sizes of proteoglycans, altered distributions of MMP-2, MMP-9, and TIMP-3, and enhances diffusion across Bruch's membrane.


Efficacy of noninvasive positive pressure ventilation in elderly patients with acute hypercapnic respiratory failure.
There have been no reports on the efficacy of noninvasive positive pressure ventilation (NPPV) in elderly patients. The purpose of this study was to clarify the efficacy and identify the predictors of a successful outcome of NPPV in patients over the age of 75 years with acute hypercapnic respiratory failure (AHRF). We retrospectively evaluated the data of 42 patients (21 men) with AHRF who were treated at our unit. The patients were divided into survivor and nonsurvivor groups, and the clinical parameters measured prior to the initiation of NPPV were compared between the 2 groups. The mean age of the patients was 83.0 ± 6.3 years. The etiology of the respiratory failure was acute exacerbation of chronic obstructive pulmonary disease in 19 patients, acute cardiogenic pulmonary edema in 18 patients, idiopathic pulmonary fibrosis in 3 patients, sequelae of tuberculosis in 1 patient, and asthma in 1 patient. Of the 42 patients, 33 (78.6%) survived. All patients with a Glasgow Coma Scale (GCS) score ≥9 and/or an APACHE II score <29 survived after the initiation of NPPV. An APACHE II score <29 and a GCS score ≥9 were predictors of a successful outcome of NPPV in elderly people.


Feather Corticosterone Measurements and Behavioral Observations in the Great White Pelican (Pelecanus onocrotalus) Living under Different Flight Restraint Conditions in German Zoos.
The pinioning of birds was previously one of the most-accepted forms of mutilation in zoos. Despite a lack of knowledge on the effects of deflighting procedures with regard to the well-being of deflighted birds, pelicans are often reversibly deflighted by feather-clipping to keep them in open enclosures, including those with ponds without netting. In the present study, we focused on the welfare implications of flight restraint on one of the most commonly kept types of birds in German zoos, the great white pelican. A combination of behavioral observations and feather corticosterone concentrations (CORTf) of pelicans with different deflighting statuses (i.e., irreversibly deflighted, reversibly deflighted, and airworthy) was used to evaluate the effects of deflighting status on pelican welfare. We observed 215 individuals in 21 different German zoos. The pelicans lived in differently designed exhibits. An ethogram for these species was developed and their behavior was evaluated by scan sampling. Feather samples from 182 individuals were collected to determine if different deflighting conditions influenced the CORTf and therefore stress levels. The hypothesis was that the CORTf values of airworthy pelicans differ from those of deflighted pelicans. Tendencies with regard to the flight status groups were found. Conversely, reversibly deflighted pelicans had higher CORTf levels than irreversible deflighted and airworthy pelicans. Tendencies with regard to CORTf values and the group size of the kept pelicans were observed. The CORTf values were lower in groups consisting of more than 10 animals. In addition, the frequency of fluttering behavior was positively associated with CORTf values. Pelicans that frequently showed fluttering had higher CORTf values. Therefore, fluttering behavior might be considered a sign of stress levels in pelicans. This study is one of the first important steps in assessing the impact of deflighting procedures on the welfare of great white pelicans kept in zoos.


Frailty in patients undergoing transcatheter aortic valve implantation: a protocol for a systematic review.
Aortic stenosis is a significant cause of morbidity and mortality in older patients. The advent of transcatheter aortic valve implantation (TAVI) offers an alternative to surgical aortic valve replacement for patients with severe symptomatic aortic stenosis who are at high or intermediate risk of adverse events. Existing evidence highlights the importance of frailty as a predictor of poor outcomes post-TAVI. The objective of this study is to review the operationalisation of frailty instruments for TAVI recipients and determine clinical outcomes and the change in quality of life in frail patients undergoing TAVI. Methods are reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 checklist. We will search relevant databases to identify published, completed but unpublished and ongoing studies. We will include studies of patients with aortic stenosis, diagnosed as frail and who underwent a TAVI procedure that report mortality, clinical outcomes or health-related quality of life. Retrospective or prospective cohort studies, randomised controlled trials and non-randomised controlled trials will be eligible for inclusion. Two researchers will independently screen articles for inclusion, with disagreements resolved by a third reviewer. One researcher will extract data with audit by a second researcher. The risk of bias in studies will be evaluated using the Quality in Prognosis Studies tool. Meta-analysis of mortality, survival curve and the change in quality of life will be performed if appropriate. Subgroup analysis, sensitivity analysis and meta-regression will be performed if necessary. Due to the nature of this study, no ethical issues are foreseen. We will disseminate the results of our systematic review through a peer-reviewed journal. CRD42018090597.


Evaluation of Volumetric Changes of Augmented Maxillary Sinus With Different Bone Grafting Biomaterials.
Extensive alveolar bone resorption because of pneumatized maxillary sinus is a common problem that limits dental implant placement. Maxillary sinus floor augmentation (MSFA) is an accepted treatment protocol that provides sufficient bone volume. The aim of this study was to evaluate the percentage of graft volume reduction following MSFA using cone beam computed tomography. In this retrospective study, cone beam computed tomography scans of MSFA were measured to evaluate the volume of the grafted sinus with deproteinized bovine bone (DBB), mineralized allograft (MA), or a mixture of MA and demineralized allograft as a composite. The volumetric changes in sinus augmentation between 2 weeks (T-I) and 6 months (T-II) after operation were analyzed. Thirty-nine patients were included in this study. The average percent volume reduction was 8.14 ± 3.76%, 19.38 ± 9.22%, and 24.66 ± 4.68% for DBB, MA, and composite graft, respectively. A significant graft volume reduction was found between T-I and T-II for all groups (P < 0.01). The DBB group showed the least volume reduction (P < 0.01). Biomaterials can influence the bone graft volume change before implant placement. Deproteinized bovine bone may offer greater volume stability during healing than mineralized and composite allografts.


Effective design of barrier enclosure to contain aerosol emissions from COVID-19 patients.
Facing shortages of personal protective equipment, some clinicians have advocated the use of barrier enclosures (typically mounted over the head, with and without suction) to contain aerosol emissions from coronavirus disease 2019 (COVID-19) patients. There is, however, little evidence for its usefulness. To test the effectiveness of such a device, we built a manikin that can expire micron-sized aerosols at flow rates close to physiological conditions. We then placed the manikin inside the enclosure and used a laser sheet to visualize the aerosol leaking out. We show that with sufficient suction, it is possible to effectively contain aerosol from the manikin, reducing aerosol exposure outside the enclosure by 99%. In contrast, a passive barrier without suction only reduces aerosol exposure by 60%.


Role of inter-hemispheric connections in functional brain networks.
Today the human brain can be modeled as a graph where nodes represent different regions and links stand for statistical interactions between their activities as recorded by different neuroimaging techniques. Empirical studies have lead to the hypothesis that brain functions rely on the coordination of a scattered mosaic of functionally specialized brain regions (modules or sub-networks), forming a web-like structure of coordinated assemblies (a network of networks. NoN). The study of brain dynamics would therefore benefit from an inspection of how functional sub-networks interact between them. In this paper, we model the brain as an interconnected system composed of two specific sub-networks, the left (L) and right (R) hemispheres, which compete with each other for centrality, a topological measure of importance in a networked system. Specifically, we considered functional scalp EEG networks (SEN) derived from high-density electroencephalographic (EEG) recordings and investigated how node centrality is shaped by interhemispheric connections. Our results show that the distribution of centrality strongly depends on the number of functional connections between hemispheres and the way these connections are distributed. Additionally, we investigated the consequences of node failure on hemispherical centrality, and showed how the abundance of inter-hemispheric links favors the functional balance of centrality distribution between the hemispheres.


First Report of Phytophthora hedraiandra Causing Rhododendron Dieback and Root Rot of Common Beech in the Czech Republic.
From 2010 to 2012, Phytophthora isolates were obtained from brownish diffusion leaf lesions usually up to 2 to 3 cm in diameter of Rhododendron caucasicum 'Cheer,' from withered twigs of Rhododendron sp. with blackish elongated lesions up to ~5 cm in length, and from rotten feeder roots of 2-year-old, chlorotic, wilting seedlings of Fagus sylvatica collected from ornamental and forest nurseries in three areas (central and eastern Bohemia and northern Moravia) in the Czech Republic. Isolates formed chrysanthemum-like to slightly stellate, appressed colonies with sparse aerial mycelium on V8 agar (V8A) plates at 20°C after 5 days, whereas on carrot agar (CA) plates the pattern was vague with no aerial mycelium. The cardinal growth temperatures were: min. 3°C, optimum 23 to 27°C, and max. 31°C. Radial growth was 5.7 to 6.6 mm/day at 20°C on V8A. The isolates were homothallic and produced colorless, smooth-walled, spherical oogonia with an average diameter 29.9 to 33.8 μm on CA. Oospores were aplerotic (avg. 26.4 to 29.3 μm), oospore wall was hyaline and averaged 1.3 to 1.7 μm thick, oospore wall index was 0.26 to 0.32. Paragynous or occasionally amphigynous antheridia averaged 13.4 to 15.0 × 10.9 to 12.5 μm (height × width). Sporangia were caducous, papillate, globose, spherical to ovoid, with short pedicels (avg. 2.1 to 2.6 μm) and averaged 30.9 to 41.5 × 25.5 to 30.6 μm, L:B ratio was 1.2 to 1.4. Chlamydospores were not observed. Morphological characters resembled those described for P. hedraiandra (1). The isolates were deposited in the collection of phytopathogenic oomycetes of RILOG Pruhonice and given accession nos. 450.11, 531.11, and 578.12. The isolates were sequenced for nuclear rDNA ITS region and partial Cox I gene. Obtained sequences were compared with sequences present in GenBank database using BLAST. The ITS sequences of all isolates (GenBank Accession Nos. KJ567081, 82, and 83) of overall length of 792 bp were identical to that of P. hedraiandra AY707987 (1). The Cox I sequences of overall length of 880 bp (KJ567084, 85, and 86) showed 99% homology (1 bp substitution) with AY769115 (1) and 100% identity with other Cox I sequences of P. hedraiandra, i.e., JN376067 (4) and EF174432 (3). Koch's postulates were confirmed by wound-inoculating of 3-year-old rhododendron and common beech plants (10 host plants per corresponding isolate). Rhododendron leaves were gently abraded near the midrib, whereas 5-mm-diameter bark plugs were removed from the beech collars. The inoculum (5-mm-diameter V8A plug with actively growing mycelium) was placed over wounds and sealed with Parafilm. Control plants were treated in the same manner with sterile agar plugs. Plants were maintained in a greenhouse at 22°C. All inoculated plants showed disease symptoms after 10 days of incubation; the lesions were up to 2 cm in rhododendron leaves and ~1 cm in beech collars. Control plants remained healthy. The pathogen was re-isolated from all infected plants. To our knowledge, this is the first report of P. hedraiandra in the Czech Republic. Besides it, the pathogen was found in southern and western Europe (Italy, Slovenia, Spain, the Netherlands) and in the United States (2). References: (1) A. W. A. M. de Cock and A. Lévesque. Stud. Mycol. 50:481, 2004. (2) D. F. Farr and A. Y. Rossman. Fungal Databases, Syst. Mycol. Microbiol. Lab., ARS, USDA. Retrieved from http://nt.ars-grin.gov/fungaldatabases/ , May 13, 2014. (4) E. Moralejo et al. Span. J. Agric. Res. 5:82, 2007. (2) X. Yang et al. Plant Dis. 96:915, 2012.


College students' sense of belonging in times of disruption: Prospective changes from before to during the COVID-19 pandemic.
The current study examined whether college students' sense of belonging changed following the onset of the COVID-19 pandemic. Participants were 252 (66.7% female) first- and second-year college students at a large public university in the United States. It was hypothesized that students would report a decrease in their sense of belonging from before to during the pandemic. It was also hypothesized that female students and racial-ethnic minority students, respectively, would report steeper declines in their sense of belonging compared to their male peers and to their White, non-Hispanic peers. Repeated-measures data were analyzed using a multilevel modeling framework to test for mean differences in students' levels of belonging from pre-COVID to during-COVID periods. No direct change in students' sense of belonging was detected. Moderation results indicated that sense of belonging decreased significantly over time for racial-ethnic minority students but not for White, non-Hispanic students. The findings encourage higher education researchers and practitioners to consider the unique experiences of racial-ethnic minority college students during the COVID-19 pandemic and beyond.


HOX D13 expression across 79 tumor tissue types.
HOX genes control normal development, primary cellular processes and are characterized by a unique genomic network organization. Locus D HOX genes play an important role in limb generation and mesenchymal condensation. Dysregulated HOXD13 expression has been detected in breast cancer, melanoma, cervical cancer and astrocytomas. We have investigated the epidemiology of HOXD13 expression in human tissues and its potential deregulation in the carcinogenesis of specific tumors. HOXD13 homeoprotein expression has been detected using microarray technology comprising more than 4,000 normal and neoplastic tissue samples including 79 different tumor categories. Validation of HOXD13 expression has been performed, at mRNA level, for selected tumor types. Significant differences are detectable between specific normal tissues and corresponding tumor types with the majority of cancers showing an increase in HOXD13 expression (16.1% normal vs. 57.7% cancers). In contrast, pancreas and stomach tumor subtypes display the opposite trend. Interestingly, detection of the HOXD13 homeoprotein in pancreas-tissue microarrays shows that its negative expression has a significant and adverse effect on the prognosis of patients with pancreatic cancer independent of the T or N stage at the time of diagnosis. Our study provides, for the first time, an overview of a HOX protein expression in a large series of normal and neoplastic tissue types, identifies pancreatic cancer as one of the most affected by the HOXD13 hoemoprotein and underlines the way homeoproteins can be associated to human cancerogenesis.


Environmental factors and respiratory hypersensitivity: the Americas.
Diverse environmental exposure profiles exist in the Americas because of widely different climates, ambient pollutants, and bioaerosols in these continents. This paper reviews selected studies from the Americas that support the broad hypothesis that environmental factors contribute to respiratory hypersensitivity. Processes influenced by environmental factors include primary immunologic sensitization, the development and exacerbation of specific immunologic diseases and the activation of nonspecific mechanisms with tissue inflammation, injury and remodeling. Endpoints resulting from these processes include respiratory symptoms, diseases such as asthma, with measures of disease severity including medication use and hospitalization rates, and death due to cardiorespiratory disease. Studies associate sensitization rates to specific allergens with environmental factors such as humidity and indices of allergen exposure. Regional variation occurs with exposure to outdoor source pollutants such as ozone, but varies by household to bioaerosols such as dust mite, cat or cockroach allergen. Indoor allergens are associated with asthma while outdoor allergens are associated with allergic rhinitis. In a national survey, the atopic sensitization rate in the USA increased with urban residence (defined as towns of population > 2500) and varied by region. Controlled human challenge studies show that ozone increases the response of allergic subjects to allergen. Increased ambient photochemical pollution concentrations, of which ozone is an important component, are associated with increased emergency room visits for asthma in cities such as Toronto, New York, Atlanta, and Mexico City. In Sao Paolo, Brazil, mortality due to childhood respiratory disease was influenced by the ambient levels of NO2. Epidemiologic studies including the recent meta-analysis of a large, longitudinal study population associate ambient concentrations of particulate matter < 10 microns and respiratory symptoms, disease severity and increased cardiorespiratory deaths. Toxicology studies show that individual variation in responsiveness is important in nonspecific inflammatory responses to irritant pollutants such as ozone and environmental tobacco smoke. These studies indicate that environmental factors influence primary allergen sensitization, secondary allergic responses, the activation of nonspecific inflammatory responses, and the severity of respiratory diseases, including asthma.


Electric pulse stimulation of cultured murine muscle cells reproduces gene expression changes of trained mouse muscle.
Adequate levels of physical activity are at the center of a healthy lifestyle. However, the molecular mechanisms that mediate the beneficial effects of exercise remain enigmatic. This gap in knowledge is caused by the lack of an amenable experimental model system. Therefore, we optimized electric pulse stimulation of muscle cells to closely recapitulate the plastic changes in gene expression observed in a trained skeletal muscle. The exact experimental conditions were established using the peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) as a marker for an endurance-trained muscle fiber. We subsequently compared the changes in the relative expression of metabolic and myofibrillar genes in the muscle cell system with those observed in mouse muscle in vivo following either an acute or repeated bouts of treadmill exercise. Importantly, in electrically stimulated C2C12 mouse muscle cells, the qualitative transcriptional adaptations were almost identical to those in trained muscle, but differ from the acute effects of exercise on muscle gene expression. In addition, significant alterations in the expression of myofibrillar proteins indicate that this stimulation could be used to modulate the fiber-type of muscle cells in culture. Our data thus describe an experimental cell culture model for the study of at least some of the transcriptional aspects of skeletal muscle adaptation to physical activity. This system will be useful for the study of the molecular mechanisms that regulate exercise adaptation in muscle.


Applications of Machine Learning for the Classification of Porcine Reproductive and Respiratory Syndrome Virus Sublineages Using Amino Acid Scores of ORF5 Gene.
Porcine reproductive and respiratory syndrome is an infectious disease of pigs caused by PRRS virus (PRRSV). A modified live-attenuated vaccine has been widely used to control the spread of PRRSV and the classification of field strains is a key for a successful control and prevention. Restriction fragment length polymorphism targeting the Open reading frame 5 (ORF5) genes is widely used to classify PRRSV strains but showed unstable accuracy. Phylogenetic analysis is a powerful tool for PRRSV classification with consistent accuracy but it demands large computational power as the number of sequences gets increased. Our study aimed to apply four machine learning (ML) algorithms, random forest, k-nearest neighbor, support vector machine and multilayer perceptron, to classify field PRRSV strains into four clades using amino acid scores based on ORF5 gene sequence. Our study used amino acid sequences of ORF5 gene in 1931 field PRRSV strains collected in the US from 2012 to 2020. Phylogenetic analysis was used to labels field PRRSV strains into one of four clades: Lineage 5 or three clades in Linage 1. We measured accuracy and time consumption of classification using four ML approaches by different size of gene sequences. We found that all four ML algorithms classify a large number of field strains in a very short time (<2.5 s) with very high accuracy (>0.99 Area under curve of the Receiver of operating characteristics curve). Furthermore, the random forest approach detects a total of 4 key amino acid positions for the classification of field PRRSV strains into four clades. Our finding will provide an insightful idea to develop a rapid and accurate classification model using genetic information, which also enables us to handle large genome datasets in real time or semi-real time for data-driven decision-making and more timely surveillance.


The TLR4 antagonist Eritoran protects mice from lethal influenza infection.
There is a pressing need to develop alternatives to annual influenza vaccines and antiviral agents licensed for mitigating influenza infection. Previous studies reported that acute lung injury caused by chemical or microbial insults is secondary to the generation of host-derived, oxidized phospholipid that potently stimulates Toll-like receptor 4 (TLR4)-dependent inflammation. Subsequently, we reported that Tlr4(-/-) mice are highly refractory to influenza-induced lethality, and proposed that therapeutic antagonism of TLR4 signalling would protect against influenza-induced acute lung injury. Here we report that therapeutic administration of Eritoran (also known as E5564)-a potent, well-tolerated, synthetic TLR4 antagonist-blocks influenza-induced lethality in mice, as well as lung pathology, clinical symptoms, cytokine and oxidized phospholipid expression, and decreases viral titres. CD14 and TLR2 are also required for Eritoran-mediated protection, and CD14 directly binds Eritoran and inhibits ligand binding to MD2. Thus, Eritoran blockade of TLR signalling represents a novel therapeutic approach for inflammation associated with influenza, and possibly other infections.


Facial skin segmentation using bacterial foraging optimization algorithm.
Nowadays, analyzing human facial image has gained an ever-increasing importance due to its various applications. Image segmentation is required as a very important and fundamental operation for significant analysis and interpretation of images. Among the segmentation methods, image thresholding technique is one of the most well-known methods due to its simplicity, robustness, and high precision. Thresholding based on optimization of the objective function is among the best methods. Numerous methods exist for the optimization process and bacterial foraging optimization (BFO) is among the most efficient and novel ones. Using this method, optimal threshold is extracted and then segmentation of facial skin is performed. In the proposed method, first, the color facial image is converted from RGB color space to Improved Hue-Luminance-Saturation (IHLS) color space, because IHLS has a great mapping of the skin color. To perform thresholding, the entropy-based method is applied. In order to find the optimum threshold, BFO is used. In order to analyze the proposed algorithm, color images of the database of Sahand University of Technology of Tabriz, Iran were used. Then, using Otsu and Kapur methods, thresholding was performed. In order to have a better understanding from the proposed algorithm; genetic algorithm (GA) is also used for finding the optimum threshold. The proposed method shows the better results than other thresholding methods. These results include misclassification error accuracy (88%), non-uniformity accuracy (89%), and the accuracy of region's area error (89%).


Black Hispanics have a worse cardiovascular risk profile than mixed Hispanics in Venezuela.
In order to characterize components of the metabolic syndrome (MS) in Venezuelan black Hispanics and compare these metabolic abnormalities with those found in the predominant mixed Hispanic population, 2336 mixed Hispanics (69% women) and 281 black Hispanics (60% women), aged 20-78 years, without prior history of diabetes and/or cardiovascular disease were evaluated in a population-based study in Zulia State, Venezuela. Blood pressure (BP), waist circumference, as well as fasting insulin, fasting blood glucose (FBG), triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C) levels were measured. The criteria proposed by the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) to identify those with metabolic abnormalities were used. We found that black Hispanics showed higher frequency of age-adjusted elevated BP than mixed Hispanics in both men (66.9% vs. 52.3%, p < 0.01) and women (39.3% vs. 30.4%, p < 0.05). In men, elevated FBG was also more frequent in black Hispanics (32.7%) than in mixed Hispanics (22.3%), despite the lack of significant differences in fasting insulin, HOMA-insulin resistance and HOMA-beta cell function values. In women low HDL-C and higher abdominal obesity were more common in black Hispanics (71.8% and 54.1%, respectively) than in mixed Hispanics (56.2% and 44.5%, respectively), despite the greater frequency of high TG in mixed Hispanics (22.6%) when compared to black Hispanics (13.3%). Furthermore, in logistic regression analysis black Hispanic race was independently associated with higher risk for hypertension, fasting hyperglycemia, and low HDL-C. These results suggest that black Hispanics have worse cardiovascular risk profile than mixed Hispanics in Zulia State, with higher BP, higher FBG, more abdominal obesity, and lower HDL-C. Identification and intervention of these high-risk subjects are important strategies for diabetes and cardiovascular disease prevention in Venezuela.


Nano-immunoassay with improved performance for detection of cancer biomarkers.
Nano-immunoassay utilizing surface-enhanced Raman scattering (SERS) effect is a promising analytical technique for early detection of cancer. In its current standing the assay is capable of discriminating samples of healthy individuals from samples of pancreatic cancer patients. Further improvements in sensitivity and reproducibility will extend practical applications of the SERS-based detection platforms to wider range of problems. In this report, we discuss several strategies designed to improve performance of the SERS-based detection system. We demonstrate that reproducibility of the platform is enhanced by using atomically smooth mica surface as a template for preparation of capture surface in SERS sandwich immunoassay. Furthermore, assay's stability and sensitivity can be further improved by using either polymer or graphene monolayer as a thin protective layer applied on top of the assay addresses. The protective layer renders signal to be more stable against photo-induced damage and carbonaceous contamination.


Using the candidate gene approach for detecting genes underlying seed oil concentration and yield in soybean.
Increasing the oil concentration in soybean seeds has been given more attention in recent years because of demand for both edible oil and biodiesel production. Oil concentration in soybean is a complex quantitative trait regulated by many genes as well as environmental conditions. To identify genes governing seed oil concentration in soybean, 16 putative candidate genes of three important gene families (GPAT: acyl-CoA:sn-glycerol-3-phosphate acyltransferase, DGAT: acyl-CoA:diacylglycerol acyltransferase, and PDAT: phospholipid:diacylglycerol acyltransferase) involved in triacylglycerol (TAG) biosynthesis pathways were selected and their sequences retrieved from the soybean database ( http://www.phytozome.net/soybean ). Three sequence mutations were discovered in either coding or noncoding regions of three DGAT soybean isoforms when comparing the parents of a 203 recombinant inbreed line (RIL) population; OAC Wallace and OAC Glencoe. The RIL population was used to study the effects of these mutations on seed oil concentration and other important agronomic and seed composition traits, including seed yield and protein concentration across three field locations in Ontario, Canada, in 2009 and 2010. An insertion/deletion (indel) mutation in the GmDGAT2B gene in OAC Wallace was significantly associated with reduced seed oil concentration across three environments and reduced seed yield at Woodstock in 2010. A mutation in the 3' untranslated (3'UTR) region of GmDGAT2C was associated with seed yield at Woodstock in 2009. A mutation in the intronic region of GmDGAR1B was associated with seed yield and protein concentration at Ottawa in 2010. The genes identified in this study had minor effects on either seed yield or oil concentration, which was in agreement with the quantitative nature of the traits. However, the novel gene-specific markers designed in the present study can be used in soybean breeding for marker-assisted selection aimed at increasing seed yield and oil concentration with no significant impact on seed protein concentration.


Noncanonical Wnt signaling and neural polarity.
The Wnt signaling pathway regulates multiple events in development and disease in both vertebrates and invertebrates. Recently, the noncanonical Wnt signaling cascades, those that do not signal through beta-catenin, have gained prominence for their role in the regulation of cellular polarity. It is not surprising that cellular polarization influences a number of different developmental events within the nervous system, including neurulation and neural tube closure, cellular migration, and uniform orientation of cells within an epithelial plane (planar cell polarity). In this review, we describe the differences between the canonical and noncanonical pathways, summarize recent data illustrating the roles of the noncanonical Wnt pathway in different polarizing events during neural development, and discuss the potential molecular mechanisms that underlie the generation of cellular asymmetry and polarity.


Engagement of monocytes, NK cells, and CD4+ Th1 cells by ALVAC-SIV vaccination results in a decreased risk of SIVmac251 vaginal acquisition.
The recombinant Canarypox ALVAC-HIV/gp120/alum vaccine regimen was the first to significantly decrease the risk of HIV acquisition in humans, with equal effectiveness in both males and females. Similarly, an equivalent SIV-based ALVAC vaccine regimen decreased the risk of virus acquisition in Indian rhesus macaques of both sexes following intrarectal exposure to low doses of SIVmac251. Here, we demonstrate that the ALVAC-SIV/gp120/alum vaccine is also efficacious in female Chinese rhesus macaques following intravaginal exposure to low doses of SIVmac251 and we confirm that CD14+ classical monocytes are a strong correlate of decreased risk of virus acquisition. Furthermore, we demonstrate that the frequency of CD14+ cells and/or their gene expression correlates with blood Type 1 CD4+ T helper cells, α4β7+ plasmablasts, and vaginal cytocidal NKG2A+ cells. To better understand the correlate of protection, we contrasted the ALVAC-SIV vaccine with a NYVAC-based SIV/gp120 regimen that used the identical immunogen. We found that NYVAC-SIV induced higher immune activation via CD4+Ki67+CD38+ and CD4+Ki67+α4β7+ T cells, higher SIV envelope-specific IFN-γ producing cells, equivalent ADCC, and did not decrease the risk of SIVmac251 acquisition. Using the systems biology approach, we demonstrate that specific expression profiles of plasmablasts, NKG2A+ cells, and monocytes elicited by the ALVAC-based regimen correlated with decreased risk of virus acquisition.


Target board test for the quantification of ataxia in tremulous patients.
The objective was to develop and assess the validity and reliability of a target board test (TBT) for quantifying ataxia and measuring dysmetria in the presence of tremor. Each subject was instructed to reach out and mark a target placed at arm's length with a pen (10 times with each hand). Ten patients performed the test twice. A hospital-based multiple sclerosis (MS) unit. Fifty-three patients with MS and upper limb tremor/ataxia and 20 healthy control subjects. The MS patients were classified into four subgroups: MS control group (n = 13), MS tremor group (n = 9), MS dysmetria group (n = 6), MS mixed (tremor and dysmetria) group (n = 25). The main outcome measures were the average radial distance away from the target (mean R) and the mean directional error (mean V) of the 10 contact points from the target. From these a dysmetria tremor index (DTI) was calculated by dividing mean V by mean R. Also used were a dysmetria scale, a dysdiadochokinesia scale and a finger-tapping test. Mean R correlated significantly with dysmetria, dysdiadochokinesia, kinetic tremor and (inversely) with the finger-tapping test (all p < 0.005). The median difference between two measurements of mean R for all 10 contact points was 11.3% and 19.0% and for mean V48.3% and 63.4% and DTI 57.2% and 50.5% for the right- and left-hand sides respectively, indicating the considerable directional variability within ataxia. The TBT provides simple quantitative objective measurements of upper limb ataxia.


Cytomegalovirus excretion in gnotobiotic pigs.
Germ-free piglets were infected intranasally with porcine cytomegalovirus (PCMV) at 1 day (group A) or 3 weeks of age (group B). Viraemia and virus excretion by the nasal, pharyngeal and conjunctival routes was studied up to the time of death or to 12 weeks. Virus was also sought in tissues at death or at slaughter, as well as in a few urine samples. Viraemia was detected in group A between days 5 and 19 after infection and in group B between days 14 and 16 inclusive. The chief route of virus excretion was the nasal mucosa, followed by the pharynx and conjunctiva; the maximal duration of excretion by these routes was 32, 25 and 14 days for pigs of group A and 9, 7 and 4 days for group B. The quantity of virus was also greater in the former group, of which died of generalized PCMV infection. A viruria was demonstrated in 2 animals. Antibody detectable in indirect immunofluorescence (IIF) tests appeared towards the end of the third week, reaching maximal titres at 5 to 7 weeks after infection. The mean peak titre of antibody in group B was lower than in group A. Corticosteroid treatment at days 56--62 after infection resulted in some recrudescence of virus excretion, accompanied in group B by about a twofold increase in IIF antibody. PCMV was isolated in cultures of lung macrophages from 4 of 7 animals killed at about 12 weeks after inoculation.


T helper cell recognition of muscle acetylcholine receptor in myasthenia gravis. Epitopes on the gamma and delta subunits.
We tested the response of CD4+ cells and/or total lymphocytes from the blood of 22 myasthenic patients and 10 healthy controls to overlapping synthetic peptides, 20 residues long, to screen the sequence of the gamma and delta subunits of human muscle acetylcholine receptor (AChR). The gamma subunit is part of the AChR expressed in embryonic muscle and is substituted in the AChRs of most adult muscles by an epsilon subunit. The delta subunit is present in both embryonic and adult AChRs. Adult extrinsic ocular muscles, which are preferentially and sometimes uniquely affected by myasthenic symptoms, and thymus, which has a still obscure but important role in the pathogenesis of myasthenia gravis, express the embryonic gamma subunit. Anti-AChR CD4+ responses were more easily detected after CD8+ depletion. All responders recognized epitopes on both the gamma and delta subunits and had severe symptoms. In four patients the CD4+ cell response was tested twice, when the symptoms were severe and during a period of remission. Consistently, the response was only detectable, or larger, when the patients were severely affected.


Metallocatanionic vesicle-mediated enhanced singlet oxygen generation and photodynamic therapy of cancer cells.
In clinics, photodynamic therapy (PDT) is established as a non-invasive therapeutic modality for certain types of cancers and skin disease. However, due to poor water solubility, photobleaching, and the dark toxicity of photosensitizers (PSs), further developments are required to improve the efficiency of PDT. Herein, we report the role of metallocatanionic vesicles (MCVs) in enhancing the phototoxicity of methylene blue (MB) against cancer cells. These MCVs were prepared via a facile and quick solution-solution mixing method using a cationic single-chain metallosurfactant (FeCPC I) in combination with anionic sodium oleate (Na Ol). For singlet oxygen (1O2) generation and PDT studies, two fractions of FeCPC I : Na Ol, i.e., 30 : 70 (V37) and 70 : 30 (V73), were chosen based on their long-term stability in aqueous media. A cationic PS MB was loaded into these vesicles. The MB-loaded MCV 30 : 70 and 70 : 30 fractions enhanced the 1O2 generation by 0.10- and 0.40-fold, respectively, compared with MB alone. Upon illumination using a 650 nm laser, these MB-loaded V73 and V37 MCVs significantly decreased the metabolic activity of MCF-7 cells by ≤50% at a concentration of 0.75 μM. Furthermore, the SOSG assay revealed that the synthesized MCVs enhanced the intracellular 1O2 compared with MB alone. The MB-loaded V73 MCVs showed the highest 1O2-mediated membrane damage and cell-killing effect, as confirmed using the differential nuclear staining assay (DNS), which is attributed to the cellular uptake profile of the different MCV fractions. Altogether, this work shows the advantage of using these biocompatible and dual-charge MCVs as promising delivery vehicles that can enhance the 1O2 generation from the PS. This work suggests the future application of these Fe-MCVs in magnetically guided PDT.


Low temperature and low salinity drive putatively adaptive growth differences in populations of threespine stickleback.
Colonisation can expose organisms to novel combinations of abiotic and biotic factors and drive adaptive divergence. Yet, studies investigating the interactive effects of multiple abiotic factors on the evolution of physiological traits remain rare. Here we examine the effects of low salinity, low temperature, and their interaction on the growth of three North American populations of threespine stickleback (Gasterosteus aculeatus). In north-temperate freshwater habitats, stickleback populations experience a combination of low salinity and low winter temperatures that are not experienced by the ancestral marine and anadromous populations. Here we show that both salinity and temperature, and their interaction, have stronger negative effects on marine and anadromous populations than a freshwater population. Freshwater stickleback showed only a ~20% reduction in specific growth rate when exposed to 4 °C, while marine and anadromous stickleback showed sharp declines (82% and 74% respectively) under these conditions. The modest decreases in growth in freshwater stickleback in fresh water in the cold strongly suggest that this population has the capacity for physiological compensation to offset the negative thermodynamic effects of low temperature on growth. These results are suggestive of adaptive evolution in response to the interactive effects of low salinity and low temperature during freshwater colonisation.


The human mirror system: a motor resonance theory of mind-reading.
Electrophysiological data confirm the existence of neurons that respond to both motor and sensory events in the macaque brain. These mirror neurons respond to execution and observation of goal-orientated actions. It has been suggested that they comprise a neural basis for encoding an internal representation of action. In this paper the evidence for a parallel system in humans is reviewed and the implications for human theory of mind processing are discussed. Different components of theory of mind are discussed; the evidence for mirror activity within subtypes is addressed. While there is substantial evidence for a human mirror system, there are weaknesses in the attempts to localize such a system in the brain. Preliminary evidence indicates that mirror neurons may be involved in theory of mind; however, these data by their very nature are reliant on the presence, and precise characterization, of the human mirror system.


Waist circumference and risk of breast cancer in Korean women: A nationwide cohort study.
Although postmenopausal breast cancer (BC) risk has been linked to adiposity, associations between adiposity and premenopausal BC remain unclear. To address this question, we investigated the association of BC risk with measures of adiposity, including body mass index (BMI) and waist circumference (WC), in a large cohort of Asian women. We used a nationwide cohort of adult Korean women selected from the National Health Insurance Corporation database merged with national health examination data from 2009 to 2015. A total of 11,227,948 women were tracked to retrospectively identify incident cases of BC. Our analysis used Cox proportional hazards models to calculate hazard ratios and assess the association of BC risk with BMI and/or WC in both pre- and postmenopausal women. BMI and WC were robustly associated with increased risk for postmenopausal BC (ptrend <0.001 for both BMI and WC) but not with premenopausal BC. Association between WC and premenopausal BC was only statistically significant when considering BMI (ptrend =0.044). In contrast, postmenopausal BC was negatively associated with WC when considering BMI (ptrend =0.011). In premenopausal women, WC may predict increased BC risk when considering BMI. However, in postmenopausal women, WC is not superior to BMI as an indicator of BC risk.


Functional dissection of regulatory models using gene expression data of deletion mutants.
Genome-wide gene expression profiles accumulate at an alarming rate, how to integrate these expression profiles generated by different laboratories to reverse engineer the cellular regulatory network has been a major challenge. To automatically infer gene regulatory pathways from genome-wide mRNA expression profiles before and after genetic perturbations, we introduced a new Bayesian network algorithm: Deletion Mutant Bayesian Network (DM_BN). We applied DM_BN to the expression profiles of 544 yeast single or double deletion mutants of transcription factors, chromatin remodeling machinery components, protein kinases and phosphatases in S. cerevisiae. The network inferred by this method identified causal regulatory and non-causal concurrent interactions among these regulators (genetically perturbed genes) that are strongly supported by the experimental evidence, and generated many new testable hypotheses. Compared to networks reconstructed by routine similarity measures or by alternative Bayesian network algorithms, the network inferred by DM_BN excels in both precision and recall. To facilitate its application in other systems, we packaged the algorithm into a user-friendly analysis tool that can be downloaded at http://www.picb.ac.cn/hanlab/DM_BN.html.


Contribution of STAT SH2 groups to specific interferon signaling by the Jak-STAT pathway.
In response to specific ligands, various STAT proteins (signal transducers and activators of transcription) are phosphorylated on tyrosine by Jak protein kinases and translocated to the nucleus to direct gene transcription. Selection of a STAT at the interferon gamma receptor as well as specific STAT dimer formation depended on the presence of particular SH2 groups (phosphotyrosine-binding domains), whereas the amino acid sequence surrounding the phosphorylated tyrosine on the STAT could vary. Thus, SH2 groups in STAT proteins may play crucial roles in specificity at the receptor kinase complex and in subsequent dimerization, whereas the kinases are relatively nonspecific.


Bilateral Lacrimal Gland Lymphoma in Sjögren Syndrome.
A 31-year-old female with Primary Sjögren Syndrome (pSS) presented with bilateral puffiness around the eye for 3 years. The lacrimal glands were hypertrophic and edematous bilaterally. Schirmer 1 score was 2 and 1 mm and tear-film break-up time was 3 and 4 seconds, in the right and the left eyes, respectively. An incisional biopsy from the left lacrimal gland revealed diffuse and intense CD20, CD5, and bcl-2 positivity with negative cyclin D1 and CD23 which supported lymphoma. Upon haematology consultation extranodal marginal zone lymphoma diagnosis was made. CHOP (cyclophosphamide, doxorubicin, vincristine, and methyl prednisolone) treatment was initiated. In conclusion, pSS is a well known autoimmune disease in which increased rate of lymphoma is present. Early detection with histopathologic confirmation and multidisciplinary approach with ophthalmology, rheumatology, and haematology are mandatory in these patients.


Study of hydration of stratum corneum in leprosy.
The study of hydration power of stratum corneum of lesions show highly significant poor water-uptake at low temperatures (p less than 0.001), a defect not recorded after removal of water soluble fractions. Secondly, the lesions show significant poor water-diffusive power (p less than 0.001). The findings suggest a qualitative alteration in the stratum corneum of leprosy patients, probably in its water-soluble protein fraction.


Carbon-13 nuclear magnetic resonance study of osmoregulation in a blue-green alga.
The process of osmoregulation in a unicellular blue-green alga, Synechococcus sp., has been studied by natural-abundance carbon-13 nuclear magnetic resonance spectroscopy of intact cells and cell extracts. 2-O-alpha-D-Glucopyranosylglycerol was identified as the major organic osmoregulatory solute. This demonstrates the presence of a major osmoregulatory solute in a blue-green alga and is also an example of an osmoregulatory role for glucosylglycerol.


Occipital artery-anterior inferior cerebellar artery bypass with microsurgical trapping for exclusively intra-meatal anterior inferior cerebellar artery aneurysm manifesting as subarachnoid hemorrhage. Case report.
A 77-year-old woman presented with an extremely rare exclusively intra-meatal anterior inferior cerebellar artery (AICA) aneurysm manifesting as subarachnoid hemorrhage. The aneurysm was located at a non-branching site of its meatal loop, deeply inside the internal auditory canal. The ipsilateral posterior inferior cerebellar artery was hypoplastic and the affected AICA supplied a wide vascular territory in the right cerebellum. The patient underwent microsurgical trapping of the distal AICA aneurysm in the acute stage. Collateral back flow to the parent artery was poor, so right occipital artery (OA)-AICA anastomosis was performed prior to aneurysm trapping. The postoperative course was uneventful, and magnetic resonance imaging after surgery did not demonstrate any ischemic change. Postoperative angiography showed complete disappearance of the AICA aneurysm and the apparently patent OA-AICA bypass. She did not suffer neurological deficit except for right incomplete hearing disturbance, and postoperative single photon emission computed tomography demonstrated absence of hemodynamic compromise in the cerebellum. OA-AICA anastomosis with aneurysm trapping could be the optimal surgical management of the AICA aneurysm located exclusively inside the internal auditory canal, especially if the parent artery supplies a wide vascular territory.


Voltage-dependent calcium channels regulate melatonin output from cultured chick pineal cells.
Chick pineal cells maintained in primary culture display a circadian rhythm of melatonin production and release, and the nocturnal increase in melatonin output is enhanced by elevating extracellular K+. The divalent cations, Co2+, Cd2+, and Mn2+, each reduce nocturnal melatonin output. Nitrendipine and nifedipine also prevent the nocturnal rise in melatonin output, while Bay K 8644 increases it, suggesting a role for voltage-dependent Ca2+ channels in regulating melatonin output. The whole-cell patch-clamp technique was used to record from individual chick pineal cells. Under conditions designed to isolate currents through voltage-dependent Ca2+ channels, biphasic inward currents are elicited by large depolarizing commands (e.g., to 0 mV) from a holding potential of -90 mV; from a holding potential of -40 mV, only a sustained inward current is elicited by steps to 0 mV. Both components of the inward current are blocked by Co2+ or Cd2+. The sustained current is increased in amplitude by Bay K 8644 and blocked by nifedipine, while the transient current is unaffected. Since there is no evidence for vesicular release of melatonin, the "L-type" calcium channels mediating the sustained calcium current appear to be involved in the pathways regulating melatonin synthesis in chick pineal cells.


Genome-wide detection of fitness genes in uropathogenic Escherichia coli during systemic infection.
Uropathogenic Escherichia coli (UPEC) is a leading etiological agent of bacteremia in humans. Virulence mechanisms of UPEC in the context of urinary tract infections have been subjected to extensive research. However, understanding of the fitness mechanisms used by UPEC during bacteremia and systemic infection is limited. A forward genetic screen was utilized to detect transposon insertion mutants with fitness defects during colonization of mouse spleens. An inoculum comprised of 360,000 transposon mutants in the UPEC strain CFT073, cultured from the blood of a patient with pyelonephritis, was used to inoculate mice intravenously. Transposon insertion sites in the inoculum (input) and bacteria colonizing the spleen (output) were identified using high-throughput sequencing of transposon-chromosome junctions. Using frequencies of representation of each insertion mutant in the input and output samples, 242 candidate fitness genes were identified. Co-infection experiments with each of 11 defined mutants and the wild-type strain demonstrated that 82% (9 of 11) of the tested candidate fitness genes were required for optimal fitness in a mouse model of systemic infection. Genes involved in biosynthesis of poly-N-acetyl glucosamine (pgaABCD), major and minor pilin of a type IV pilus (c2394 and c2395), oligopeptide uptake periplasmic-binding protein (oppA), sensitive to antimicrobial peptides (sapABCDF), putative outer membrane receptor (yddB), zinc metallopeptidase (pqqL), a shikimate pathway gene (c1220) and autotransporter serine proteases (pic and vat) were further characterized. Here, we report the first genome-wide identification of genes that contribute to fitness in UPEC during systemic infection in a mammalian host. These fitness factors may represent targets for developing novel therapeutics against UPEC.


Elongated versions of Vlp surface lipoproteins protect Mycoplasma hyorhinis escape variants from growth-inhibiting host antibodies.
Variation in Vlp surface proteins of Mycoplasma hyorhinis was evaluated in terms of its role in determining susceptibility of organisms to growth inhibition by host antibodies (Abs). High-frequency switching of Vlp surface lipoproteins has been studied in isogenic lineages of M. hyorhinis SK76. In these lineages, the products of three genes, vlpA, vlpB, and vlpC, are subject to phase and size variation in vitro, which occur through distinct mutator elements that independently govern the expression of each vlp gene (promoter mutations) or the size of the vlp gene product (by intragenic expansion or contraction of a 3' region containing tandem repeats). Isogenic clonal variants of M. hyorhinis SK76 expressing distinct profiles of Vlp products were assessed for their susceptibility to complement-independent growth inhibition by serum Abs of swine experimentally infected with the arthritigenic SK76 strain. Invariably, variants expressing longer versions of VlpA, VlpB, or VlpC (each expressed individually) were completely resistant to host immune serum Abs, whereas variants expressing shorter allelic versions of each Vlp were susceptible. The target of growth-inhibiting Abs was not the Vlp products, since removal of anti-Vlp Abs had no effect on the inhibitory activity of the host immune serum on susceptible variants. Escape variant populations derived by propagating susceptible variants in an immune (versus control) host serum revealed a strong selection for the long-Vlp phenotype, irrespective of the identity of the Vlp expressed. Apparent mutational pathways of acquiring the protective phenotype included mutational switches to express long vlp genes that had been transcriptionally silent or switches to elongate expressed vlp genes. These results suggest that a major function of the Vlp system is to shield the wall-less mycoplasma surface from host Abs capable of binding vital (and as-yet-unidentified) surface antigens of this organism.


An implementation framework of blockchain-based hazardous waste transfer management system.
The rapid increase in volume and types of hazardous waste (HW) due to China's continuous economic growth makes it significant to conduct HW safety management. However, due to the information asymmetry between the regulators and regulated institutions, problems such as illegal dumping and statistical fraud are common in hazardous waste transfer (HWT) activities. Moreover, there is a severe problem of information isolated island among waste production, transportation, and treatment companies in the HW market. Promoting the information monitoring and tracking of the whole process of HWT is the main challenge for HW management. Blockchain provides an ideal solution to overcome the above challenges. This study developed a framework for the blockchain-based HWT management system, which could support government regulators to obtain relevant information in HWT and improve the efficiency of HWT. The HWT management system was introduced in detail from different perspectives, including infrastructure, blockchain service, functions, and users, emphasizing six information management functions. Finally, the positive impact and various challenges encountered in implementing blockchain in HWT management were discussed. This study applies blockchain to the research field of HWT management, which expands the application of blockchain in the field of solid waste management with great theoretical and practical significance.


Does sleep facilitate the consolidation of allocentric or egocentric representations of implicitly learned visual-motor sequence learning?
Sleep facilitates the consolidation (i.e., enhancement) of simple, explicit (i.e., conscious) motor sequence learning (MSL). MSL can be dissociated into egocentric (i.e., motor) or allocentric (i.e., spatial) frames of reference. The consolidation of the allocentric memory representation is sleep-dependent, whereas the egocentric consolidation process is independent of sleep or wake for explicit MSL. However, it remains unclear the extent to which sleep contributes to the consolidation of implicit (i.e., unconscious) MSL, nor is it known what aspects of the memory representation (egocentric, allocentric) are consolidated by sleep. Here, we investigated the extent to which sleep is involved in consolidating implicit MSL, specifically, whether the egocentric or the allocentric cognitive representations of a learned sequence are enhanced by sleep, and whether these changes support the development of explicit sequence knowledge across sleep but not wake. Our results indicate that egocentric and allocentric representations can be behaviorally dissociated for implicit MSL. Neither representation was preferentially enhanced across sleep nor were developments of explicit awareness observed. However, after a 1-wk interval performance enhancement was observed in the egocentric representation. Taken together, these results suggest that like explicit MSL, implicit MSL has dissociable allocentric and egocentric representations, but unlike explicit sequence learning, implicit egocentric and allocentric memory consolidation is independent of sleep, and the time-course of consolidation differs significantly.


Single Center Trends in Acute Coronary Syndrome Volume and Outcomes During the COVID-19 Pandemic.
The coronavirus disease 2019 (COVID-19) pandemic has greatly affected healthcare delivery across the world. In this report, we aim to further characterize the changes in cardiac catheterization at our institution, specifically in the setting of acute coronary syndrome (ACS). We performed a retrospective analysis of patients undergoing cardiac catheterization between December 23, 2019 and April 12, 2020 at our institution. All patients with cardiac catheterizations for ACS, ST-elevation myocardial infarction (STEMI) activation, and out-of-hospital cardiac arrest (OHCA) were analyzed. Cardiac catheterization volume, as well as clinical and procedural characteristics of patients undergoing cardiac catheterization, was compared before and during the COVID-19 pandemic. Patients presenting with ACS and OHCA were similar in terms of demographics and comorbidities during both time periods. The mean monthly volume for ACS cases dropped by 26% during the pandemic, which was consistent among both unstable angina/non-ST-elevation myocardial infarction (UA/NSTEMI) and STEMI cases. OHCA volume decreased significantly as well (five cases per month before to zero cases during the pandemic, P = 0.01). Among patients with STEMI, initial markers of cardiac injury, door-to-balloon time, and all-cause mortality were similar in both time periods. With the start of the COVID-19 pandemic, there was a reduction in cardiac catheterization volume across the spectrum of ACS at our institution, which was consistent with reports from other centers across the globe. Patients with STEMI during the initial phase of the COVID-19 pandemic did not seem to have delays in presentation or significant differences in all-cause mortality at our institution.


Thin-film limit formalism applied to surface defect absorption.
The thin-film limit is derived by a nonconventional approach and equations for transmittance, reflectance and absorptance are presented in highly versatile and accurate form. In the thin-film limit the optical properties do not depend on the absorption coefficient, thickness and refractive index individually, but only on their product. We show that this formalism is applicable to the problem of ultrathin defective layer e.g. on a top of a layer of amorphous silicon. We develop a new method of direct evaluation of the surface defective layer and the bulk defects. Applying this method to amorphous silicon on glass, we show that the surface defective layer differs from bulk amorphous silicon in terms of light soaking.


Cortical Pathways During Postural Control: New Insights From Functional EEG Source Connectivity.
Postural control is a complex feedback system that relies on vast array of sensory inputs in order to maintain a stable upright stance. The brain cortex plays a crucial role in the processing of this information and in the elaboration of a successful adaptive strategy to external stimulation preventing loss of balance and falls. In the present work, the participants postural control system was challenged by disrupting the upright stance via a mechanical skeletal muscle vibration applied to the calves. The EEG source connectivity method was used to investigate the cortical response to the external stimulation and highlight the brain network primarily involved in high-level coordination of the postural control system. The cortical network reconfiguration was assessed during two experimental conditions of eyes open and eyes closed and the network flexibility (i.e. its dynamic reconfiguration over time) was correlated with the sample entropy of the stabilogram sway. The results highlight two different cortical strategies in the alpha band: the predominance of frontal lobe connections during open eyes and the strengthening of temporal-parietal network connections in the absence of visual cues. Furthermore, a high correlation emerges between the flexibility in the regions surrounding the right temporo-parietal junction and the sample entropy of the CoP sway, suggesting their centrality in the postural control system. These results open the possibility to employ network-based flexibility metrics as markers of a healthy postural control system, with implications in the diagnosis and treatment of postural impairing diseases.


Impact of socioeconomic status on coronary artery calcification.
Background Low socioeconomic status is associated with an increased risk of coronary artery disease, but few studies have investigated the potential link between living in an area with a low versus a high socioeconomic status and coronary artery calcification, a marker of subclinical coronary artery disease. Design The design of this study was a cross-sectional study. Methods We evaluated 1067 participants with no history of coronary artery disease from the pilot phase of the Swedish CArdioPulmonary bioImage Study (SCAPIS). Men and women aged 50-64 years were recruited from three high-socioeconomic status ( n = 541) and three low-socioeconomic status ( n = 526) areas in the city of Gothenburg (550,000 inhabitants). The coronary artery calcification score was assessed with the Agatston method using computed tomography, with individuals classified into either no coronary calcification ( n = 625; mean age, 57 years) or any coronary artery calcification ( n = 442; mean age, 59 years (men, 68.5%)). Results Coronary artery calcification was present in 244 (46.3%) and 198 (36.6%) individuals from the low- and high-socioeconomic status areas, respectively. Participants from the low-socioeconomic status areas had a significantly higher risk factor burden. In a multivariable logistic regression model with adjustment for age, sex and cardiovascular risk factors, the odds for coronary artery calcification were not significantly higher among persons living in low-socioeconomic status areas (odds ratio = 1.18, 95% confidence interval = 0.87-1.60). Conclusion In this relatively small cross-sectional study, we observed an association between living in a low-socioeconomic status area and coronary artery calcification. However, this was mostly explained by higher levels of cardiovascular disease risk factors, indicating that the effect of socioeconomic status on the atherosclerotic process works through an increased burden of cardiovascular disease risk factors.


Assessment of the Methods Used to Develop Vitamin D and Calcium Recommendations-A Systematic Review of Bone Health Guidelines.
There are numerous guidelines developed for bone health. Yet, it is unclear whether the differences in guideline development methods explain the variability in the recommendations for vitamin D and calcium intake. The objective of this systematic review was to collate and compare recommendations for vitamin D and calcium across bone health guidelines, assess the methods used to form the recommendations, and explore which methodological factors were associated with these guideline recommendations. We searched MEDLINE, EMBASE, CINAHL, and other databases indexing guidelines to identify records in English between 2009 and 2019. Guidelines or policy statements on bone health or osteoporosis prevention for generally healthy adults aged ≥40 years were eligible for inclusion. Two reviewers independently extracted recommendations on daily vitamin D and calcium intake, supplement use, serum 25 hydroxyvitamin D [25(OH)D] level, and sunlight exposure; assessed guideline development methods against 25 recommended criteria in the World Health Organization (WHO) handbook for guideline development; and, identified types identified types of evidence underpinning the recommendations. we included 47 eligible guidelines from 733 records: 74% of the guidelines provided vitamin D (200~600-4000 IU/day) and 70% provided calcium (600-1200 mg/day) recommendations, 96% and 88% recommended vitamin D and calcium supplements, respectively, and 70% recommended a specific 25(OH)D concentration. On average, each guideline met 10 (95% CI: 9-12) of the total of 25 methodological criteria for guideline development recommended by the WHO Handbook. There was uncertainty in the association between the methodological criteria and the proportion of guidelines that provided recommendations on daily vitamin D or calcium. Various types of evidence, including previous bone guidelines, nutrient reference reports, systematic reviews, observational studies, and perspectives/editorials were used to underpin the recommendations. There is considerable variability in vitamin D and calcium recommendations and in guideline development methods in bone health guidelines. Effort is required to strengthen the methodological rigor of guideline development and utilize the best available evidence to underpin nutrition recommendations in evidence-based guidelines on bone health.


Molecular signatures and new candidates to target the pathogenesis of rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease of unknown etiology and pronounced interpatient heterogeneity. To characterize RA at the molecular level and to uncover pathomechanisms, we performed genome-wide gene expression analysis. We identified a set of 1,054 genes significantly deregulated in pair-wise comparisons between RA and osteoarthritis (OA) patients, RA and normal donors (ND), or OA and ND. Correlation analysis revealed gene sets regulated identically in all three groups. As a prominent example secreted phosphoprotein 1 (SPP1) was identified to be significantly upregulated in RA compared with both OA and ND. SPP1 expression was found to correlate with genes expressed during an inflammatory response, T-cell activation and apoptosis, suggesting common underlying regulatory networks. A subclassification of RA patients was achieved on the basis of proteoglycan 4 (PRG4) expression, distinguishing PRG4 high and low expressors and reflecting the heterogeneity of the disease. In addition, we found that low PRG4 expression was associated with a more aggressive disease stage, which is in accordance with PRG4 loss-of-function mutations causing camptodactyly-arthropathy-coxa vara-pericarditis syndrome. Altogether we provide evidence for molecular signatures of RA and RA subclasses, sets of new candidate genes as well as for candidate gene networks, which extend our understanding of disease mechanisms and may lead to an improved diagnosis.


2-Nitrophenylcarbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N - methylamide (SDZ NKT 343), a potent human NK1 tachykinin receptor antagonist with good oral analgesic activity in chronic pain models.
A lead compound which had sub-micromolar affinity for the rabbit NK1 receptor but negligible affinity for rat NK1 receptors, 3a, was discovered by directed screening. 2-Substitution in the ring of the benzylthiourea substituent in the initial lead was found to be important, and halogens (Cl, Br) in this position were found to improve affinity for the human receptor. The activity of a series of 2-halo-substituted benzylthioureas was then optimized by modification of the proline diphenylmethyl amide, guided by a simple conceptual model based on structural overlay between these early antagonists and NK1 selective peptides. In this way, aromatic amino acid amides were identified which had improved affinity with respect to the starting diphenylmethyl (DPM) amides. The first sub-nanomolar ligand for the human NK1 receptor which arose from this series, 4af, combined a 2-chlorobenzylthiourea unit with a 2-naphthylalanine amide. Contemporaneously it was discovered that the benzylthiourea unit could be simplified to a phenylthiourea providing that an appropriate 2-substituent was also incorporated. Combination of these two series gave 2-NO2 phenylthiourea analogues which led directly to the analogous urea, 5f (2-nitrophenylcarbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benz yl- N-methylamide, SDZ NKT 343), a highly potent ligand for the human NK1 receptor (Ki = 0.16 nM). In addition to its high in vitro potency, 5f proved to be a potent orally active analgesic in guinea pig models of chronic inflammatory and neuropathic pain. The nature of the 2-aryl substituent was found to be critical for oral activity in this series. Clinical evaluation of 5f as a novel analgesic agent is currently underway.


The Role of Symptom Clusters in Triage of COVID-19 Patients.
COVID-19 manifests with a broad range of symptoms. This study investigates whether clusters of respiratory, gastrointestinal, or neurological symptoms can be used to diagnose COVID-19. We surveyed symptoms of 483 subjects who had completed COVID-19 laboratory tests in the last 30 days. The survey collected data on demographic characteristics, self-reported symptoms for different types of infections within 14 days of onset of illness, and self-reported COVID-19 test results. Robust LASSO regression was used to create 3 nested models. In all 3 models, the response variable was the COVID-19 test result. In the first model, referred to as the "main effect model," the independent variables were demographic characteristics, history of chronic symptoms, and current symptoms. The second model, referred to as the "hierarchical clustering model," added clusters of variables to the list of independent variables. These clusters were established through hierarchical clustering. The third model, referred to as the "interaction-terms model," also added clusters of variables to the list of independent variables; this time clusters were established through pairwise and triple-way interaction terms. Models were constructed on a randomly selected 80% of the data and accuracy was cross-validated on the remaining 20% of the data. The process was bootstrapped 30 times. Accuracy of the 3 models was measured using the average of the cross-validated area under the receiver operating characteristic curves (AUROCs). In 30 bootstrap samples, the main effect model had an AUROC of 0.78. The hierarchical clustering model had an AUROC of 0.80. The interaction-terms model had an AUROC of 0.81. Both the hierarchical cluster model and the interaction model were significantly different from the main effect model (α = .04). Patients with different races/ethnicities, genders, and ages presented with different symptom clusters. Using clusters of symptoms, it is possible to more accurately diagnose COVID-19 among symptomatic patients.


[Fundamentals of internal medicine].
The most important diagnostic tools of the internist are the patient history and physical examination, after which a plan must be made for further diagnostic evaluation and treatment. For this the internist uses clinical reasoning based on his or her knowledge of evidence-based medicine and pathobiology. Pathobiology is primarily concerned with the question of how something works; evidence-based medicine is concerned with whether something works, and if so, how often or how much on average. Diseases do not exist in their own right and diagnostic criteria are based on consensus. A diagnosis of a 'disease' is based on our observation of patients as well as our opinions, whether right or wrong, regarding its cause. It is important to distinguish between 'partial causes' and a 'causative complement'. As a result of this concept, the biological relevance of a partial cause in the development of a disease cannot be derived from the strength of the link between it and the disease. Our opinions regarding the cause of disease appear to be based on induction. However, induction is not a good foundation from which to determine causation. Hypotheses on the cause of disease cannot be proved. They can, however, be disproved. Education, training, research and patient care all depend on effective communication. Communication is enhanced if the thesis is given first and thereafter the arguments. Hence, transfer of patient information such as during a morning report should begin with a working diagnosis (the 'thesis') and thereafter the findings of patient history, et cetera (the 'arguments'). At this time, too little attention is given to these branches of clinical reasoning and communication in education and continuing education in internal medicine.