Identification of differentially activated cell-signaling networks associated with pichinde virus pathogenesis by using systems kinomics.
Phosphorylation plays a key role in regulating many signaling pathways. Although studies investigating the phosphorylated forms of signaling pathways are now commonplace, global analysis of protein phosphorylation and kinase activity has lagged behind genomics and proteomics. We have used a kinomics approach to study the effect of virus infection on host cell signaling in infected guinea pigs. Delineating the host responses which lead to clearance of a pathogen requires the use of a matched, comparative model system. We have used two passage variants of the arenavirus Pichinde, used as a biosafety level 2 model of Lassa fever virus as it produces similar pathologies in guinea pigs and humans, to compare the host cell responses between infections which lead to either a mild, self-limiting infection or lethal disease. Using this model, we can begin to understand the differences in signaling events which give rise to these markedly different outcomes. By contextualizing these data using pathway analysis, we have identified key differences in cellular signaling matrices. By comparing these differentially involved networks, we have identified a number of key signaling "nodes" which show differential phosphorylations between mild and lethal infections. We believe that these nodes provide potential targets for the development of antiviral therapies by acting at the level of the host response rather than by directly targeting viral proteins.


Indolent lymphoma: the pathologist's viewpoint.
Indolent lymphomas have recently been the object of numerous studies, which have focused on new aspects relevant both for the better comprehension of their histogenesis and the identification of new therapeutic strategies. As marginal-zone lymphoma (MZL) represents the category of indolent lymphomas that has obtained more benefit from such an approach, the authors focused on the most recent achievements and not yet solved controversies in this area. In spite of their postulated common derivation, the three categories of MZL of the WHO Classification appear dissimilar. In fact, they show significant molecular differences among them as well as a certain heterogeneity within each group. By no means, there is a cogent need of more refined tools to revise these neoplasms and to produce a more rational grouping. The recent identification of the IRTA gene family corresponding to IG-like receptors differentially expressed in B-cells might contribute to their better understanding.


Long-term variation in serum 25-hydroxyvitamin D concentration among participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.
Molecular epidemiologic studies of vitamin D and risk of cancer and other health outcomes usually involve a single measurement of the biomarker 25-hydroxyvitamin D [25(OH)D] in serum or plasma. However, the extent to which 25(OH)D concentration at a single time point is representative of an individual's long-term vitamin D status is unclear. To address this question, we evaluated within-person variability in 25(OH)D concentrations across serum samples collected at three time points over a 5-year period among 29 participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Blood collection took place year-round, although samples for a given participant were collected in the same month each year. The within-person coefficient of variation and intraclass correlation coefficient were calculated using variance components estimated from random effects models. Spearman rank correlation coefficients were calculated to evaluate agreement between measurements at different collection times (baseline, +1 year, +5 years). The within-subject coefficient of variation was 14.9% [95% confidence interval (CI), 12.4-18.1%] and the intraclass correlation coefficient was 0.71 (95% CI, 0.63-0.88). Spearman rank correlation coefficients comparing baseline to +1 year, +1 year to +5 years, and baseline to +5 years were 0.65 (95% CI, 0.37-0.82), 0.61 (0.29-0.81), and 0.53 (0.17-0.77), respectively. Slightly stronger correlations were observed after restricting to non-Hispanic Caucasian subjects. These findings suggest that serum 25(OH)D concentration at a single time point may be a useful biomarker of long-term vitamin D status in population-based studies of various diseases.


A pericentric inversion of chromosome six in a patient with Peutz-Jeghers' syndrome and the use of FISH to localise the breakpoints on a genetic map.
Karyotypic analysis in a patient with Peutz-Jeghers' syndrome demonstrated a pericentric inversion on chromosome 6. Further investigation was undertaken using fluorescence in situ hybridisation (FISH) with yeast artificial chromosome clones selected to contain genetic markers from chromosome 6, and a probe for the centromeric alphoid repeat array. This analysis located one inversion breakpoint within the alphoid array, in a 1-cM interval between D6S257 and D6S402, and the other in a 4-cM interval between D6S403 and D6S311. The oestrogen receptor gene locus (ESR) is excluded from the latter interval.


Increased ex vivo cell death of central memory CD4 T cells in treated HIV infected individuals with unsatisfactory immune recovery.
High levels of ex vivo CD4 T-cell death and the accumulation of highly differentiated and/or immunosenescent T cells have been associated with poor CD4 T-cell recovery in treated HIV-infected individuals. However, the relationship between cell death and T-cell differentiation is still unclear. We have analyzed cell death, immunosenescence and differentiation parameters in HAART-treated subjects (VL <50 copies/mL for more than 2 years) with CD4 T-cell count <350 cells/μL (immunodiscordant, n = 23) or >400 cells/μL (immunoconcordant, n = 33). We included 11 healthy individuals as reference. As expected, suboptimal CD4 T-cell recovery was associated with low frequencies of naïve cells, high frequencies of transitional and effector memory cells and a subsequent low ratio of central/transitional memory cells in the CD4 compartment. These alterations correlated with spontaneous CD4 T-cell death. A deeper analysis of cell death in CD4 T-cell subsets showed increased cell death in memory cells of immunodiscordant individuals, mainly affecting central memory cells. Immunosenescence was also higher in immunodiscordant individuals albeit unrelated to cell death. The CD8 compartment was similar in both HIV-infected groups, except for an underrepresentation of naïve cells in immunodiscordant individuals. Immunodiscordant individuals show alterations in memory CD4 T-cell differentiation associated with a short ex vivo lifespan of central memory cells and an in vivo low central/transitional memory cell ratio. These alterations may contribute to poor CD4 T-cell repopulation.


Polypyrimidine tract binding protein stabilizes the encephalomyocarditis virus IRES structure via binding multiple sites in a unique orientation.
Polypyrimidine tract binding (PTB) protein is a regulator of alternative pre-mRNA splicing, and also stimulates the initiation of translation dependent on many viral internal ribosome entry segments/sites (IRESs). It has four RNA-binding domains (RBDs), but although the contacts with many IRESs have been mapped, the orientation of binding (i.e., which RBD binds to which site in the IRES) is unknown. To answer this question, 16 derivatives of PTB1, each with a single cysteine flanking the RNA-binding surface in an RBD, were constructed and used in directed hydroxyl radical probing with the encephalomyocarditis virus IRES. The results, together with mass spectrometry data on the stoichiometry of PTB binding to different IRES derivatives, show that the minimal IRES binds a single PTB in a unique orientation, with RBD1 and RBD2 binding near the 3' end, and RBD3 contacting the 5' end, thereby constraining and stabilizing the three-dimensional structural fold of the IRES.


Skeletal myogenic differentiation of human periodontal ligament stromal cells isolated from orthodontically extracted premolars.
To investigate the stem cell-like characteristics of human periodontal ligament (PDL) stromal cells outgrown from orthodontically extracted premolars and to evaluate the potential for myogenic differentiation. PDL stromal cells were obtained from extracted premolars by using the outgrowth method. Cell morphological features, self-replication capability, and the presence of cell-surface markers, along with osteogenic, adipogenic, and chondrogenic differentiation, were confirmed. In addition, myogenic differentiation was induced by the use of 5-aza-2'-deoxycytidine (5-Aza) for DNA demethylation. PDL stromal cells showed growth patterns and morphological features similar to those of fibroblasts. In contrast, the proliferation rates of premolar PDL stromal cells were similar to those of bone marrow and adipogenic stem cells. PDL stromal cells expressed surface markers of human mesenchymal stem cells (i.e., CD90 and CD105), but not those of hematopoietic stem cells (i.e., CD31 and CD34). PDL stromal cells were differentiated into osteogenic, adipogenic, and chondrogenic lineages. Myotube structures were induced in PDL stromal cells after 5-Aza pretreatment, but not in the absence of 5-Aza pretreatment. PDL stromal cells isolated from extracted premolars can potentially be a good source of postnatal stem cells for oromaxillofacial regeneration in bone and muscle.


Microsatellite alterations at 5q21, 11p13, and 11p15.5 do not predict survival in non-small cell lung cancer.
We investigated the clinical implications of allelic deletions at three common sites of loss of heterozygosity (LOH) in regions 5q21, 11p15.5, and 11p13 in 86 patients with non-small cell lung cancer (NSCLC). We performed a PCR-based microsatellite polymorphism assay for detection of LOH. The microsatellite markers used were D5S82 (proximal to the APC gene), MCC (within the MCC gene), D11S904 (11p13), HRAS (within the H-ras gene), and D11S860 (11p15.5). Of the 68 informative cases at 5q21 loci, LOH was found in 14 cases (20%), whereas LOH frequency in 11p15.5 and 11p13 was 31% (19 of 61 informative cases) and 19% (12 of 63 informative cases), respectively. There was a significant correlation between 5q21 LOH and mediastinal lymph node involvement (P = 0.03). However, no differences were observed in median survival times (26 months in patients with 5q21 LOH versus 37 months in the remainder; P = 0.33) nor in patients with 11p LOH (38 months versus 32 months, respectively; P = 0.72). Cox's proportional hazards model predicted that stage was the only independent poor prognostic marker in the entire cohort of NSCLC patients. Thus, the present study revealed two important abnormalities, LOH at chromosome 5q21 and LOH at chromosome 11p, both implied in NSCLC development.


Maternal obesity and initiation and duration of breastfeeding: data from the longitudinal study of Australian children.
The aim of this paper is to investigate whether the lower rate of breastfeeding at 6 months by overweight and obese mothers is primarily due to these women giving up breastfeeding in the first week postpartum using a cross-sectional population survey. The sample is children from the infant cohort (about 12 months of age) of Wave 1 (2004) of the Longitudinal Study of Australian Children for whom breastfeeding and maternal information were available (n = 3075). Definitions used: normal-weight body mass index (BMI, kg/m(2)) 20 to <25, overweight BMI 25 to <30, obese BMI > or =30. Breastfeeding initiation was 95.1% for normal-weight women, 92.8% for overweight women and 87.1% for obese women. At 6 months, 64% of normal-weight women were breastfeeding, compared with 54% of overweight and 44% of obese women. On multivariate analysis, for women who initiated breastfeeding, overweight women had an odds ratio (OR) of 1.52 [95% confidence interval (CI) 1.02, 2.28] and obese women had an OR of 2.54 (95% CI 1.70, 3.79) of stopping breastfeeding by 1 week compared with normal-weight women (adjusted for maternal age, education, smoking, level of socio-economic disadvantage, caesarean birth, admission to special care nursery). For women who breastfed for at least 1 week, overweight women had an adjusted OR of 1.26 (1.04, 1.53) and obese women had an adjusted OR of 1.38 (1.10, 1.73) of ceasing to breastfeed before 6 months, compared with normal-weight women. In conclusion, among overweight/obese women who initiate breastfeeding, higher rates of cessation of breastfeeding in both the immediate postpartum period and in the first 6 months contribute to the shorter duration.


Excited state intramolecular proton transfer in 2-(2'-arylsulfonamidophenyl)benzimidazole derivatives: insights into the origin of donor substituent-induced emission energy shifts.
Donor-substituted 2-(2'-arylsulfonamidophenyl)benzimidazoles undergo efficient excited-state intramolecular proton transfer (ESIPT) upon photoexcitation. The tautomer emission energy depends strongly on the substituent attachment position on the fluorophore pi-system. While substitution with a donor group in the para-position relative to the sulfonamide moiety yields an emission energy that is red-shifted relative to the unsubstituted fluorophore, fluorescence of the meta-substituted derivative appears blue-shifted. To elucidate the origin of the surprisingly divergent emission shifts, we performed detailed photophysical and quantum chemical studies with a series of methoxy- and pyrrole-substituted derivatives. The nature and contribution of solvent-solute interactions on the emission properties were analyzed on the basis of solvatochromic shift data using Onsager's reaction field model, Reichardt's empirical solvent polarity scale ET(30), as well as Kamlet-Abboud-Taft's empirical solvent index. The studies revealed that all ESIPT tautomers emit from a moderately polarized excited-state whose dipole moment is not strongly influenced by the donor-attachment position. Furthermore, the negative solvatochromic shift behavior was most pronounced in protic solvents presumably due to specific hydrogen-bonding interactions. The extrapolated gas-phase emission energies correlated qualitatively well with the trends in Stokes shifts, suggesting that solute-solvent interactions do not play a significant role in explaining the divergent emission energy shifts. Detailed quantum chemical calculations not only confirmed the moderately polarized nature of the ESIPT tautomers but also provided a rational for the observed emission shifts based on the differential change in the HOMO and LUMO energies. The results gained from this study should provide guidelines for tuning the emission properties of this class of ESIPT fluorophores with potential applications in analytical chemistry, biochemistry, or materials science.


Human Frequency Following Responses to Vocoded Speech.
Vocoders offer an effective platform to simulate the effects of cochlear implant speech processing strategies in normal-hearing listeners. Several behavioral studies have examined the effects of varying spectral and temporal cues on vocoded speech perception; however, little is known about the neural indices of vocoded speech perception. Here, the scalp-recorded frequency following response (FFR) was used to study the effects of varying spectral and temporal cues on brainstem neural representation of specific acoustic cues, the temporal envelope periodicity related to fundamental frequency (F0) and temporal fine structure (TFS) related to formant and formant-related frequencies, as reflected in the phase-locked neural activity in response to vocoded speech. In experiment 1, FFRs were measured in 12 normal-hearing, adult listeners in response to a steady state English back vowel /u/ presented in an unaltered, unprocessed condition and six sine-vocoder conditions with varying numbers of channels (1, 2, 4, 8, 16, and 32), while the temporal envelope cutoff frequency was fixed at 500 Hz. In experiment 2, FFRs were obtained from 14 normal-hearing, adult listeners in response to the same English vowel /u/, presented in an unprocessed condition and four vocoded conditions where both the temporal envelope cutoff frequency (50 versus 500 Hz) and carrier type (sine wave versus noise band) were varied separately with the number of channels fixed at 8. Fast Fourier Transform was applied to the time waveforms of FFR to analyze the strength of brainstem neural representation of temporal envelope periodicity (F0) and TFS-related peaks (formant structure). Brainstem neural representation of both temporal envelope and TFS cues improved when the number of channels increased from 1 to 4, followed by a plateau with 8 and 16 channels, and a reduction in phase-locking strength with 32 channels. For the sine vocoders, peaks in the FFRTFS spectra corresponded with the low-frequency sine-wave carriers and side band frequencies in the stimulus spectra. When the temporal envelope cutoff frequency increased from 50 to 500 Hz, an improvement was observed in brainstem F0 representation with no change in brainstem representation of spectral peaks proximal to the first formant frequency (F1). There was no significant effect of carrier type (sine- versus noise-vocoder) on brainstem neural representation of F0 cues when the temporal envelope cutoff frequency was 500 Hz. While the improvement in neural representation of temporal envelope and TFS cues with up to 4 vocoder channels is consistent with the behavioral literature, the reduced neural phase-locking strength noted with even more channels may be because of the narrow bandwidth of each channel as the number of channels increases. Stronger neural representation of temporal envelope cues with higher temporal envelope cutoff frequencies is likely a reflection of brainstem neural phase-locking to F0-related periodicity fluctuations preserved in the 500-Hz temporal envelopes, which are unavailable in the 50-Hz temporal envelopes. No effect of temporal envelope cutoff frequency was seen for neural representation of TFS cues, suggesting that spectral side band frequencies created by the 500-Hz temporal envelopes did not improve neural representation of F1 cues over the 50-Hz temporal envelopes. Finally, brainstem F0 representation was not significantly affected by carrier type with a temporal envelope cutoff frequency of 500 Hz, which is inconsistent with previous results of behavioral studies examining pitch perception of vocoded stimuli.


Monitoring non-invasive cardiac output and stroke volume during experimental human hypovolaemia and resuscitation.
Multiple methods for non-invasive measurement of cardiac output (CO) and stroke volume (SV) exist. Their comparative capabilities are not clearly established. Healthy human subjects (n=21) underwent central hypovolaemia through progressive lower body negative pressure (LBNP) until the onset of presyncope, followed by termination of LBNP, to simulate complete resuscitation. Measurement methods were electrical bioimpedance (EBI) of the thorax and three measurements of CO and SV derived from the arterial blood pressure (ABP) waveform: the Modelflow (MF) method, the long-time interval (LTI) method, and pulse pressure (PP). We computed areas under receiver-operating characteristic curves (ROC AUCs) for the investigational metrics, to determine how well they discriminated between every combination of LBNP levels. LTI and EBI yielded similar reductions in SV during progressive hypovolaemia and resuscitation (correlation coefficient 0.83) with ROC AUCs for distinguishing major LBNP (-60 mm Hg) vs resuscitation (0 mm Hg) of 0.98 and 0.99, respectively. MF yielded very similar reductions and ROC AUCs during progressive hypovolaemia, but after resuscitation, MF-CO did not return to baseline, yielding lower ROC AUCs (ΔROC AUC range, -0.18 to -0.26, P < 0.01). PP declined during hypovolaemia but tended to be an inferior indicator of specific LBNP levels, and PP did not recover during resuscitation, yielding lower ROC curves (P < 0.01). LTI, EBI, and MF were able to track progressive hypovolaemia. PP decreased during hypovolaemia but its magnitude of reduction underestimated reductions in SV. PP and MF were inferior for the identification of resuscitation.


Characterization of the major regulatory element upstream of the human alpha-globin gene cluster.
The major positive regulatory activity of the human alpha-globin gene complex has been localized to an element associated with a strong erythroid-specific DNase I hypersensitive site (HS -40) located 40 kb upstream of the zeta 2-globin mRNA cap site. Footprint and gel shift analyses of the element have demonstrated the presence of four binding sites for the nuclear factor GATA-1 and two sites corresponding to the AP-1 consensus binding sequence. This region resembles one of the major elements of the beta-globin locus control region in its constitution and characteristics; this together with evidence from expression studies suggests that HS -40 is a primary element controlling alpha-globin gene expression.


Repetition across successive sentences facilitates young children's word learning.
Young children who hear more child-directed speech (CDS) tend to have larger vocabularies later in childhood, but the specific characteristics of CDS underlying this link are currently underspecified. The present study sought to elucidate how the structure of language input boosts learning by investigating whether repetition of object labels in successive sentences-a common feature of natural CDS-promotes young children's efficiency in learning new words. Using a looking-while-listening paradigm, 2-year-old children were taught the names of novel objects, with exposures either repeated across successive sentences or distributed throughout labeling episodes. Results showed successful learning only when label-object pairs had been repeated in blocks of successive sentences, suggesting that immediate opportunities to detect recurring structure facilitate young children's learning. These findings offer insight into how the information flow within CDS might influence vocabulary development, and we consider the findings alongside research showing the benefits of distributing information across time. (PsycINFO Database Record


Cohort profile: a migratory cohort study of US Marines who train in Australia.
In 2012, US Marines and Sailors began annual deployments to Australia to participate in joint training exercises with the Australian Defence Force and other partners in the region. During their training, US service members are exposed to a variety of infectious disease threats not normally encountered by American citizens. This paper describes a cohort of US Marines and Sailors enrolled during five rotations to Australia between 2016 and 2020. Study participation is strictly voluntary. Group informational sessions are held prior to deployment to describe the study structure and goals, as well as the infectious disease threats that participants may encounter while in Australia. All participants provided written informed consent. Consented participants complete a pre-deployment questionnaire to collect data including basic demographic information, military occupational specialty, travel history, family history, basic health status and personal habits such as alcohol consumption. Blood is collected for serum, plasma and peripheral blood mononuclear cells (PBMC) processing. Data and specimen collection is repeated up to three times: before, during and after deployment. From the five rotations that comprised the 2016-2020 Marine Rotational Force-Darwin, we enrolled 1289 volunteers. Enrolments during this period were overwhelmingly white male under the age of 24 years. Most of the enrollees were junior enlisted and non-commissioned officers, with a smaller number of staff non-commissioned officers and commissioned officers, and minimal warrant officers. Over half of the enrollees had occupational specialty designations for infantry. In the future, we will screen samples for serological evidence of infection with Burkholderia pseudomallei, Coxiella burnetii, Ross River virus, SARS-CoV-2 and other operationally relevant pathogens endemic in Australia. Antigenic stimulation assays will be performed on PBMCs collected from seropositive individuals to characterise the immune response to these infections in this healthy American population.


Improving reading speed for people with central vision loss through perceptual learning.
Perceptual learning has been shown to be effective in improving visual functions in the normal adult visual system, as well as in adults with amblyopia. In this study, the feasibility of applying perceptual learning to enhance reading speed in people with long-standing central vision loss was evaluated. Six observers (mean age, 73.8) with long-standing central vision loss practiced an oral sentence-reading task, with words presented sequentially using rapid serial visual presentation (RSVP). A pre-test consisted of measurements of visual acuities, RSVP reading speeds for six print sizes, the location of the preferred retinal locus for fixation (fPRL), and fixation stability. Training consisted of six weekly sessions of RSVP reading, with 300 sentences presented per session. A post-test, identical with the pre-test, followed the training. All observers showed improved RSVP reading speed after training. The improvement averaged 53% (range, 34-70%). Comparisons of pre- and post-test measurements revealed little changes in visual acuity, critical print size, location of the fPRL, and fixation stability. The specificity of the learning effect, and the lack of changes to the fPRL location and fixation stability suggest that the improvements are not due to observers adopting a retinal location with better visual capability, or an improvement in fixation. Rather, the improvements are likely to represent genuine plasticity of the visual system despite the older ages of the observers, coupled with long-standing sensory deficits. Perceptual learning might be an effective way of enhancing visual performance for people with central vision loss.


Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy to diagnose osteoarthritis in equine serum.
Reliable and validated biomarkers for osteoarthritis (OA) are currently lacking. To develop an accurate and minimally invasive method to assess OA-affected horses and provide potential spectral markers indicative of disease. Observational, cross-sectional study. Our cohort consisted of 15 horses with OA and 48 without clinical signs of the disease, which were used as controls. Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy was used to investigate serum samples (50 μL) collected from these horses. Spectral processing and multivariate analysis revealed differences and similarities, allowing for detection of spectral biomarkers that discriminated between the two cohorts. A supervised classification algorithm, namely principal component analysis coupled with quadratic discriminant analysis (PCA-QDA), was applied to evaluate the diagnostic accuracy. Segregation between the two different cohorts, OA-affected and controls, was achieved with 100% sensitivity and specificity. The six most discriminatory peaks were attributed to proteins and lipids. Four of the spectral peaks were elevated in OA horses, which could be potentially due to an increase in lipids, protein expression levels and collagen, all of which have been previously reported in OA. Two peaks were found decreased and were tentatively assigned to the reduction of proteoglycan content that is observed during OA. The control group had a wide range of ages and breeds. Presymptomatic OA cases were not included. Therefore, it remains unknown whether this test could also be used as an early diagnostic tool. This spectrochemical approach could provide an accurate and cost-effective blood test, facilitating point-of-care diagnosis of equine OA.


Elevated chromium levels and prosthetic joint implants.
Chromium is a naturally occurring, toxic heavy metal used in many industrial processes. The U.S. Department of Labor's Occupational Safety and Health Administration has established specific limits for occupational exposure levels of chromium and guidelines for medical surveillance of individuals who have been exposed to chromium. The author presents a case in which a 54-year-old man who had been working with chromium exhibited persistent elevations of urinary chromium levels after the cessation of occupational exposure. The author determined that the elevated chromium levels were caused by the patient's knee prostheses, which were made of cobalt-chromium alloy. The author also discusses mandates and screening guidelines for occupational chromium exposure and reviews the literature on chromium levels in individuals with prosthetic joint implants.


Multi-channel search for squarks and gluinos in [Formula: see text]pp collisions with the ATLAS detector at the LHC.
A search for supersymmetric particles in final states with zero, one, and two leptons, with and without jets identified as originating from b-quarks, in 4.7 fb-1 of [Formula: see text]pp collisions produced by the Large Hadron Collider and recorded by the ATLAS detector is presented. The search uses a set of variables carrying information on the event kinematics transverse and parallel to the beam line that are sensitive to several topologies expected in supersymmetry. Mutually exclusive final states are defined, allowing a combination of all channels to increase the search sensitivity. No deviation from the Standard Model expectation is observed. Upper limits at 95 % confidence level on visible cross-sections for the production of new particles are extracted. Results are interpreted in the context of the constrained minimal supersymmetric extension to the Standard Model and in supersymmetry-inspired models with diverse, high-multiplicity final states.


Epidermal-specific defect of GPI anchor in Pig-a null mice results in Harlequin ichthyosis-like features.
We previously demonstrated that the epidermal-specific glycosylphosphatidylinositol (GPI)-anchor-deficient mice, generated by Pig-a gene disruption (Pig-a null mice), exhibited wrinkled and dry skin with hyperkeratosis and abnormal differentiation, and they died within a few days after birth. Here, we investigated the basis for the early demise of these animals, and the potential role of epidermal structural and biochemical abnormalities. The rapid demise of these animals was associated with both diminished epidermal permeability barrier function and decreased stratum corneum (SC) water content. The barrier abnormality could be attributed abnormal internal contents of lamellar bodies, with a downstream failure to generate normal extracellular lamellar bilayers in the SC. Moreover, processing profilaggrin to its monomeric form was impaired in Pig-a null mouse epidermis, while levels of the differentiation-specific proteins, involucrin, loricrin and profilaggrin were normal. Failure of filaggrin processing was accompanied by decreased activity of protein phosphatase 2A, an enzyme involved in profilaggrin to filaggrin processing. Thus, these studies demonstrate a critical role for GPI anchor and GPI-anchored proteins in divergent arms of epidermal terminal differentiation. While the permeability barrier abnormality can be attributed to defects in the lamellar body secretory system, the hydration abnormality is, in part, due to lack of availability of filaggrin-derived proteolytic products. Finally, since the dual abnormalities in the lamellar body secretory system and filaggrin processing resemble two key features of human Harlequin ichthyosis, Pig-a null mice could provide an appropriate analog for further studies of this disease.


The gain and loss of genes during 600 million years of vertebrate evolution.
Gene duplication is assumed to have played a crucial role in the evolution of vertebrate organisms. Apart from a continuous mode of duplication, two or three whole genome duplication events have been proposed during the evolution of vertebrates, one or two at the dawn of vertebrate evolution, and an additional one in the fish lineage, not shared with land vertebrates. Here, we have studied gene gain and loss in seven different vertebrate genomes, spanning an evolutionary period of about 600 million years. We show that: first, the majority of duplicated genes in extant vertebrate genomes are ancient and were created at times that coincide with proposed whole genome duplication events; second, there exist significant differences in gene retention for different functional categories of genes between fishes and land vertebrates; third, there seems to be a considerable bias in gene retention of regulatory genes towards the mode of gene duplication (whole genome duplication events compared to smaller-scale events), which is in accordance with the so-called gene balance hypothesis; and fourth, that ancient duplicates that have survived for many hundreds of millions of years can still be lost. Based on phylogenetic analyses, we show that both the mode of duplication and the functional class the duplicated genes belong to have been of major importance for the evolution of the vertebrates. In particular, we provide evidence that massive gene duplication (probably as a consequence of entire genome duplications) at the dawn of vertebrate evolution might have been particularly important for the evolution of complex vertebrates.


Do latitudinal gradients exist in New Zealand stream invertebrate metacommunities?
That biodiversity declines with latitude is well known, but whether a metacommunity process is behind this gradient has received limited attention. We tested the hypothesis that dispersal limitation is progressively replaced by mass effects with increasing latitude, along with a series of related hypotheses. We explored these hypotheses by examining metacommunity structure in stream invertebrate metacommunities spanning the length of New Zealand's two largest islands (∼1,300 km), further disentangling the role of dispersal by deconstructing assemblages into strong and weak dispersers. Given the highly dynamic nature of New Zealand streams, our alternative hypothesis was that these systems are so unpredictable (at different stages of post-flood succession) that metacommunity structure is highly context dependent from region to region. We rejected our primary hypotheses, pinning this lack of fit on the strong unpredictability of New Zealand's dynamic stream ecosystems and fauna that has evolved to cope with these conditions. While local community structure turned over along this latitudinal gradient, metacommunity structure was highly context dependent and dispersal traits did not elucidate patterns. Moreover, the emergent metacommunity types exhibited no trends, nor did the important environmental variables. These results provide a cautionary tale for examining singular metacommunities. The considerable level of unexplained contingency suggests that any inferences drawn from one-off snapshot sampling may be misleading and further points to the need for more studies on temporal dynamics of metacommunity processes.


Cortical preparatory activity: representation of movement or first cog in a dynamical machine?
The motor cortices are active during both movement and movement preparation. A common assumption is that preparatory activity constitutes a subthreshold form of movement activity: a neuron active during rightward movements becomes modestly active during preparation of a rightward movement. We asked whether this pattern of activity is, in fact, observed. We found that it was not: at the level of a single neuron, preparatory tuning was weakly correlated with movement-period tuning. Yet, somewhat paradoxically, preparatory tuning could be captured by a preferred direction in an abstract "space" that described the population-level pattern of movement activity. In fact, this relationship accounted for preparatory responses better than did traditional tuning models. These results are expected if preparatory activity provides the initial state of a dynamical system whose evolution produces movement activity. Our results thus suggest that preparatory activity may not represent specific factors, and may instead play a more mechanistic role.


The Risk of Allergic Reaction to SARS-CoV-2 Vaccines and Recommended Evaluation and Management: A Systematic Review, Meta-Analysis, GRADE Assessment, and International Consensus Approach.
Concerns for anaphylaxis may hamper severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunization efforts. We convened a multidisciplinary group of international experts in anaphylaxis composed of allergy, infectious disease, emergency medicine, and front-line clinicians to systematically develop recommendations regarding SARS-CoV-2 vaccine immediate allergic reactions. Medline, EMBASE, Web of Science, the World Health Organizstion (WHO) global coronavirus database, and the gray literature (inception, March 19, 2021) were systematically searched. Paired reviewers independently selected studies addressing anaphylaxis after SARS-CoV-2 vaccination, polyethylene glycol (PEG) and polysorbate allergy, and accuracy of allergy testing for SARS-CoV-2 vaccine allergy. Random effects models synthesized the data to inform recommendations based on the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach, agreed upon using a modified Delphi panel. The incidence of SARS-CoV-2 vaccine anaphylaxis is 7.91 cases per million (n = 41,000,000 vaccinations; 95% confidence interval [95% CI] 4.02-15.59; 26 studies, moderate certainty), the incidence of 0.15 cases per million patient-years (95% CI 0.11-0.2), and the sensitivity for PEG skin testing is poor, although specificity is high (15 studies, very low certainty). We recommend vaccination over either no vaccination or performing SARS-CoV-2 vaccine/excipient screening allergy testing for individuals without history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient, and a shared decision-making paradigm in consultation with an allergy specialist for individuals with a history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient. We recommend further research to clarify SARS-CoV-2 vaccine/vaccine excipient testing utility in individuals potentially allergic to SARS-CoV2 vaccines or their excipients.


The cultural context of trauma recovery: Considering the posttraumatic stress disorder practice guideline and intersectionality.
The American Psychological Association's (2017) Clinical Practice Guideline for the Treatment of Posttraumatic Stress Disorder (PTSD) in Adults endorsed by the American Psychological Association notes that attention to cultural context is a required component of trauma-informed mental health care provision. Despite the inclusion of this statement, the Treatment of PTSD Guideline does not give adequate attention to culture in the defining of trauma, review of the trauma literature, the criteria adopted for evaluation of PTSD treatments, and, resultantly, the determination of treatment recommendations. Culture plays a significant role in the vulnerability to, experience of, and recovery from mental health sources of distress, including interpersonal trauma (Bryant-Davis, 2005). Approaches to trauma-focused psychotherapy that are ethically sound call for a prioritizing of cultural competence (awareness, knowledge, and skills), as well as cultural humility (Harvey & Tammala-Nara, 2007). Trauma survivors, however, hold multiple identities simultaneously that influence their conceptualizations of trauma, therapy, and the recovery process (Brown, 2008). Intersectionality refers to the way in which a multiply marginalized person experiences cultural identity and oppression that is qualitatively different than the experience of trauma survivors from dominant cultural groups (Crenshaw, 2005). The realities of racism, sexism, heterosexism, and classism, as well as their influence on the trauma recovery process, are examined, while noting the minimal attention that has been given to additional forms of oppression such as religious intolerance and able-bodyism. This critical review of the literature will examine the theoretical and empirical literature, which has examined the framework and strategies that have been cultivated in service to trauma survivors who have been traditionally underserved. Attention will be given in particular to benefits, limitations, and critiques of evidence-based interventions, as well as benefits, limitations, and future research needs of both culturally modified interventions and culturally emergent trauma interventions. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Preservation of a critical epitope core region is associated with the high degree of flaviviral cross-reactivity exhibited by a dengue-specific CD4+ T cell clone.
Dengue is a member of the Flaviviridae, a large group of related viruses some of which co-circulate in certain regions (e.g. dengue and Yellow fever in South America). Immune responses cross-reactive between different dengue serotypes are important in the pathogenesis of dengue disease but it is not known whether previous infection with one flavivirus might affect the clinical course of subsequent infections with other members of the family. CD4+ T cells have been shown to be important in the production of cytokines in response to dengue infection and can demonstrate significant epitope cross-reactivity. Here, we describe the generation and characterisation of CD4+ T cell clones from a patient experiencing acute dengue infection. These clones were DRB1*15+ and recognised epitope variants not only within other dengue viruses but certain other flaviviruses. This cross-reactivity was dependent upon the presence of a five-amino acid core region, consistent with structural observations of class II MHC binding to TCR demonstrating that only a subset of residues within an epitope bound to a class II molecule are "read out" by the TCR. This capacity of CD4+ T cell clones to recognise a given epitope despite considerable variation between viruses may be of pathological significance, particularly in regions where related viruses co-circulate.


Cost-benefit analysis of communities that care outcomes at eighth grade.
This paper presents a cost-benefit analysis of the Communities That Care (CTC) prevention system, a public health approach to reducing risk, enhancing protection, and reducing the prevalence of adolescent health and behavior problems community wide. The analysis is based on outcomes from a panel of students followed from Grade 5 through Grade 8 in a randomized controlled trial involving 24 communities in 7 states. Previous analyses have shown that CTC prevented the initiation of cigarette smoking, alcohol use, and delinquency by the end of 8th grade in CTC communities compared to controls. This paper estimates long-term monetary benefits associated with significant intervention effects on cigarette smoking and delinquency as compared to the cost of conducting the intervention. Under conservative cost assumptions, the net present benefit is $5,250 per youth, including $812 from the prevention of cigarette smoking and $4,438 from the prevention of delinquency. The benefit-cost ratio indicates a return of $5.30 per $1.00 invested. Under less conservative but still viable cost assumptions, the benefit-cost ratio due to prevention of cigarette smoking and delinquency increases to $10.23 per $1.00 invested. Benefits from CTC's reduction in alcohol initiation as well as broader inclusion of quality-of-life gains would further increase CTC's benefit-cost ratio. Results provide evidence that CTC is a cost-beneficial preventive intervention and a good investment of public dollars, even under very conservative cost and benefit assumptions.


Quantifying crustal thickness over time in magmatic arcs.
We present global and regional correlations between whole-rock values of Sr/Y and La/Yb and crustal thickness for intermediate rocks from modern subduction-related magmatic arcs formed around the Pacific. These correlations bolster earlier ideas that various geochemical parameters can be used to track changes of crustal thickness through time in ancient subduction systems. Inferred crustal thicknesses using our proposed empirical fits are consistent with independent geologic constraints for the Cenozoic evolution of the central Andes, as well as various Mesozoic magmatic arc segments currently exposed in the Coast Mountains, British Columbia, and the Sierra Nevada and Mojave-Transverse Range regions of California. We propose that these geochemical parameters can be used, when averaged over the typical lifetimes and spatial footprints of composite volcanoes and their intrusive equivalents to infer crustal thickness changes over time in ancient orogens.


Analysis of the space filling modes of photonic crystal fibers.
We study the cladding modes of photonic crystal fibers (PCFs) using a fully vectorial method. This approach enables us to analyze the modes and incorporate material dispersion in a straightforward fashion. We find the field flow lines, intensity distribution and polarization properties of these modes. The effective cladding indices of different PCFs are investigated in detail.


SNP Assay Development for Linkage Map Construction, Anchoring Whole-Genome Sequence, and Other Genetic and Genomic Applications in Common Bean.
A total of 992,682 single-nucleotide polymorphisms (SNPs) was identified as ideal for Illumina Infinium II BeadChip design after sequencing a diverse set of 17 common bean (Phaseolus vulgaris L) varieties with the aid of next-generation sequencing technology. From these, two BeadChips each with >5000 SNPs were designed. The BARCBean6K_1 BeadChip was selected for the purpose of optimizing polymorphism among market classes and, when possible, SNPs were targeted to sequence scaffolds in the Phaseolus vulgaris 14× genome assembly with sequence lengths >10 kb. The BARCBean6K_2 BeadChip was designed with the objective of anchoring additional scaffolds and to facilitate orientation of large scaffolds. Analysis of 267 F2 plants from a cross of varieties Stampede × Red Hawk with the two BeadChips resulted in linkage maps with a total of 7040 markers including 7015 SNPs. With the linkage map, a total of 432.3 Mb of sequence from 2766 scaffolds was anchored to create the Phaseolus vulgaris v1.0 assembly, which accounted for approximately 89% of the 487 Mb of available sequence scaffolds of the Phaseolus vulgaris v0.9 assembly. A core set of 6000 SNPs (BARCBean6K_3 BeadChip) with high genotyping quality and polymorphism was selected based on the genotyping of 365 dry bean and 134 snap bean accessions with the BARCBean6K_1 and BARCBean6K_2 BeadChips. The BARCBean6K_3 BeadChip is a useful tool for genetics and genomics research and it is widely used by breeders and geneticists in the United States and abroad.


A cell cycle regulator potentially involved in genesis of many tumor types.
A putative tumor suppressor locus on the short arm of human chromosome 9 has been localized to a region of less than 40 kilobases by means of homozygous deletions in melanoma cell lines. This region contained a gene, Multiple Tumor Suppressor 1 (MTS1), that encodes a previously identified inhibitor (p16) of cyclin-dependent kinase 4. MTS1 was homozygously deleted at high frequency in cell lines derived from tumors of lung, breast, brain, bone, skin, bladder, kidney, ovary, and lymphocyte. Melanoma cell lines that carried at least one copy of MTS1 frequently carried nonsense, missense, or frameshift mutations in the gene. These findings suggest that MTS1 mutations are involved in tumor formation in a wide range of tissues.


Active Pacific meridional overturning circulation (PMOC) during the warm Pliocene.
An essential element of modern ocean circulation and climate is the Atlantic meridional overturning circulation (AMOC), which includes deep-water formation in the subarctic North Atlantic. However, a comparable overturning circulation is absent in the Pacific, the world's largest ocean, where relatively fresh surface waters inhibit North Pacific deep convection. We present complementary measurement and modeling evidence that the warm, ~400-ppmv (parts per million by volume) CO2 world of the Pliocene supported subarctic North Pacific deep-water formation and a Pacific meridional overturning circulation (PMOC) cell. In Pliocene subarctic North Pacific sediments, we report orbitally paced maxima in calcium carbonate accumulation rate, with accompanying pigment and total organic carbon measurements supporting deep-ocean ventilation-driven preservation as their cause. Together with high accumulation rates of biogenic opal, these findings require vigorous bidirectional communication between surface waters and interior waters down to ~3 km in the western subarctic North Pacific, implying deep convection. Redox-sensitive trace metal data provide further evidence of higher Pliocene deep-ocean ventilation before the 2.73-Ma (million years) transition. This observational analysis is supported by climate modeling results, demonstrating that atmospheric moisture transport changes, in response to the reduced meridional sea surface temperature gradients of the Pliocene, were capable of eroding the halocline, leading to deep-water formation in the western subarctic Pacific and a strong PMOC. This second Northern Hemisphere overturning cell has important implications for heat transport, the ocean/atmosphere cycle of carbon, and potentially the equilibrium response of the Pacific to global warming.


Maternal mosaicism confounds the neonatal diagnosis of type 1 Timothy syndrome.
The presence of 2 distinct populations of somatic or germline cells within a single individual harboring different genotypes is termed mosaicism. Recent reports suggest that parental mosaicism is involved in the heritability of type 1 Timothy syndrome (TS1), an extremely rare and life-threatening multisystem disorder characterized by severe QT interval prolongation, syndactyly, and several other complications. Although full TS1 is caused by a single missense mutation in the CACNA1C-encoded cardiac calcium channel, mosaic TS1 parents can display isolated syndactyly without additional phenotypic manifestations. A newborn boy presented with syndactyly at birth. The presence of syndactyly in his mother led to a diagnosis of benign familial syndactyly. However, at 9 months of age, during his first syndactyly-corrective surgery, intraoperative electrocardiograms revealed extreme QT prolongation and 2:1 atrioventricular block. A comprehensive cardiac evaluation was performed, and both mother and child were tested genetically, confirming a clinical suspicion of TS1. Only the patient tested positive for the TS1 mutation; however, more extensive molecular testing revealed a limited presence of the mutation in maternally-derived DNA. This case illustrates the potential of parental mosaicism to confound the diagnosis of potentially life-threatening genetic diseases, such as TS1. Here, a mother with a partial TS1 phenotype and genetically confirmed mosaicism transmitted the TS1-causative mutation to her son, resulting in fully expressive TS1. Thus, a shared partial phenotype should not be dismissed as a benign or insignificant finding, but should be evaluated further to rule out the possibility of parental mosaicism concealing a potentially fatal heritable disease.


Consistency of cerebral blood flow and evoked potential alterations with reversible focal ischemia in cats.
To enhance the consistency of the ischemic insult caused by reversible transorbital middle cerebral artery occlusion, we investigated the variability of somatosensory evoked potential amplitudes and regional cerebral blood flow in 26 anesthetized cats using four procedures to induce transient ischemia. These procedures included 60 minutes of left middle cerebral artery occlusion with or without left common carotid artery occlusion and 120 minutes of left middle cerebral artery occlusion with or without bilateral common carotid artery occlusion. Blood flow in the left middle cerebral artery territory was markedly and consistently reduced to less than 20 ml/min/100 g with simultaneous occlusion of the left middle cerebral artery and both common carotid arteries. The standard deviation of blood flow with this procedure (5.4) was less than that with the other three procedures (13-25). The amplitudes of ipsilateral somatosensory evoked potentials were decreased to approximately 20% of control during ischemia with all four procedures. During reperfusion, amplitudes recovered more slowly, to half of control, after both procedures involving 120 minutes of ischemia. After 120 minutes of reperfusion, the range of amplitudes was smallest in the group exposed to middle cerebral artery occlusion with bilateral common carotid artery occlusion. The degree of recovery of the somatosensory evoked potentials correlated with residual blood flow in both the ipsilateral middle cerebral artery territory and in the white matter during ischemia. We conclude that the most consistent model of focal ischemia and reperfusion in cats in which there is partial recovery of somatosensory evoked potentials is occlusion of one middle cerebral artery and both common carotid arteries for 120 minutes.


Three proposals to increase Australia's organ supply.
In 2008 the Australian Government introduced a national reform agenda to increase organ and tissue donation. Australia continues to perform poorly by international standards on measures of organ procurement, however. This paper outlines three proposals to improve donation rates and considers the empirical evidence available for each. A number of ethical objections frequently given to resist such proposals are also addressed. Firstly, it is recommended that Australia implement an 'opt-out' system of organ donation. Secondly, the existing veto rules should be changed to better protect the wishes of those who wish to donate. Finally, a numer of incentives should be offered to increase donation rates; these could include incentives of financial value, but also non-financial incentives such as prioritisation for the receipt of organs for previous donors.


A systematic review of medical practice variation in OECD countries.
Major variations in medical practice have been documented internationally. Variations raise questions about the quality, equity, and efficiency of resource allocation and use, and have important implications for health care and health policy. To perform a systematic review of the peer-reviewed literature on medical practice variations in OECD countries. We searched MEDLINE to find publications on medical practice variations in OECD countries published between 2000 and 2011. We present an overview of the characteristics of published studies as well as the magnitude of variations for select high impact conditions. A total of 836 studies were included. Consistent with the gray literature, there were large variations across regions, hospitals and physician practices for almost every condition and procedure studied. Many studies focused on high-impact conditions, but very few looked at the causes or outcomes of medical practice variations. While there were an overwhelming number of publications on medical practice variations the coverage was broad and not often based on a theoretical construct. Future studies should focus on conditions and procedures that are clinically important, policy relevant, resource intensive, and have high levels of public awareness. Further study of the causes and consequences of variations is important.


The Vpx lentiviral accessory protein targets SAMHD1 for degradation in the nucleus.
Sterile alpha motif domain- and HD domain-containing protein 1 (SAMHD1) is a deoxynucleoside triphosphohydrolase that restricts the replication of lentiviruses in myeloid cells by hydrolyzing the cellular deoxynucleotide triphosphates to a level below that which is required for reverse transcription. Human immunodeficiency virus type 2 (HIV-2) and some simian immunodeficiency viruses (SIVs) encode the accessory protein viral protein X (Vpx) that counteracts SAMHD1. Vpx recruits SAMHD1 to a cullin4A-RING E3 ubiquitin ligase (CRL4), which targets the enzyme for proteasomal degradation. Vpx and SAMHD1 both localize to the nucleus of the cell. We identified the nuclear localization sequence (NLS) of SAMHD1 as a conserved KRPR sequence at amino acid residues 11 to 14. SAMHD1 lacking a functional NLS localized to the cytoplasm but retained its triphosphohydrolase and antiviral activities. However, cytoplasmic SAMHD1 was resistant to Vpx-induced degradation, and its antiviral activity was not counteracted by Vpx. Cytoplasmic SAMHD1 interacted with Vpx and retained it in the cytoplasm. The inhibition of nuclear export with leptomycin B did not impair the ability of Vpx to degrade SAMHD1. These findings suggest that SAMHD1 is targeted by Vpx for ubiquitination and degradation in the nucleus.


Synthesis by cultured human umbilical vein endothelial cells of two proteins structurally and immunologically related to platelet membrane glycoproteins IIb and IIIa.
Human platelets participate in a number of adhesive interactions, including binding to exposed subendothelium after vascular injury, and platelet-platelet cohesion to form large aggregates. Platelet membrane glycoproteins (GP) IIb and IIIa constitute a receptor for fibrinogen that, together with fibrinogen and calcium, is largely responsible for mediating the formation of the primary hemostatic plug. Using highly specific polyclonal and monoclonal antibodies as probes, we could detect the presence of both of these glycoproteins in cultured human umbilical vein endothelial cells. Western-blot analysis showed that the endothelial cell analogues were similar in size to their platelet counterparts, and were present in cells that had been in culture for over 2 mo. Metabolic labeling of endothelium with [35S]methionine demonstrated that both GPIIb and GPIIIa were actively synthesized in culture. Using the technique of crossed immunoelectrophoresis, evidence was obtained that the endothelial cell forms of GPIIb and GPIIIa may exist complexed to one another after solubilization in Triton X-100. The presence of GPIIb-IIIa analogues in cultured endothelial cells may provide an opportunity to examine the structure, function, and synthesis of these two membrane glycoproteins, as well as provide a source of genetic material with which to begin detailed molecular genetic studies.


A New and Stable Estimation Method of Country Economic Fitness and Product Complexity.
We present a new metric estimating fitness of countries and complexity of products by exploiting a non-linear non-homogeneous map applied to the publicly available information on the goods exported by a country. The non homogeneous terms guarantee both convergence and stability. After a suitable rescaling of the relevant quantities, the non homogeneous terms are eventually set to zero so that this new metric is parameter free. This new map almost reproduces the results of the original homogeneous metrics already defined in literature and allows for an approximate analytic solution in case of actual binarized matrices based on the Revealed Comparative Advantage (RCA) indicator. This solution is connected with a new quantity describing the neighborhood of nodes in bipartite graphs, representing in this work the relations between countries and exported products. Moreover, we define the new indicator of country net-efficiency quantifying how a country efficiently invests in capabilities able to generate innovative complex high quality products. Eventually, we demonstrate analytically the local convergence of the algorithm involved.


[Classification of pharmaceutical services from the viewpoint of patient satisfaction/dissatisfaction].
A survey was conducted to examine what the public expects of pharmacists. We created 26 questions based on 26 different situations that patients encounter at pharmacies in order to assess patient satisfaction/dissatisfaction. Some questions were designed to compare pairs of symmetrical situations. The survey was carried out in February and March 2001. The surveys were conducted with patients and/or patients' relatives who brought their prescriptions to pharmacies and with employees of pharmaceutical companies and their family members. A factor analysis extracted two factors among the 26 variables, the first being patient dissatisfaction and the second being patient satisfaction. However, factor loadings for some paired situations were not necessarily symmetrical and thus the absolute values of the scores were not equal. The results suggest that satisfaction on one side does not entail dissatisfaction on the other side and thus satisfaction and dissatisfaction can be examined as separate and distinct entities. Based on these results, we classified pharmaceutical services into two types. The first type is referred to as instrumental service. In this situation patients do not feel great satisfaction even if such service is provided. However, they feel great dissatisfaction if the service is not provided. The second type is referred to as expressive service. These patients feel some satisfaction if such service is provided, however, they do not feel a fatal dissatisfaction if the service is not provided. Our research documents that when examining data based on the assumption that there is a different dimensionality for patient satisfaction and dissatisfaction, it is possible to gain insights into new aspects of pharmaceutical services that are otherwise impossible to assess.


Malaria vaccine adjuvants: latest update and challenges in preclinical and clinical research.
There is no malaria vaccine currently available, and the most advanced candidate has recently reported a modest 30% efficacy against clinical malaria. Although many efforts have been dedicated to achieve this goal, the research was mainly directed to identify antigenic targets. Nevertheless, the latest progresses on understanding how immune system works and the data recovered from vaccination studies have conferred to the vaccine formulation its deserved relevance. Additionally to the antigen nature, the manner in which it is presented (delivery adjuvants) as well as the immunostimulatory effect of the formulation components (immunostimulants) modulates the immune response elicited. Protective immunity against malaria requires the induction of humoral, antibody-dependent cellular inhibition (ADCI) and effector and memory cell responses. This review summarizes the status of adjuvants that have been or are being employed in the malaria vaccine development, focusing on the pharmaceutical and immunological aspects, as well as on their immunization outcomings at clinical and preclinical stages.


Immediate effects of cervicothoracic junction mobilization versus thoracic manipulation on the range of motion and pain in mechanical neck pain with cervicothoracic junction dysfunction: a pilot randomized controlled trial.
Cervicothoracic (CT) junction hypomobility has been proposed as a contributing factor for neck pain. However, there are limited studies that compared the effect of CT junction mobilization against an effective intervention in neck pain. Thoracic spine manipulation is a nonspecific intervention for neck pain where remote spinal segments are treated based on the concept of regional interdependence. The effectiveness of segment-specific spinal mobilization in the cervical spine has been researched in the last few years, and no definite conclusions could be made from the previous studies. The above reasons warrant the investigation of the effects of a specific CT junction mobilization against a nonspecific thoracic manipulation intervention in neck pain. The present study aims to compare the immediate effects of C7-T1 Maitland mobilization with thoracic manipulation in individuals with mechanical neck pain presenting with CT junction dysfunction specifically. A randomized clinical trial is conducted where participants with complaints of mechanical neck pain and CT junction dysfunction randomly assigned to either C7-T1 level Maitland mobilization group or mid-thoracic (T3-T6) manipulation group (active control group). In both the groups, the post graduate student (SJ) pursuing Master's in orthopedic physiotherapy delivered the intervention. The outcomes of cervical flexion, extension, side flexion & rotation range of motion (ROM) were measured before & after the intervention with a cervical range of motion (CROM) device. Self-reported pain intensity was measured with the numerical pain rating scale (NPRS). The post-intervention between-group comparison was performed using a one-way ANCOVA test. Forty-two participants with mean age CT junction group: 35.14 ± 10.13 and Thoracic manipulation group: 38.47 ± 11.47 were recruited for the study. No significant differences in the post-intervention baseline adjusted outcomes of cervical ROM & self-reported pain intensity were identified between the groups after the treatment (p = 0.08, 0.95, 0.01, 0.39, 0.29, 0.27for flexion, extension, bilateral lateral flexion & rotations respectively) & neck pain intensity (p = 0.68). However, within-group, pre, and post comparison showed significant improvements in cervical ROM and pain in both groups. This preliminary study identified that CT junction mobilization is not superior to thoracic manipulation on the outcomes of cervical ROM and neck pain when level-specific CT junction mobilization was compared with remote mid-thoracic manipulation in individuals with mechanical neck pain and CT junction dysfunction. CTRI: 2018/04/013088, Registered 6 April 2018, http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=24418.


Sexual boundaries in dental practice: Part 1.
Sexual contact between doctors and patients is unethical, legally perilous, cause for professional discipline at times, and often viewed as an outrageous transgression by the public. While it is true that some provider-patient couples go on to get married and "live happily ever after," this is not always the case. However, if these relationships fail, a now embittered ex-paramour is empowered with the options of bringing legal and/or disciplinary action against the doctor and may be motivated by the distinct possibility of significant financial reward. Patients place enormous trust and respect in their health care providers. In addition, patients reveal sensitive, confidential information to doctors and do so with the expectation that it will be used only for their best interests. This dynamic creates a substantial power imbalance between doctors and patients and this power differential must never be exploited. Dentists who find themselves romantically attracted to patients must either avoid initiating a more intimate relationship or refer the patient to another provider. Dentists who are the recipients of romantic inquiries by patients should establish clear boundaries. If the dentist is available and interested in the patient, dating may occur only after the patient has been reassigned to another dentist and a suitable time period has elapsed.


APOBEC3 proteins: major players in intracellular defence against LINE-1-mediated retrotransposition.
Mammalian genomes are littered with enormous numbers of transposable elements interspersed within and between single-copy endogenous genes. The only presently spreading class of human transposable elements comprises non-LTR (long terminal repeat) retrotransposons, which cover approx. 34% of the human genome. Non-LTR retrotransposons include the widespread autonomous LINEs (long interspersed nuclear elements) and non-autonomous elements such as processed pseudogenes, SVAs [named after SINE (short interspersed nuclear element), VNTR (variable number of tandem repeats) and Alu] and SINEs. Mobilization of these elements affects the host genome, can be deleterious to the host cell, and cause genetic disorders and cancer. In order to limit negative effects of retrotransposition, host genomes have adopted several strategies to curb the proliferation of transposable elements. Recent studies have demonstrated that members of the human APOBEC3 (apolipoprotein B mRNA editing enzyme catalytic polypeptide 3) protein family inhibit the mobilization of the non-LTR retrotransposons LINE-1 and Alu significantly and participate in the intracellular defence against retrotransposition by mechanisms unknown to date. The striking coincidence between the expansion of the APOBEC3 gene cluster and the abrupt decline in retrotransposon activity in primates raises the possibility that these genes may have been expanded to prevent genomic instability caused by endogenous retroelements.


The effects of juice processing on black mulberry antioxidants.
Black mulberry fruit is processed to juice at significant scale in Turkey. The effect of industrial-scale juice production on black mulberry antioxidants was evaluated using samples collected from the main steps of processing; including the selection of fruits, washing, mechanical milling, mashing, cold pressing, pasteurization, and filling-packing. Two major anthocyanins (cyanidin-3-glucoside and cyanidin-3-rutinoside), two phenolic acids (3- and caffeoylquinic acid) and 3 flavonols (rutin, quercetin-3-glucoside, and quercetin-malonyl-glucoside) were identified using LC-QTOF-MS and were quantified using HPLC. Approximately, 60-70% of the fruit anthocyanins were retained in the final juice, which also contained high levels of caffeoylquinic acids, relative to the fruit. Mashing and pressing were the steps which were effective for the recovery of fruit polyphenolics into the juice fraction. Moreover, an in vitro gastrointestinal digestion model, applied to determine the effect of processing on the bioavailability of mulberry antioxidants, indicated a higher anthocyanin bioavailability for the fruit matrix than for the juice matrix.


Complementary and alternative medicine use in children with type 1 diabetes: a pilot survey of parents.
The aim of this study was to examine the prevalence and characteristics of complementary and alternative medicine (CAM) use among children with diabetes. Anonymous surveys were completed by guardians of children with diabetes attending an urban diabetes clinic over three months. The survey included demographics, parent and child CAM use (excluding vitamins), and perceived opinions of health providers about CAM use. The representativeness of the surveyed sample was evaluated and analyses examined associations with child CAM use. Children in the analysis (N = 86, 33% response rate) were similar to the potential population for age, gender, insurance type, and age at diabetes diagnosis. Children analyzed were mean 10.9 years of age (SD 3.9), 56% male, 71% Caucasian, 83% privately insured, and 90% spoke English at home. Parents were 22% foreign born and 45% college graduates; 19% of children and 45% of parents had tried CAM. There were 30 CAM use occurrences among 16 children; 60% were CAM activities (ie, faith healing, chiropractic treatments, relaxation techniques) and 40% were CAM supplements (ie, herbs, nutritional supplements, herbal teas). Child CAM use was more common if a parent had used CAM (33% vs 6%; P = .002) and among children with foreign-born parents (37% vs 13%; P = .04). CAM was used to decrease diabetes complications and improve overall health. Parents were comfortable discussing CAM with the diabetes team and their child's primary care provider. Children with diabetes were using CAM as an adjunctive therapy for diabetes. The diabetes healthcare team needs an increased awareness about CAM.


CWD prions remain infectious after passage through the digestive system of coyotes (Canis latrans).
Chronic wasting disease (CWD) is a geographically expanding prion disease of wild and captive cervids in North America. Disease can be transmitted directly, animal to animal, or indirectly via the environment. CWD contamination can occur residually in the environment via soil, water, and forage following deposition of bodily fluids such as urine, saliva, and feces, or by the decomposition of carcasses. Recent work has indicated that plants may even take up prions into the stems and leaves. When a carcass or gut pile is present in the environment, a large number of avian and mammalian species visit and consume the carrion. Additionally, predators like coyotes, likely select for disease-compromised cervids. Natural cross-species CWD transmission has not been documented, however, passage of infectious prion material has been observed in the feces of crows. In this study we evaluated the ability of CWD-infected brain material to pass through the gastrointestinal tract of coyotes (Canis latrans) following oral ingestion, and be infectious in a cervidized transgenic mouse model. Results from this study indicate that coyotes can pass infectious prions via their feces for at least 3 days post ingestion, demonstrating that mammalian scavengers could contribute to the translocation and contamination of CWD in the environment.


A new approach to solving the feature-binding problem in primate vision.
We discuss a recently proposed approach to solve the classic feature-binding problem in primate vision that uses neural dynamics known to be present within the visual cortex. Broadly, the feature-binding problem in the visual context concerns not only how a hierarchy of features such as edges and objects within a scene are represented, but also the hierarchical relationships between these features at every spatial scale across the visual field. This is necessary for the visual brain to be able to make sense of its visuospatial world. Solving this problem is an important step towards the development of artificial general intelligence. In neural network simulation studies, it has been found that neurons encoding the binding relations between visual features, known as binding neurons, emerge during visual training when key properties of the visual cortex are incorporated into the models. These biological network properties include (i) bottom-up, lateral and top-down synaptic connections, (ii) spiking neuronal dynamics, (iii) spike timing-dependent plasticity, and (iv) a random distribution of axonal transmission delays (of the order of several milliseconds) in the propagation of spikes between neurons. After training the network on a set of visual stimuli, modelling studies have reported observing the gradual emergence of polychronization through successive layers of the network, in which subpopulations of neurons have learned to emit their spikes in regularly repeating spatio-temporal patterns in response to specific visual stimuli. Such a subpopulation of neurons is known as a polychronous neuronal group (PNG). Some neurons embedded within these PNGs receive convergent inputs from neurons representing lower- and higher-level visual features, and thus appear to encode the hierarchical binding relationship between features. Neural activity with this kind of spatio-temporal structure robustly emerges in the higher network layers even when neurons in the input layer represent visual stimuli with spike timings that are randomized according to a Poisson distribution. The resulting hierarchical representation of visual scenes in such models, including the representation of hierarchical binding relations between lower- and higher-level visual features, is consistent with the hierarchical phenomenology or subjective experience of primate vision and is distinct from approaches interested in segmenting a visual scene into a finite set of objects.


Natriuretic effect of propranolol on dogs with chronic bile-duct ligation.
1. Chronic ligation of the bile duct in dogs is associated with salt retention and a blunted natriuretic response to extracellular volume expansion. The mechanism of this phenomenon has not been clarified. 2. We have examined the influence of chronic beta-adrenergic blockade on sodium excretion in dogs with bile-duct ligation during extracellular hypotonic volume expansion. 3. Urinary excretion of sodium and fractional excretion of sodium rose significantly after 5 days of oral DL-propranolol administration to dogs with bile-duct ligation. 4. The antinatriuresis after bile-duct ligation was not followed by a significant alteration in the mean peripheral plasma renin activity as compared with control values. 5. It is suggested that propranolol can partially reverse the antinatriuresis of chronic bile-duct ligation, and that this is mediated by an extrarenal effect of the beta-adrenergic blockade.


Hypocholesterolemic effects of different bulk-forming hydrophilic fibers as adjuncts to dietary therapy in mild to moderate hypercholesterolemia.
Hypercholesterolemia is a significant risk factor for coronary heart disease, and the hypocholesterolemic effects of psyllium are well established. This placebo-controlled, parallel study compared psyllium with methylcellulose, calcium polycarbophil, and placebo as dietary adjuncts in treating mild to moderate hypercholesterolemia. Of 163 men and women recruited with serum cholesterol levels above 5.17 mmol/L (200 mg/dL), 105 completed 8 weeks of an American Heart Association step I diet and then augmented the diet with one of the fiber supplements for 8 additional weeks. Incremental differences from placebo for low-density lipoprotein cholesterol were -8.8% for psyllium, -3.2% for methylcellulose (not significant), and +8.7% for calcium polycarbophil; and for total cholesterol the differences were -4.3% for psyllium (not significant), -1.4% for methylcellulose (not significant), and +5.9% for calcium polycarbophil. Compliance was 94% to 96%, and only mild gastrointestinal side effects were observed. In managing mild to moderate hypercholesterolemia, methylcellulose and calcium polycarbophil provide little or no additional benefit, while psyllium significantly enhances the American Heart Association diet effects.


[The health and risks of fishermen and crab catchers of Guanabara Bay].
The article discusses the health, risks and the work of fishermen and crab catchers in region of APA Guapimirim in Guanabara Bay. Fishermen and crab catchers are typical informal workers, they suffer from lack of protection and working guarantee. They are exposed to working risks day by day such as accidents with fishing boat, fishing equipment, the own fish, drowning, as well as a lot of radiation and climatic variation. There are still the weight and work overload, as well as the activities done at night that increase the potential risks. A sample of 100 fishermen and crab catchers had told by quantitative-qualitative research that it was possible to draw a profile of these workers. They are workers that have little schooling, 63% of these workers have incomplete elementary school and 12% are illiterate. 44% of these workers reported that they get diseases or health problems. These diseases are related to the weight overload, the long working hours and all situation of danger that they have on their work activities. As a conclusion the article identified a lot of difficulties of these workers while performing their work and realizes that is necessary to find measures to could improve their life and work conditions.


Operating parameters' effects on the outcome of pure and simple competition between two populations in configurations of two interconnected chemostats.
It is known from the literature that two microbial populations competing purely and simply for a common substrate in a spatially inhomogeneous environment may under certain conditions coexist in a steady state. This paper studies pure and simple competition between two microbial species in three alternate configurations of two interconnected ideal chemostats and focuses on the effects of the operating parameters-dilution rate, substrate concentration in the feed to the vessels, recycle ratio, and volume ratio of the two vessels, splitting ratio of the external feed to the chemostats-on the coexistence of the two competitors. It is shown that the coexistence steady state is practically feasible in the sense that it occurs in a finite domain of the operating parameters space. Theoretical and numerical results are presented, some of them in the form of operating diagrams projected on the two-dimensional subspace. A comparison of the three possible configurations is offered.


Common polymorphisms in the folate pathway predict efficacy of combination regimens containing methotrexate and sulfasalazine in early rheumatoid arthritis.
To study genetic polymorphisms in the folate pathway, a site of action of methotrexate (MTX) and sulfasalazine (SSZ), as predictors of efficacy of combination disease modifying antirheumatic drug (DMARD) regimens containing MTX and SSZ in early rheumatoid arthritis (RA). Ninety-eight Caucasian patients with early RA received MTX with SSZ, hydroxychloroquine, and folate according to a standardized protocol. Efficacy was evaluated using the Disease Activity Score (DAS28) and European League Against Rheumatism response criteria at 12 months. Nine polymorphisms in 7 genes of the folate pathway were studied. Response to therapy was associated with SLC19A1, MTR, and TYMS polymorphisms. Two favorable allele combinations associated with responder status at 12 months were identified: the MTR 2756A allele in combination with either the SLC19A1 80A allele or the TYMS 3R-del6 haplotype (multivariate analysis, p = 0.0002, p = 0.009 respectively). Seventy of the 72 patients with these allele combinations responded compared to 12/24 patients without [odds ratio (OR) 35.0, 95% confidence interval (CI) 6.9-176, p < 0.0001]. An association with remission (DAS28 < 2.6) was also observed (OR 3.4, 95% CI 1.1-10.0, p = 0.04). When analyzed over 3 years, both the change in DAS score from baseline and the final DAS scores were significantly higher and lower, respectively, with the favorable genotype group (p < 0.0001, p < 0.0001). Polymorphic variations in the MTR, SLC19A1, and TYMS genes were associated with better clinical response to combination DMARD regimens containing MTX and SSZ. Allele combinations of these genes may predict response to combination DMARD and assist in treatment decisions in patients with early RA.


Health preemption behind closed doors: trade agreements and fast-track authority.
Noncommunicable diseases result from consuming unhealthy products, including tobacco, which are promoted by transnational corporations. The tobacco industry uses preemption to block or reverse tobacco control policies. Preemption removes authority from jurisdictions where tobacco companies' influence is weak and transfers it to jurisdictions where they have an advantage. International trade agreements relocate decisions about tobacco control policy to venues where there is little opportunity for public scrutiny, participation, and debate. Tobacco companies are using these agreements to preempt domestic authority over tobacco policy. Other transnational corporations that profit by promoting unhealthy foods could do the same. "Fast-track authority," in which Congress cedes ongoing oversight authority to the President, further distances the public from the debate. With international agreements binding governments to prioritize trade over health, transparency and public oversight of the trade negotiation process is necessary to safeguard public health interests.


Rod-shape theranostic nanoparticles facilitate antiretroviral drug biodistribution and activity in human immunodeficiency virus susceptible cells and tissues.
Human immunodeficiency virus theranostics facilitates the development of long acting (LA) antiretroviral drugs (ARVs) by defining drug-particle cell depots. Optimal drug formulations are made possible based on precise particle composition, structure, shape and size. Through the creation of rod-shaped particles of defined sizes reflective of native LA drugs, theranostic probes can be deployed to measure particle-cell and tissue biodistribution, antiretroviral activities and drug retention. Methods: Herein, we created multimodal rilpivirine (RPV) 177lutetium labeled bismuth sulfide nanorods (177LuBSNRs) then evaluated their structure, morphology, configuration, chemical composition, biological responses and adverse reactions. Particle biodistribution was analyzed by single photon emission computed tomography (SPECT/CT) and laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) imaging. Results: Nanoformulated RPV and BSNRs-RPV particles showed comparable physicochemical and cell biological properties. Drug-particle pharmacokinetics (PK) and biodistribution in lymphoid tissue macrophages proved equivalent, one with the other. Rapid particle uptake and tissue distribution were observed, without adverse reactions, in primary blood-derived and tissue macrophages. The latter was seen within the marginal zones of spleen. Conclusions: These data, taken together, support the use of 177LuBSNRs as theranostic probes as a rapid assessment tool for PK LA ARV measurements.


TMPRSS2-ERG fusions linked to prostate cancer racial health disparities: A focus on Africa.
The androgen-regulated gene TMPRSS2 to the ETS transcription factor gene ERG fusion is the most common genomic alteration acquired during prostate tumorigenesis and biased toward men of European ancestry. In contrast, African American men present with more advanced disease, yet their tumors are less likely to acquire TMPRSS2-ERG. Data for Africa is scarce. RNA was made available for genomic analyses from 181 prostate tissue biopsy cores from Black South African men, 94 with and 87 without pathological evidence for prostate cancer. Reverse transcription polymerase chain reaction was used to screen for the TMPRSS2-ERG fusion, while transcript junction coordinates and isoform frequencies, including novel gene fusions, were determined using targeted RNA sequencing. Here we report a frequency of 13% for TMPRSS2-ERG in tumors from Black South Africans. Present in 12/94 positive versus 1/87 cancer negative prostate tissue cores, this suggests a 92.62% predictivity for a positive cancer diagnosis (P = 0.0031). At a frequency of almost half that reported for African Americans and roughly a quarter of that reported for men of European ancestry, acquisition of TMPRSS2-ERG appears to be inversely associated with aggressive prostate cancer. Further support was provided by linking the presence of TMPRSS2-ERG to low-grade disease in younger patients (P = 0.0466), with higher expressing distal ERG fusion junction coordinates. Only the second study of its kind for the African continent, we support a link between TMPRSS2-ERG status and prostate cancer racial health disparity beyond the borders of the United States. We call for urgent evaluation of androgen deprivation therapy within Africa.


Sex distribution of study samples reported in American Society of Biomechanics annual meeting abstracts.
Study samples should be appropriately selected to maximize generalizability of results. Excluding one sex from studies of conditions that affect both sexes is problematic and has received attention as a public policy issue in the United States, resulting in legislation and recommendations made by the National Institutes of Health to address this deficiency of study designs. It is unknown to what extent biomechanical studies have inappropriately excluded one sex. The objective of this study was to provide objective data on this question. A retrospective review of random samples of abstracts presented at American Society of Biomechanics annual meetings from 1983 to 2013 was conducted to assess reporting of sex of study samples and whether the study samples were approximately balanced with respect to sex. We did not find a statistically significant increasing trend in the percentage of abstracts reporting sex over time. However, increasing trends were noted in the percentage of abstracts including both sexes (p < 0.05) and percentage of abstracts having an "approximately balanced" study sample containing 50 ± 20% females (p > 0.05). In 2013 the percentage of abstracts reporting studies having approximately balanced study samples was only 28%, far from the ideal level of 100%. While there has been modest change since 1983, there remains significant room for improvement in the reporting and composition of experimental studies reported at American Society of Biomechanics annual meetings.


Microstructural evolution and mechanical properties of biomedical Co-Cr-Mo alloy subjected to high-pressure torsion.
The effects of severe plastic deformation through high-pressure torsion (HPT) on the microstructure and tensile properties of a biomedical Co-Cr-Mo (CCM) alloy were investigated. The microstructure was examined as a function of torsional rotation number, N and equivalent strain, εeq in the HPT processing. Electron backscatter diffraction analysis (EBSD) shows that a strain-induced martensitic transformation occurs by the HPT processing. Grain diameter decreases with increasing εeq, and the HPT-processed alloy (CCMHPT) for εeq=45 exhibits an average grain diameter of 47nm, compared to 70μm for the CCM alloy before HPT processing. Blurred and wavy grain boundaries with low-angle of misorientation in the CCMHPT sample for εeq<45 become better-defined grain boundaries with high-angle of misorientation after HPT processing for εeq=45. Kernel average misorientation (KAM) maps from EBSD indicate that KAM inside grains increases with εeq for εeq<45, and then decreases for εeq=45. The volume fraction of the ε (hcp) phase in the CCMHPT samples slightly increases at εeq=9, and decreases at εeq=45. In addition, the strength of the CCMHPT samples increases at εeq=9, and then decrease at εeq=45. The decrease in the strength is attributed to the decrease in the volume fraction of ε phase, annihilation of dislocations, and decrease in strain in the CCMHPT sample processed at εeq=45 by HPT.


Antiandrogenic actions of medroxyprogesterone acetate on epithelial cells within normal human breast tissues cultured ex vivo.
Medroxyprogesterone acetate (MPA), a component of combined estrogen-progestin therapy (EPT), has been associated with increased breast cancer risk in EPT users. MPA can bind to the androgen receptor (AR), and AR signaling inhibits cell growth in breast tissues. Therefore, the aim of this study was to investigate the potential of MPA to disrupt AR signaling in an ex vivo culture model of normal human breast tissue. Histologically normal breast tissues from women undergoing breast surgical operation were cultured in the presence or in the absence of the native AR ligand 5α-dihydrotestosterone (DHT), MPA, or the AR antagonist bicalutamide. Ki67, bromodeoxyuridine, B-cell CLL/lymphoma 2 (BCL2), AR, estrogen receptor α, and progesterone receptor were detected by immunohistochemistry. DHT inhibited the proliferation of breast epithelial cells in an AR-dependent manner within tissues from postmenopausal women, and MPA significantly antagonized this androgenic effect. These hormonal responses were not commonly observed in cultured tissues from premenopausal women. In tissues from postmenopausal women, DHT either induced or repressed BCL2 expression, and the antiandrogenic effect of MPA on BCL2 was variable. MPA significantly opposed the positive effect of DHT on AR stabilization, but these hormones had no significant effect on estrogen receptor α or progesterone receptor levels. In a subset of postmenopausal women, MPA exerts an antiandrogenic effect on breast epithelial cells that is associated with increased proliferation and destabilization of AR protein. This activity may contribute mechanistically to the increased risk of breast cancer in women taking MPA-containing EPT.


The Role of Anti-Drug Antibodies in the Pharmacokinetics, Disposition, Target Engagement, and Efficacy of a GITR Agonist Monoclonal Antibody in Mice.
Administration of biologics to enhance T-cell function is part of a rapidly growing field of cancer immunotherapy demonstrated by the unprecedented clinical success of several immunoregulatory receptor targeting antibodies. While these biologic agents confer significant anti-tumor activity through targeted immune response modulation, they can also elicit broad immune responses potentially including the production of anti-drug antibodies (ADAs). DTA-1, an agonist monoclonal antibody against GITR, is a highly effective anti-tumor treatment in preclinical models. We demonstrate that repeated dosing with murinized DTA-1 (mDTA-1) generates ADAs with corresponding reductions in drug exposure and engagement of GITR on circulating CD3(+) CD4(+) T cells, due to rapid hepatic drug uptake and catabolism. Mice implanted with tumors after induction of preexisting mDTA-1 ADA show no anti-tumor efficacy when given 3 mg/kg mDTA-1, an efficacious dose in naive mice. Nonetheless, increasing mDTA-1 treatment to 30 mg/kg in ADA-positive mice restores mDTA-1 exposure and GITR engagement on circulating CD3(+) CD4(+) T cells, thereby partially restoring anti-tumor efficacy. Formation of anti-mDTA-1 antibodies and changes in drug exposure and disposition does not occur in GITR(-/-) mice, consistent with a role for GITR agonism in humoral immunity. Finally, the administration of muDX400, a murinized monoclonal antibody against the checkpoint inhibitor PD-1, dosed alone or combined with mDTA-1 did not result in reduced muDX400 exposure, nor did it change the nature of the anti-mDTA-1 response. This indicates that anti-GITR immunogenicity may not necessarily impact the pharmacology of coadministered monoclonal antibodies, supporting combination immunomodulatory strategies.


Objective Structured Clinical Examinations: a guide to development and implementation in orthopaedic residency.
Objective Structured Clinical Examinations (OSCEs) have been used extensively in medical schools and residency programs to evaluate various skills, including the six core competencies outlined by the Accreditation Council for Graduate Medical Education (ACGME). Orthopaedic surgery residency programs will be required by the ACGME to assess residents on core competencies in the Milestone Project. Thus, it is important that evaluations be made in a consistent, objective manner. Orthopaedic residency programs can also use simulation models in the examination to accurately and objectively assess residents' skills as they progress through training. The use of these models will become essential as resident work hours are decreased and opportunities to observe skills become more limited. In addition to providing a method to assess competency, OSCEs are a valuable tool for residents to develop and practice important clinical skills. Here, we describe a method for developing a successful OSCE for use in orthopaedic surgical resident training.


Environmental Risks Perception Among Citizens Living Near Industrial Plants: A Cross-Sectional Study.
The present work is a cross-sectional study aimed at assessing the risk perception and evaluating the community outrage linked to environmental factors among a self-selected sample of citizens living in an area characterized by the presence of industrial structures of high emotional impact. An anonymous questionnaire was administered to the population by publishing a Google form URL code in local and regional newspapers and via social media. The resulting data were entered on Excel and analyzed. Qualitative variables were summarized with absolute and relative (percentage) frequencies. The results showed that the event that causes the greatest worry was air pollution, with 92.6% of the respondents stating that they perceived the problem as "very" or "quite" worrying. Furthermore, all the health problems investigated in relation to environmental quality aroused concern among the interviewees, with 93.1% believing there was a cause-effect relationship between environmental quality and health. Overall, as other studies had previously underlined, the survey shows that the perceived risks are not always in line with the real ones, Thus, it is imperative to articulate interventions aimed at offering the population objective tools to enable them to interpret the risks themselves. In this regard, a fundamental role is played by adequate communication between the competent bodies and political decision-makers and the population.


Changing leaders: the board's role in CEO succession ... roundtable discussion.
The selection of a CEO is one of the most important- and risky-events in the life of any company. Yet the way CEOs are chosen remains little discussed and little understood. The succession process has traditionally unfolded behind closed doors--some observers have even likened it to the election of a pope. To shed light on what works and what doesn't in CEO succession, the authors lead a roundtable discussion with five distinguished corporate directors: Philip Caldwell, George D. Kennedy, G. G. Michelson, Henry Wendt, and Alfred M. Zeien. Collectively, the five directors have participated in dozens of successions, either as board members or as CEOs. In a lively and frank exchange of views and experiences, the roundtable participants explore a broad range of questions: What can a company do to ensure a successful succession? How should management-development and succession processes be managed? How should the board work with the sitting chief executive during the process? What makes for a strong CEO candidate? When should outside candidates be considered? How much competition should be encouraged among potential CEO candidates? What role should executive search firms play? What role should former CEOs play after they are succeeded? Their conversation illuminates a corporate challenge that is as difficult as it is important.