Evaluation of computerized decision support for oral anticoagulation management based in primary care.
Increasing indications for oral anticoagulation has led to pressure on general practices to undertake therapeutic monitoring. Computerized decision support (DSS) has been shown to be effective in hospitals for improving clinical management. Its usefulness in primary care has previously not been investigated. To test the effectiveness of using DSS for oral anticoagulation monitoring in primary care by measuring the proportions of patients adequately controlled, defined as within the appropriate therapeutic range of International Normalised Ratio (INR). All patients receiving warfarin from two Birmingham inner city general practices were invited to attend a practice-based anticoagulation clinic. In practice A all patients were managed using DSS. In practice B patients were randomized to receive dosing advice either through DSS or through the local hospital laboratory. Clinical outcomes, adverse events and patient acceptability were recorded. Forty-nine patients were seen in total. There were significant improvements in INR control from 23% to 86% (P > 0.001) in the practice where all patients received dosing through DSS. In the practice where patients were randomized to either DSS or hospital dosing, logistic regression showed a significant trend for improvement in intervention patients which was not apparent in the hospital-dosed patients (P < 0.001). Mean recall times were significantly extended in patients who were dosed by the practice DSS through the full 12 months (24 days to 36 days) (P = 0.033). Adverse events were comparable between hospital and practice-dosed patients, although a number of esoteric events occurred. Patient satisfaction with the practice clinics was high. Computerized DSS enables the safe and effective transfer of anticoagulation management from hospital to primary care and may result in improved patient outcome in terms of the level of control, frequency of review and general acceptability.


Complete nucleotide sequence of a unique HLA class I C locus product expressed on the human choriocarcinoma cell line BeWo.
We have used Northern blot analysis to detect mRNA from class I HLA genes in the human choriocarcinoma cell line BeWo, which has been previously shown to express an atypical HLA class I molecule, in the absence of HLA A and B. Hybridization was seen with three class I DNA probes, the strongest being seen with the probe pC800, which corresponds to an 800-bp section of the Cw3 gene. We have made cDNA libraries from BeWo cells and screened for positive clones by using class I DNA probes. Of the clones isolated, we determined the complete sequence of one and partial sequence of five shorter clones. They all code for an identical C locus-related product, which does not correspond to published C locus sequences.


The capacity of transvaginal hydrolaparoscopy versus hysterosalpingography to diagnose tubal pathology in the work-up of subfertile women, a randomised clinical trial.
To assess the capacity of transvaginal hydrolaparoscopy (THL) versus hysterosalpingography (HSG) as a primary tool to diagnose tubal pathology. We performed a multicenter RCT (NTR3462) in 4 teaching hospitals in the Netherlands, comparing THL and HSG as first line tubal test in subfertile women. The primary outcome of the trial was cumulative live birth rate at 24 months. Here, we present the secondary outcomes, the diagnostic findings of both THL and HSG as well as performance defined as failures, complications and pain- and acceptability scores. Between May 2013 and October 2016, we allocated 149 women to THL and 151 to HSG, of which 17 women in the THL group (11.4%) and 12 in the HSG group (7.9%) conceived naturally before the scheduled procedure, while 13 HSGs and 5 THLs were not performed for other reasons (withdrawal of informed consent, not willing to undergo tubal testing and protocol violations). A total of 119 THLs and 134 HSGs were carried out. Failures were seen more in the THL group (n = 8, 5.6%) than in the HSG group (n = 1, 0.7%) (p = 0.014). Complications did not differ significantly between the groups (THL n = 4; 2.8% vs HSG n = 1; 0.7%) (p = 0.20). Bilateral tubal occlusion was detected in one versus three women (0.9% versus 2.2%) of the THL group and HSG group, while unilateral tubal occlusion was detected in seven (6.2%) versus eight (5.9%) women, respectively. Normal findings were seen in 96 (79.3%) women randomised to THL and in 119 (87.5%) in women randomised for HSG (RR 0.91 95%CI 0.81-1.01, p = 0.08). The pain score was significantly less for THL (VAS 4.7 (SD: 2.5)) than for HSG (VAS 5.4 (SD:2.5)) (p 0.038). The acceptability rate of THL and was high and comparable. THL and HSG have a comparable capacity in diagnosing tubal pathology with comparable performance in safety, pain and acceptability.


Sulcal effacement with preserved gray-white junction: a sign of reversible ischemia.
Sulcal effacement with preserved underlying gray-white matter junction (isolated sulcal effacement [ISE]) in acute ischemic stroke may not represent irreversible parenchymal injury. We aimed to evaluate the frequency and significance of ISE in patients with large vessel occlusion acute ischemic stroke. Consecutive acute ischemic stroke patients with middle cerebral artery M1 or internal carotid artery terminus occlusions who underwent computed tomography angiogram/perfusion followed by intra-arterial therapy were screened for ISE. Out of the 568 patients who underwent intra-arterial therapy between March 2011 and September 2014, 108 fulfilled inclusion criteria. ISE was present in 8 (7.4%) patients (age 55.7±10.5 years, 6 female, baseline National Institutes of Health Stroke Scale 16.1±3.8, 5 middle cerebral artery-M1, and 3 internal carotid artery terminus occlusions). Computed tomography angiogram revealed engorged/dilated leptomeningeal vessels obliterating the sulci within the areas of effacement, whereas computed tomography perfusion indicated normal-to-increased cerebral blood volume and prolonged Tmax in all patients. Modified treatment in cerebral ischemia (mTICI) 2b-3 reperfusion was achieved in all patients. Follow-up imaging confirmed no infarct in the ISE area in all patients, and 5 (62%) had modified Rankin Scale 0 to 2 at 3 months. Sulcal effacement with preserved gray-white delineation is occasionally visualized in patients with proximal occlusion strokes, relates to robust leptomeningeal collaterals, and indicates preserved underlying parenchyma. ISE should not be used to exclude patients from thrombectomy.


Tailored exercise management (TEMPO) versus usual care for people aged 80 years or older with hip/knee osteoarthritis: study protocol for a feasibility randomised controlled trial.
Exercise is recommended for all people with osteoarthritis. However, these recommendations are based on randomised clinical trials including people with an average age between 60 and 70 years, and these findings cannot reliably be generalised to people aged 80 years or older. Rapid loss of muscle occurs after 70 years of age, and older people are more likely to also have other health conditions that contribute to difficulties with daily activities and impact on their response to exercise. To improve care for people aged 80 or older with osteoarthritis, it is thought that a tailored exercise intervention targeting both osteoarthritis and any other health conditions they have, may be needed. The aim of this study will be to test if it is possible to conduct a randomised controlled trial (RCT) for people over 80 years of age with hip/knee osteoarthritis of a tailored exercise intervention. A multicentre, parallel, 2-group, feasibility RCT with embedded qualitative study, conducted in ≥ 3 UK NHS physiotherapy outpatient services. Participants (n ≥ 50) with clinical knee and/or hip osteoarthritis and ≥ 1 comorbidity will be recruited by screening referrals to participating NHS physiotherapy outpatient services, via screening of general practice records and via identification of eligible individuals from a cohort study run by our research group. Participants will be randomised (computer-generated: 1:1) to receive either: a 12-week education and tailored exercise intervention (TEMPO); or usual care and written information. The primary feasibility objectives are to estimate: (1) ability to screen and recruit eligible participants; (2) retention of participants, measured by the proportion of participants who provide outcome data at 14-week follow-up. Secondary quantitative objectives are to estimate: (1) participant engagement assessed by physiotherapy session attendance and home exercise adherence; (2) sample size calculation for a definitive RCT. One-to-one semi-structured interviews will explore the experiences of trial participants and physiotherapists delivering the TEMPO programme. Progression criteria will be used to determine whether a definitive trial to evaluate the clinical and cost-effectiveness of the TEMPO programme is considered feasible with or without modifications to the intervention or trial design. ISRCTN75983430. Registered 3/12/2021. https://www.isrctn.com/ISRCTN75983430.


Early life-history consequences of growth-hormone transgenesis in rainbow trout reared in stream ecosystem mesocosms.
There is persistent commercial interest in the use of growth modified fishes for shortening production cycles and increasing overall food production, but there is concern over the potential impact that transgenic fishes might have if ever released into nature. To explore the ecological consequences of transgenic fish, we performed two experiments in which the early growth and survival of growth-hormone transgenic rainbow trout (Oncorhynchus mykiss) were assessed in naturalized stream mesocosms that either contained predators or were predator-free. We paid special attention to the survival bottleneck that occurs during the early life-history of salmonids, and conducted experiments at two age classes (first-feeding fry and 60 days post-first-feeding) that lie on either side of the bottleneck. In the late summer, the first-feeding transgenic trout could not match the growth potential of their wild-type siblings when reared in a hydrodynamically complex and oligotrophic environment, irrespective of predation pressure. Furthermore, overall survival of transgenic fry was lower than in wild-type (transgenic = 30% without predators, 8% with predators; wild-type = 81% without predators, 31% with predators). In the experiment with 60-day old fry, we explored the effects of the transgene in different genetic backgrounds (wild versus domesticated). We found no difference in overwinter survival but significantly higher growth by transgenic trout, irrespective of genetic background. We conclude that the high mortality of GH-transgenic trout during first-feeding reflects an inability to sustain the basic metabolic requirements necessary for life in complex, stream environments. However, when older, GH-transgenic fish display a competitive advantage over wild-type fry, and show greater growth and equal survival as wild-type. These results demonstrate how developmental age and time of year can influence the response of genotypes to environmental conditions. We therefore urge caution when extrapolating the results of GH-transgenesis risk assessment studies across multiple life-history or developmental stages.


Plasma proteome and metabolome characterization of an experimental human thyrotoxicosis model.
Determinations of thyrotropin (TSH) and free thyroxine (FT4) represent the gold standard in evaluation of thyroid function. To screen for novel peripheral biomarkers of thyroid function and to characterize FT4-associated physiological signatures in human plasma we used an untargeted OMICS approach in a thyrotoxicosis model. A sample of 16 healthy young men were treated with levothyroxine for 8 weeks and plasma was sampled before the intake was started as well as at two points during treatment and after its completion, respectively. Mass spectrometry-derived metabolite and protein levels were related to FT4 serum concentrations using mixed-effect linear regression models in a robust setting. To compile a molecular signature discriminating between thyrotoxicosis and euthyroidism, a random forest was trained and validated in a two-stage cross-validation procedure. Despite the absence of obvious clinical symptoms, mass spectrometry analyses detected 65 metabolites and 63 proteins exhibiting significant associations with serum FT4. A subset of 15 molecules allowed a robust and good prediction of thyroid hormone function (AUC = 0.86) without prior information on TSH or FT4. Main FT4-associated signatures indicated increased resting energy expenditure, augmented defense against systemic oxidative stress, decreased lipoprotein particle levels, and increased levels of complement system proteins and coagulation factors. Further association findings question the reliability of kidney function assessment under hyperthyroid conditions and suggest a link between hyperthyroidism and cardiovascular diseases via increased dimethylarginine levels. Our results emphasize the power of untargeted OMICs approaches to detect novel pathways of thyroid hormone action. Furthermore, beyond TSH and FT4, we demonstrated the potential of such analyses to identify new molecular signatures for diagnosis and treatment of thyroid disorders. This study was registered at the German Clinical Trials Register (DRKS) [DRKS00011275] on the 16th of November 2016.


Solid-core photonic bandgap fibers for cladding-pumped Raman amplification.
Cladding-pumped solid-core photonic bandgap Raman fiber amplifiers are analyzed theoretically as possible candidates for power scaling. An example fiber design with a mode field diameter of 46 µm and a cladding diameter of 250 µm is calculated to exhibit 0.12 dB/km of confinement loss at the first Stokes wavelength and >10 dB/m at the second Stokes wavelength for a pump wavelength of 1.567 µm while maintaining low loss and large mode area in realistic coiling configurations. A Raman amplifier based on this fiber with 85 kW of output power, 78% optical conversion efficiency, a maximum heat load of 130 W/m, and a length of 235 m is simulated.


Chronic lymphocytic inflammation specifies the organ tropism of prions.
Prions typically accumulate in nervous and lymphoid tissues. Because proinflammatory cytokines and immune cells are required for lymphoid prion replication, we tested whether inflammatory conditions affect prion pathogenesis. We administered prions to mice with five inflammatory diseases of the kidney, pancreas, or liver. In all cases, chronic lymphocytic inflammation enabled prion accumulation in otherwise prion-free organs. Inflammatory foci consistently correlated with lymphotoxin up-regulation and ectopic induction of FDC-M1+ cells expressing the normal cellular prion protein PrPC. By contrast, inflamed organs of mice lacking lymphotoxin-alpha or its receptor did not accumulate the abnormal isoform PrPSc, nor did they display infectivity upon prion inoculation. By expanding the tissue distribution of prions, chronic inflammatory conditions may act as modifiers of natural and iatrogenic prion transmission.


Long-term oncologic outcomes of laparoscopic radical nephrectomy for kidney cancer resection: Dundee cohort and metaanalysis of observational studies.
The long-term oncologic outcome of laparoscopic radical nephrectomy compared with that of open radical nephrectomy remains unclear. A few case series with follow-up periods longer than 5 years are reported in the literature. The existing literature is focused primarily on early and intermediate outcomes of laparoscopic radical nephrectomy. This study aimed to assess the outcome of laparoscopic radical nephrectomy for localized disease compared with open surgery. The search strategy was designed to identify observational and experimental studies conducted in any country that investigated the long-term oncologic outcomes of laparoscopic radical nephrectomy compared with open surgical resection, published in any language. We searched the MEDLINE (1996 to May 2010), EMBASE (1996 to May 2010), and Cochrane databases using the OVID interrogation software. The study included 77 men from the Dundee cohort referred for clinically localized renal cell carcinoma who underwent open or laparoscopic radical nephrectomy between January 1998 and 2004, with at least 5 years of follow-up evaluation for each. These men were included in a metaanalysis of observational studies reporting on 438 patients with a mean or median follow-up period of 5 years. The data was analyzed using Minitab statistical software and Cochrane RevMan 5.4 using the random model. The five studies (including the Dundee cohort) investigating the effects of the laparoscopic approach on renal cancer management showed no significant differences in 5 years survival between laparoscopic and open surgical approaches for the resection of kidney cancer. The resulting pooled odds ratio (OR) did not differ markedly between the two groups (pooled OR, 0.82; 95% confidence interval [CI], 0.48-1.39). Similar to overall survival, the laparoscopic and open surgical approaches for renal cancer surgery did not differ significantly (Figs. 4, 5). The pooled ORs for the two outcomes were 0.76 (955 CI, 0.36-1.56) for laparoscopic surgery and 0.73 (95% CI, 0.32-1.69) for open surgery. The quality of the studies was poor. The reported designs of the studies were prone to selection, confounding, and reporting biases. The current retrospective data (observational studies) comparing long-term oncologic outcomes between laparoscopic and open radical nephrectomy did not demonstrate any significant differences during a follow-up period of 5 years.


In vitro antioxidant and anticataractogenic potential of silver nanoparticles biosynthesized using an ethanolic extract of Tabernaemontana divaricata leaves.
Silver nanoparticles (AgNPs) have been found useful in biological systems and in medicine since they possess a large surface area to volume ratio, which confers on them several unique properties. In the present study, AgNPs that had been biosynthesized using an ethanolic extract of Tabernaemontana divaricata leaf were evaluated for putative antioxidant potential and efficacy in preventing experimental in-vitro selenite-induced opacification of the ocular lens (cataractogenesis). The antioxidant potential of the AgNPs was evaluated in-vitro by looking for radical-scavenging activity on 1,1-diphenyl-2-picrylhydrazyl (DPPH) and hydrogen peroxide (H2O2) free radicals as well as by determining reducing power. The anticataractogenic potential of the AgNPs was evaluated in an in-vitro model of selenite-induced cataractogenesis in five groups of Wistar rat lenses cultured in Dulbecco's modified Eagle's medium (DMEM) for 24h: Group I lenses (negative control) were cultured in DMEM alone; Group II lenses were exposed to sodium selenite alone (100μM); Group III lenses were exposed simultaneously to sodium selenite and the T. divaricata extract (250μg/ml); Group IV lenses were exposed simultaneously to sodium selenite and the biosynthesized AgNPs (125μg/ml); and Group V lenses were exposed to the AgNPs alone. In these lenses, gross morphological changes, as well as activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione-S-transferase (GST), and levels of reduced glutathione (GSH) and malondialdehyde (MDA), were determined. In-vitro, the AgNPs (which were spherical in shape with an average diameter ranging from 15 to 50nm) showed potent and concentration-dependent radical-scavenging activity on DPPH and H2O2 free radicals as well as reducing power. The gross morphological changes seen in the cultured rat lenses were: all eight control (Group I) lenses remained transparent; dense opacification was noted in all eight selenite-challenged untreated (Group II) lenses; in selenite-challenged, simultaneously T. divaricata extract-treated (Group III) lenses, no opacification occurred in seven of eight (87.5%) lenses and only minimal opacification in one (12.5%) lens; all the eight Group IV (selenite-challenged, simultaneously AgNPs-treated) lenses did not show any opacification; and all the eight Group V lenses (exposed to AgNPs alone) remained as transparent as control lenses. The mean activities of CAT, SOD, GPx and GST, and the mean levels of GSH, were significantly (p<0.05) lower in Group II lenses than those in Groups I, III, IV and V lenses, while the mean MDA level was significantly (p<0.05) higher in Group II lenses than those in Groups I, III, IV and V lenses; oxidative damage possibly occurred in Group II lenses, whereas this appears to have been prevented in Groups III and IV lenses. These observations suggest that the T. divaricata leaf ethanolic extract, and also the AgNPs biosynthesized using the T. divaricata extract, possess effective in-vitro antioxidant activity and the potential to prevent experimental selenite-induced opacification in cultured Wistar rat lenses.


Morphine down-regulates melanocortin-4 receptor expression in brain regions that mediate opiate addiction.
Melanocortin peptides are reported to antagonize opiate dependence and tolerance, but the neural substrates underlying these actions are unknown. In this study, we characterize the rat melanocortin-4 receptor (MC4-R) and demonstrate that this receptor is regulated by opiate administration. The rat MC4-R is 95% identical to the human MC4-R, and the potency of melanocortin peptides to stimulate cAMP production is similar in these two species homologs (alpha-melanocyte-stimulating hormone = adrenocorticotropic hormone > gamma-melanocyte-stimulating hormone). Expression of MC4-R mRNA was found to be enriched in the striatum, nucleus accumbens, and periaque-ductal gray, all of which are regions implicated in the behavioral effects of opiates. In contrast, MC1-, MC3-, and MC5-R are expressed at very low or undetectable levels in these brain regions. Chronic administration of morphine (5 days) resulted in a time-dependent down-regulation of MC4-R mRNA expression in the striatum and periaqueductal gray. Expression of MC4-R mRNA was also decreased in the nucleus accumbens/ olfactory tubercle, but this effect was observed after 1 or 3 days of morphine treatment. In the striatum, the reduction of MC4-R mRNA was accompanied by a concomitant decrease in melanocortin receptor levels, shown by quantitative radioligand binding and autoradiography. In contrast, morphine administration did not influence levels of MC4-R mRNA in several other brain regions, including frontal cortex, olfactory bulb, hypothalamus, and ventral tegmentum/substantia nigra. In light of previous findings that melanocortins antagonize opiate self-administration, analgesic tolerance, and physical dependence, we hypothesize that decreased melanocortin function, via down-regulation of MC4-R expression, may contribute to the development of these opiate-induced behaviors.


The impact of evidence reliability on sensitivity and bias in decision confidence.
Human observers effortlessly and accurately judge their probability of being correct in their decisions, suggesting that metacognitive evaluation is an integral part of decision making. It remains a challenge for most models of confidence, however, to explain how metacognitive judgments are formed and which internal signals influence them. While the decision-making literature has suggested that confidence is based on privileged access to the evidence that gives rise to the decision itself, other lines of research on confidence have commonly taken the view of a multicue model of confidence. The present study aims at manipulating one such cue: the perceived reliability of evidence supporting an initial decision. Participants made a categorical judgment of the average color of an array of eight colored shapes, for which we critically manipulated both the distance of the mean color from the category boundary (evidence strength) and the variability of colors across the eight shapes (evidence reliability). Our results indicate that evidence reliability has a stronger impact on confidence than evidence strength. Specifically, we found that evidence reliability affects metacognitive readout, the mapping from subjectively experienced certainty to expressed confidence, allowing participants to adequately adjust their confidence ratings to match changes in objective task performance across conditions. (PsycINFO Database Record


Developmental Environment Effects on Sexual Selection in Male and Female Drosophila melanogaster.
The developmental environment can potentially alter the adult social environment and influence traits targeted by sexual selection such as body size. In this study, we manipulated larval density in male and female Drosophila melanogaster, which results in distinct adult size phenotypes-high (low) densities for small (large) adults-and measured sexual selection in experimental groups consisting of adult males and females from high, low, or a mixture of low and high larval densities. Overall, large adult females (those reared at low larval density) had more matings, more mates and produced more offspring than small females (those reared at high larval density). The number of offspring produced by females was positively associated with their number of mates (i.e. there was a positive female Bateman gradient) in social groups where female size was experimentally varied, likely due to the covariance between female productivity and mating rate. For males, we found evidence that the larval environment affected the relative importance of sexual selection via mate number (Bateman gradients), mate productivity, paternity share, and their covariances. Mate number and mate productivity were significantly reduced for small males in social environments where males were of mixed sizes, versus social environments where all males were small, suggesting that social heterogeneity altered selection on this subset of males. Males are commonly assumed to benefit from mating with large females, but in contrast to expectations we found that in groups where both the male and female size varied, males did not gain more offspring per mating with large females. Collectively, our results indicate sex-specific effects of the developmental environment on the operation of sexual selection, via both the phenotype of individuals, and the phenotype of their competitors and mates.


Deep learning as a predictive tool for fetal heart pregnancy following time-lapse incubation and blastocyst transfer.
Can a deep learning model predict the probability of pregnancy with fetal heart (FH) from time-lapse videos? We created a deep learning model named IVY, which was an objective and fully automated system that predicts the probability of FH pregnancy directly from raw time-lapse videos without the need for any manual morphokinetic annotation or blastocyst morphology assessment. The contribution of time-lapse imaging in effective embryo selection is promising. Existing algorithms for the analysis of time-lapse imaging are based on morphology and morphokinetic parameters that require subjective human annotation and thus have intrinsic inter-reader and intra-reader variability. Deep learning offers promise for the automation and standardization of embryo selection. A retrospective analysis of time-lapse videos and clinical outcomes of 10 638 embryos from eight different IVF clinics, across four different countries, between January 2014 and December 2018. The deep learning model was trained using time-lapse videos with known FH pregnancy outcome to perform a binary classification task of predicting the probability of pregnancy with FH given time-lapse video sequence. The predictive power of the model was measured using the average area under the curve (AUC) of the receiver operating characteristic curve over 5-fold stratified cross-validation. The deep learning model was able to predict FH pregnancy from time-lapse videos with an AUC of 0.93 [95% CI 0.92-0.94] in 5-fold stratified cross-validation. A hold-out validation test across eight laboratories showed that the AUC was reproducible, ranging from 0.95 to 0.90 across different laboratories with different culture and laboratory processes. This study is a retrospective analysis demonstrating that the deep learning model has a high level of predictability of the likelihood that an embryo will implant. The clinical impacts of these findings are still uncertain. Further studies, including prospective randomized controlled trials, are required to evaluate the clinical significance of this deep learning model. The time-lapse videos collected for training and validation are Day 5 embryos; hence, additional adjustment would need to be made for the model to be used in the context of Day 3 transfer. The high predictive value for embryo implantation obtained by the deep learning model may improve the effectiveness of previous approaches used for time-lapse imaging in embryo selection. This may improve the prioritization of the most viable embryo for a single embryo transfer. The deep learning model may also prove to be useful in providing the optimal order for subsequent transfers of cryopreserved embryos. D.T. is the co-owner of Harrison AI that has patented this methodology in association with Virtus Health. P.I. is a shareholder in Virtus Health. S.C., P.I. and D.G. are all either employees or contracted with Virtus Health. D.G. has received grant support from Vitrolife, the manufacturer of the Embryoscope time-lapse imaging used in this study. The equipment and time for this study have been jointly provided by Harrison AI and Virtus Health.


Tillage and manure application effects on mineral nitrogen leaching from seasonally frozen soils.
Land application of manure is a common practice in the Upper Midwest of the United States. Recently, there have been concerns regarding the effect of this practice on water quality, especially when manure is applied during winter over frozen soils. A study undertaken on a Rozetta silt loam (fine-silty, mixed, superactive, mesic Typic Hapludalfs) at Lancaster, WI, evaluated the effects of tillage and timing of manure application on surface and subsurface water quality. The daily scrape and haul liquid dairy manure was applied either in the fall (before snow) or in winter (over snow with frozen soil underneath) to be compared with no manure under two tillage systems (no-till and chisel-plowing). In this paper, we report results on the effects of the above treatments on mineral N leaching. Percolation and mineral N leaching during the nongrowing season were, respectively, 72 and 78% of the annual losses, mainly because of the absence of plant water and N uptake. Percolation was generally higher from no-till compared with chisel-plow but there was no significant effect of tillage on mineral N concentration of the leachate or mineral N losses via leaching. Mineral N leaching was statistically higher from the manure-applied vs. no-manure treatment, but there was no difference between winter-applied manure and no-manure treatments. There were significant tillage by manure interactions with fall manure application followed by chisel-plowing resulting in highest N leaching losses. Averaged over the two years, N leaching rates were 52, 38, and 28 kg N ha(-1) yr(-1) from fall-applied, winter-applied, and no-manure treatments, respectively. These results show that there is substantial N leaching from these soils even when no fertilizer or manure is applied. Furthermore, fall-applied manure followed by fall tillage significantly increases N leaching due to enhanced mineralization of both soil and manure organic N.


Electrical manipulation of magnetization reversal in a ferromagnetic semiconductor.
We report electrical manipulation of magnetization processes in a ferromagnetic semiconductor, in which low-density carriers are responsible for the ferromagnetic interaction. The coercive force HC at which magnetization reversal occurs can be manipulated by modifying the carrier density through application of electric fields in a gated structure. Electrically assisted magnetization reversal, as well as electrical demagnetization, has been demonstrated through the effect. This electrical manipulation offers a functionality not previously accessible in magnetic materials and may become useful for reversing magnetization of nanoscale bits for ultrahigh-density information storage.


FOOTSTEP: a randomized controlled trial investigating the clinical and cost effectiveness of a patient self-management program for basic foot care in the elderly.
Podiatry (chiropody) services are one of the most frequently requested services in primary care. The elderly are given priority access to podiatry services in the UK blocking access for other priority groups. To evaluate the clinical and cost-effectiveness of a self-management program as a means of managing nonurgent demands for podiatry services by the elderly without compromising foot-related disability. Randomized clinical trial with blinded 6-month follow-up and economic evaluation. People aged 60+ seeking self-initiated or primary referred podiatric consultation were screened. Five hundred ninety-nine were excluded on the basis of health status, and 259 refused to participate or did not attend initially. Seventy-eight were randomized to receive a self-management program, and 75 usual care. The main outcome measure was foot disability, as measured by the Manchester Foot Disability Questionnaire. At 6 months, self-management program participants had lower foot disability scores than the usual care group (difference between scores -1, 95% C.I. -2, 0), and returned for fewer treatments within the 6-month study period (39 vs. 92 treatments). The cost per patient for the self-management program (pound sterling 10.92) was found to be the same as for usual care (pound sterling 10.71), but this included the cost of nail care packs. In this group a self-care program for routine foot care did not compromise therapeutic outcomes, and may be more cost effective in the long term. Further work is required to extend self-management programs to other target groups, such as people with diabetes at low risk for foot problems.


The kinetics of inhibitor production resulting from hydrothermal deconstruction of wheat straw studied using a pressurised microwave reactor.
The use of a microwave synthesis reactor has allowed kinetic data for the hydrothermal reactions of straw biomass to be established from short times, avoiding corrections required for slow heating in conventional reactors, or two-step heating. Access to realistic kinetic data is important for predictions of optimal reaction conditions for the pretreatment of biomass for bioethanol processes, which is required to minimise production of inhibitory compounds and to maximise sugar and ethanol yields. The gravimetric loss through solubilisation of straw provided a global measure of the extent of hydrothermal deconstruction. The kinetic profiles of furan and lignin-derived inhibitors were determined in the hydrothermal hydrolysates by UV analysis, with concentrations of formic and acetic acid determined by HPLC. Kinetic analyses were either carried out by direct fitting to simple first order equations or by numerical integration of sequential reactions. A classical Arrhenius activation energy of 148 kJmol-1 has been determined for primary solubilisation, which is higher than the activation energy associated with historical measures of reaction severity. The gravimetric loss is primarily due to depolymerisation of the hemicellulose component of straw, but a minor proportion of lignin is solubilised at the same rate and hence may be associated with the more hydrophilic lignin-hemicellulose interface. Acetic acid is liberated primarily from hydrolysis of pendant acetate groups on hemicellulose, although this occurs at a rate that is too slow to provide catalytic enhancement to the primary solubilisation reactions. However, the increase in protons may enhance secondary reactions leading to the production of furans and formic acid. The work has suggested that formic acid may be formed under these hydrothermal conditions via direct reaction of sugar end groups rather than furan breakdown. However, furan degradation is found to be significant, which may limit ultimate quantities generated in hydrolysate liquors.


Design of catalytic substrates for uniform graphene films: from solid-metal to liquid-metal.
The controllable synthesis of uniform graphene with a specific layer number is crucial for both fundamental research and emerging applications due to the high sensitivity of the various extraordinary physicochemical properties of graphene to its layer numbers. However, the excessive segregation of extra C, the inactivation of the self-limiting of Cu and the superabundant nucleation at grain boundaries and defect sites render that the controllable synthesis of uniform graphene is still a challenge. By the employment of various solid and liquid metals with quasi-atomically smooth surfaces to avoid defects or grain boundaries, a series of studies have been performed and significant improvements have been achieved in the controllable synthesis of uniform graphene films. In this review, the representative strategies of designing catalytic substrates, including polycrystalline metals, single-crystalline metals, binary metal alloys and liquid metals, are highlighted. The future of the controllable synthesis of uniform graphene is also discussed.


Impact of a national external quality assessment scheme for breast pathology in the UK.
This article presents the results and observed effects of the UK National Health Service Breast Screening Programme (NHSBSP) external quality assurance scheme in breast histopathology. The major objectives were to monitor and improve the consistency of diagnoses made by pathologists and the quality of prognostic information in pathology reports. The scheme is based on a twice yearly circulation of 12 cases to over 600 registered participants. The level of agreement was generally measured using kappa statistics. Four main situations were encountered with respect to diagnostic consistency, namely: (1) where consistency is naturally very high-this included diagnosing in situ and invasive carcinomas (and certain distinctive subtypes) and uncomplicated benign lesions; (2) where the level of consistency was low but could be improved by making guidelines more detailed and explicit-this included histological grading; (3) where consistency could be improved but only by changing the system of classification-this included classification of ductal carcinoma in situ; and (4) where no improvement in consistency could be achieved-this included diagnosing atypical hyperplasia and reporting vascular invasion. Size measurements were more consistent for invasive than in situ carcinomas. Even in cases where there is a high level of agreement on tumour size, a few widely outlying measurements were encountered, for which no explanation is readily forthcoming. These results broadly confirm the robustness of the systems of breast disease diagnosis and classification adopted by the NHSBSP, and also identify areas where improvement or new approaches are required.


Catalytic peptide assemblies.
Self-assembly of molecules often results in new emerging properties. Even very short peptides can self-assemble into structures with a variety of physical and structural characteristics. Remarkably, many peptide assemblies show high catalytic activity in model reactions reaching efficiencies comparable to those found in natural enzymes by weight. In this review, we discuss different strategies used to rationally develop self-assembled peptide catalysts with natural and unnatural backbones as well as with metal-containing cofactors.


Fast Screening Technology for Drug Emergency Management: Predicting Suspicious SNPs for ADR with Information Theory-based Models.
The genetic polymorphism of Cytochrome P450 (CYP 450) is considered as one of the main causes for adverse drug reactions (ADRs). In order to explore the latent correlations between ADRs and potentially corresponding single-nucleotide polymorphism (SNPs) in CYP450, three algorithms based on information theory are used as the main method to predict the possible relation. The study uses a retrospective case-control study to explore the potential relation of ADRs to specific genomic locations and single-nucleotide polymorphism (SNP). The genomic data collected from 53 healthy volunteers are applied for the analysis, another group of genomic data collected from 30 healthy volunteers excluded from the study are used as the control group. The SNPs respective on five loci of CYP2D6*2,*10,*14 and CYP1A2*1C, *1F are detected by the Applied Biosystem 3130xl. The raw data is processed by ChromasPro to detect the specific alleles on the above loci from each sample. The secondary data are reorganized and processed by R combined with the reports of ADRs from clinical reports. Three information theory based algorithms are implemented for the screening task: JMI, CMIM, and mRMR. If a SNP is selected by more than two algorithms, we are confident to conclude that it is related to the corresponding ADR. The selection results are compared with the control decision tree + LASSO regression model. In the study group where ADRs occur, 10 SNPs are considered relevant to the occurrence of a specific ADR by the combined information theory model. In comparison, only 5 SNPs are considered relevant to a specific ADR by the decision tree + LASSO regression model. In addition, the new method detects more relevant pairs of SNP and ADR which are affected by both SNP and dosage. This implies that the new information theory based model is effective to discover correlations of ADRs and CYP 450 SNPs and is helpful in predicting the potential vulnerable genotype for some ADRs. The newly proposed information theory based model has superiority performance in detecting the relation between SNP and ADR compared to the decision tree + LASSO regression model. The new model is more sensitive to detect ADRs compared to the old method, while the old method is more reliable. Therefore, the selection criteria for selecting algorithms should depend on the pragmatic needs.


Routes of success: influences on the occupational attainment of young British males.
Using data from the National Child Development Study, the paper develops a complex path model predicting the occupational grade achieved by 4,298 employed British males at age 33. Most British social mobility research has been based in the 'class structurationist' tradition, and the paper begins by comparing this with the 'status attainment' tradition, which is more common in the USA. The class structurationist approach has rarely analysed the factors influencing individual occupational attainment, and those working in this tradition in Britain have often assumed that people from working-class origins fare worse on average than those from the middle class because of factors associated with their class disadvantage rather than any difference in individual characteristics such as ability or ambition. Status attainment research, however, has generally found that individual ability and motivation are the key factors influencing occupational attainment, and that class origins count for comparatively little. Using various measures of class origins, parental support, qualifications, and individual ability and ambition, the paper goes on to develop a linear structural equations model which achieves a good fit to the data. The model demonstrates that individual ability is by far the strongest influence on occupational achievement, that motivation is also important, and that factors like class background and parental support, while significant, are relatively much weaker. The paper concludes that occupational selection in Britain appears to take place largely on meritocratic principles.


Stimulation of aquaporin-mediated fluid transport by cyclic GMP in human retinal pigment epithelium in vitro.
The retinal pigment epithelium (RPE) expresses aquaporin-1 (AQP1) and components of the natriuretic peptide signaling pathway. We hypothesized that stimulation of the natriuretic signaling pathway in RPE with atrial natriuretic peptide (ANP) and with membrane-permeable analogs of cGMP would induce a net apical-to-basal transport of fluid. The hypothesis was tested using human RPE cultures that retain properties seen in vivo. Confluent monolayers were treated with ANP or membrane-permeable cGMP analogs in the presence of anantin, H-8, and an AQP1 inhibitor, AqB013. Fluid movement from the apical to basal chambers was measured by weight and used to calculate net fluid transport. Our results demonstrated a 40% increase in net apical-to-basal fluid transport by ANP (5 μM) that was inhibited completely by the ANP receptor antagonist anantin and a 60% increase in net apical-to-basal fluid transport in response to the extracellularly applied membrane-permeable cGMP analog pCPT-cGMP (50 μM), which was not affected by the protein kinase G inhibitor H-8. The aquaporin antagonist AqB013 (20 μM) inhibited the cGMP-stimulated RPE fluid flux. The effect of cGMP is consistent with an enhancement of the net fluid flux in RPE mediated by AQP1 channels. Pharmacologic activation of cGMP signaling and concomitant stimulation of fluid uptake from the subretinal space could offer insights into a new approach to treating or reducing the risk of retinal detachment.


SARS-CoV-2 501Y.V2 variants lack higher infectivity but do have immune escape.
The 501Y.V2 variants of SARS-CoV-2 containing multiple mutations in spike are now dominant in South Africa and are rapidly spreading to other countries. Here, experiments with 18 pseudotyped viruses showed that the 501Y.V2 variants do not confer increased infectivity in multiple cell types except for murine ACE2-overexpressing cells, where a substantial increase in infectivity was observed. Notably, the susceptibility of the 501Y.V2 variants to 12 of 17 neutralizing monoclonal antibodies was substantially diminished, and the neutralization ability of the sera from convalescent patients and immunized mice was also reduced for these variants. The neutralization resistance was mainly caused by E484K and N501Y mutations in the receptor-binding domain of spike. The enhanced infectivity in murine ACE2-overexpressing cells suggests the possibility of spillover of the 501Y.V2 variants to mice. Moreover, the neutralization resistance we detected for the 501Y.V2 variants suggests the potential for compromised efficacy of monoclonal antibodies and vaccines.


Vitamin D Levels Do Not Predict Risk of Metatarsal Fractures.
In the literature, there is conflicting data regarding the relationship between vitamin D and fractures. Reports on the effects of vitamin D levels on pathologies of the foot and ankle are limited. The purpose of this study is to assess the prevalence of vitamin D insufficiency in patients who have sustained low-energy metatarsal fractures compared to foot or ankle sprains without osseous involvement. Between May 2012 and August 2014, vitamin D levels and demographic data were collected prospectively in a total of 99 patients; 71 with metatarsal fractures and 28 with sprains, both from a low-energy mechanism of injury. Data between the metatarsal fracture group and sprain group were compared through univariate and multivariate analyses. Mean vitamin D in the fracture group was 26.9 ng/mL (range = 78.0-4.3), and in the sprain group it was 27.1 ng/mL (range = 64.1-8.3; P = .93). Vitamin D insufficiency (<30 ng/mL) was present in 47 (66%) of fracture patients and 20 (71%) of sprain patients ( P = .81). A high incidence of hypovitaminosis D was seen in all foot and ankle patients. There was no difference in mean vitamin D level or incidence of vitamin D insufficiency between patients with metatarsal fractures or sprains resulting from similar low-energy mechanisms. Level III: Prospective, case-control study.


Promoting the 3Rs to enhance the OECD fish toxicity testing framework.
Fish toxicity testing has been conducted since the 1860's in order to help define safe levels of chemical contaminants in lakes, rivers and coastal waters. The historical emphasis on acute lethality testing of chemicals has more recently focussed on long term sublethal effects of chemicals on fish and their prey species. Fish toxicity testing is now embedded in much environment legislation on chemical safety while it is recognized that animal use should be Replaced, Reduced and Refined (the 3Rs) where possible. The OECD Fish Toxicity Testing Framework provides a useful structure with which to address the needs of environmental safety assessment whilst implementing the 3Rs. This commentary aims to promote the implementation of the recommendations of the OECD Fish Toxicity Testing Framework.


Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants.
Hypertension can be detected at the primary health-care level and low-cost treatments can effectively control hypertension. We aimed to measure the prevalence of hypertension and progress in its detection, treatment, and control from 1990 to 2019 for 200 countries and territories. We used data from 1990 to 2019 on people aged 30-79 years from population-representative studies with measurement of blood pressure and data on blood pressure treatment. We defined hypertension as having systolic blood pressure 140 mm Hg or greater, diastolic blood pressure 90 mm Hg or greater, or taking medication for hypertension. We applied a Bayesian hierarchical model to estimate the prevalence of hypertension and the proportion of people with hypertension who had a previous diagnosis (detection), who were taking medication for hypertension (treatment), and whose hypertension was controlled to below 140/90 mm Hg (control). The model allowed for trends over time to be non-linear and to vary by age. The number of people aged 30-79 years with hypertension doubled from 1990 to 2019, from 331 (95% credible interval 306-359) million women and 317 (292-344) million men in 1990 to 626 (584-668) million women and 652 (604-698) million men in 2019, despite stable global age-standardised prevalence. In 2019, age-standardised hypertension prevalence was lowest in Canada and Peru for both men and women; in Taiwan, South Korea, Japan, and some countries in western Europe including Switzerland, Spain, and the UK for women; and in several low-income and middle-income countries such as Eritrea, Bangladesh, Ethiopia, and Solomon Islands for men. Hypertension prevalence surpassed 50% for women in two countries and men in nine countries, in central and eastern Europe, central Asia, Oceania, and Latin America. Globally, 59% (55-62) of women and 49% (46-52) of men with hypertension reported a previous diagnosis of hypertension in 2019, and 47% (43-51) of women and 38% (35-41) of men were treated. Control rates among people with hypertension in 2019 were 23% (20-27) for women and 18% (16-21) for men. In 2019, treatment and control rates were highest in South Korea, Canada, and Iceland (treatment >70%; control >50%), followed by the USA, Costa Rica, Germany, Portugal, and Taiwan. Treatment rates were less than 25% for women and less than 20% for men in Nepal, Indonesia, and some countries in sub-Saharan Africa and Oceania. Control rates were below 10% for women and men in these countries and for men in some countries in north Africa, central and south Asia, and eastern Europe. Treatment and control rates have improved in most countries since 1990, but we found little change in most countries in sub-Saharan Africa and Oceania. Improvements were largest in high-income countries, central Europe, and some upper-middle-income and recently high-income countries including Costa Rica, Taiwan, Kazakhstan, South Africa, Brazil, Chile, Turkey, and Iran. Improvements in the detection, treatment, and control of hypertension have varied substantially across countries, with some middle-income countries now outperforming most high-income nations. The dual approach of reducing hypertension prevalence through primary prevention and enhancing its treatment and control is achievable not only in high-income countries but also in low-income and middle-income settings. WHO.


Cross-modal visuo-haptic mental rotation: comparing objects between senses.
The simple experience of a coherent percept while looking and touching an object conceals an intriguing issue: different senses encode and compare information in different modality-specific reference frames. We addressed this problem in a cross-modal visuo-haptic mental rotation task. Two objects in various orientations were presented at the same spatial location, one visually and one haptically. Participants had to identify the objects as same or different. The relative angle between viewing direction and hand orientation was manipulated (Aligned versus Orthogonal). In an additional condition (Delay), a temporal delay was introduced between haptic and visual explorations while the viewing direction and the hand orientation were orthogonal to each other. Whereas the phase shift of the response time function was close to 0 degrees in the Aligned condition, we observed a consistent phase shift in the hand's direction in the Orthogonal condition. A phase shift, although reduced, was also found in the Delay condition. Counterintuitively, these results mean that seen and touched objects do not need to be physically aligned for optimal performance to occur. The present results suggest that the information about an object is acquired in separate visual and hand-centered reference frames, which directly influence each other and which combine in a time-dependent manner.


Reconciling isothermal titration calorimetry analyses of interactions between complexin and truncated SNARE complexes.
Neurotransmitter release depends on the SNARE complex formed by syntaxin-1, synaptobrevin and SNAP-25, as well as on complexins, which bind to the SNARE complex and play active and inhibitory roles. A crystal structure of a Complexin-I fragment bearing a so-called 'superclamp' mutation bound to a truncated SNARE complex lacking the C-terminus of the synaptobrevin SNARE motif (SNAREΔ60) suggested that an 'accessory' α-helix of Complexin-I inhibits release by inserting into the C-terminus of the SNARE complex. Previously, isothermal titration calorimetry (ITC) experiments performed in different laboratories yielded apparently discrepant results in support or against the existence of such binding mode in solution (Trimbuch et al., 2014; Krishnakumar et al., 2015). Here, ITC experiments performed to solve these discrepancies now show that the region containing the Complexin-I accessory helix and preceding N-terminal sequences does interact with SNAREΔ60, but the interaction requires the polybasic juxtamembrane region of syntaxin-1 and is not affected by the superclamp mutation within the experimental error of these experiments.


Antidepressant utilization after hospitalization with depression: a comparison between non-Western immigrants and Danish-born residents.
Antidepressant (AD) therapy is recommended for patients 4-12 months after remission from depression. The aim was to examine whether immigrants (refugees or family reunited immigrants) from non-Western countries are at greater risk than Danish-born residents of 1) not initiating AD therapy after discharge and 2) early AD discontinuation. A cohort of immigrants from non-Western countries (n = 132) and matched Danish-born residents (n = 396) discharged after first admission with moderate to severe depression between 1 January 1996 and 31 May 2008 was followed in the Danish registries.Logistic regression models were applied to explore AD initiation within 30 days after discharge, estimating odds ratio (OR) for immigrants versus Danish-born residents.Early discontinuation was explored by logistic regression, estimating OR for no AD dispensing within 180 days after the first dispensing, and by Cox regression, estimating hazard ratio (HR) for discontinuation (maximum drug supply gap) within 180 days. Immigrants had higher odds for not initiating AD treatment after discharge than Danish-born residents (OR = 1.55; 95% CI: 1.01-2.38). When income was included in the model, the strength of the association was attenuated. Odds for early discontinuation was non-significantly higher among immigrants than Danish-born residents (OR = 1.80; 0.87-3.73). Immigrants also had a non-significantly higher hazard of early discontinuation (HR = 1.46; 95% CI: 0.87-2.45). Including income had only minor impact on these associations. Immigrants seem less likely to receive the recommended AD treatment after hospitalization with depression. This may indicate a need for a better understanding of the circumstances of this vulnerable group.


Context-aware patch-based image inpainting using Markov random field modeling.
In this paper, we first introduce a general approach for context-aware patch-based image inpainting, where textural descriptors are used to guide and accelerate the search for well-matching (candidate) patches. A novel top-down splitting procedure divides the image into variable size blocks according to their context, constraining thereby the search for candidate patches to nonlocal image regions with matching context. This approach can be employed to improve the speed and performance of virtually any (patch-based) inpainting method. We apply this approach to the so-called global image inpainting with the Markov random field (MRF) prior, where MRF encodes a priori knowledge about consistency of neighboring image patches. We solve the resulting optimization problem with an efficient low-complexity inference method. Experimental results demonstrate the potential of the proposed approach in inpainting applications like scratch, text, and object removal. Improvement and significant acceleration of a related global MRF-based inpainting method is also evident.


Mapping of quantitative trait loci underlying ethanol metabolism in BXD recombinant inbred mouse strains.
Genetic factors are well known to play an important role in determining individual differences in the metabolism of ethanol (EtOH), and several specific polymorphic loci have been identified that significantly contribute to the variability of EtOH metabolism in humans. However, these variant genes are either alcohol or aldehyde dehydrogenases, and the identification of new gene products that contribute to variation in alcohol metabolism would be useful. To identify quantitative trait loci (QTLs), we correlated variation in polymorphic markers with blood EtOH concentration and the rate of EtOH metabolism (beta) in C57BL/6J and DBA/2J strains and in 25 of their recombinant inbred strains after 2 and 3 g/kg of EtOH intraperitoneally. A QTL associated with beta values for both doses was definitively mapped to the proximal region of chromosome 17, syntenic with human chromosome 6q25-27. Seven to 12 chromosomal regions were provisionally identified for each phenotype; several were associated with 2 or more phenotypes. Each QTL suggests the location of a gene or genes affecting EtOH pharmacokinetics. Candidate genes suggested by these analyses included several whose gene products are known to be induced by EtOH (e.g., superoxide dismutase, glutathione transferase, and cytochrome P450 2E1), as well as several whose gene products have signaling functions likely to contribute to this induction. These studies provide evidence for the existence of genes affecting EtOH metabolism in multiple chromosomal regions. Future studies will be required to identify the chromosome 17 gene product. Use of other genetic populations, such as B6D2F2 crosses, will be required to determine which of the provisional loci represent true and which represent false-positive associations.


Volumetric and texture analysis of pretherapeutic 18F-FDG PET can predict overall survival in medullary thyroid cancer patients treated with Vandetanib.
The metabolically most active lesion in 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) PET/CT can predict progression-free survival (PFS) in patients with medullary thyroid carcinoma (MTC) starting treatment with the tyrosine kinase inhibitor (TKI) vandetanib. However, this metric failed in overall survival (OS) prediction. In the present proof of concept study, we aimed to explore the prognostic value of intratumoral textural features (TF) as well as volumetric parameters (total lesion glycolysis, TLG) derived by pre-therapeutic 18F-FDG PET. Eighteen patients with progressive MTC underwent baseline 18F-FDG PET/CT prior to and 3 months after vandetanib initiation. By manual segmentation of the tumor burden at baseline and follow-up PET, intratumoral TF and TLG were computed. The ability of TLG, imaging-based TF, and clinical parameters (including age, tumor marker doubling times, prior therapies and RET (rearranged during transfection) mutational status) for prediction of both PFS and OS were evaluated. The TF Complexity and the volumetric parameter TLG obtained at baseline prior to TKI initiation successfully differentiated between low- and high-risk patients. Complexity allocated 10/18 patients to the high-risk group with an OS of 3.3 y (vs. low-risk group, OS = 5.3 y, 8/18, AUC = 0.78, P = 0.03). Baseline TLG designated 11/18 patients to the high-risk group (OS = 3.5 y vs. low-risk group, OS = 5 y, 7/18, AUC = 0.83, P = 0.005). The Hazard Ratio for cancer-related death was 6.1 for Complexity (TLG, 9.5). Among investigated clinical parameters, the age at initiation of TKI treatment reached significance for PFS prediction (P = 0.02, OS, n.s.). The TF Complexity and the volumetric parameter TLG are both independent parameters for OS prediction.


Parvulin 17 promotes microtubule assembly by its peptidyl-prolyl cis/trans isomerase activity.
The parvulin-type peptidyl-prolyl cis/trans isomerases (PPIases) have been shown to be involved in tumor progression and the pathogenesis of Alzheimer's disease and were therefore a subject of intense research. Here, we describe a role for parvulin 17 in microtubule assembly. Co-precipitation experiments and sedimentation assays demonstrated that parvulin 17 interacts with tubulin in a GTP-dependent manner and thereby promotes the formation of microtubules, as shown by transmission electron microscopy and a microtubule polymerization assay. The microtubule-assembly-promoting properties of parvulin 17 seem to depend on its PPIase activity. Thus, catalytic deficient variants of parvulin 17 were not able to promote microtubule formation. Accordingly, inhibitors of parvulin 17 activity also prevent parvulin-catalyzed tubulin polymerization. The analysis of tubulin interaction sites on parvulin using peptide microarrays revealed that tubulin interacts with the substrate binding pocket of parvulin. Additionally, β-tubulin peptide scan on microarrays demonstrates interaction of parvulin 17 with an Arg-Pro-Asp motif corresponding to proline residue 87 of β-tubulin. Confocal laser scanning microscopy points to a function of parvulin 17 in microtubule dynamics as well. Parvulin 17 is predominantly found in the cytosol and colocalizes with microtubules.


Radial shearing interferometers using a laser source.
Radial shearing interferometers have been devised by several workers earlier. All of them were based on conventional light sources, and consequently full white light compensation was required. It is possible to devise several schemes of radial shearing interferometers ignoring the condition of white light compensation when a laser source is used in place of a conventional source. Some of these arrangements are described in the present paper.


Proximal tumors are associated with greater mortality in colon cancer.
Colon cancer is the third leading cause of death from cancer in the United States. Recent studies report on increasing proportions of proximal cancers. The etiology behind this epidemiological trend is unclear, and its implication on survival outcomes is unknown. Further analysis of the impact of anatomic site of disease among a large multiethnic population will help facilitate research and education to improve colon cancer screening and treatment. To investigate the association between proximal tumor location and survival in patients with colon cancer. A large retrospective cohort study in the US utilizing the Surveillance, Epidemiology, and End Results (SEER) cancer registry analyzed survival outcomes of patients with colon cancer. Multivariable logistic regression analyses investigated sex-specific, race/ethnicity-specific, and anatomic site-specific disparities in survival. Five-year survival outcomes from colon cancer. Our study demonstrated significant disparities in survival by sex, race/ethnicity, and anatomic site. Across all time periods and among most cohorts, patients with proximal cancers had significantly worse survival outcomes. When compared to distal cancers, patients with proximal cancers were 13% less likely to survive 5 years (OR 0.87; 95% CI, 0.82-0.91). When compared to non-Hispanic whites, blacks were 30% less likely to survive 5 years (OR 0.70; 95% CI, 0.68-0.73). Stage-specific multivariable regression analysis of localized cancers demonstrated similar findings. Significant race-specific, sex-specific, and anatomic site-specific disparities in colon cancer survival exist. Proximal cancers are associated with worse survival odds. These disparities may reflect differences in the genotype and phenotype of colon cancer among these groups. A modified risk assessment tool that incorporates these variations may be more effective in the early detection and treatment of colon cancer.


The role of peripheral inflammatory markers in dementia and Alzheimer's disease: a meta-analysis.
Studies that have investigated the association between markers of inflammation and risk of dementia are conflicting. Therefore, the researchers conducted a systematic review and meta-analysis of observational studies with the hypothesis that an increased level of peripheral proinflammatory markers would be associated with risk of all-cause dementia or Alzheimer's disease (AD). The researchers conducted a literature search of observational studies indexed in the PubMed and PsycInfo databases. Selected studies included those with at least one peripheral inflammatory biomarker and its association with risk of all-cause dementia or AD. Random effects models were used to generate pooled hazard ratios (HRs) comparing the top versus bottom quantile of inflammatory marker level. Heterogeneity was assessed using the I (2) statistic. Seven studies were identified, combining for a total 5,717 participants, 746 cases of all-cause dementia and 565 cases of AD. An increased level of C-reactive protein was associated with a 45% increased risk of all-cause dementia (HR: 1.45; 95% CI: 1.10, 1.91). Similarly, a higher level of interleukin-6 was associated with a 32% increased risk (HR: 1.32; 95% CI: 1.06, 1.64) of all-cause dementia. For AD alone, the association with C-reactive protein was less pronounced (HR: 1.21; 95% CI: 1.03, 1.42) and interleukin-6 was not associated with risk of AD (HR: 1.06; 95% CI: 0.83, 1.35). No significant heterogeneity was found in any of the meta-analyses (I (2) = 0%-40%, p ≥ .16). An increased peripheral level of inflammatory markers is associated with a modest increase in risk of all-cause dementia. Evidence for an association with risk of AD alone is limited.


Maternal and child contributions to cortisol response to emotional arousal in young children from low-income, rural communities.
Relations of maternal and child characteristics to child cortisol reactivity to and recovery from emotional arousal were examined prospectively at approximately 7 months of age (infancy) and then again at approximately 15 months of age (toddlerhood). The sample was diverse and population based (N = 1,292 mother-infant dyads) and included families from predominantly low-income, rural communities. Maternal behavior, family income-to-need ratio and social advantage, and child temperament, attention, and mental development were assessed, and children's saliva was sampled before and after standardized procedures designed to elicit emotional arousal. Maternal engagement in infancy was associated with greater cortisol reactivity at the infancy assessment and with reduced overall cortisol level at the toddler assessment. Also at the toddler assessment, child attention, mental development, and temperamental distress to novelty were associated with increased cortisol reactivity and regulation, whereas temperamental distress to limitations and African American ethnicity were associated with reduced cortisol reactivity. Findings are consistent with prior work linking early caregiving to the development of the hypothalamic-pituitary-adrenal axis stress response system and with a conceptual model in which developing temperament is characterized by the interplay of emotional reactivity and the emergence of the ability to effortfully regulate this reactivity using attention.


piClust: a density based piRNA clustering algorithm.
Piwi-interacting RNAs (piRNAs) are recently discovered, endogenous small non-coding RNAs. piRNAs protect the genome from invasive transposable elements (TE) and sustain integrity of the genome in germ cell lineages. Small RNA-sequencing data can be used to detect piRNA activations in a cell under a specific condition. However, identification of cell specific piRNA activations requires sophisticated computational methods. As of now, there is only one computational method, proTRAC, to locate activated piRNAs from the sequencing data. proTRAC detects piRNA clusters based on a probabilistic analysis with assumption of a uniform distribution. Unfortunately, we were not able to locate activated piRNAs from our proprietary sequencing data in chicken germ cells using proTRAC. With a careful investigation on data sets, we found that a uniform or any statistical distribution for detecting piRNA clusters may not be assumed. Furthermore, small RNA-seq data contains many different types of RNAs which was not carefully taken into account in previous studies. To improve piRNA cluster identification, we developed piClust that uses a density based clustering approach without assumption of any parametric distribution. In previous studies, it is known that piRNAs exhibit a strong tendency of forming piRNA clusters in syntenic regions of the genome. Thus, the density based clustering approach is effective and robust to the existence of non-piRNAs or noise in the data. In experiments with piRNA data from human, mouse, rat and chicken, piClust was able to detect piRNA clusters from total small RNA-seq data from germ cell lines, while proTRAC was not successful. piClust outperformed proTRAC in terms of sensitivity and running time (up to 200 folds). piClust is currently available as a web service at http://epigenomics.snu.ac.kr/piclustweb.


The Business Case for Expanded Clozapine Utilization.
In most settings, less than 25% of patients with treatment-resistant schizophrenia receive clozapine, the only medication proven effective for treatment-resistant schizophrenia. Therefore, a business case analysis was conducted to assess whether increasing clozapine utilization for treatment-resistant schizophrenia in a health care system would result in direct health care cost savings. Veterans with treatment-resistant schizophrenia who were treated in the Veterans Health Administration (VHA) were studied. Treatment response, suicides, adverse drug reactions (and associated mortality), and effects on inpatient hospitalization related to clozapine were derived from a systematic review of published studies. A one-factor sensitivity analysis and a probabilistic sensitivity analysis (PSA) with Monte Carlo simulation were conducted to calculate the cost-benefits of increased clozapine utilization. Despite monitoring costs, in the base case analysis, the VHA would save $22,444 per veteran with treatment-resistant schizophrenia over the first year of clozapine therapy, primarily from 18.6 fewer inpatient days per patient. If current utilization was doubled, and 50% of those veterans continued clozapine treatment for one year, VHA would save an estimated $80 million. Cost savings were most sensitive to the proportion of treatment-resistant patients who received clozapine, decrease in inpatient days, cost of inpatient stays, clozapine response rate, and number of patients with treatment-resistant schizophrenia. In the PSA, initiation of clozapine for all VHA patients with treatment-resistant schizophrenia who were not currently treated with clozapine would save at least $290 million in 95% of simulations. Increased clozapine utilization would result in net cost savings for the VHA.


Identification, detection, and spatial resolution of Clostridium populations responsible for cellulose degradation in a methanogenic landfill leachate bioreactor.
An anaerobic landfill leachate bioreactor was operated with crystalline cellulose and sterile landfill leachate until a steady state was reached. Cellulose hydrolysis, acidogenesis, and methanogenesis were measured. Microorganisms attached to the cellulose surfaces were hypothesized to be the cellulose hydrolyzers. 16S rRNA gene clone libraries were prepared from this attached fraction and also from the mixed fraction (biomass associated with cellulose particles and in the planktonic phase). Both clone libraries were dominated by Firmicutes phylum sequences (100% of the attached library and 90% of the mixed library), and the majority fell into one of five lineages of the clostridia. Clone group 1 (most closely related to Clostridium stercorarium), clone group 2 (most closely related to Clostridium thermocellum), and clone group 5 (most closely related to Bacteroides cellulosolvens) comprised sequences in Clostridium group III. Clone group 3 sequences were in Clostridium group XIVa (most closely related to Clostridium sp. strain XB90). Clone group 4 sequences were affiliated with a deeply branching clostridial lineage peripherally associated with Clostridium group VI. This monophyletic group comprises a new Clostridium cluster, designated cluster VIa. Specific fluorescence in situ hybridization (FISH) probes for the five groups were designed and synthesized, and it was demonstrated in FISH experiments that bacteria targeted by the probes for clone groups 1, 2, 4, and 5 were very abundant on the surfaces of the cellulose particles and likely the key cellulolytic microorganisms in the landfill bioreactor. The FISH probe for clone group 3 targeted cells in the planktonic phase, and these organisms were hypothesized to be glucose fermenters.


Cost-effectiveness analysis of timely dialysis referral after renal transplant failure in Spain.
A cost-effectiveness analysis of timely dialysis referral after renal transplant failure was undertaken from the perspective of the Public Administration. The current Spanish situation, where all the patients undergoing graft function loss are referred back to dialysis in a late manner, was compared to an ideal scenario where all the patients are timely referred. A Markov model was developed in which six health states were defined: hemodialysis, peritoneal dialysis, kidney transplantation, late referral hemodialysis, late referral peritoneal dialysis and death. The model carried out a simulation of the progression of renal disease for a hypothetical cohort of 1,000 patients aged 40, who were observed in a lifetime temporal horizon of 45 years. In depth sensitivity analyses were performed in order to ensure the robustness of the results obtained. Considering a discount rate of 3 %, timely referral showed an incremental cost of 211 €, compared to late referral. This cost increase was however a consequence of the incremental survival observed. The incremental effectiveness was 0.0087 quality-adjusted life years (QALY). When comparing both scenarios, an incremental cost-effectiveness ratio of 24,390 €/QALY was obtained, meaning that timely dialysis referral might be an efficient alternative if a willingness-to-pay threshold of 45,000 €/QALY is considered. This result proved to be independent of the proportion of late referral patients observed. The acceptance probability of timely referral was 61.90 %, while late referral was acceptable in 38.10 % of the simulations. If we however restrict the analysis to those situations not involving any loss of effectiveness, the acceptance probability of timely referral was 70.10 %, increasing twofold that of late referral (29.90 %). Timely dialysis referral after graft function loss might be an efficient alternative in Spain, improving both patients' survival rates and health-related quality of life at an affordable cost. Spanish Public Health authorities might therefore promote the inclusion of specific recommendations for this group of patients within the existing clinical guidelines.


United but divided: Policy responses and people's perceptions in the EU during the COVID-19 outbreak.
To understand the public sentiment toward the measures used by policymakers for COVID-19 containment, a survey among representative samples of the population in seven European countries was carried out in the first two weeks of April 2020. The study addressed people's support for containment policies, worries about COVID-19 consequences, and trust in sources of information. Citizens were overall satisfied with their government's response to the pandemic; however, the extent of approval differed across countries and policy measures. A north-south divide in public opinion was noticeable across the European states. It was particularly pronounced for intrusive policy measures, such as mobile data use for movement tracking, economic concerns, and trust in the information from the national government. Considerable differences in people's attitudes were noticed within countries, especially across individual regions and age groups. The findings suggest that the epidemic acts as a stressor, causing health and economic anxieties even in households that were not directly affected by the virus. At the same time, the burden of stress was unequally distributed across regions and age groups. Based on the data collected, we draw lessons from the containment stage and identify several insights that can facilitate the design of lockdown exit strategies and future containment policies so that a high level of compliance can be expected.


Medical versus surgical interventions for open angle glaucoma.
Open angle glaucoma (OAG) is a common cause of blindness. To assess the effects of medication compared with initial surgery in adults with OAG. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 7), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to August 2012), EMBASE (January 1980 to August 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to August 2012), Biosciences Information Service (BIOSIS) (January 1969 to August 2012), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (January 1937 to August 2012), OpenGrey (System for Information on Grey Literature in Europe) (www.opengrey.eu/), Zetoc, the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 1 August 2012. The National Research Register (NRR) was last searched in 2007 after which the database was archived. We also checked the reference lists of articles and contacted researchers in the field. We included randomised controlled trials (RCTs) comparing medications with surgery in adults with OAG. Two authors independently assessed trial quality and extracted data. We contacted study authors for missing information. Four trials involving 888 participants with previously untreated OAG were included. Surgery was Scheie's procedure in one trial and trabeculectomy in three trials. In three trials, primary medication was usually pilocarpine, in one trial it was a beta-blocker.The most recent trial included participants with on average mild OAG. At five years, the risk of progressive visual field loss, based on a three unit change of a composite visual field score, was not significantly different according to initial medication or initial trabeculectomy (odds ratio (OR) 0.74, 95% confidence interval (CI) 0.54 to 1.01). In an analysis based on mean difference (MD) as a single index of visual field loss, the between treatment group difference in MD was -0.20 decibel (dB) (95% CI -1.31 to 0.91). For a subgroup with more severe glaucoma (MD -10 dB), findings from an exploratory analysis suggest that initial trabeculectomy was associated with marginally less visual field loss at five years than initial medication, (mean difference 0.74 dB (95% CI -0.00 to 1.48). Initial trabeculectomy was associated with lower average intraocular pressure (IOP) (mean difference 2.20 mmHg (95% CI 1.63 to 2.77) but more eye symptoms than medication (P = 0.0053). Beyond five years, visual acuity did not differ according to initial treatment (OR 1.48, 95% CI 0.58 to 3.81).From three trials in more severe OAG, there is some evidence that medication was associated with more progressive visual field loss and 3 to 8 mmHg less IOP lowering than surgery. In the longer-term (two trials) the risk of failure of the randomised treatment was greater with medication than trabeculectomy (OR 3.90, 95% CI 1.60 to 9.53; hazard ratio (HR) 7.27, 95% CI 2.23 to 25.71). Medications and surgery have evolved since these trials were undertaken.In three trials the risk of developing cataract was higher with trabeculectomy (OR 2.69, 95% CI 1.64 to 4.42). Evidence from one trial suggests that, beyond five years, the risk of needing cataract surgery did not differ according to initial treatment policy (OR 0.63, 95% CI 0.15 to 2.62).Methodological weaknesses were identified in all the trials. Primary surgery lowers IOP more than primary medication but is associated with more eye discomfort. One trial suggests that visual field restriction at five years is not significantly different whether initial treatment is medication or trabeculectomy. There is some evidence from two small trials in more severe OAG, that initial medication (pilocarpine, now rarely used as first line medication) is associated with more glaucoma progression than surgery. Beyond five years, there is no evidence of a difference in the need for cataract surgery according to initial treatment.The clinical and cost-effectiveness of contemporary medication (prostaglandin analogues, alpha2-agonists and topical carbonic anhydrase inhibitors) compared with primary surgery is not known.Further RCTs of current medical treatments compared with surgery are required, particularly for people with severe glaucoma and in black ethnic groups. Outcomes should include those reported by patients. Economic evaluations are required to inform treatment policy.


Adenoviral-mediated delivery of gastrin-releasing peptide receptor results in specific tumor localization of a bombesin analogue in vivo.
Radioimmunotherapy is hindered by a variety of factors linked to the utilization of monoclonal antibodies. These limitations include restricted tumor penetration as well as low levels of intratumoral antigen expression. To address the latter problem, we used a gene therapy approach to induce tumor cells to express enhanced levels of receptor with high binding affinity for a radiolabeled peptide. In this regard, a radiolabeled bombesin analogue was used in conjunction with a recombinant adenoviral vector encoding the murine gastrin-releasing peptide receptor (mGRPr). A panel of human carcinoma cell lines was infected in vitro with the recombinant adenoviral vector encoding the mGRPr vector to examine the induced binding of a 125I-labeled bombesin peptide. All cell lines examined displayed high levels of induced peptide binding, with approximately 60-80% of the radioactivity bound to the cells, in a live-cell binding assay. The human ovarian carcinoma cell line SKOV3.ip1 was chosen for in vivo analysis of radiolabeled bombesin analogue tumor localization in biodistribution and pharmacokinetic studies in athymic nude mice. Genetic induction of mGRPr in vivo resulted in selective tumor uptake of the radiolabeled peptide and high tumor:blood ratios. The biodistribution results compared favorably to those obtained with 131I-labeled e21 anti-erbB-2 monoclonal antibody in animals bearing i.p. SKOV3.ip1 tumors that endogenously express erbB-2. Thus, a novel method to combine gene transfer and radioimmunotherapy may result in augmented tumor cell targeting of radiopharmaceuticals.


The inhibition of automatic imitation: A meta-analysis and synthesis of fMRI studies.
Humans copy other people without their conscious awareness, a behaviour known as automatic imitation. Although automatic imitation forms a key part of daily social interactions, we do not copy other people indiscriminately. Instead, we control imitative tendencies by prioritising some actions and inhibiting others. To date, neuroimaging studies investigating the control of automatic imitation have produced inconsistent findings. Some studies suggest that imitation control relies on a domain-specific neural circuit related to social cognition (the theory-of-mind network). In contrast, other studies show engagement of a domain-general neural circuit that is engaged during a diverse range of cognitive control tasks (the multiple demand network). Given the inconsistency of prior findings, in the current paper we avoided problems associated with interpreting individual studies by performing a meta-analysis. To do so, we used a multi-level kernel density analysis to quantitatively identify consistent patterns of activation across functional magnetic resonance imaging studies investigating the control of imitation. Our results show clear and consistent evidence across studies that the control of automatic imitation is guided by brain regions in the multiple demand network including dorsolateral frontoparietal cortex. In contrast, there was only limited evidence that regions in the theory of mind network were engaged. Indeed, medial prefrontal cortex showed no consistent engagement and right temporoparietal junction engagement may reflect spatial rather than imitative control. As such, the current meta-analysis reinforces the role of domain-general control mechanisms and provides limited evidence in support of the role of domain-specific processes in regulating imitative tendencies. Consequently, neurocognitive models of imitation need updating to place more emphasis on domain-general control mechanisms, as well as to consider more complex organisational structures of control, which may involve contributions from multiple cognitive systems.


How do price minimizing behaviors impact smoking cessation? Findings from the International Tobacco Control (ITC) Four Country Survey.
This paper examines how price minimizing behaviors impact efforts to stop smoking. Data on 4,988 participants from the International Tobacco Control Policy Evaluation (ITC) Four-Country Survey who were smokers at baseline (wave 5) and interviewed at a 1 year follow-up were used. We examined whether price minimizing behaviors at baseline predicted: (1) cessation, (2) quit attempts, and (3) successful quit attempts at one year follow up using multivariate logistic regression modeling. A subset analysis included 3,387 participants who were current smokers at waves 5 and 6 and were followed through wave 7 to explore effects of changing purchase patterns on cessation. Statistical tests for interaction were performed to examine the joint effect of SES and price/tax avoidance behaviors on cessation outcomes. Smokers who engaged in any price/tax avoidance behaviors were 28% less likely to report cessation. Persons using low/untaxed sources were less likely to quit at follow up, those purchasing cartons were less likely to make quit attempts and quit, and those using discount cigarettes were less likely to succeed, conditional on making attempts. Respondents who utilized multiple behaviors simultaneously were less likely to make quit attempts and to succeed. SES did not modify the effects of price minimizing behaviors on cessation outcomes. The data from this paper indicate that the availability of lower priced cigarette alternatives may attenuate public health efforts aimed at to reduce reducing smoking prevalence through price and tax increases among all SES groups.


Gene expression programs of mouse endothelial cells in kidney development and disease.
Endothelial cells are remarkably heterogeneous in both morphology and function, and they play critical roles in the formation of multiple organ systems. In addition endothelial cell dysfunction can contribute to disease processes, including diabetic nephropathy, which is a leading cause of end stage renal disease. In this report we define the comprehensive gene expression programs of multiple types of kidney endothelial cells, and analyze the differences that distinguish them. Endothelial cells were purified from Tie2-GFP mice by cell dissociation and fluorescent activated cell sorting. Microarrays were then used to provide a global, quantitative and sensitive measure of gene expression levels. We examined renal endothelial cells from the embryo and from the adult glomerulus, cortex and medulla compartments, as well as the glomerular endothelial cells of the db/db mutant mouse, which represents a model for human diabetic nephropathy. The results identified the growth factors, receptors and transcription factors expressed by these multiple endothelial cell types. Biological processes and molecular pathways were characterized in exquisite detail. Cell type specific gene expression patterns were defined, finding novel molecular markers and providing a better understanding of compartmental distinctions. Further, analysis of enriched, evolutionarily conserved transcription factor binding sites in the promoters of co-activated genes begins to define the genetic regulatory network of renal endothelial cell formation. Finally, the gene expression differences associated with diabetic nephropathy were defined, providing a global view of both the pathogenic and protective pathways activated. These studies provide a rich resource to facilitate further investigations of endothelial cell functions in kidney development, adult compartments, and disease.


Amazonian amphibian diversity is primarily derived from late Miocene Andean lineages.
The Neotropics contains half of remaining rainforests and Earth's largest reservoir of amphibian biodiversity. However, determinants of Neotropical biodiversity (i.e., vicariance, dispersals, extinctions, and radiations) earlier than the Quaternary are largely unstudied. Using a novel method of ancestral area reconstruction and relaxed Bayesian clock analyses, we reconstructed the biogeography of the poison frog clade (Dendrobatidae). We rejected an Amazonian center-of-origin in favor of a complex connectivity model expanding over the Neotropics. We inferred 14 dispersals into and 18 out of Amazonia to adjacent regions; the Andes were the major source of dispersals into Amazonia. We found three episodes of lineage dispersal with two interleaved periods of vicariant events between South and Central America. During the late Miocene, Amazonian, and Central American-Chocoan lineages significantly increased their diversity compared to the Andean and Guianan-Venezuelan-Brazilian Shield counterparts. Significant percentage of dendrobatid diversity in Amazonia and Chocó resulted from repeated immigrations, with radiations at <10.0 million years ago (MYA), rather than in situ diversification. In contrast, the Andes, Venezuelan Highlands, and Guiana Shield have undergone extended in situ diversification at near constant rate since the Oligocene. The effects of Miocene paleogeographic events on Neotropical diversification dynamics provided the framework under which Quaternary patterns of endemism evolved.


Effect of low-dose oral contraceptives on androgenic markers and acne.
Oral contraceptives (OC) suppress excess androgen production; however, different progestins in combination with low-dose estrogens produce divergent effects on sex hormone-binding globulin (SHBG) and testosterone that may influence clinical outcomes. This multicenter, open-label, randomized study compared biochemical androgen profiles and clinical outcomes associated with two OC containing the same amounts of ethinyl estradiol (EE, 20 micrograms) but different progestins, levonorgestrel (LNG, 100 micrograms), and norethindrone acetate (NETA, 1000 micrograms). Fifty-eight healthy women (18-28 years old) received three cycles of treatment with LNG/EE (n = 30) or NETA/EE (n = 28). The results showed that LNG reduced androgen levels in three compartments--adrenal, ovarian, and peripheral. NETA reduced only adrenal and peripheral androgens. Despite a 2.2-fold greater relative increase in SHBG with NETA than LNG, bioavailable testosterone (T) was reduced by the same amount with LNG and NETA. Both treatments improved acne and were well tolerated. Low-dose OC (EE, 20 micrograms) are effective in reducing circulating androgens and acne lesions without causing weight gain. Although LNG and NETA affected secondary markers differently, both OC formulations produced an equivalent decrease in bioavailable.


Synaptic plasticity and spatial working memory are impaired in the CD mouse model of Williams-Beuren syndrome.
Mice heterozygous for a complete deletion (CD) equivalent to the most common deletion found in individuals with Williams-Beuren syndrome (WBS) recapitulate relevant features of the neurocognitive phenotype, such as hypersociability, along with some neuroanatomical alterations in specific brain areas. However, the pathophysiological mechanisms underlying these phenotypes still remain largely unknown. We have studied the synaptic function and cognition in CD mice using hippocampal slices and a behavioral test sensitive to hippocampal function. We have found that long-term potentiation (LTP) elicited by theta burst stimulation (TBS) was significantly impaired in hippocampal field CA1 of CD animals. This deficit might be associated with the observed alterations in spatial working memory. However, we did not detect changes in presynaptic function, LTP induction mechanisms or AMPA and NMDA receptor function. Reduced levels of Brain-derived neurotrophic factor (BDNF) were present in the CA1-CA3 hippocampal region of CD mice, which could account for LTP deficits in these mice. Taken together, these results suggest a defect of CA1 synapses in CD mice to sustain synaptic strength after stimulation. These data represent the first description of synaptic functional deficits in CD mice and further highlights the utility of the CD model to study the mechanisms underlying the WBS neurocognitive profile.


Advanced echocardiography for the critical care physician: part 2.
This article is the second part of a series that describes practical techniques in advanced critical care echocardiography and their use in the management of hemodynamic instability. Measurement of left ventricular function and segmental wall motion abnormalities, evaluation of left ventricular filling pressures, assessment of right-sided heart function, and determination of preload sensitivity, including passive leg raising, are discussed. Video examples help to demonstrate techniques described in the text.


Sustained viremia suppression by SHIVSF162P3CN-recalled effector-memory CD8+ T cells after PD1-based vaccination.
HIV-1 functional cure requires sustained viral suppression without antiretroviral therapy. While effector-memory CD8+ T lymphocytes are essential for viremia control, few vaccines elicit such cellular immunity that could be potently recalled upon viral infection. Here, we investigated a program death-1 (PD1)-based vaccine by fusion of simian immunodeficiency virus capsid antigen to soluble PD1. Homologous vaccinations suppressed setpoint viremia to undetectable levels in vaccinated macaques following a high-dose intravenous challenge by the pathogenic SHIVSF162P3CN. Poly-functional effector-memory CD8+ T cells were not only induced after vaccination, but were also recalled upon viral challenge for viremia control as determined by CD8 depletion. Vaccine-induced effector memory CD8+ subsets displayed high cytotoxicity-related genes by single-cell analysis. Vaccinees with sustained viremia suppression for over two years responded to boost vaccination without viral rebound. These results demonstrated that PD1-based vaccine-induced effector-memory CD8+ T cells were recalled by AIDS virus infection, providing a potential immunotherapy for functional cure.


Nanostructural hybrid sensitizers for photodynamic therapy.
Photodynamic therapy (PDT) is a clinically approved method for treatment of cancer, microbial infections, and some other diseases. PDT has proved effective in the treatment of malignancies of various organs, including lung, bladder, gastrointestinal tract, and skin, and in the therapy of bacterial infection of skin wounds and carious lesions. It employs a combination of light and a drug (photosensitizer, PS) to induce phototoxicity against cancerous cells or bacteria. The efficiency of currently used PSs is limited due to their hydrophobic nature, which causes aggregation of the PS in aqueous media and low tumor selectivity (a low value of the tumor-to-normal tissue ratio). The purpose of this review is to present some aspects of the current state of knowledge on nanostructural carriers for the PS delivery. In this paper we reviewed studies on the development of nanostructural materials for PDT, especially those based on the polymeric and liposomal formulation of PS. We focused mainly on the nanostructural PSs obtained by the covalent attachment of hydrophilic polymer chain to the low-molecular-weight PS, the incorporation of PS into polymeric nanostructures such as micelles, and the solubilization of PS in liposome carriers.