Inhibition of c-Jun NH2-terminal kinase activity improves ischemia/reperfusion injury in rat lungs.
Although c-Jun NH(2)-terminal kinase (JNK) has been implicated in the pathogenesis of transplantation-induced ischemia/reperfusion (I/R) injury in various organs, its significance in lung transplantation has not been conclusively elucidated. We therefore attempted to measure the transitional changes in JNK and AP-1 activities in I/R-injured lungs. Subsequently, we assessed the effects of JNK inhibition by the three agents including SP600125 on the degree of lung injury assessed by means of various biological markers in bronchoalveolar lavage fluid and histological examination including detection of apoptosis. In addition, we evaluated the changes in p38, extracellular signal-regulated kinase, and NF-kappaB-DNA binding activity. I/R injury was established in the isolated rat lung preserved in modified Euro-Collins solution at 4 degrees C for 4 h followed by reperfusion at 37 degrees C for 3 h. We found that AP-1 was transiently activated during ischemia but showed sustained activation during reperfusion, leading to significant lung injury and apoptosis. The change in AP-1 was generally in parallel with that of JNK, which was activated in epithelial cells (bronchial and alveolar), alveolar macrophages, and smooth muscle cells (bronchial and vascular) on immunohistochemical examination. The change in NF-kappaB qualitatively differed from that of AP-1. Protein leakage, release of lactate dehydrogenase and TNF-alpha into bronchoalveolar lavage fluid, and lung injury were improved, and apoptosis was suppressed by JNK inhibition. In conclusion, JNK plays a pivotal role in mediating lung injury caused by I/R. Therefore, inhibition of JNK activity has potential as an effective therapeutic strategy for preventing I/R injury during lung transplantation.


Exposure to multiple pesticides and neurobehavioral outcomes among smallholder farmers in Uganda.
Multiple epidemiological studies have shown that exposure to single pesticide active ingredients or chemical groups is associated with adverse neurobehavioral outcomes in farmers. In agriculture, exposure to multiple pesticide active ingredients is the rule, rather than exception. Therefore, occupational studies on neurobehavioral effects of pesticides should account for potential co-exposure confounding. We conducted a cross-sectional study of 288 Ugandan smallholder farmers between September and December 2017. We collected data on self-reported use of pesticide products during the 12 months prior to survey and estimated yearly exposure-intensity scores for 14 pesticide active ingredients using a semi-quantitative exposure algorithm. We administered 11 neurobehavioral tests to assess five neurobehavioral domains. We implemented a Bayesian Model-Averaging (BMA) approach to examine the association between exposure to multiple pesticides and neurobehavioral outcomes, while accounting for multiple testing. We applied two levels of inference to determine (1) which neurobehavioral outcomes were associated with overall pesticide exposure (marginal inclusion probability (MIP) for covariate-only models <0.5) and (2) which specific pesticide active ingredients were associated with these outcomes (MIP for models where active ingredient was included >0.5). Seventy-two percent of farmers reported use of pesticide products that contained at least one of 14 active ingredients, while the applicators used in median three different active ingredients (interquartile range (IQR) 4) in the 12 months prior to the study. The most widely used active ingredients were glyphosate (79%), cypermethrin (60%), and mancozeb (55%). We found that overall pesticide exposure was associated with impaired visual memory (Benton Visual Retention Test (BVRT)), language (semantic verbal fluency test), perceptual-motor function (Finger tapping test), and complex attention problems (Trail making A test and digit symbol test). However, when we looked at the associations for individual active ingredients, we only observed a positive association between glyphosate exposure and impaired visual memory (-0.103 [95% Bayesian Credible Interval (BCI)] [-0.24, 0] units in BVRT scores per interquartile range (IQR) increase in annual exposure to glyphosate, relative to a median [IQR] of 6 [3] units in BVRT across the entire study population). We found that overall pesticide exposure was associated with several neurobehavioral outcome variables. However, when we examined individual pesticide active ingredients, we observed predominantly null associations, except for a positive association between glyphosate exposure and impaired visual memory. Additional epidemiologic studies are needed to evaluate glyphosate's neurotoxicity, while accounting for co-pollutant confounding.


Ultralow protein adsorbing coatings from clickable PEG nanogel solutions: benefits of attachment under salt-induced phase separation conditions and comparison with PEG/albumin nanogel coatings.
Clickable nanogel solutions were synthesized by using the copper catalyzed azide/alkyne cycloaddition (CuAAC) to partially polymerize solutions of azide and alkyne functionalized poly(ethylene glycol) (PEG) monomers. Coatings were fabricated using a second click reaction: a UV thiol-yne attachment of the nanogel solutions to mercaptosilanated glass. Because the CuAAC reaction was effectively halted by the addition of a copper-chelator, we were able to prevent bulk gelation and limit the coating thickness to a single monolayer of nanogels in the absence of the solution reaction. This enabled the inclusion of kosmotropic salts, which caused the PEG to phase-separate and nearly double the nanogel packing density, as confirmed by quartz crystal microbalance with dissipation (QCM-D). Protein adsorption was analyzed by single molecule counting with total internal reflection fluorescence (TIRF) microscopy and cell adhesion assays. Coatings formed from the phase-separated clickable nanogel solutions attached with salt adsorbed significantly less fibrinogen than other 100% PEG coatings tested, as well as poly(L-lysine)-g-PEG (PLL-g-PEG) coatings. However, PEG/albumin nanogel coatings still outperformed the best 100% PEG clickable nanogel coatings. Additional surface cross-linking of the clickable nanogel coating in the presence of copper further reduced levels of fibrinogen adsorption closer to those of PEG/albumin nanogel coatings. However, this step negatively impacted long-term resistance to cell adhesion and dramatically altered the morphology of the coating by atomic force microscopy (AFM). The main benefit of the click strategy is that the partially polymerized solutions are stable almost indefinitely, allowing attachment in the phase-separated state without danger of bulk gelation, and thus producing the best performing 100% PEG coating that we have studied to date.


Catching Fish and Avoiding Sharks: Investigating Factors That Influence Developmentally Appropriate Measurement of Preschoolers' Inhibitory Control.
Although researchers agree that the first 5 years of life are critical for children's developing executive functions (EFs), further advances are hindered by a lack of consensus on the design and selection of developmentally appropriate EF tasks for young children. Given this debate, well-established adult measures of EF routinely have been adapted for young children. Given young children's comparatively limited cognitive capacities, however, such adaptations do not guarantee that the task's critical EF demands are retained. To investigate this possibility, the current study examined the characteristics that optimize measurement of young children's EFs-specifically, their inhibitory control-using the go/no-go (GNG) task as an exemplar. Sixty preschoolers completed six GNG tasks differing in stimulus animation, presentation time, and response location. Comparison EF tasks were administered to examine concurrent validity of GNG variants. Results indicated effects of stimulus presentation time and response location, with animation further enhancing task validity and reliability. This suggests that current GNG tasks deflate estimates of young children's ability to inhibit, with implications for future design and selection of developmentally appropriate EF tasks.


Impact of comprehensive care on health care use among a cohort of marginalized people living with hepatitis C in Toronto.
The majority of new hepatitis C (HCV) cases occur among people who inject drugs. In recent years, multidisciplinary models of HCV treatment have emerged that demonstrate successful treatment outcomes for this population, as well as broad positive individual- and system-level impacts. Our objective was to evaluate changes in health care use among a cohort of people living with HCV before and after engagement with one such program. Program data were uniquely linked to provincial health administrative databases. Rates of emergency department (ED) visits and hospital admissions of clients from 2011 through 2015 (N = 103) were evaluated using linkages with administrative data for the 2 years before and after program initiation. Data were evaluated using negative binomial regression models with a covariance structure to account for within-individual correlations. Results: Of participants, 72.8% were men (mean age 47 years), and 38% experienced high rates of physical and mental health comorbidity (Aggregated Diagnosis Group score ≥10). Female clients had significantly fewer ED visits 2 years after program initiation (5.04 versus 3.12; risk ratio [RR] 0.61 [95% CI 0.44% to 0.86%]). ED visits for infectious diseases and soft tissue injury were significantly lower for the cohort overall (RRs 0.58 0.51 [95% CIs 0.35% to 0.95% and 0.29% to 0.90%], respectively). Co-locating HCV treatment within comprehensive primary care and harm reduction services appears to have benefits beyond HCV, including a reduction in ED visits among women and a decrease in ED visits for soft tissue infections for all participants.


Gene selection in cancer classification using sparse logistic regression with Bayesian regularization.
Gene selection algorithms for cancer classification, based on the expression of a small number of biomarker genes, have been the subject of considerable research in recent years. Shevade and Keerthi propose a gene selection algorithm based on sparse logistic regression (SLogReg) incorporating a Laplace prior to promote sparsity in the model parameters, and provide a simple but efficient training procedure. The degree of sparsity obtained is determined by the value of a regularization parameter, which must be carefully tuned in order to optimize performance. This normally involves a model selection stage, based on a computationally intensive search for the minimizer of the cross-validation error. In this paper, we demonstrate that a simple Bayesian approach can be taken to eliminate this regularization parameter entirely, by integrating it out analytically using an uninformative Jeffrey's prior. The improved algorithm (BLogReg) is then typically two or three orders of magnitude faster than the original algorithm, as there is no longer a need for a model selection step. The BLogReg algorithm is also free from selection bias in performance estimation, a common pitfall in the application of machine learning algorithms in cancer classification. The SLogReg, BLogReg and Relevance Vector Machine (RVM) gene selection algorithms are evaluated over the well-studied colon cancer and leukaemia benchmark datasets. The leave-one-out estimates of the probability of test error and cross-entropy of the BLogReg and SLogReg algorithms are very similar, however the BlogReg algorithm is found to be considerably faster than the original SLogReg algorithm. Using nested cross-validation to avoid selection bias, performance estimation for SLogReg on the leukaemia dataset takes almost 48 h, whereas the corresponding result for BLogReg is obtained in only 1 min 24 s, making BLogReg by far the more practical algorithm. BLogReg also demonstrates better estimates of conditional probability than the RVM, which are of great importance in medical applications, with similar computational expense. A MATLAB implementation of the sparse logistic regression algorithm with Bayesian regularization (BLogReg) is available from http://theoval.cmp.uea.ac.uk/~gcc/cbl/blogreg/


Effects of alpha lipoic acid as a supplement in obese children and adolescents.
Obesity is significantly associated with inflammatory process and oxidative stress. Alpha lipoic acid (ALA) is a potent antioxidant that has been reported for reducing weight in animals and obese adults in several studies but no data are available in pediatrics. We investigated the possible beneficial role of ALA in obese children. Eighty obese children and adolescents were randomized into two groups; the treatment group (n = 40) who received 300 mg of ALA twice daily for 3 months and the control group (n = 40) who received placebo for 3 months. Measurements of weight, body mass index (BMI), lipid profile, fasting blood glucose (FBG), malondialdhyde (MDA), tumor necrosis factor alpha (TNF-α), leptin and adiponectin were carried out before and 3 months after the treatment. ALA treatment group had a significant reduction of the weight, BMI, MDA, TNF-α, and leptin levels but a significant increase of adiponectin level (P < 0.05) compared to the control group. However, it had no effect on FBG or lipid profile (P > 0.05). ALA may be a promising supplement in the weight reduction in obese children and adolescents.


Behavioural flexibility allows an invasive vertebrate to survive in a semi-arid environment.
Plasticity or evolution in behavioural responses are key attributes of successful animal invasions. In northern Australia, the invasive cane toad (Rhinella marina) recently invaded semi-arid regions. Here, cane toads endure repeated daily bouts of severe desiccation and thermal stress during the long dry season (April-October). We investigated whether cane toads have shifted their ancestral nocturnal rehydration behaviour to one that exploits water resources during the day. Such a shift in hydration behaviour could increase the fitness of individual toads by reducing exposure to desiccation and thermal stress suffered during the day even within terrestrial shelters. We used a novel method (acoustic tags) to monitor the daily hydration behaviour of 20 toads at two artificial reservoirs on Camfield station, Northern Territory. Remarkably, cane toads visited reservoirs to rehydrate during daylight hours, with peaks in activity between 9.00 and 17.00. This diurnal pattern of rehydration activity contrasts with nocturnal rehydration behaviour exhibited by adult toads in their native geographical range and more mesic parts of Australia. Our results demonstrate that cane toads phase shift a key behaviour to survive in a harsh semi-arid landscape. Behavioural phase shifts have rarely been reported in invasive species but could facilitate ongoing invasion success.


Influence of contact heterogeneity on TB reproduction ratio R0 in a free-living brushtail possum Trichosurus vulpecula population.
Social network analyses were used to investigate contact patterns in a free-living possum Trichosurus vulpecula population and to estimate the influence of contact on R(0) for bovine tuberculosis (TB). Using data collected during a five-year capture-mark-recapture study of a free-living possum population, observed estimates of R(0) were computed and compared with R(0) computed from random networks of similar size that approximated a random mixing process. All networks displayed a heterogeneous pattern of contact with the average number of contacts per possum ranging from 20 to 26 per year. The networks consistently showed small-world and single-scale features. The mean estimates of R(0) for TB using the observed contact networks were 1.78, 1.53, 1.53, 1.51, and 1.52 times greater than the corresponding random networks (P <0.05). We estimate that TB would spread if an average of between 1.94 and 1.97 infective contacts occurred per year per infected possum, which is approximately half of that expected from a random network. These results have implications for the management of TB in New Zealand where the possum is the principal wildlife reservoir host of Mycobacterium bovis, the causal agent of bovine TB. This study argues the relevance of refining epidemiological models used to inform disease management policy to account for contact heterogeneity.


Genetic risk prediction in complex disease.
Attempting to classify patients into high or low risk for disease onset or outcomes is one of the cornerstones of epidemiology. For some (but by no means all) diseases, clinically usable risk prediction can be performed using classical risk factors such as body mass index, lipid levels, smoking status, family history and, under certain circumstances, genetics (e.g. BRCA1/2 in breast cancer). The advent of genome-wide association studies (GWAS) has led to the discovery of common risk loci for the majority of common diseases. These discoveries raise the possibility of using these variants for risk prediction in a clinical setting. We discuss the different ways in which the predictive accuracy of these loci can be measured, and survey the predictive accuracy of GWAS variants for 18 common diseases. We show that predictive accuracy from genetic models varies greatly across diseases, but that the range is similar to that of non-genetic risk-prediction models. We discuss what factors drive differences in predictive accuracy, and how much value these predictions add over classical predictive tests. We also review the uses and pitfalls of idealized models of risk prediction. Finally, we look forward towards possible future clinical implementation of genetic risk prediction, and discuss realistic expectations for future utility.


Angiotensin-(1-7) Receptor Mas in Hemodynamic and Thermoregulatory Dysfunction After High-Level Spinal Cord Injury in Mice: A Pilot Study.
Spinal cord injury (SCI) above mid-thoracic levels leads to autonomic dysfunction affecting both the cardiovascular system and thermoregulation. The renin-angiotensin system (RAS) which is a potent regulator of blood pressure, including its novel beneficial arm with the receptor Mas could be an interesting target in post-SCI hemodynamics. To test the hypothesis that hemodynamics, activity and diurnal patterns of those are more affected in the Mas deficient mice post-SCI we used a mouse model of SCI with complete transection of spinal cord at thoracic level 4 (T4-Tx) and performed telemetric monitoring of blood pressure (BP) and heart rate (HR). Our data revealed that hypothermia deteriorated physiological BP and HR control. Preserving normothermia by keeping mice at 30°C prevented severe hypotension and bradycardia post-SCI. Moreover, it facilitated rapid return of diurnal regulation of BP, HR and activity in wild type (WT) mice. In contrast, although Mas deficient mice had comparable reacquisition of diurnal HR rhythm, they showed delayed recovery of diurnal rhythmicity in BP and significantly lower nocturnal activity. Exposing mice with T4-Tx (kept in temperature-controlled cages) to 23°C room temperature for one hour at different time-points post-SCI, demonstrated their inability to maintain core body temperature, Mas deficient mice being significantly more impaired than WT littermates. We conclude that Mas deficient mice were more resistant to acute hypotension, delayed nocturnal recovery, lower activity and more severely impaired thermoregulation. The ambient temperature had significant effect on hemodynamics and, thus it should be taken into account when assessing cardiovascular parameters post-SCI in mice.


Role of Mitogen-Activated Protein Kinases in Myocardial Ischemia-Reperfusion Injury during Heart Transplantation.
In solid organ transplantation, ischemia/reperfusion (IR) injury during organ procurement, storage and reperfusion is an unavoidable detrimental event for the graft, as it amplifies graft inflammation and rejection. Intracellular mitogen-activated protein kinase (MAPK) signaling pathways regulate inflammation and cell survival during IR injury. The four best-characterized MAPK subfamilies are the c-Jun NH2-terminal kinase (JNK), extracellular signal- regulated kinase-1/2 (ERK1/2), p38 MAPK, and big MAPK-1 (BMK1/ERK5). Here, we review the role of MAPK activation during myocardial IR injury as it occurs during heart transplantation. Most of our current knowledge regarding MAPK activation and cardioprotection comes from studies of preconditioning and postconditioning in nontransplanted hearts. JNK and p38 MAPK activation contributes to myocardial IR injury after prolonged hypothermic storage. p38 MAPK inhibition improves cardiac function after cold storage, rewarming and reperfusion. Small-molecule p38 MAPK inhibitors have been tested clinically in patients with chronic inflammatory diseases, but not in transplanted patients, so far. Organ transplantation offers the opportunity of starting a preconditioning treatment before organ procurement or during cold storage, thus modulating early events in IR injury. Future studies will need to evaluate combined strategies including p38 MAPK and/or JNK inhibition, ERK1/2 activation, pre- or postconditioning protocols, new storage solutions, and gentle reperfusion.


Hospital Readmissions After Continuous-Flow Left Ventricular Assist Device Implantation: Incidence, Causes, and Cost Analysis.
We investigated the incidence and causes of unplanned hospital readmissions after continuous-flow (CF) left ventricular assist device (LVAD) implantation. We also analyzed the impact of unplanned readmissions on post-CF-LVAD survival and the costs associated with each cause of readmission. We retrospectively reviewed 126 patients who underwent implantation with a CF-LVAD from January 2007 to December 2013. The timing of readmissions, hospital length of stay, and total length of device support were evaluated. Patients were followed up while receiving support, until transplantation, or until death. Direct hospital costs associated with each readmission were analyzed. In all, 103 patients underwent implantation for bridge to transplantation and 19 patients for destination therapy; 68 patients were readmitted 156 times (2.2 times/patient) as of the end of follow-up. The median follow-up period was 11 months. While receiving device support, patients spent 93% of their time out of the hospital. The causes of readmission included gastrointestinal bleeding (19%), driveline infection (13%), and stroke (8%). The median time to first readmission was 35 days. Thirty (44%) patients were readmitted within 30 days after discharge. The median direct hospital cost of a single readmission was $7,546. Device malfunction and arrhythmias were the most costly causes of readmission. There was no significant difference in long-term survival between readmitted patients and those who were not readmitted. Gastrointestinal bleeding and CF-LVAD-related infections were the leading causes of readmission. Patients with a CF-LVAD spent 93% of their time out of hospital after implantation, and readmissions did not have a negative impact on long-term survival. New approaches to minimize these adverse events will continue to improve the efficacy and decrease the cost of CF-LVAD therapy.


Analysis of replication error (RER+) phenotypes in cervical carcinoma.
Infection of epithelial cells with human papillomavirus is an important early event in the development of cervical dysplasia. However, progression to overt malignancy appears dependent upon further genetic and/or epigenetic events. We have recently developed methodologies for the simultaneous analysis of loss of heterozygosity (LOH) at multiple PCR-based microsatellite loci using semiautomated fluorescent DNA sequencing technology to determine the locations of tumor suppressor genes which are inactivated during tumor progression. While examining 30 microsatellite loci for LOH on chromosomes 3p, 4, and 11q, we detected novel tumor-specific alleles indicative of microsatellite instability (MI). The methodology allowed rapid and accurate comparison of over 3000 genotypes from 89 primary tumors and 10 cervical carcinoma-derived cell lines and showed that five tumors (5.6%) and one human papillomavirus-negative cell line, C33A, had genetic features consistent with a replication error (RER+) phenotype as defined by MI at two or more loci. In each of the RER+ tumors, LOH was also observed at one or more loci on each of the three chromosomes examined. These findings suggest that defects in DNA repair-associated genes are rarely acquired and do not supersede allelic loss during cervical carcinogenesis. In addition, the semiautomated multiplex approach has proven unequivocal in the detection and interpretation of MI and should greatly accelerate the rapidity and accuracy of analysis of such defects in tumors. Moreover, the number of loci that can be relatively easily examined in this way will also allow a detailed statistical consideration of the importance of such events.


Functionally important residues in the predicted 3(rd) transmembrane domain of the type IIa sodium-phosphate co-transporter (NaPi-IIa).
The type IIa Na(+)/P(i), cotransporter (NaPi-IIa) mediates electrogenic transport of three Na(+) and one divalent P(i) ion (and one net positive charge) across the cell membrane. Sequence comparison of electrogenic NaPi-IIa and IIb isoforms with the electroneutral NaPi-IIc isoform pointed to the third transmembrane domain (TMD-3) as a possibly significant determinant of substrate binding. To elucidate the role of TMD-3 in the topology and mechanism underlying NaPi-IIa function we subjected it to cysteine scanning mutagenesis. The constructs were expressed in Xenopus oocytes and P(i) transport kinetics were assayed by electrophysiology and radiotracer uptake. Cys substitution resulted in only marginally altered kinetics of P(i) transport in those mutants providing sufficient current for analysis. Only one site, at the extracellular end of TMD-3, appeared to be accessible to methanethiosulfonate reagents. However, additional mutations carried out at D224 (replaced by E, G or N) and N227 (replaced by D or Q) resulted in markedly altered voltage and substrate dependencies of the P(i)-dependent currents. Replacing Asp-224 (highly conserved in electrogenic a and b isoforms) with Gly (the residue found in the electroneutral c isoform) resulted in a mutant that mediated electroneutral Na(+)-dependent P(i) transport. Since electrogenic NaPi-II transports 3 Na(+)/transport cycle, whereas electroneutral NaPi-IIc only transports 2, we speculate that this loss of electrogenicity might result from the loss of one of the three Na(+) binding sites in NaPi-IIa.


Sparse representation based image interpolation with nonlocal autoregressive modeling.
Sparse representation is proven to be a promising approach to image super-resolution, where the low-resolution (LR) image is usually modeled as the down-sampled version of its high-resolution (HR) counterpart after blurring. When the blurring kernel is the Dirac delta function, i.e., the LR image is directly down-sampled from its HR counterpart without blurring, the super-resolution problem becomes an image interpolation problem. In such cases, however, the conventional sparse representation models (SRM) become less effective, because the data fidelity term fails to constrain the image local structures. In natural images, fortunately, many nonlocal similar patches to a given patch could provide nonlocal constraint to the local structure. In this paper, we incorporate the image nonlocal self-similarity into SRM for image interpolation. More specifically, a nonlocal autoregressive model (NARM) is proposed and taken as the data fidelity term in SRM. We show that the NARM-induced sampling matrix is less coherent with the representation dictionary, and consequently makes SRM more effective for image interpolation. Our extensive experimental results demonstrate that the proposed NARM-based image interpolation method can effectively reconstruct the edge structures and suppress the jaggy/ringing artifacts, achieving the best image interpolation results so far in terms of PSNR as well as perceptual quality metrics such as SSIM and FSIM.


Three-bit representation of three-dimensional range data.
Our previous research has shown that 3D range data sizes can be substantially reduced if they are converted into regular 2D images using the Holoimage technique. Yet, this technique requires all 24 bits of a standard image to represent one 3D point, making it impossible for a regular 2D image to carry 2D texture information as well. This paper proposes an approach to represent 3D range data with 3 bits, further reducing the data size. We demonstrate that more than an 8.2:1 compression ratio can be achieved with compression root-mean-square error of only 0.34%. Moreover, we can use another bit to represent a black-and-white 2D texture, and thus both 3D data and 2D texture images can be stored into an 8 bit grayscale image. Both simulation and experiments are presented to verify the performance of the proposed technique.


Graduate Education and Social Stratification.
Graduate and professional education play an increasingly important role in economic inequality and elite formation in the United States, but sociologists have not subjected stratification in and through graduate education to the same level of scrutiny recently applied to undergraduate and sub-baccalaureate education. In this review, we discuss how prominent stratification theories might be extended to studies of the role of graduate and professional education, and we review research about stratification at junctures along student pathways into and through postbaccalaureate education to the labor market. Especially in doctoral and professional education, we find persistent stratification, including pronounced educational inheritance and disparities in participation and degree attainment by race/ethnicity and gender. We propose future directions for inquiry, highlighting unanswered questions and conceptual issues concerning how the field of and pathways through postbaccalaureate education contribute to social stratification.


Use of octreotide in the symptomatic management of diarrhea induced by graft-versus-host disease in patients with hematologic malignancies.
Diarrhea associated with acute gastrointestinal (GI) graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT) can result in severe morbidity and mortality. A pilot study was conducted to evaluate the efficacy and toxicity of octreotide in the management of diarrhea in patients with GVHD after allogeneic BMT. Twenty-one patients entered the study. Patients received either peripheral-blood stem cells (n = 13) or bone marrow (n = 8). Seven patients had grade 4, 13 grade 3, and one grade 2 GVHD. Intravenous (I.V.) octreotide 500 microg every 8 hours for 7 days was administered. Octreotide treatment was discontinued if no response was observed after 7 days or for grade 4 toxicity. Fifteen (71%) of 21 treated patients had a complete response within 7 days of the initiation of octreotide; three (14%) had a partial response and three (14%) failed to respond to treatment. Toxicities were minimal; hyperglycemia was seen in four patients and one patient developed a partial ileus. Octreotide was discontinued and the ileus resolved within 48 hours. If initiated early in the course of GI GVHD, octreotide appears to be an effective, well-tolerated agent in reducing severe voluminous diarrhea. Octreotide should be discontinued within 24 hours after the resolution of diarrhea to avoid the development of ileus. Because no additional reduction in the volume of diarrhea occurred after 7 days of therapy, continuation of the drug beyond this time is not cost effective.


First-time events between parents and preterm infants are affected by the designs and routines of neonatal intensive care units.
Early parental bonding with preterm babies is particularly important, and the aim of our study was to explore when parents experienced what they regarded as important events for the first time while their infant was in the neonatal intensive care unit (NICU). The study was part of a longitudinal project on Kangaroo Mother Care at two Swedish university hospitals. The parents of 81 infants completed questionnaires during their infants' hospital stay. Most parents saw and touched their infants immediately after birth, but only a few could hold them skin to skin or swaddle them. Other important events identified by parents included the first time they performed care giving activities and did so independently, interaction and closeness with the infant, signs of the infant's recovery and integration into the family. The timing of the events depended on the physical design of the NICU, whether parents' could stay with their infant round-the-clock and when they were allowed to provide care under supervision and on their own. The design and routines of the NICU dictated when parents first interacted with their infants. Clinical guidelines that facilitate early contact with preterm babies can help parents to make the transition to their parental role.


Structure and ligand based drug design strategies in the development of novel 5- LOX inhibitors.
Lipoxygenases (LOXs) are non-heme iron containing dioxygenases involved in the oxygenation of polyunsaturated fatty acids (PUFAs) such as arachidonic acid (AA). Depending on the position of insertion of oxygen, LOXs are classified into 5-, 8-, 9-, 12- and 15-LOX. Among these, 5-LOX is the most predominant isoform associated with the formation of 5-hydroperoxyeicosatetraenoic acid (5- HpETE), the precursor of non-peptido (LTB4) and peptido (LTC4, LTD4, and LTE4) leukotrienes. LTs are involved in inflammatory and allergic diseases like asthma, ulcerative colitis, rhinitis and also in cancer. Consequently 5-LOX has become target for the development of therapeutic molecules for treatment of various inflammatory disorders. Zileuton is one such inhibitor of 5-LOX approved for the treatment of asthma. In the recent times, computer aided drug design (CADD) strategies have been applied successfully in drug development processes. A comprehensive review on structure based drug design strategies in the development of novel 5-LOX inhibitors is presented in this article. Since the crystal structure of 5-LOX has been recently solved, efforts to develop 5-LOX inhibitors have mostly relied on ligand based rational approaches. The present review provides a comprehensive survey on these strategies in the development of 5-LOX inhibitors.


Acetylcholinesterase in Hirschsprung's disease.
The association between the congenital absence of colonic ganglion cells and an increased acetylcholinesterase (AChE) expression in the affected tissue is of diagnostic importance in Hirschsprung's disease (HSCR). Investigation of AChE's function in development may also help unravel some of the complex pathophysiology in HSCR. Normal nerves do not stain for AChE, but increased AChE expression is associated with the hypertrophied extrinsic nerve fibres of the aganglionic segment in HSCR. Although a high degree of histochemical diagnostic accuracy exists, results are not always uniform, and false positives and false negatives are reported. False negative results are primarily related to age, and an absence of AChE reaction does not exclude HSCR in neonates within the first 3 weeks after birth. AChE staining results may lack uniformity, resulting in a number of technical modifications that have been made to improve standardization of AChE staining. At least two distinct histological patterns are described, types A and B. The interpretation of increased AChE staining patterns in ganglionated bowel at the time of surgical pull-through remains a problem in patients with HSCR. The development of rapid staining techniques has helped to identify normal ganglionated bowel with greater certainty. The presence of fine AChE neurofibrils in the ganglionated segment has contributed to the debate surrounding intestinal neuronal dysplasia. Quantitative assay of cholinesterase activity confirms the pattern of histochemical staining. AChE is particularly increased in relation to butrylcholinesterase, with one molecular form, the G4 tetrameric form, predominating. It is likely that the raised levels of AChE in aganglionic tissue are the transcriptional consequence of the abnormalities in signalling molecules that characterize HSCR. Evidence suggests that this AChE is functioning in a nonenzymatic capacity to promote cell adhesion and differentiation and that the hypertrophied nerves and neurofibrils may be the result of this increased AChE expression.


Laminin peptides stimulate human neutrophil motility.
Laminin, isolated from Engelbreth-Holm-Swarm tumor, and 10 chemically synthesized peptides, corresponding to various regions of the laminin A and B1 chains, were compared for their abilities to stimulate human peripheral blood polymorphonuclear leukocyte (PMN) chemotaxis and chemokinesis through polycarbonate membrane filters in a 48-well microchemotaxis assay. Peptides F-9, F-11, F-12, and F-13 were derived from the B1 chain of laminin at the intersection of the cross, and six peptides were derived from the laminin A chain: peptide TG-1 from the amino-terminal top globule; peptides GD-1, GD-3, GD-6, and GD-7 from the carboxyl-terminal globular domain; and peptide AG-1 from above the carboxyl-terminal globular domain. Laminin and the peptides were evaluated over a concentration range of 1 to 200 micrograms/ml in motility assays. Six of the peptides, F-9, F-12, GD-1, GD-3, GD-6, and TG-1, stimulated human PMN migration in the absence of a gradient (chemokinesis). A fluorescein conjugate of the most active laminin peptide, GD-1, exhibited nonspecific, nonsaturable binding to PMN. Intact laminin and the other peptides failed to stimulate human PMN migration. In contrast, intact Engelbreth-Holm-Swarm laminin stimulated rabbit peripheral blood PMN chemokinesis. These results demonstrate that rabbit and human peripheral blood PMNs have divergent migratory responses to intact laminin. These findings suggest that intact basement membrane laminin does not directly stimulate human blood PMN motility in vivo, but that selected laminin peptide sequences, which may be generated during proteolytic digestion of laminin, can activate human PMN migration.


Hard-x-ray lensless imaging of extended objects.
We demonstrate a hard-x-ray microscope that does not use a lens and is not limited to a small field of view or an object of finite size. The method does not suffer any of the physical constraints, convergence problems, or defocus ambiguities that often arise in conventional phase-retrieval diffractive imaging techniques. Calculation times are about a thousand times shorter than in current iterative algorithms. We need no a priori knowledge about the object, which can be a transmission function with both modulus and phase components. The technique has revolutionary implications for x-ray imaging of all classes of specimen.


Pd-Catalyzed C-H aziridination of 3,3,5,5-tetrasubstituted piperazin-2-ones.
A palladium mediated C-H aziridination reaction of 3,3,5,5-substituted-piperazin-2-ones has been developed using phenyliodonium diacetate (PIDA) and succinic acid to give synthetically useful bicyclic aziridines, in moderate to good yields. Succinic acid was found to be key for selectively promoting C-N bond formation (aziridination) and suppressing competitive acetoxylation. Analysis of the reaction kinetics revealed the role of succinic acid in promoting an equilibrium between monomeric and dimeric palladium species in the rate determining step of the reaction. The aziridines can be ring-opened by nucleophiles under Lewis or Brønsted acidic conditions to give formal C-H functionalized products. The reaction conditions can be further manipulated to produce acetoxylated, diacetoxylated and even triacetoxylated materials through the use of acetic acid and increased oxidant stoichiometry.


Movement distributions of stroke survivors exhibit distinct patterns that evolve with training.
While clinical assessments provide tools for characterizing abilities in motor-impaired individuals, concerns remain over their repeatability and reliability. Typical robot-assisted training studies focus on repetition of prescribed actions, yet such movement data provides an incomplete account of abnormal patterns of coordination. Recent studies have shown positive effects from self-directed movement, yet such a training paradigm leads to challenges in how to quantify and interpret performance. With data from chronic stroke survivors (n = 10, practicing for 3 days), we tabulated histograms of the displacement, velocity, and acceleration for planar motion, and examined whether modeling of distributions could reveal changes in available movement patterns. We contrasted these results with scalar measures of the range of motion. We performed linear discriminant analysis (LDA) classification with selected histogram features to compare predictions versus actual subject identifiers. As a basis of comparison, we also present an age-matched control group of healthy individuals (n = 10, practicing for 1 day). Analysis of range of motion did not show improvement from self-directed movement training for the stroke survivors in this study. However, examination of distributions indicated that increased multivariate normal components were needed to accurately model the patterns of movement after training. Stroke survivors generally exhibited more complex distributions of motor exploration compared to the age-matched control group. Classification using linear discriminant analysis revealed that movement patterns were identifiable by individual. Individuals in the control group were more difficult to identify using classification methods, consistent with the idea that motor deficits contribute significantly to unique movement signatures. Distribution analysis revealed individual patterns of abnormal coordination in stroke survivors and changes in these patterns with training. These findings were not apparent from scalar metrics that simply summarized properties of motor exploration. Our results suggest new methods for characterizing motor capabilities, and could provide the basis for powerful tools for designing customized therapy.


Regional Cerebral Abnormalities Measured by Frequency-Domain Near-Infrared Spectroscopy in Pediatric Patients During Extracorporeal Membrane Oxygenation.
Extracorporeal membrane oxygenation (ECMO) is a form of advanced cardiorespiratory support provided to critically ill patients with severe respiratory or cardiovascular failure. While children undergoing ECMO therapy have significant risk for neurological morbidity, currently there is a lack of reliable bedside tool to detect the neurologic events for patients on ECMO. This study assessed the feasibility of frequency-domain near-infrared spectroscopy (NIRS) for detection of intracranial complications during ECMO therapy. The frequency-domain NIRS device measured the absorption coefficient (µa) and reduced scattering coefficient (µs') at six cranial positions from seven pediatric patients (0-16 years) during ECMO support and five healthy controls (2-14 years). Regional abnormalities in both absorption and scattering were identified among ECMO patients. A main finding in this study is that the abnormalities in scattering appear to be associated with lower-than-normal µs' values in regional areas of the brain. Because light scattering originates from the intracellular structures (such as nuclei and mitochondria), a reduction in scattering primarily reflects loss or decreased density of the brain matter. The results from this study indicate a potential to use the frequency-domain NIRS as a safe and complementary technology for detection of intracranial complications during ECMO therapy.


The CDC's Second National Report on Biochemical Indicators of Diet and Nutrition in the U.S. Population is a valuable tool for researchers and policy makers.
The CDC's National Report on Biochemical Indicators of Diet and Nutrition in the U.S. Population (Nutrition Report) is a serial publication that provides ongoing assessment of the population's nutritional status. The Nutrition Report presents data on blood and urine biomarker concentrations (selected water- and fat-soluble vitamins and nutrients, trace elements, dietary bioactive compounds) from a representative sample of the population participating in the NHANES. The Second Nutrition Report (released in 2012) contains reference information (means and percentiles) for 58 biomarkers measured during all or part of 2003-2006, stratified by age, sex, and race-ethnicity. Where available, we presented cutoff-based prevalence data during 2003-2006 and data on changes in biomarker concentrations or prevalence since 1999. Blood vitamin concentrations were generally higher in older (≥ 60 y) than in younger (20-39 y) adults and lower in Mexican Americans and non-Hispanic blacks than in non-Hispanic whites. Nearly 80% of Americans (aged ≥ 6 y) were not at risk of deficiencies in any of the 7 vitamins studied (vitamins A, B-6, B-12, C, D, and E and folate). Deficiency rates varied by age, sex, and race-ethnicity. Approximately 90% of women (aged 12-49 y) were not at risk of iron deficiency, but only 68% were not at risk of deficiencies in iron and all 7 vitamins. Young women (20-39 y) had median urine iodine concentrations bordering on insufficiency. First-time data are presented on plasma concentrations of 24 saturated and mono- and polyunsaturated fatty acids. Tabulation and graphical presentation of NHANES data in the Second Nutrition Report benefits those organizations involved in developing and evaluating nutrition policy.


Fragile X premutation carriers: characteristic MR imaging findings of adult male patients with progressive cerebellar and cognitive dysfunction.
Our purpose was to characterize the findings of MR imaging of the brain of adult male fragile X premutation carriers with a recently identified disorder characterized by ataxia, tremor, rigidity, and cognitive dysfunction. MR imaging studies of the brain of 17 male patients were characterized for signal intensity and for size of ventricles, cerebral and cerebellar sulci, and brain stem. Comparison was made with age- and sex-matched control participants. Southern blot and/or polymerase chain reaction methods were used to analyze CGG trinucleotide repeats in the fragile X mental retardation 1 gene. Fifteen of 17 patients showed symmetrically decreased T1 and increased T2 signal intensity in cerebellar white matter lateral, superior, and inferior to the dentate nuclei. Fourteen of 17 had similar signal intensity alterations in the middle cerebellar peduncles. Cerebellar cortical atrophy was present in 16 of 17 and cerebral atrophy in 17 of 17. Evan's Index as a measure of ventricular size averaged 0.35 (range, 0.25-0.46), with that for age-matched control participants averaging 0.28 (range, 0.24-0.31) (P <.005). The mean third ventricle width was 11 mm (for control participants, 6 mm; P <.01). Corpus callosum was thinned in 14 of 16 participants. Middle cerebellar peduncles were atrophic when compared with those of control participants (P <.005). Pontine transverse dimension was 25 mm (for control participants, 31 mm; P <.005), and rostral-caudal length averaged 26 mm (for control participants, 29 mm; P <.005). CGG repeats clustered in the low to mid premutation range (86 +/- 10 CGG repeats) in the 17 patients. MR imaging findings in symptomatic male fragile X premutation carriers are characteristic of this disorder. Recognition of these alterations may support a specific diagnosis and may have implications for the potential occurrence of fragile X syndrome in the children of reproductive age female relatives.


LRRTM1 on chromosome 2p12 is a maternally suppressed gene that is associated paternally with handedness and schizophrenia.
Left-right asymmetrical brain function underlies much of human cognition, behavior and emotion. Abnormalities of cerebral asymmetry are associated with schizophrenia and other neuropsychiatric disorders. The molecular, developmental and evolutionary origins of human brain asymmetry are unknown. We found significant association of a haplotype upstream of the gene LRRTM1 (Leucine-rich repeat transmembrane neuronal 1) with a quantitative measure of human handedness in a set of dyslexic siblings, when the haplotype was inherited paternally (P=0.00002). While we were unable to find this effect in an epidemiological set of twin-based sibships, we did find that the same haplotype is overtransmitted paternally to individuals with schizophrenia/schizoaffective disorder in a study of 1002 affected families (P=0.0014). We then found direct confirmatory evidence that LRRTM1 is an imprinted gene in humans that shows a variable pattern of maternal downregulation. We also showed that LRRTM1 is expressed during the development of specific forebrain structures, and thus could influence neuronal differentiation and connectivity. This is the first potential genetic influence on human handedness to be identified, and the first putative genetic effect on variability in human brain asymmetry. LRRTM1 is a candidate gene for involvement in several common neurodevelopmental disorders, and may have played a role in human cognitive and behavioral evolution.


Orthology relations, symbolic ultrametrics, and cographs.
Orthology detection is an important problem in comparative and evolutionary genomics and, consequently, a variety of orthology detection methods have been devised in recent years. Although many of these methods are dependent on generating gene and/or species trees, it has been shown that orthology can be estimated at acceptable levels of accuracy without having to infer gene trees and/or reconciling gene trees with species trees. Thus, it is of interest to understand how much information about the gene tree, the species tree, and their reconciliation is already contained in the orthology relation on the underlying set of genes. Here we shall show that a result by Böcker and Dress concerning symbolic ultrametrics, and subsequent algorithmic results by Semple and Steel for processing these structures can throw a considerable amount of light on this problem. More specifically, building upon these authors' results, we present some new characterizations for symbolic ultrametrics and new algorithms for recovering the associated trees, with an emphasis on how these algorithms could be potentially extended to deal with arbitrary orthology relations. In so doing we shall also show that, somewhat surprisingly, symbolic ultrametrics are very closely related to cographs, graphs that do not contain an induced path on any subset of four vertices. We conclude with a discussion on how our results might be applied in practice to orthology detection.


Cancer Core Europe: A translational research infrastructure for a European mission on cancer.
Cancer Core Europe is a European legal alliance consisting of seven leading cancer centres - most of them Comprehensive Cancer Centres (CCCs) - with a single portal system to engage in various research projects with partners. Cancer Core Europe was established to create a sustainable, high-level, shared research infrastructure platform hosting research collaborations and task forces (data sharing, clinical trials, genomics, immunotherapy, imaging, education and training, and legal and ethical issues), with a controlled expansion agenda. Translational cancer research covers the cancer research continuum from basic to preclinical to early clinical, late clinical, and outcomes research. Basic-preclinical research serves as the 'engine' for early clinical research by bridging the early translational research gap and is the primary and current focus of the consortium as exemplified by the launching of the Basket of Baskets trial, Europe's largest precision cancer medicine trial. Inspired by the creation of Cancer Core Europe, the prevention community established Cancer Prevention Europe, a consortium of ten cancer prevention centres aimed at supporting the complete prevention research continuum. Presently, Cancer Core Europe and Cancer Prevention Europe are integrating therapeutics and prevention strategies to address in partnership the widening cancer problem. By providing innovative approaches for cancer research, links to healthcare systems, development of quality-assured multidisciplinary cancer care, and assessment of long-term outcomes, the virtual infrastructure will serve as a hub to connect and interact with other centres across Europe and beyond. Together, Cancer Core Europe and Cancer Prevention Europe are prepared to function as a central engine to tackle, in collaboration with various partners, a potential 'mission on cancer' addressing the cancer burden.


From ecological risk assessments to risk governance: evaluation of the Norwegian management system for contaminated sediments.
Managing of contaminated sediments is a complex process that will naturally have to balance scientific, political, and economic interests. This study evaluates the Norwegian system for managing contaminated sediments toward a generic system for risk governance encompassing both knowledge, legally prescribed procedures, and social values. The review has been performed examining the management plans for 17 prioritized contaminated fjord systems in Norway. The results indicate a strong focus in the Norwegian management system on ecological risk assessment. This facilitates selection of local sustainable remediation measures, but may also complicate the balance toward other relevant interests in a decision-making process. The Norwegian system lacks management tools to identify and handle ambiguity through concern assessments and stakeholder involvement, and the decision-making process seems to a large extent based on ad hoc decisions, making it difficult to incorporate and document multicriteria evaluations into the management process. To develop a sustainable management system, encompassing environmental, economical, and social interests, a stronger focus on concern assessment and multicriteria evaluations is required.


Bright environmental light ameliorates deficient subjective 'liking' in insomnia: an experience sampling study.
Altered comfort sensing and reduced gray matter volume in the orbitofrontal cortex of the brain in people suffering from insomnia disorder (ID) suggest compromised processes of motivation and hedonia. The experience sampling (ES) method was used to evaluate whether, in naturalistic conditions, people with ID differ from those without sleep complaints with respect to subjective Wanting and Liking, two major dimensions of the reward system. Since light affects brain circuits involved in affect and reward, ES was combined with ambulatory monitoring of light intensity fluctuations to evaluate their effect on subjective Wanting and Liking. Participants with ID (n = 17, 12 females, 56.8 ± 6.5 mean ± standard deviation years of age) and matched controls without sleep complaints (n = 18, 12 females, 57.0 ± 8.6 years of age) were probed by a smartphone alarm to log their subjective Wanting, Liking, and mood nine times a day for 7 days. Using an ambulatory light recorder, light intensity exposure was sampled simultaneously and averaged over the intervals between subsequent ES alarms. Mixed-effect models were used to evaluate how ID and varying light intensity affected subjective assessments. The results indicated significantly lower subjective Liking and Wanting in people suffering from ID, particularly at low environmental light intensity. Wanting and Liking, rather than more commonly used mood adjectives, showed an increased sensitivity to detect deficient hedonic and reward processing in insomnia during everyday life. Deficient Liking may in part be rescued by exposure to bright environmental light.


Clothing comfort during physical exercise - Determining the critical factors.
Clothing comfort is determined by multiple material and design factors. Wetness at the skin-clothing interface mainly impacts wear comfort. The current study investigated the combined effect of fabric contact area, fabric absolute sweat content and fabric moisture saturation percentage on wetness and stickiness sensations, during exercise. Moreover, factors causing wear (dis)comfort during exercise were identified. Higher fabric saturation percentage induced greater stickiness sensation, despite lower fabric contact area and absolute sweat content (typically associated with lower stickiness). Wetness perception did not change between fabrics with different saturation percentages, contact areas and sweat contents. Therefore, fabric saturation percentage mainly affects stickiness sensation of wet fabrics, overruling the impact of fabric contact area and absolute sweat content. No overall model of wear discomfort across all data could be developed, however, models for different time points were produced, with texture and stickiness sensations being the best predictors of wear discomfort at baseline and during exercise, respectively. This suggests that the factors determining clothing (dis)comfort are dynamics and alter importance during exercise activity.


Passive Heating: Reviewing Practical Heat Acclimation Strategies for Endurance Athletes.
Heat acclimation protocols-both active and passive-have been employed by athletes in an effort to attenuate the detrimental effects of heat stress on physical capacities and sports performance. Active strategies have been extensively reviewed, but have various practical and economic limitations. The purpose of this review was therefore to provide an overview of the passive strategies that have received less attention, yet may be more practical or economically viable; recommendations for athletes are also provided. With a systematic search of the relevant databases ending in June 2018, 16 articles on passive heat acclimation that met the inclusion criteria were included in the review. The review highlighted that passive heat acclimation strategies can successfully induce heat adaptations, evident by reports of improved exercise performance, thermoregulatory, cardiovascular, and perceptual responses accompanying such interventions. Based on the review it is apparent that the use of sauna, hot-water immersion and environmental chambers may be used to provide heat stress under passive conditions, for the purpose of acclimation. To maximize the thermoregulatory-adaptive responses, exercise bouts should be employed prior to passive heat stress, rather than passive heating alone, with a minimal delay between exercise and the application of heat stress. Heating bouts should have a minimum duration of 30 min per session and be employed on consecutive days, when possible, with a minimum of 6-7 exposures to induce adaptation. This review identified that information regarding the magnitude of performance changes that can occur, as well as the perceptual responses to passive heating protocols is limited. Future research should investigate the use of passive heat exposures before and/or after repeated heat training sessions, to assess if a further boost to heat adaptation can be achieved with this strategy.


Severe injury is associated with insulin resistance, endoplasmic reticulum stress response, and unfolded protein response.
We determined whether postburn hyperglycemia and insulin resistance are associated with endoplasmic reticulum (ER) stress/unfolded protein response (UPR) activation leading to impaired insulin receptor signaling. Inflammation and cellular stress, hallmarks of severely burned and critically ill patients, have been causally linked to insulin resistance in type 2 diabetes via induction of ER stress and the UPR. Twenty severely burned pediatric patients were compared with 36 nonburned children. Clinical markers, protein, and GeneChip analysis were used to identify transcriptional changes in ER stress and UPR and insulin resistance-related signaling cascades in peripheral blood leukocytes, fat, and muscle at admission and up to 466 days postburn. Burn-induced inflammatory and stress responses are accompanied by profound insulin resistance and hyperglycemia. Genomic and protein analysis revealed that burn injury was associated with alterations in the signaling pathways that affect insulin resistance, ER/sarcoplasmic reticulum stress, inflammation, and cell growth/apoptosis up to 466 days postburn. Burn-induced insulin resistance is associated with persistent ER/sarcoplasmic reticulum stress/UPR and subsequent suppressed insulin receptor signaling over a prolonged period of time.


Prognostic implications of severe coronary calcification in patients undergoing coronary artery bypass surgery: an analysis of the SYNTAX study.
To investigate the prognostic implications of the presence of severe lesion calcification in patients undergoing coronary artery bypass graft (CABG) operation. There is robust evidence that lesion calcification is a predictor of worse prognosis in patients undergoing percutaneous coronary intervention; however, there is limited data about the prognostic implication of lesion calcium in patients treated with CABG. We retrospectively analyzed data from 1,545 patients who underwent CABG and were recruited in the SYNTAX study and CABG registry. Two experts reviewed the angiographic data and classified patients in two groups: those with severely calcified coronary arteries and those without severe lesion calcification. Clinical outcomes at 5-year follow-up were collected and compared in the two groups. One out of three patients exhibited severe lesion calcification (n = 588). Patients with calcified coronaries had an increased mortality at 5-year follow-up (17.1% vs. 9.9%, P < 0.001) and a higher event rate of death-myocardial infarction (MI) compared with those without (19.4% vs. 13.2%, P = 0.003), but there was no statistical significant difference between the two groups for major adverse cardiovascular events (MACE, 26.8% vs. 21.8%, P = 0.057). In multivariate Cox regression analysis severe lesion calcification was an independent predictor of an increased all-cause mortality (hazard ratio: 1.39, 95% confidence interval: 1.02-1.89; P = 0.037) but it was not an independent predictor of the combined end-points death-MI or MACE. Severe lesion calcification is associated with an increased mortality in patients undergoing CABG, but it is not an independent predictor of death-MI or MACE. This paradox can be attributed to the fact that CABG allows perfusion of the healthy coronaries bypassing the diseased arteries and thus it minimizes the risk of coronary events due to progressive atherosclerosis.


Opioid Prescriptions After Total Joint Arthroplasty.
Prescription opioids are commonly prescribed for pain relief after total joint arthroplasty (TJA), yet little is known about the quantity of opioids prescribed after surgery. This study retrospectively reviewed a consecutive series of 1000 TJAs from April 2014 through September 2015. Postoperative opioid prescriptions were quantified using standardized morphine milligram equivalents (MME). Eighty-four percent of total knee arthroplasty (TKA) and 77% of total hip arthroplasty (THA) patients were opioid naïve. The median opioid volume of the first prescription for those undergoing TKA was greater than for those undergoing THA (600 vs. 450 MME), as was the proportion of individuals requiring one or more refills (48% vs. 32%). The total volume of opioids after TKA was also higher than for total hip replacement (870 vs. 525 MME). Patients who were not opioid naïve were prescribed substantially more opioids than their counterparts after TKA (mean 1593 vs. 1064 MME, p < .001) and THA (mean 1031 vs. 663 MME, p < .001). Decreasing opioid use before surgery may decrease total volume of opioid prescriptions after TJA. (Journal of Surgical Orthopaedic Advances 27(3):231-236, 2018).


Coached Peer Review: Developing the Next Generation of Authors.
Publishing in academic journals is challenging for learners. Those who pass the initial stages of internal review by an editor often find the anonymous peer review process harsh. Academic blogs offer alternate avenues for publishing medical education material. Many blogs, however, lack a peer review process, which some consumers argue compromises the quality of materials published. CanadiEM (formerly BoringEM) is an academic educational emergency medicine blog dedicated to publishing high-quality materials produced by learners (i.e., residents and medical students). The editorial team has designed and implemented a collaborative "coached peer review" process that comprises an open exchange among the learner-author, editors, and reviewers. The goal of this process is to facilitate the publication of high-quality academic materials by learner-authors while providing focused feedback to help them develop academic writing skills. The authors of this Innovation Report surveyed (February-June 2015) their blog's learner-authors and external expert "staff" reviewers who had participated in coached peer review for their reactions to the process. The survey results revealed that participants viewed the process positively compared with both traditional journal peer review and academic blog publication processes. Participants found the process friendly, easy, efficient, and transparent. Learner-authors also reported increased confidence in their published material. These outcomes met the goals of coached peer review. CanadiEM aims to inspire continued participation in, exposure to, and high-quality production of academic writing by promoting the adoption of coached peer review for online educational resources produced by learners.


Direct observation of light focusing by single photoreceptor cell nuclei.
The vertebrate retina is inverted with respect to its optical function, which requires light to pass through the entire tissue prior to detection. The last significant barrier for photons to overcome is the outer nuclear layer formed by photoreceptor cell (PRC) nuclei. Here we experimentally characterise the optical properties of PRC nuclei using bright-field defocusing microscopy to capture near-field intensity distributions behind individual nuclei. We find that some nuclei efficiently focus incident light confirming earlier predictions based on comparative studies of chromatin organisation in nocturnal and diurnal mammals. The emergence of light focusing during the development of mouse nuclei highlights the acquired nature of the observed lens-like behaviour. Optical characterisation of these nuclei is an important first step towards an improved understanding of how light transmission through the retina is influenced by its constituents.


When human immunodeficiency virus (HIV) treatment goals conflict with guideline-based opioid prescribing: A qualitative study of HIV treatment providers.
Human immunodeficiency virus (HIV)-infected patients have a high prevalence of chronic pain and opioid use, making HIV care a critical setting for improving the safety of opioid prescribing. Little is known about HIV treatment providers' perspectives about opioid prescribing to patients with chronic pain. The authors administered a questionnaire and conducted semistructured telephone interviews with 18 HIV treatment providers (infectious disease specialists, general internists, family medicine physicians, nurse practitioners, and physician assistants) in Bronx, NY. Open-ended interview questions focused on providers' experiences, beliefs, and attitudes about opioid prescribing and about the use of guideline-based opioid prescribing practices (conservative prescribing, and monitoring for and responding to misuse). Transcripts were thematically analyzed using a modified grounded theory approach. Eighteen HIV treatment providers included 13 physicians, four nurse practitioners, and one physician assistant. They were 62% female, 56% white, and practiced as HIV treatment providers for a mean of 14.6 years. Most reported always or almost always using opioid treatment agreements (56%) and urine drug testing (61%) with their patients on long-term opioid therapy. HIV treatment providers tended to view opioid prescribing for chronic pain within the "HIV paradigm," a set of priorities and principles defined by three key themes: (1) primacy of HIV goals, (2) familiarity with substance use, and (3) the clinician as ally. The HIV paradigm sometimes supported, and sometimes conflicted with, guideline-based opioid prescribing practices. For HIV treatment providers, perceived alignment with the HIV paradigm determined whether and how guideline-based opioid prescribing practices were adopted. For example, the primacy of HIV goals superseded conservative opioid prescribing when providers prescribed opioids with the goal of retaining patients in HIV care. These findings highlight unique factors in HIV care that influence adoption of guideline-based opioid prescribing practices. These factors should be considered in future research and initiatives to address opioid prescribing in HIV care.


Phenotypic changes in peripheral blood monocytes of cynomolgus monkeys acutely infected with simian immunodeficiency virus.
The quantitative and phenotypic changes of peripheral blood monocytes during the acute stage of simian immunodeficiency virus infection were investigated. We inoculated intravenously three cynomolgus monkeys (Macaca fascicularis) with 100 TCID50 of SIVmac239 and collected whole blood twice a week until 35 days postinoculation. We found that the relative number of monocytes in peripheral blood leukocytes significantly increased at 7-17 days postinoculation. This increase was concomitant with the peak of primary SIV antigenemia. To determine if the monocytes observed during the acute stage were phenotypically altered, they were periodically examined for the expression of surface markers (i.e., CD11b, CD14, CD16, CD29, D32, CD56, CD62L, CD64, CD80, and MHC-II-DR) by flow cytometry. The results showed that the expression levels of CD14 and CD56 on most of the monocytes were remarkably reduced at 7-17 days postinoculation, and a new subpopulation, CD14lowCD16+CD80+ monocytes, was clearly detected at 10 days postinoculation. These results indicate that the phenotypic alteration of peripheral blood monocytes occurs during the primary SIV infection.


Fast structural responses of gap junction membrane domains to AB5 toxins.
Gap junctions (GJs) represent connexin-rich membrane domains that connect interiors of adjoining cells in mammalian tissues. How fast GJs can respond to bacterial pathogens has not been known previously. Using Bessel beam plane illumination and confocal spinning disk microscopy, we found fast (~500 ms) formation of connexin-depleted regions (CDRs) inside GJ plaques between cells exposed to AB5 toxins. CDR formation appears as a fast redistribution of connexin channels within GJ plaques with minor changes in outline or geometry. CDR formation does not depend on membrane trafficking or submembrane cytoskeleton and has no effect on GJ conductance. However, CDR responses depend on membrane lipids, can be modified by cholesterol-clustering agents and extracellular K(+) ion concentration, and influence cAMP signaling. The CDR response of GJ plaques to bacterial toxins is a phenomenon observed for all tested connexin isoforms. Through signaling, the CDR response may enable cells to sense exposure to AB5 toxins. CDR formation may reflect lipid-phase separation events in the biological membrane of the GJ plaque, leading to increased connexin packing and lipid reorganization. Our data demonstrate very fast dynamics (in the millisecond-to-second range) within GJ plaques, which previously were considered to be relatively stable, long-lived structures.


Preventing tomorrow's sudden cardiac death today: part II: Translating sudden cardiac death risk assessment strategies into practice and policy.
Although current evidence supporting a more precise strategy for identifying patients at highest risk for sudden cardiac death (SCD) is sparse, strategies for translating existing and future evidence into clinical practice and policy are needed today. A great many unanswered questions exist. Examples include the following: At what level of risk for SCD should we pursue further testing or therapy? How should clinical strategies ethically and economically balance alternative outcomes? How can we best translate optimal strategies into clinical practice so as to prevent tomorrow's SCDs? On July 20 and 21, 2006, a group of individuals with expertise in clinical cardiovascular medicine, biostatistics, economics, and health policy was joined by government (Food and Drug Administration; Centers for Medicare and Medicaid Services; National Heart, Lung, and Blood Institute; Agency for Healthcare Research and Quality), professional societies (Heart Rhythm Society), and industry to discuss strategies for risk assessment and prevention of SCD. The meeting was organized by the Duke Center for the Prevention of Sudden Cardiac Death and the Duke Clinical Research Institute. This article, the second of 2 documents, summarizes the policy discussions of that meeting, discusses an analytic framework for evaluating the risks and benefits associated with SCD prevention and risk stratification, and addresses the translation of SCD risk assessment strategies into practice and policy.


Actions of cytochalasins on the organization of actin filaments and microtubules in a neuronal growth cone.
Actions of cytochalasin B (CB) on cytoskeletons and motility of growth cones from cultured Aplysia neurons were studied using a rapid flow perfusion chamber and digital video light microscopy. Living growth cones were observed using differential interference contrast optics and were also fixed at various time points to assay actin filament (F-actin) and microtubule distributions. Treatment with CB reversibly blocked motility and eliminated most of the phalloidin-stainable F-actin from the leading lamella. The loss of F-actin was nearly complete within 2-3 min of CB application and was largely reversed within 5-6 min of CB removal. The loss and recovery of F-actin were found to occur with a very distinctive spatial organization. Within 20-30 s of CB application, F-actin networks receded from the entire peripheral margin of the lamella forming a band devoid of F-actin. This band widened as F-actin receded at rates of 3-6 microns/min. Upon removal of CB, F-actin began to reappear within 20-30 s. The initial reappearance of F-actin took two forms: a coarse isotropic matrix of F-actin bundles throughout the lamella, and a denser matrix along the peripheral margin. The denser peripheral matrix then expanded in width, extending centrally to replace the coarse matrix at rates again between 3-6 microns/min. These results suggest that actin normally polymerizes at the leading edge and then flows rearward at a rate between 3-6 microns/min. CB treatment was also observed to alter the distribution of microtubules, assayed by antitubulin antibody staining. Normally, microtubules are restricted to the neurite shaft and a central growth cone domain. Within approximately 5 min after CB application, however, microtubules began extending into the lamellar region, often reaching the peripheral margin. Upon removal of CB, the microtubules were restored to their former central localization. The timing of these microtubule redistributions is consistent with their being secondary to effects of CB on lamellar F-actin.


How to strengthen a health research system: WHO's review, whose literature and who is providing leadership?
Health research is important for the achievement of the Sustainable Development Goals. However, there are many challenges facing health research, including securing sufficient funds, building capacity, producing research findings and using both local and global evidence, and avoiding waste. A WHO initiative addressed these challenges by developing a conceptual framework with four functions to guide the development of national health research systems. Despite some progress, more is needed before health research systems can meet their full potential of improving health systems. The WHO Regional Office for Europe commissioned an evidence synthesis of the systems-level literature. This Opinion piece considers its findings before reflecting on the vast additional literature available on the range of specific health research system functions related to the various challenges. Finally, it considers who should lead research system strengthening. The evidence synthesis identifies two main approaches for strengthening national health research systems, namely implementing comprehensive and coherent strategies and participation in partnerships. The literature describing these approaches at the systems level also provides data on ways to strengthen each of the four functions of governance, securing financing, capacity-building, and production and use of research. Countries effectively implementing strategies include England, Ireland and Rwanda, whereas West Africa experienced effective partnerships. Recommended policy approaches for system strengthening are context specific. The vast literature on each function and the ever-growing evidence-base are illustrated by considering papers in just one key journal, Health Research Policy and Systems, and analysing the contribution of two national studies. A review of the functions of the Iranian system identifies over 200 relevant and mostly national records; an analysis of the creation of the English National Institute for Health Research describes the key leadership role played by the health department. Furthermore, WHO is playing leadership roles in helping coordinate partnerships within and across health research systems that have been attempting to tackle the COVID-19 crisis. The evidence synthesis provides a firm basis for decision-making by policy-makers and research leaders looking to strengthen national health research systems within their own national context. It identifies five crucial policy approaches - conducting situation analysis, sustaining a comprehensive strategy, engaging stakeholders, evaluating impacts on health systems, and partnership participation. The vast and ever-growing additional literature could provide further perspectives, including on crucial leadership roles for health ministries.


Genetic alterations in prostate cancer.
A number of genetic changes have been documented in prostate cancer, ranging from allelic loss to point mutations and changes in DNA methylation patterns (summarized in Fig. 1). To date, the most consistent changes are those of allelic loss events, with the majority of tumors examined showing loss of alleles from at least one chromosomal arm. The short arm of chromosome 8, followed by the long arm of chromosome 16, appear to be the most frequent regions of loss, suggesting the presence of novel tumor suppressor genes. Deletions of one copy of the Rb and p53 genes are less frequent, as are mutations of the p53 gene, and accumulating evidence suggests the presence of an additional tumor suppressor gene on chromosome 17p, which is frequently inactivated in prostate cancer. Alterations in the E-cadherin/alpha-catenin-mediated cell-cell adhesion mechanism appear to be present in almost half of all prostate cancers and may be critical to the acquisition of metastatic potential of aggressive prostate cancers. Finally, altered DNA methylation patterns have been found in the majority of prostate cancers examined, suggesting widespread alterations in methylation-modulated gene expression. The presence of multiple changes in these tumors is consistent with the multistep nature of the transformation process. Finally, efforts to identify prostate cancer susceptibility loci are under way and may elucidate critical early events in prostatic carcinogenesis.


Long-term in vivo monitoring of mouse and human hematopoietic stem cell engraftment with a human positron emission tomography reporter gene.
Positron emission tomography (PET) reporter genes allow noninvasive whole-body imaging of transplanted cells by detection with radiolabeled probes. We used a human deoxycytidine kinase containing three amino acid substitutions within the active site (hdCK3mut) as a reporter gene in combination with the PET probe [(18)F]-L-FMAU (1-(2-deoxy-2-(18)fluoro-β-L-arabinofuranosyl)-5-methyluracil) to monitor models of mouse and human hematopoietic stem cell (HSC) transplantation. These mutations in hdCK3mut expanded the substrate capacity allowing for reporter-specific detection with a thymidine analog probe. Measurements of long-term engrafted cells (up to 32 wk) demonstrated that hdCK3mut expression is maintained in vivo with no counter selection against reporter-labeled cells. Reporter cells retained equivalent engraftment and differentiation capacity being detected in all major hematopoietic lineages and tissues. This reporter gene and probe should be applicable to noninvasively monitor therapeutic cell transplants in multiple tissues.


Birth weight and attention-deficit/hyperactivity symptoms in childhood and early adolescence: a prospective Swedish twin study.
To determine whether low birth weight increases the risk of attention-deficit/hyperactivity disorder (ADHD) in childhood and early adolescence. In a population-based sample of 1,480 twin pairs born in the period 1985-1986 ascertained from the Swedish Twin Registry, birth weight was collected prospectively through the Medical Birth Registry. ADHD symptoms were measured with a 14-item checklist covering DSM-III-R criteria (parental rating) at age 8 to 9 years and 13 to 14 years. We used both a dichotomous approach for birth weight (>400 g or 15% weight difference) and ADHD (eight or more symptoms) and continuous measures to investigate between- and within-twin pair effects. Our results showed that low birth weight was a risk factor for symptoms of ADHD and the associations did not diminish when we controlled for genetic influence. The lighter twin in birth weight-discordant pairs had on average 13% higher ADHD symptom score at age 8 to 9 years (p = .006) and 12% higher ADHD score at age 13 to 14 years (p = .018) compared with the heavier twin. The genetic correlations suggest modest or no genetic overlap between birth weight and ADHD. The hypothesis that low birth weight is associated with the development of ADHD symptoms was supported in this prospective twin study. Fetal growth restriction seems to represent a modest but fairly consistent environmental influence on the development of ADHD symptoms.


Vitamin D-enhanced eggs are protective of wintertime serum 25-hydroxyvitamin D in a randomized controlled trial of adults.
Despite numerous animal studies that have illustrated the impact of additional vitamin D in the diet of hens on the resulting egg vitamin D content, the effect of the consumption of such eggs on vitamin D status of healthy individuals has not, to our knowledge, been tested. We performed a randomized controlled trial (RCT) to investigate the effect of the consumption of vitamin D-enhanced eggs (produced by feeding hens at the maximum concentration of vitamin D3 or serum 25-hydroxyvitamin D [25(OH)D3] lawfully allowed in feed) on winter serum 25(OH)D in healthy adults. We conducted an 8-wk winter RCT in adults aged 45-70 y (n = 55) who were stratified into 3 groups and were requested to consume ≤2 eggs/wk (control group, in which status was expected to decline), 7 vitamin D3-enhanced eggs/wk, or seven 25(OH)D3-enhanced eggs/wk. Serum 25(OH)D was the primary outcome. Although there was no significant difference (P > 0.1; ANOVA) in the mean preintervention serum 25(OH)D in the 3 groups, it was ∼7-8 nmol/L lower in the control group than in the 2 groups who consumed vitamin D-enhanced eggs. With the use of an ANCOVA, in which baseline 25(OH)D was accounted for, vitamin D3-egg and 25(OH)D3-egg groups were shown to have had significantly higher (P ≤ 0.005) postintervention serum 25(OH)D than in the control group. With the use of a within-group analysis, it was shown that, although serum 25(OH)D in the control group significantly decreased over winter (mean ± SD: -6.4 ± 6.7 nmol/L; P = 0.001), there was no change in the 2 groups who consumed vitamin D-enhanced eggs (P > 0.1 for both). Weekly consumption of 7 vitamin D-enhanced eggs has an important impact on winter vitamin D status in adults. This trial was registered at clinicaltrials.gov as NCT02678364.


European Code against Cancer 4th Edition: Obesity, body fatness and cancer.
It is estimated that over half the population of the European Union (EU) is overweight or obese due to an imbalance between energy expenditure and energy intake; this is related to an obesogenic environment of sociocultural, economic and marketing challenges to the control of body weight. Excess body fat is associated with nine cancer sites - oesophagus, colorectum, gall bladder, pancreas, postmenopausal breast, endometrium, ovary, kidney and prostate (advanced) - and 4-38% of these cancers (depending on site and gender) can be attributed to overweight/obesity status. Metabolic alterations which accompany excess body weight are accompanied by increased levels of inflammation, insulin, oestrogens and other hormonal factors. There are some indications that intentional weight loss is associated with reduced cancer incidence (notably in postmenopausal breast and endometrial cancers). Excess body weight is also a risk factor for several other diseases, including diabetes and heart disease, and is related to higher risk of premature death. In reviewing the current evidence related to excess body fat and cancer, the European Code against Cancer Nutrition Working Group has developed the following recommendation: 'Take action to be a healthy body weight'.


General distribution of the nitrogen control gene ntcA in cyanobacteria.
The ntcA gene from Synechococcus sp. strain PCC 7942 encodes a regulatory protein which is required for the expression of all of the genes known to be subject to repression by ammonium in that cyanobacterium. Homologs to ntcA have now been cloned by hybridization from the cyanobacteria Synechocystis sp. strain PCC 6803 and Anabaena sp. strain PCC 7120. Sequence analysis has shown that these ntcA genes would encode polypeptides strongly similar (77 to 79% identity) to the Synechococcus NtcA protein. Sequences hybridizing to ntcA have been detected in the genomes of nine other cyanobacteria that were tested, including strains of the genera Anabaena, Calothrix, Fischerella, Nostoc, Pseudoanabaena, Synechococcus, and Synechocystis.


Establishment of a gnotobiotic silkworm model.
Gnotobiotic animals are useful for investigation of the effects of specific lactic acid bacteria on individual animals. Here we report that lactic acid bacteria colonize and proliferate in the intestinal tract of germ-free silkworms. When silkworms hatching from formalin-treated eggs were reared to fifth-instar larvae with an artificial diet containing antibiotics, bacteria and fungi were not observed in their intestines. An antibiotic-free diet supplemented with viable lactic acid bacteria, such as Enterococcus faecalis 0831-07, Lactococcus lactis 11/19-B1, or Leuconostoc carnosum #7-2, was fed to the germ-free silkworms for 1 day. After feeding the larvae on a diet without lactic acid bacteria for 5 days, each type of lactic acid bacterium was found in the intestine. Moreover, an increase in the number of Enterococcus faecalis 0831-07 was observed in the intestine 2-5 days after ingestion. These findings suggest that we successfully established a method to construct a gnotobiotic silkworm model.


Spectroscopy of prospective interstellar ions and radicals isolated in para-hydrogen matrices.
para-Hydrogen (p-H2) serves as a new host in matrix-isolation experiments for an investigation of species of astrochemical interest. Protonated and mono-hydrogenated species are produced upon electron bombardment during deposition of p-H2 containing a precursor in a small proportion. The applications of this novel technique to generate protonated polycyclic aromatic hydrocarbons (H+PAH), protonated polycyclic nitrogen heterocycles (H+PANH), and their neutral counterparts, which are important in the identification of interstellar unidentified infrared emission bands, demonstrate its superiority over other methods. The clean production with little fragmentation, ease of distinction between protonated and neutral species, narrow lines and reliable relative infrared intensities of the lines, and broad coverage of the spectral range associated with this method enable us to assign the isomers unambiguously. The application of this method to the protonation of small molecules is more complicated partly because of the feasible fragmentation and reactions, and partly because of the possible proton sharing between the species of interest and H2, but, with isotopic experiments and secondary photolysis, definitive assignments are practicable. Furthermore, the true relative infrared intensities are critical to a comparison of experimental results with data from theoretical calculations. The spectra of a proton-shared species in solid p-H2 might provide insight into a search for spectra of proton-bound species in interstellar media. Investigations of hydrogenated species involving the photolysis of Cl2 or precursors of OH complement those using electron bombardment and provide an improved ratio of signal to noise. With careful grouping of observed lines after secondary photolysis and a comparison with theoretical predictions, various isomers of these species have been determined. This photolytic technique has been applied in an investigation of hydrogenated PAH and PANH, and the hydrogenation reactions of small molecules, which are important in interstellar ice and the evolution of life. The electronic transitions of molecules in solid p-H2 have been little investigated. The matrix shift of the origins of transitions and the spectral width seem to be much smaller than those of noble-gas matrices; these features might facilitate a direct comparison of matrix spectra with diffuse interstellar bands, but further data are required to assess this possibility. The advantages and disadvantages of applying these techniques of p-H2 matrix isolation to astrochemical research and their future perspectives are discussed.


Ocular permeation and inhibition of retinal inflammation: an examination of data and expert opinion on the clinical utility of nepafenac.
The efficacy of topical nonsteroidal anti-inflammatory drugs (NSAIDs) for inflammation in the anterior segment, and pain control after cataract surgery, is well established. However, their effectiveness in the posterior segment has not been as well studied. Nepafenac ophthalmic suspension, 0.1% is a new topical NSAID pro-drug that has been approved by the US Food and Drug Administration (FDA) for the treatment of pain and inflammation after cataract surgery. Preclinical data suggest nepafenac may also provide unique efficacy in the posterior segment. We searched the PubMed database from 1966 to 2005 for various combinations of the search terms 'nepafenac', 'ophthalmic', 'inflammation', 'anterior segment', and 'posterior segment'. We review here the three articles identified in the search, and also include findings from three recent clinical trials. Nepafenac's corneal permeability characteristics are superior to those of ketorolac tromethamine, diclofenac sodium, and bromfenac sodium. Nepafenac is hydrolyzed by intraocular tissues to amfenac, a potent cyclooxygenase inhibitor. In addition to a limited hydrolysis in the cornea, significant bioactivation occurs in the iris/ciliary body and retina/choroid. Nepafenac administration significantly suppresses PGE2 synthesis in the retina/choroid. Topical nepafenac administration also significantly inhibits prostaglandin (PG)-mediated blood-retinal barrier breakdown and concurrent protein extravasation into the vitreous. In these studies, topical ketorolac and diclofenac failed to inhibit these key markers of inflammation. Nepafenac's clinical effectiveness in the posterior segment may be explained by its superior corneal permeation, biodistribution, and bioactivation to amfenac by the target tissues (i.e., iris, ciliary body, retina, and choroid) known to generate PGs. Nepafenac's ability to inhibit PG synthesis in the retina/choroid following topical administration indicates the drug also targets suppression of PG synthesis in the posterior segment. Nepafenac may therefore have a clinical role in conditions that are caused by PG-mediated vascular leakage, such as anterior chamber inflammation and cystoid macular edema following cataract surgery.


Comparative Effectiveness of Vertical Sleeve Gastrectomy Versus Roux-en-Y Gastric Bypass for Diabetes Treatment: A Claims-based Cohort Study.
The aim of the study was to compare diabetes outcomes following vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB). There are few comparative studies on diabetes outcomes after VSG and RYGB. We used a US-wide commercial insurance claims database to identify adults with diabetes undergoing VSG or RYGB in 2010 to 2016. We matched patients on baseline insulin use, total diabetes medication burden, age, presence of diabetes complications, and follow-up duration, and used adjusted Cox proportional hazards models to compare diabetes medication discontinuation between procedures. We used difference-in-differences analyses to compare changes in medication use intensity up to 2 years after surgery. The matched cohort included 1111 VSG and 922 RYGB patients: 16% were younger than 40 years, 11% were 60 years or older, 67% were women, 67% had a body mass index of 40 kg/m2 or higher, and 23% were on insulin at the time of surgery. Thirteen percent were lost to follow-up at 1 year, and 30% at 2 years after surgery. Patients with VSG were less likely than matched RYGB patients to discontinue all diabetes medications (hazard ratio 0.80, 95% confidence interval 0.72-0.88). Although both groups had substantial decreases in medication use after surgery, RYGB patients had an 86% (32%, 140%) lower total diabetes medication dose than VSG by the second half of postoperative year 2. In a large claims-based, nationwide cohort of bariatric patients with diabetes, those undergoing RYGB were more likely to come off all medications than those undergoing VSG. Patients with diabetes should consider this potential benefit of RYGB when making informed decisions about obesity treatments.


Transition to Adult IBD Care: A Pilot Multi-Site, Telehealth Hybrid Intervention.
Transition to adult IBD care continues to be a challenge. Efficacious models of improving transition to adult care in the United States are lacking. We present data from a pilot, prospective, non-randomized, intervention implemented at IBD centers in the Midwest and Southeast United States. Adolescents and young adults (AYAs; 16-20 years) with IBD and their parents completed a 4- to 5-month transition program (1 in-person group session; 4 individual telehealth sessions). Primary outcomes were feasibility (i.e., recruitment, retention, fidelity) and acceptability (i.e., program satisfaction). Secondary outcomes were changes in transition readiness, self-management skill acquisition, perceived readiness to transfer to adult care, and disease knowledge. The study exceeded goals for recruitment (target N = 20; actual: 36) and retention (target: 80%; actual: 86.11%). On average, it took participants 20.91 ± 3.15 weeks to complete our 4- to 5-month intervention and there were no deviations from the study protocol. Participant ratings for overall program satisfaction, perceived helpfulness, and program length and format were positive. Increases in transition readiness, t(30) = 8.30, d = 1.49, p < .001, self-management skill acquisition, t(30) = 3.93, d = 0.70, p < .001, and disease knowledge, t(30) = 8.20, d = 1.58, p < .001 were noted. AYA- and parent-perceived transfer readiness also improved (p's < .05; d's = 0.76-1.68). This article presents feasibility and acceptability data for a 4- to 5-month transition intervention. Improvements in AYA transition readiness, self-management skill acquisition, IBD knowledge, and AYA/parent perceived transfer readiness were also observed.


Effects of fluoride on the expression of NCAM, oxidative stress, and apoptosis in primary cultured hippocampal neurons.
The mechanisms underlying the neurotoxicity of endemic fluorosis still remain unknown. To investigate the expression level of neural cell adhesion molecules (NCAM), oxidative stress, and apoptosis induced by fluoride, the primary rat hippocampal neurons were incubated with 20, 40, and 80 mg/l sodium fluoride for 24 h in vitro. The results showed that the cell survival rate in the 80 mg/l fluoride-treated group was significantly lower than that of the control group. Forty and 80 mg/l of fluoride induced significantly increased lactate dehydrogenase release, intracellular reactive oxygen species, and the percentage of apoptosis. Compared with control group, the malondialdehyde levels were significantly elevated while glutathione levels and glutathione peroxidase activities were decreased in all fluoride-treated groups, accompanied by the markedly reduced superoxide dismutase activity in 80 mg/l fluoride-treated group. With respect to NCAM mRNA expression levels, a significant dose-dependent decrease was observed in 40 and 80 mg/l fluoride-treated groups against the control group. In addition, as compared to the control group, the protein expression levels of NCAM-180 in 40 and 80 mg/l fluoride-treated groups, NCAM-140 in all fluoride-treated groups, and NCAM-120 in the 80 mg/l fluoride-treated group were significantly decreased. Our study herein suggested that fluoride could cause oxidative stress, apoptosis, and decreased mRNA and protein expression levels of NCAM in rat hippocampal neurons, contributing to the neurotoxicity induced by fluoride.