Heparin, low molecular weight heparin and physical methods for preventing deep vein thrombosis and pulmonary embolism following surgery for hip fractures.
Hip fracture patients have a high risk of thrombo-embolic complications following surgical management. To examine the effects of heparin (unfractionated (U), and low molecular weight (LMW) heparins), and physical methods (compression stockings, calf or foot pumps) for prevention of deep venous thrombosis (DVT) and pulmonary embolism after surgery for hip fracture in the elderly. We searched the Cochrane Musculoskeletal Injuries Group specialised register (up to March 2002), MEDLINE (1966 to March 2002), EMBASE (1980 to March 2002), CINAHL (1982 to February week 4 2002), Current Contents (1993 week 26 to 2002 week 12), reference lists of published articles and contacted trialists and other workers in the field. Date of most recent search: March 2002. Randomised and quasi-randomised trials evaluating the use of heparins and physical agents for prevention of DVT and pulmonary embolism in patients undergoing surgery for hip fracture. Two reviewers independently assessed methodological quality and extracted data. Trials were grouped into five categories (heparin versus control, mechanical versus control, LMW heparin versus U heparin, heparin versus mechanical, and miscellaneous) and results pooled where possible. The 31 included trials involved at least 2958 predominantly female and elderly patients. Overall, trial quality was disappointing. Ten trials involving 826 patients which compared U heparin with control, and five trials of 373 patients which compared LMW heparin with control, showed a reduction in the incidence of lower limb DVT (124/474 (26%) versus 219/519 (42%); relative risk (RR) 0.60; 95% confidence interval (CI) 0.50 to 0.71). There were insufficient data to confirm the efficacy of either agent in the prevention of pulmonary embolism. There was no statistically significant difference in overall mortality (42/356 (12%) versus 38/374 (10%); RR 1.16; 95%CI 0.77 to 1.74). Data were inadequate for all other outcomes including wound complications. There is insufficient evidence from five trials, involving 644 patients, to establish if LMW heparin was superior to U heparin. Most trials evaluating heparins had methodological defects. Five trials, involving 487 patients, testing mechanical pumping devices were also methodologically flawed, and so pooled results need to be viewed cautiously. Mechanical pumping devices may protect against DVT (16/221 (7%) versus 52/229 (22%); RR 0.31; 95%CI 0.19 to 0.51) and pulmonary embolism. Data were insufficient to establish any effect on the incidence of fatal pulmonary embolism and overall mortality. Problems with skin abrasion and compliance were reported. U and LMW heparins protect against lower limb DVT. There is insufficient evidence to confirm either protection against pulmonary embolism or an overall benefit, or to distinguish between various applications of heparin. Foot and calf pumping devices appear to prevent DVT, may protect against pulmonary embolism, and reduce mortality, but compliance remains a problem. Good quality trials of mechanical methods as well as direct comparisons with heparin and low dose aspirin should be considered.


Family planning funding through four federal-state programs, FY 1997.
The maternal and child health (MCH) and the social services block grants have long played an important role in the provision of family planning services in the United States. The extent to which states have incorporated family planning services into the newer federally funded, but state-controlled, programs--Temporary Aid to Needy Families (TANF) and the State Children's Health Insurance Program (CHIP)--has yet to be identified. The health and social services agencies in all U.S. states, the District of Columbia and five federal jurisdictions were queried regarding their family planning expenditures and activities through the MCH and social services block grants and the TANF program in FY 1997. In addition, the states' CHIP plans were analyzed following their approval by the federal government. Because of differences in methodology, these findings cannot be compared with those of previous attempts to determine public expenditures for contraceptive services and supplies. In FY 1997, 42 states, the District of Columbia and two federal jurisdictions spent $41 million on family planning through the MCH program. Fifteen states reported spending $27 million through the social services block grant. Most of these jurisdictions indicated that they provide direct patient care services, most frequently contraceptive services and supplies. Indirect services--most often population-based efforts such as outreach and public education--were reported to have been provided more often through the MCH program than through the social services program. MCH block grant funds were more likely to go to local health departments, while social services block grant funds were more likely to be channeled through Planned Parenthood affiliates. Four states reported family planning activities funded under TANF in FY 1997, the first year of the program's operation. Virtually all state plans for the implementation of the CHIP program appear to include coverage of family planning services and supplies for the adolescents covered under the program, even when not specifically required to do so by federal law. Joining two existing--but frequently overlooked--block grants, two new, largely state-controlled programs are poised to become important sources of support for publicly funded family planning services. Now more than ever, supporters of family planning services need to look beyond the traditional sources of support--Title X and Medicaid--as well as beyond the federal level to the states, where important program decisions are increasingly being made.


Association of β-blocker therapy with risks of adverse cardiovascular events and deaths in patients with ischemic heart disease undergoing noncardiac surgery: a Danish nationwide cohort study.
Clinical guidelines have been criticized for encouraging the use of β-blockers in noncardiac surgery despite weak evidence. Relevant clinical trials have been small and have not convincingly demonstrated an effect of β-blockers on hard end points (ie, perioperative myocardial infarction, ischemic stroke, cardiovascular death, and all-cause death). To assess the association of β-blocker treatment with major cardiovascular adverse events (MACE) and all-cause mortality in patients with ischemic heart disease undergoing noncardiac surgery. DESIGN, SETTING, PARTICIPANTS, AND EXPOSURE: Individuals with ischemic heart disease with or without heart failure (HF) and with and without a history of myocardial infarction undergoing noncardiac surgery between October 24, 2004, and December 31, 2009, were identified from nationwide Danish registries. Adjusted Cox regression models were used to calculate the 30-day risks of MACE (ischemic stroke, myocardial infarction, or cardiovascular death) and all-cause mortality associated with β-blocker therapy. Thirty-day risk of MACE and all-cause mortality. Of 28,263 patients with ischemic heart disease undergoing surgery, 7990 (28.3%) had HF and 20,273 (71.7%) did not. β-Blockers were used in 4262 (53.3%) with and 7419 (36.6%) without HF. Overall, use of β-blockers was associated with a hazard ratio (HR) of 0.90 (95% CI, 0.79-1.02) for MACE and 0.95 (0.85-1.06) for all-cause mortality. Among patients with HF, use of β-blockers was associated with a significantly lower risk of MACE (HR, 0.75; 95% CI, 0.70-0.87) and all-cause mortality (0.80; 0.70-0.92), whereas among patients without HF, there was no significant association of β-blocker use with MACE (1.11; 0.92-1.33) or mortality (1.15; 0.98-1.35) (P < .001 for interactions). Among patients without HF, β-blockers were also associated with a lowered risk among those with a recent myocardial infarction (<2 years), with HRs of 0.54 (95% CI, 0.37-0.78) for MACE and 0.80 (0.53-1.21) for all-cause mortality (P < .02 for interactions between β-blockers and time period after myocardial infarction), but with no significant association in the remaining patients. Results were similar in propensity score-matched analyses. Among patients with ischemic heart disease undergoing noncardiac surgery, use of β-blockers was associated with lower risk of 30-day MACE and mortality only among those with HF or recent myocardial infarction.


Monitoring of particulate matter outdoors.
Recent studies of the size and composition of atmospheric particulate matter (PM) have demonstrated the usefulness of separating atmospheric PM into its fine and coarse components. The need to measure the mass and composition of fine and coarse PM separately has been emphasized by research in exposure, epidemiology, and toxicology of atmospheric PM. This paper provides a background on the size distribution and properties of PM relevant to the differences between fine and coarse particles. Various decisions that must be made when deciding how to separate, collect, and measure PM are discussed. Techniques for monitoring fine and coarse particles, including the US Federal Reference Method for PM2.5 and several techniques for PM10-2.5, are presented. Problems encountered in collecting semivolatile PM and in weighing atmospheric PM collected on a filter are described. Continuous monitoring methods for PM mass and for PM components (carbon, nitrate, and sulfate) are described and brief descriptions are given of analytical techniques for the chemical characterization of collected PM. This information should be especially useful for environmental workers familiar with monitoring methods for total suspended particles or PM10 but who will need to measure PM2, and PM10-2.5 in the future.


Glutamine deamidation and dysfunction of ubiquitin/NEDD8 induced by a bacterial effector family.
A family of bacterial effectors including Cif homolog from Burkholderia pseudomallei (CHBP) and Cif from Enteropathogenic Escherichia coli (EPEC) adopt a functionally important papain-like hydrolytic fold. We show here that CHBP was a potent inhibitor of the eukaryotic ubiquitination pathway. CHBP acted as a deamidase that specifically and efficiently deamidated Gln40 in ubiquitin and ubiquitin-like protein NEDD8 both in vitro and during Burkholderia infection. Deamidated ubiquitin was impaired in supporting ubiquitin-chain synthesis. Cif selectively deamidated NEDD8, which abolished the activity of neddylated Cullin-RING ubiquitin ligases (CRLs). Ubiquitination and ubiquitin-dependent degradation of multiple CRL substrates were impaired by Cif in EPEC-infected cells. Mutations of substrate-contacting residues in Cif abolished or attenuated EPEC-induced cytopathic phenotypes of cell cycle arrest and actin stress fiber formation.


Gamma-Rhythmic Gain Modulation.
Cognition requires the dynamic modulation of effective connectivity, i.e., the modulation of the postsynaptic neuronal response to a given input. If postsynaptic neurons are rhythmically active, this might entail rhythmic gain modulation, such that inputs synchronized to phases of high gain benefit from enhanced effective connectivity. We show that visually induced gamma-band activity in awake macaque area V4 rhythmically modulates responses to unpredictable stimulus events. This modulation exceeded a simple additive superposition of a constant response onto ongoing gamma-rhythmic firing, demonstrating the modulation of multiplicative gain. Gamma phases leading to strongest neuronal responses also led to shortest behavioral reaction times, suggesting functional relevance of the effect. Furthermore, we find that constant optogenetic stimulation of anesthetized cat area 21a produces gamma-band activity entailing a similar gain modulation. As the gamma rhythm in area 21a did not spread backward to area 17, this suggests that postsynaptic gamma is sufficient for gain modulation.


DHEA in bone: the role in osteoporosis and fracture healing.
Dehydroepiandrosterone (DHEA) is a metabolic intermediate in the biosynthesis of estrogens and androgens with a past clouded in controversy and bold claims. It was once touted as a wonder drug, a fountain of youth that could cure all ailments. However, in the 1980s DHEA was banned by the FDA given a lack of documented health benefits and long-term use data. DHEA had a revival in 1994 when it was released for open market sale as a nutritional supplement under the Dietary Supplement Health and Safety Act. Since that time, there has been encouraging research on the hormone, including randomized controlled trials and subsequent meta-analyses on various conditions that DHEA may benefit. Bone health has been of particular interest, as many of the metabolites of DHEA are known to be involved in bone homeostasis, specifically estrogen and testosterone. Studies demonstrate a significant association between DHEA and increased bone mineral density, likely due to DHEA's ability to increase osteoblast activity and insulin like growth factor 1 (IGF-1) expression. Interestingly, IGF-1 is also known to improve fracture healing, though DHEA, a potent stimulator of IGF-1, has never been tested in this scenario. The aim of this review is to discuss the history and mechanisms of DHEA as they relate to the skeletal system, and to evaluate if DHEA has any role in treating fractures.


Phylogenetic congruence and discordance among one morphological and three molecular data sets from Pontederiaceae.
A morphological data set and three sources of data from the chloroplast genome (two genes and a restriction site survey) were used to reconstruct the phylogenetic history of the pickerelweed family Pontederiaceae. The chloroplast data converged towards a single tree, presumably the true chloroplast phylogeny of the family. Unrooted trees estimated from each of the three chloroplast data sets were identical or extremely similar in shape to each other and mostly robustly supported. There was no evidence of significant heterogeneity among the data sets, and the few topological differences seen among unrooted trees from each chloroplast data set are probably artifacts of sampling error on short branches. Despite well-documented differences in rates of evolution for different characters in individual data sets, equally weighted parsimony permits accurate reconstructions of chloroplast relationships in Pontederiaceae. A separate morphology-based data set yielded trees that were very different from the chloroplast trees. Although there was substantial support from the morphological evidence for several major clades supported by chloroplast trees, most of the conflicting phylogenetic structure on the morphology trees was not robust. Nonetheless, several statistical tests of incongruence indicate significant heterogeneity between molecules and morphology. The source of this apparent incongruence appears to be a low ratio of phylogenetic signal to noise in the morphological data.


Severity of ocean acidification following the end-Cretaceous asteroid impact.
Most paleo-episodes of ocean acidification (OA) were either too slow or too small to be instructive in predicting near-future impacts. The end-Cretaceous event (66 Mya) is intriguing in this regard, both because of its rapid onset and also because many pelagic calcifying species (including 100% of ammonites and more than 90% of calcareous nannoplankton and foraminifera) went extinct at this time. Here we evaluate whether extinction-level OA could feasibly have been produced by the asteroid impact. Carbon cycle box models were used to estimate OA consequences of (i) vaporization of up to 60 × 10(15) mol of sulfur from gypsum rocks at the point of impact; (ii) generation of up to 5 × 10(15) mol of NOx by the impact pressure wave and other sources; (iii) release of up to 6,500 Pg C as CO2 from vaporization of carbonate rocks, wildfires, and soil carbon decay; and (iv) ocean overturn bringing high-CO2 water to the surface. We find that the acidification produced by most processes is too weak to explain calcifier extinctions. Sulfuric acid additions could have made the surface ocean extremely undersaturated (Ωcalcite <0.5), but only if they reached the ocean very rapidly (over a few days) and if the quantity added was at the top end of literature estimates. We therefore conclude that severe ocean acidification might have been, but most likely was not, responsible for the great extinctions of planktonic calcifiers and ammonites at the end of the Cretaceous.


Charting the landscape of priority problems in psychiatry, part 1: classification and diagnosis.
Contemporary psychiatry faces major challenges. Its syndrome-based disease classification is not based on mechanisms and does not guide treatment, which largely depends on trial and error. The development of therapies is hindered by ignorance of potential beneficiary patient subgroups. Neuroscientific and genetics research have yet to affect disease definitions or contribute to clinical decision making. In this challenging setting, what should psychiatric research focus on? In two companion papers, we present a list of problems nominated by clinicians and researchers from different disciplines as candidates for future scientific investigation of mental disorders. These problems are loosely grouped into challenges concerning nosology and diagnosis (this Personal View) and problems related to pathogenesis and aetiology (in the companion Personal View). Motivated by successful examples in other disciplines, particularly the list of Hilbert's problems in mathematics, this subjective and eclectic list of priority problems is intended for psychiatric researchers, helping to re-focus existing research and providing perspectives for future psychiatric science.


Function of transmembrane domain IX in the Na+/proline transporter PutP.
Selected residues of transmembrane domain (TM) IX were previously shown to play key roles in ligand binding and transport in members of the Na(+)/solute symporter family. Using the Na(+)/proline transporter PutP as a model, a complete Cys scanning mutagenesis of TM IX (positions 324 to 351) was performed here to further investigate the functional significance of the domain. G328, S332, Q345, and L346 were newly identified as important for Na(+)-coupled proline uptake. Placement of Cys at one of these positions altered K(m(pro)) (S332C and L346C, 3- and 21-fold decreased, respectively; Q345C, 38-fold increased), K(0.5(Na+)) (S332C, 13-fold decreased; Q345C, 19-fold increased), and/or V(max) [G328C, S332C, Q345C, and L346C, 3-, 22-, 2-, and 8-fold decreased compared to PutP(wild type), respectively]. Membrane-permeant N-ethylmaleimide inhibited proline uptake into cells containing PutP with Cys at distinct positions in the middle (T341C) and cytoplasmic half of TM IX (C344, L347C, V348C, and S351C) and had little or no effect on all other single Cys PutP variants. The inhibition pattern was in agreement with the pattern of labeling with fluorescein-5-maleimide. In addition, Cys placed into the cytoplasmic half of TM IX (C344, L347C, V348C, and S351C) was protected from fluorescein-5-maleimide labeling by proline while Na(+) alone had no effect. Membrane-impermeant methanethiosulfonate ethyltrimethylammonium modified Cys in the middle (A337C and T341C) and periplasmic half (L331C) but not in the cytoplasmic half of TM IX in intact cells. Furthermore, Cys at the latter positions was partially protected by Na(+) but not by proline. Based on these results, a model is discussed according to which residues of TM IX participate in the formation of ligand-sensitive, hydrophilic cavities in the protein that may reconstitute part of the Na(+) and/or proline translocation pathway of PutP.


A study of fitness distance correlation as a difficulty measure in genetic programming.
We present an approach to genetic programming difficulty based on a statistical study of program fitness landscapes. The fitness distance correlation is used as an indicator of problem hardness and we empirically show that such a statistic is adequate in nearly all cases studied here. However, fitness distance correlation has some known problems and these are investigated by constructing an artificial landscape for which the correlation gives contradictory indications. Although our results confirm the usefulness of fitness distance correlation, we point out its shortcomings and give some hints for improvement in assessing problem hardness in genetic programming.


Integrating biologically inspired nanomaterials and table-top stereolithography for 3D printed biomimetic osteochondral scaffolds.
The osteochondral interface of an arthritic joint is notoriously difficult to regenerate due to its extremely poor regenerative capacity and complex stratified architecture. Native osteochondral tissue extracellular matrix is composed of numerous nanoscale organic and inorganic constituents. Although various tissue engineering strategies exist in addressing osteochondral defects, limitations persist with regards to tissue scaffolding which exhibit biomimetic cues at the nano to micro scale. In an effort to address this, the current work focused on 3D printing biomimetic nanocomposite scaffolds for improved osteochondral tissue regeneration. For this purpose, two biologically-inspired nanomaterials have been synthesized consisting of (1) osteoconductive nanocrystalline hydroxyapatite (nHA) (primary inorganic component of bone) and (2) core-shell poly(lactic-co-glycolic) acid (PLGA) nanospheres encapsulated with chondrogenic transforming growth-factor β1 (TGF-β1) for sustained delivery. Then, a novel table-top stereolithography 3D printer and the nano-ink (i.e., nHA + nanosphere + hydrogel) were employed to fabricate a porous and highly interconnected osteochondral scaffold with hierarchical nano-to-micro structure and spatiotemporal bioactive factor gradients. Our results showed that human bone marrow-derived mesenchymal stem cell adhesion, proliferation, and osteochondral differentiation were greatly improved in the biomimetic graded 3D printed osteochondral construct in vitro. The current work served to illustrate the efficacy of the nano-ink and current 3D printing technology for efficient fabrication of a novel nanocomposite hydrogel scaffold. In addition, tissue-specific growth factors illustrated a synergistic effect leading to increased cell adhesion and directed stem cell differentiation.


Effects of cyclosporine and tacrolimus (FK 506) on acute pancreatitis in mice.
To use mice to examine the effects of cyclosporine and tacrolimus (FK 506) on two forms of acute pancreatitis often seen after clinical organ transplantation. In the first experiment, male CD-1 mice received cyclosporine (10 mg/kg), tacrolimus (0.32 mg/kg), or saline solution (control) subcutaneously once a day for 10 days. On the 11th day, acute edematous pancreatitis was induced by ceruletide (cerulein). In the second experiment, female ICR mice were fed with a choline-deficient, ethionine-supplemented (CDE) diet for 72 hours to induce necrotizing pancreatitis. After 30 hours on the CDE diet, the mice received cyclosporine (10 mg/kg), tacrolimus (0.32 mg/kg), or saline solution (control) subcutaneously twice daily for 3 days. The pancreatic dry-to-wet weight ratios after ceruletide injections significantly decreased in mice treated with cyclosporine but did not with tacrolimus. Cyclosporine also significantly increased serum amylase levels, but tacrolimus did not. Cyclosporine or tacrolimus alone did not produce pancreatitis. In the CDE diet groups there was a significant difference in survival among the cyclosporine-treated, the tacrolimus-treated, and the control groups. Cyclosporine or tacrolimus given alone does not induce acute pancreatitis. In contrast, cyclosporine can adversely affect the course of acute edematous pancreatitis, and both immunosuppressants may worsen the survival of mice with acute hemorrhagic necrotizing pancreatitis. This study also demonstrated that the deteriorating effect of tacrolimus is less potent than that of cyclosporine.


Chemical mutagenesis induced two high bone density mouse mutants map to a concordant distal chromosome 4 locus.
Phenotype-driven mutagenesis approach in the mouse holds much promise as a method for revealing gene function. Earlier, we have described an N-ethyl-N-nitrosourea (ENU) mutagenesis screen to create genome-wide dominant mutations in the mouse model. Using this approach, we describe identification of two high bone density mutants in C57BL/6J (B6) background. The mutants, named as 12184 and 12137, have been bred more than five generations with wild-type B6 mice, each producing >200 backcross progeny. The average total body areal bone mineral density (aBMD) was 13-17% higher in backcrossed progeny from both mutant lines between 6 and 10 weeks of age, as compared to wild-type (WT) B6 mice (n=60-107). At 3 weeks of age the aBMD of mutant progeny was not significantly affected as compared to WT B6 mice. Data from 10- and 16-week old progeny show that increased aBMD was mainly related to a 14-20% higher bone mineral content, whereas bone size was marginally increased. In addition, the average volumetric BMD (vBMD) was 5-15% higher at the midshaft tibia or femur, as compared to WT mice. Histomorphometric analysis revealed that bone resorption was 23-34% reduced in both mutant mice. Consistent with histomorphometry data, the mRNA expression of genes that regulate osteoclast differentiation and survival were altered in the 12137 mutant mice. To determine the chromosomal location of the ENU mutation, we intercrossed both mutant lines with C3H/HeJ (C3H) mice to generate B6C3H F2 mice (n=164 for line 12137 and n=137 F2 for line 12184). Interval mapping using 60 microsatellite markers and aBMD phenotype revealed only one significant or suggestive linkage on chromosome 4. Since body weight was significantly higher in mutant lines, we also used body weight as additive and interactive covariate for interval mapping; both analyses showed higher LOD scores for both 12137 and 12184 mutants without affecting the chromosomal location. The large phenotype in the mutant mice compared to generally observed QTL effects (<5%) would increase the probability of identifying the mutant gene.


Sexual behavior in high-functioning male adolescents and young adults with autism spectrum disorder.
Group home caregivers of 24 institutionalized, male, high-functioning adolescents and young adults with Autism Spectrum Disorder, were interviewed with the Interview Sexuality Autism. Most subjects were reported to express sexual interest and to display some kind of sexual behavior. Knowledge of socio-sexual skills existed, but practical use was moderate. Masturbation was common. Many subjects were seeking physical contact with others. Half of the sample had experienced a relationship, while three were reported to have had sexual intercourse. The number of bisexual orientations appeared high. Ritual-sexual use of objects and sensory fascination with a sexual connotation were sometimes present. A paraphilia was present in two subjects. About one third of the group needed intervention regarding sexual development or behavior.


Accuracy of Component Positioning in 1980 Total Hip Arthroplasties: A Comparative Analysis by Surgical Technique and Mode of Guidance.
The purpose of this multi-surgeon study was to assess and compare the accuracy of acetabular component placement, leg length discrepancy (LLD), and global offset difference (GOD) between six different surgical techniques and modes of guidance in total hip arthroplasty (THA). A total of 1980 THAs met inclusion criteria. Robotic- and navigation-guided techniques were more consistent than other techniques in placing the acetabular cup into Lewinnek's safe zone (P<0.005 and P<0.05, respectively). Robotic-guided surgery was more consistent than other techniques in placing the acetabular component within Callanan's safe zone (P<0.005). No statistically significant differences were found between groups in the frequency of patients with excessive LLD. Clinically significant differences between groups were not found in the frequency of patients with excessive GOD. Level of Evidence: IV.


Radioembolization With Yttrium-90 Resin Microspheres in Hepatocellular Carcinoma: A Multicenter Prospective Study.
The aim of this prospective study was to reveal the efficacy and safety of Yttrium-90 (Y) radioembolization in Korean patients with hepatocellular carcinoma (HCC). A total of 40 HCC patients were prospectively recruited from 7 centers. The response to treatment was assessed on the basis of the modified Response Evaluation Criteria in Solid Tumors criteria. The time to progression and overall survival were also evaluated, and the assessment of safety was done according to National Cancer Institute Common Terminology Criteria, Version 3.0. Forty-two treatments of Y radioembolization were carried out. Median follow-up was 29 months. At 3 months, the complete response, partial response (PR), and stable disease were seen in 4 (10.0%), 19 (47.5%), and 15 (37.5%) patients, respectively. The response rate was 57.5% (23/40), and disease control rate was 95% (38/40) at 3 months. The response rate at 6 months was 63.9% (23/36), and disease control rate was 83.3% (30/36). The median time to progression was 18 months. During follow-up, 10 HCC-related deaths occurred and the 3-year survival rate was 75%. In 19 patients with Barcelona Clinic Liver Cancer-B stage, the 3-year survival rate was 50%. The tumor number (>5) was the only significant predictor associated with survival. The most common adverse event was abdominal pain of mild to moderate degree, and all the complications were manageable. Twenty-six (65%) patients underwent other treatments such as transarterial chemoembolization because of local progression or remnant viable lesion. Y radioembolization might be a safe and effective treatment modality in intermediate-stage to advanced-stage HCC.


Whole Grain Consumption and Inflammatory Markers: A Systematic Literature Review of Randomized Control Trials.
Whole grain foods are rich in nutrients, dietary fibre, a range of antioxidants, and phytochemicals, and may have potential to act in an anti-inflammatory manner, which could help impact chronic disease risk. This systematic literature review aimed to examine the specific effects of whole grains on selected inflammatory markers from human clinical trials in adults. As per the Preferred Reporting Items for Systematic Reviews (PRISMA) protocol, the online databases MEDLINE, Embase, Cochrane, CINAHL, and Scopus were searched from inception through to 31 August 2021. Randomized control trials (RCTs) ≥ 4 weeks in duration, reporting ≥1 of the following: C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor (TNF), were included. A total of 31 RCTs were included, of which 16 studies recruited overweight/obese individuals, 12 had pre-existing conditions, two were in a healthy population, and one study included participants with prostate cancer. Of these 31 RCTs, three included studies with two intervention arms. A total of 32 individual studies measured CRP (10/32 were significant), 18 individual studies measured IL-6 (2/18 were significant), and 13 individual studies measured TNF (5/13 were significant). Most often, the overweight/obese population and those with pre-existing conditions showed significant reductions in inflammatory markers, mainly CRP (34% of studies). Overall, consumption of whole grain foods had a significant effect in reducing at least one inflammatory marker as demonstrated in 12/31 RCTs.


Roles for Gcn5p and Ada2p in transcription and nucleotide excision repair at the Saccharomyces cerevisiae MET16 gene.
Chromatin structure, transcription and repair of cyclobutane pyrimidine dimers at the MET16 gene of wild type, gcn5Delta and ada2Delta Saccharomyces cerevisiae cells were studied under repressing or derepressing conditions. These two components of the SAGA/ADA chromatin remodelling complexes are expendable for the basal transcription of MET16 but are mandatory for its full transcription induction. Despite their influence on transcription neither protein induces major changes in MET16 chromatin structure, but some minor ones occur. Repair at the coding region of the transcribed strand is faster than repair at non-transcribed regions in all strains and either growth condition. Moreover, the more MET16 is transcribed the faster the repair. The data show that by changing the transcription extent the rate of repair at each DNA strand is altered in a different way, confirming that repair at this locus is strongly modulated by its chromatin structure and transcription level. Deletion of GCN5 or ADA2 reduces repair at MET16. The results are discussed in light of the current understanding of Gcn5p and Ada2p functions, and they are the first to report a role for Ada2p in the nucleotide excision repair of the regulatory and transcribed regions of a gene.


DNA barcodes for 1/1000 of the animal kingdom.
This study reports DNA barcodes for more than 1300 Lepidoptera species from the eastern half of North America, establishing that 99.3 per cent of these species possess diagnostic barcode sequences. Intraspecific divergences averaged just 0.43 per cent among this assemblage, but most values were lower. The mean was elevated by deep barcode divergences (greater than 2%) in 5.1 per cent of the species, often involving the sympatric occurrence of two barcode clusters. A few of these cases have been analysed in detail, revealing species overlooked by the current taxonomic system. This study also provided a large-scale test of the extent of regional divergence in barcode sequences, indicating that geographical differentiation in the Lepidoptera of eastern North America is small, even when comparisons involve populations as much as 2800 km apart. The present results affirm that a highly effective system for the identification of Lepidoptera in this region can be built with few records per species because of the limited intra-specific variation. As most terrestrial and marine taxa are likely to possess a similar pattern of population structure, an effective DNA-based identification system can be developed with modest effort.


Association between coffee intake and the risk of oral cavity cancer: a meta-analysis of observational studies.
The association between coffee intake and the risk of oral cavity cancer has been inconsistent in previous studies. Therefore, we conducted a meta-analysis to summarize the evidence regarding the strength of association between coffee intake and oral cavity cancer. PubMed, Embase, and Cochrane Library were searched to select studies on the relationship between coffee intake and oral cavity cancer conducted up to September 2018. Case-control or cohort studies and those that have reported about the effect estimates with 95% confidence intervals (CIs) of oral cavity cancer according to the different categories of coffee intake were included. The odds ratio (OR) and its corresponding 95% CI were calculated using the random-effects model. Fourteen case-control and five cohort studies that recruited 6456 patients with oral cavity cancer were included in the final quantitative meta-analysis. High versus low coffee intake was associated with a reduced risk of oral cavity cancer (OR: 0.68; 95% CI: 0.56-0.82; P < 0.001) in case-control studies (OR: 0.70; 95% CI: 0.55-0.90; P = 0.006) and cohort studies (OR: 0.65; 95% CI: 0.48-0.87; P = 0.004). Moreover, intermediate coffee intake was significantly associated with a reduced risk of oral cavity cancer (OR: 0.85; 95% CI: 0.77-0.94; P = 0.002), and such associations were mainly observed in case-control studies (OR: 0.86; 95% CI: 0.76-0.98; P = 0.021) but not in cohort studies (OR: 0.83; 95% CI: 0.67-1.02; P = 0.071). High or intermediate coffee intake might have protective effects against oral cavity cancer. However, the underlying mechanisms must be further evaluated in large-scale prospective cohort studies.


Searching for principles of microbial ecology across levels of biological organization.
Microbial communities play pivotal roles in ecosystems across different scales, from global elemental cycles to household food fermentations. These complex assemblies comprise hundreds or thousands of microbial species whose abundances vary over time and space. Unraveling the principles that guide their dynamics at different levels of biological organization, from individual species, their interactions, to complex microbial communities is a major challenge. To what extent are these different levels of organization governed by separate principles, and how can we connect these levels to develop predictive models for the dynamics and function of microbial communities? Here, we will discuss recent advances that point towards principles of microbial communities, rooted in various disciplines from physics, biochemistry, and dynamical systems. By considering the marine carbon cycle as a concrete example, we demonstrate how the integration of levels of biological organization can offer deeper insights into the impact of increasing temperatures, such as those associated with climate change, on ecosystem-scale processes. We argue that by focusing on principles that transcend specific microbiomes, we can pave the way for a comprehensive understanding of microbial community dynamics and the development of predictive models for diverse ecosystems.


Establishment and characterization of chromosomal aberrations in human cholangiocarcinoma cell lines by cross-species color banding.
Cholangiocarcinoma (CC), a malignant neoplasm of the biliary epithelium, is usually fatal because of difficulty in early diagnosis and lack of availability of effective therapy. Furthermore, little is known about the genetics and biology of CC. Only a few reports concerning cytogenetic studies of CC have been published, and few cell lines have been established. We recently established four CC cell lines, designated as SCK, JCK, Cho-CK, and Choi-CK, and report the first application of cross-species color banding (RxFISH) and multiple chromosome painting for the characterization of the chromosomal rearrangements of these CC cell lines. Each cell line had unique modal karyotypic characteristics and showed a variable number of numerical and structural clonal cytogenetic aberrations. Chromosomes 3, 6, 7, 8, 12, 14, 17, and 18 were commonly involved in structural abnormalities. Homogeneously staining regions were determined in SCK and JCK, and double minute chromosomes were found in Cho-CK. The chromosomal aberrations of the four CC cell lines were effectively analyzed by RxFISH and FISH with multiple chromosome painting probes. The nonrandom rearrangements suggest candidate regions for isolation of genes related to CC.


How reliable are Psychopathy Checklist-Revised scores in Canadian criminal trials? A case law review.
The Psychopathy Checklist-Revised (PCL-R; Hare, 2003) is a professional rating scale that enjoys widespread use in forensic and correctional settings, primarily as a tool to inform risk assessments in a variety of types of cases (e.g., parole determinations, sexually violent predator [SVP] civil commitment). Although widely described as "reliable and valid" in research reports, several recent field studies have suggested that PCL-R scores provided by examiners in forensic cases are significantly less reliable than the interrater reliability values reported in research studies. Most of these field studies, however, have had small samples and only examined SVP civil commitment cases. This study builds on existing research by examining the reliability of PCL-R scores provided by forensic examiners in a much more extensive sample of Canadian criminal cases. Using the LexisNexis database, we identified 102 cases in which at least 2 scores were reported (of 257 total PCL-R scores). The single-rater intraclass correlation coefficient (ICC(A1)) was .59, indicating that a large percentage of the variance in individual scores was attributable to some form of error. ICC values were somewhat higher for sexual offending cases (.66) than they were for nonsexual offending cases (.46), indicating that poor interrater reliability was not restricted specifically to the assessment of sexual offenders. These and earlier findings concerning field reliability in legal cases suggest that the standard error of measurement for PCL-R scores that are provided to the courts is likely to be much larger than the value of 2.90 reported in the instrument's manual.


Approach to the patient with incidental papillary microcarcinoma.
Analysis of the Surveillance Epidemiology and End Results database reveals that since 1995 a 2.4-fold increase in thyroid cancer has occurred. A concomitant rise in cases of thyroid microcarcinoma has also been noted, with the frequency rising by approximately 50% as well. Increased detection of thyroid nodules, many of them below 1 cm in size, is at least partly responsible for this trend. The wide use of sensitive imaging modalities for various indications leads to the incidental discovery of thyroid nodules, some of which contain thyroid cancer, including cases of microcarcinoma. Although the vast majority of patients with thyroid cancer foci smaller than 1 cm will do exceedingly well long term, exceptions do occur, with some patients experiencing recurrence either locally or less frequently with distant metastasis. There has been some debate on the optimal management for these patients to include: extent of surgery required, the usefulness of ablation with radioactive iodine, as well as the optimal level for TSH suppression. In this article, we will review the available data and recommendations surrounding the management of patients with incidental thyroid microcarcinoma.


The role of patient advocacy organizations in shaping medical research: the Pompe model.
The Pompe model is the term used by the Pompe community to describe the relationship that exists between the patient community, the medical/scientific community, and industry. The development of the Pompe model represented a new paradigm for the involvement of patients in new treatments-and also for scientists and pharmaceutical companies. It saw patients developing a sense of agency, of involvement in the process of treatment development rather than powerless recipients or (if lucky) occasional spectators. At the same time, as described below, it benefited the other partners in the process with the result that the different components of the model added up to more than the sum of their parts. However, in order for this to happen, each part had to undergo a transformation in mindset. The development of enzyme replacement therapy (ERT) for Pompe disease represented a unique set of circumstances and individuals that helped to bring about this change and, in doing so, created a model that has had far wider applications.


Reactive oxygen species in pulmonary vascular remodeling.
The pathogenesis of pulmonary hypertension is a complex multifactorial process that involves the remodeling of pulmonary arteries. This remodeling process encompasses concentric medial thickening of small arterioles, neomuscularization of previously nonmuscular capillary-like vessels, and structural wall changes in larger pulmonary arteries. The pulmonary arterial muscularization is characterized by vascular smooth muscle cell hyperplasia and hypertrophy. In addition, in uncontrolled pulmonary hypertension, the clonal expansion of apoptosis-resistant endothelial cells leads to the formation of plexiform lesions. Based upon a large number of studies in animal models, the three major stimuli that drive the vascular remodeling process are inflammation, shear stress, and hypoxia. Although, the precise mechanisms by which these stimuli impair pulmonary vascular function and structure are unknown, reactive oxygen species (ROS)-mediated oxidative damage appears to play an important role. ROS are highly reactive due to their unpaired valence shell electron. Oxidative damage occurs when the production of ROS exceeds the quenching capacity of the antioxidant mechanisms of the cell. ROS can be produced from complexes in the cell membrane (nicotinamide adenine dinucleotide phosphate-oxidase), cellular organelles (peroxisomes and mitochondria), and in the cytoplasm (xanthine oxidase). Furthermore, low levels of tetrahydrobiopterin (BH4) and L-arginine the rate limiting cofactor and substrate for endothelial nitric oxide synthase (eNOS), can cause the uncoupling of eNOS, resulting in decreased NO production and increased ROS production. This review will focus on the ROS generation systems, scavenger antioxidants, and oxidative stress associated alterations in vascular remodeling in pulmonary hypertension.


Coffee consumption and risk of non-Hodgkin's lymphoma: evidence from the Italian multicentre case-control study.
Several investigations have analysed the association between coffee intake and risk of cancer. Contradictory results were reported by the studies conducted in non-Hodgkin's lymphomas (NHL) few of which report results according to main NHL subgroups. The present study is aimed at evaluating the association between coffee consumption and the risk of NHL by analysing data from a large Italian multicentre case-control study that included 1,418 interviewed cases (1,301 B cell and 117 T cell NHL), diagnosed between 1990 and 1993, and 1,774 population healthy controls. The association was evaluated by standard logistic regression analysis. Odds ratio (OR) estimates were adjusted for gender, age, residence area, educational level, previous chemotherapy treatment, smoking habit and exposure to electromagnetic fields, radiation, pesticides and aromatic hydrocarbons. For all B cell lymphomas, an increased risk (OR 1.6, 95% CI 1.2-2.0) was observed in the highest exposure category (consumption >4 cups per day for at least 30 years), but without a clear dose-response trend. Subgroup analyses highlighted an increased risk for drinkers of at least four cups per day for follicular lymphoma (OR 2.0, 95% CI 1.2-3.4). The risk increased with years of exposure and was more elevated among current smokers. Consumption of more than four cups of coffee per day enhances the risk of lymphoma, especially the follicular subtype. Further investigations based on large cohorts and accurate measures of exposure are needed to confirm the observed associations.


Detection of non-coding RNAs on the basis of predicted secondary structure formation free energy change.
Non-coding RNAs (ncRNAs) have a multitude of roles in the cell, many of which remain to be discovered. However, it is difficult to detect novel ncRNAs in biochemical screens. To advance biological knowledge, computational methods that can accurately detect ncRNAs in sequenced genomes are therefore desirable. The increasing number of genomic sequences provides a rich dataset for computational comparative sequence analysis and detection of novel ncRNAs. Here, Dynalign, a program for predicting secondary structures common to two RNA sequences on the basis of minimizing folding free energy change, is utilized as a computational ncRNA detection tool. The Dynalign-computed optimal total free energy change, which scores the structural alignment and the free energy change of folding into a common structure for two RNA sequences, is shown to be an effective measure for distinguishing ncRNA from randomized sequences. To make the classification as a ncRNA, the total free energy change of an input sequence pair can either be compared with the total free energy changes of a set of control sequence pairs, or be used in combination with sequence length and nucleotide frequencies as input to a classification support vector machine. The latter method is much faster, but slightly less sensitive at a given specificity. Additionally, the classification support vector machine method is shown to be sensitive and specific on genomic ncRNA screens of two different Escherichia coli and Salmonella typhi genome alignments, in which many ncRNAs are known. The Dynalign computational experiments are also compared with two other ncRNA detection programs, RNAz and QRNA. The Dynalign-based support vector machine method is more sensitive for known ncRNAs in the test genomic screens than RNAz and QRNA. Additionally, both Dynalign-based methods are more sensitive than RNAz and QRNA at low sequence pair identities. Dynalign can be used as a comparable or more accurate tool than RNAz or QRNA in genomic screens, especially for low-identity regions. Dynalign provides a method for discovering ncRNAs in sequenced genomes that other methods may not identify. Significant improvements in Dynalign runtime have also been achieved.


Studies on the basis for the toxicity of acrolein mercapturates.
Acrolein, 3-oxopropyl glutathione (oxoPrGSH), and S-3-hydroxypropyl N-acetylcysteine (hydroxyPrMCA) are confirmed metabolic products of cyclophosphamide. Other potential metabolites include the mercapturic acid S-3-oxopropyl N-acetylcysteine (oxoPrMCA), its sulfoxide, and their corresponding diacid forms. The reactivity of acrolein would appear to preclude its movement from the main site of formation (liver) to the sites of toxicity (lung and bladder). However, the rerelease of acrolein from various thiol conjugates via a beta-elimination reaction is possible. It is also possible that the parent conjugate is directly toxic. The current study examined the toxicity of various acrolein-thiol conjugates and related analogs to human lung adenoma A549 cells. The expected enhancement of acrolein, oxoPrMCA, and oxoPrMCA S-oxide toxicity (assessed as cell proliferation by the alamarBlue assay) following a 2-hr exposure of cells treated with diethyl maleate (DEM) to deplete GSH was observed. OxoPrGSH was toxic when present for 24 hr, and this toxicity was also enhanced by pretreatment with DEM. When treated with these conjugates alone, the depletion of intracellular GSH only occurred at doses above those needed to significantly inhibit cell proliferation. There were no changes in protein thiols as determined using the membrane impermeant fluorescent thiol probe para-sulfobenzoyloxybromobimane. The diacid conjugate was not toxic to A549 cells indicating further oxidation products of the mercapturic acids are not a factor in toxicity. ButanoneMCA, an analog of oxoPrMCA that cannot exist in the geminal diol form, inhibited A549 cell growth only slightly less effectively than oxoPrMCA, suggesting the geminal diol is not toxicologically significant. OxoBuMCA, which cannot undergo beta-elimination of acrolein, showed no toxicity to these cells, suggesting that the release of acrolein could be required. Exogenous GSH provided protection from all toxic compounds suggesting that the toxic species is electrophilic. Overall, the data suggest that toxicity, in terms of an inhibition of cell proliferation, is not due to the parent molecule but rather is the result of rereleased acrolein that then affects factors necessary for cell proliferation.


Negative response elements in keratin genes mediate transcriptional repression and the cross-talk among nuclear receptors.
Very little is known about the mechanisms responsible for the findings that binding of nuclear receptors (NR) to some promoter elements leads to transcriptional activation, whereas binding to others leads to repression. Case in point is the group of epidermal keratin genes and their DNA sequences responsible for repression by NR. Keratin response elements (KREs) interact with receptors for retinoic acid, thyroid hormone, and glucocorticoids. KREs, by their structure and sequence, direct the binding of retinoic acid and thyroid hormone as homodimers and glucocorticoids as monomers. Such specific DNA-receptor interactions are crucial for the repression signal of transcription. In this paper we have analyzed the interactions between the KREs and NR that lead to such repression. We have found that KREs are promoter-independent. They not only provide a docking platform for the receptors, but also play a key role in directing the receptors to bind into particular configurations and coordinating the interactions among different receptors. Both an intact KRE and an intact receptor DNA-binding domain are necessary for the regulation to occur, which emphasizes the importance of interaction between the DNA and NR for proper signaling. Furthermore, KREs allow simultaneous binding of multiple receptors, thus providing fine-tuning of transcriptional regulation. The DNA/DNA-binding domain interactions in keratin promoters exemplify tissue and gene specificity of hormone action.


Symmetry of discrete and oscillatory elbow movements: does it depend on torque that the agonist and antagonist muscle can exert?
The hypothesis that strength of active muscles affects the symmetry of the velocity profiles of voluntary movements was tested. In particular, it was assumed that the duration of acceleration and deceleration phases reflects the ability of the antagonistic muscles to exert torque in such a way that stronger muscle requires less time for action. Twelve subjects performed consecutive 50 flexions and extensions in blocks of either discrete or oscillatory movements. They were tested under high and moderate speed conditions, as well as within different ranges of elbow joint angles. The symmetry ratio (SR; acceleration time divided by deceleration time) was calculated in order to assess movement symmetry. The results demonstrated SR > 1 under most of the discrete and, particularly, oscillatory movement conditions. A velocity-associated increase in SR was recorded, while different ranges of elbow movements, assumed to provide different torques of the agonist and antagonist muscles, also provided different SR. The findings were generally in line with the predicted effects of movement conditions on muscle strength, particularly those related to elbow angle and elbow angular velocity. Deviations from the ideal movement symmetricity have usually been interpreted as either weakness of various motor control models and hypotheses, or as a sub-optimal control of movements in certain subject populations; the present study suggests an alternative interpretation based upon the ability of active muscles to exert torque


Four days of bed rest increases intrinsic mitochondrial respiratory capacity in young healthy males.
Bed rest leads to impaired glucose tolerance. Whether this is linked to maladaptation's in skeletal muscle mitochondrial function and in particular to the level of reactive oxygen species (ROS) is at present unknown. The aim of this longitudinal study was to quantify skeletal muscle mitochondrial function (respiratory capacity and ROS production) together with glucose tolerance after 4 days of strict bed rest in healthy young male subjects (n = 14). Mitochondrial function was determined in permeabilized muscle fibers using high-resolution respirometry and fluorometry, mitochondrial content (citrate synthase [CS] activity) and antioxidant protein expression levels were assessed in parallel to this. Glucose tolerance was determined by means of oral glucose tolerance tests. Intrinsic mitochondrial respiratory capacity was augmented after the bed rest period (CI + IIP : 0.43 ± 0.12 vs. 0.55 ± 0.14 [pmol/sec/mg]/CS activity), due to a decreased CS activity (158 ± 39 vs. 129 ± 25 mU/mg dw.). No differences were observed in ROS production (per mg of tissue or when normalized to CS activity). Furthermore, the protein content for catalase was increased while superoxide dismutase and glutathione peroxidase remained unaffected. These findings were accompanied by an impaired glucose tolerance after the bed rest period (Matsuda index: 12 ± 6 vs. 9 ± 5). The change in intrinsic mitochondrial respiratory capacity could be an early indication in the development of impaired glucose tolerance. The increased catalase protein content might explain that no change was seen in ROS production after 4 days of bed rest. Whether these findings can be extrapolated to lifestyle-dependent decrements in physical activity and the development of type-2-diabetes remains unknown.


Transcriptional coordination of the metabolic network in Arabidopsis.
Patterns of coexpression can reveal networks of functionally related genes and provide deeper understanding of processes requiring multiple gene products. We performed an analysis of coexpression networks for 1,330 genes from the AraCyc database of metabolic pathways in Arabidopsis (Arabidopsis thaliana). We found that genes associated with the same metabolic pathway are, on average, more highly coexpressed than genes from different pathways. Positively coexpressed genes within the same pathway tend to cluster close together in the pathway structure, while negatively correlated genes typically occupy more distant positions. The distribution of coexpression links per gene is highly skewed, with a small but significant number of genes having numerous coexpression partners but most having fewer than 10. Genes with multiple connections (hubs) tend to be single-copy genes, while genes with multiple paralogs are coexpressed with fewer genes, on average, than single-copy genes, suggesting that the network expands through gene duplication, followed by weakening of coexpression links involving duplicate nodes. Using a network-analysis algorithm based on coexpression with multiple pathway members (pathway-level coexpression), we identified and prioritized novel candidate pathway members, regulators, and cross pathway transcriptional control points for over 140 metabolic pathways. To facilitate exploration and analysis of the results, we provide a Web site (http://www.transvar.org/at_coexpress/analysis/web) listing analyzed pathways with links to regression and pathway-level coexpression results. These methods and results will aid in the prioritization of candidates for genetic analysis of metabolism in plants and contribute to the improvement of functional annotation of the Arabidopsis genome.


A Smartphone-Based Tool for Rapid, Portable, and Automated Wide-Field Retinal Imaging.
High-quality, wide-field retinal imaging is a valuable method for screening preventable, vision-threatening diseases of the retina. Smartphone-based retinal cameras hold promise for increasing access to retinal imaging, but variable image quality and restricted field of view can limit their utility. We developed and clinically tested a smartphone-based system that addresses these challenges with automation-assisted imaging. The system was designed to improve smartphone retinal imaging by combining automated fixation guidance, photomontage, and multicolored illumination with optimized optics, user-tested ergonomics, and touch-screen interface. System performance was evaluated from images of ophthalmic patients taken by nonophthalmic personnel. Two masked ophthalmologists evaluated images for abnormalities and disease severity. The system automatically generated 100° retinal photomontages from five overlapping images in under 1 minute at full resolution (52.3 pixels per retinal degree) fully on-phone, revealing numerous retinal abnormalities. Feasibility of the system for diabetic retinopathy (DR) screening using the retinal photomontages was performed in 71 diabetics by masked graders. DR grade matched perfectly with dilated clinical examination in 55.1% of eyes and within 1 severity level for 85.2% of eyes. For referral-warranted DR, average sensitivity was 93.3% and specificity 56.8%. Automation-assisted imaging produced high-quality, wide-field retinal images that demonstrate the potential of smartphone-based retinal cameras to be used for retinal disease screening. Enhancement of smartphone-based retinal imaging through automation and software intelligence holds great promise for increasing the accessibility of retinal screening.


Photosynthetic efficiency of Chlamydomonas reinhardtii in flashing light.
Efficient light to biomass conversion in photobioreactors is crucial for economically feasible microalgae production processes. It has been suggested that photosynthesis is enhanced in short light path photobioreactors by mixing-induced flashing light regimes. In this study, photosynthetic efficiency and growth of the green microalga Chlamydomonas reinhardtii were measured using LED light to simulate light/dark cycles ranging from 5 to 100 Hz at a light-dark ratio of 0.1 and a flash intensity of 1000 µmol m(-2) s(-1). Light flashing at 100 Hz yielded the same photosynthetic efficiency and specific growth rate as cultivation under continuous illumination with the same time-averaged light intensity (i.e., 100 µmol m(-2) s(-1)). The efficiency and growth rate decreased with decreasing flash frequency. Even at 5 Hz flashing, the rate of linear electron transport during the flash was still 2.5 times higher than during maximal growth under continuous light, suggesting storage of reducing equivalents during the flash which are available during the dark period. In this way the dark reaction of photosynthesis can continue during the dark time of a light/dark cycle. Understanding photosynthetic growth in dynamic light regimes is crucial for model development to predict microalgal photobioreactor productivities.


A non-reflecting metamaterial slab under the finite-embedded coordinate transformation.
Under the restrictions that the mapping functions of transformation are defined in extended two-dimensional (2D) forms and the incident waves are 2D propagating fields, the conditions for non-reflecting boundaries in a finite-embedded coordinate transformation metamaterial slab are derived. By exploring several examples, including some reported in the literatures and some novel ones developed in this study, we show that our approach can be efficiently used to determine the condition for a finite-embedded coordinate transformed metamaterial slab to be non-reflecting.


Rhabdomyolysis and acute encephalopathy in late onset medium chain acyl-CoA dehydrogenase deficiency.
A previously asymptomatic 30 year old man presented with rhabdomyolysis, muscle weakness, and acute encephalopathy after strenuous exertion in the cold without adequate food intake. Serum and muscle carnitine concentrations were decreased. Urinary excretion of carnitine and glycine esters and biochemical examination of skeletal muscle and fibroblasts led to the diagnosis of medium chain acyl-CoA dehydrogenase (MCAD) deficiency. A point mutation at nucleotide position 985 of the coding region of the MCAD gene was found. The MCAD protein was synthesised in the patient's fibroblasts at a normal rate, but was unstable. In general, patients in whom the 985 point mutation has been established show much more severe clinical symptoms and other symptoms than those seen in this patient. The relation of the 985 point mutation and the residual MACD activity to the symptoms is not as straightforward as previously thought.


Human Milk Short-Chain Fatty Acid Composition is Associated with Adiposity Outcomes in Infants.
Presumed benefits of human milk (HM) in avoiding rapid infancy weight gain and later obesity could relate to its nutrient composition. However, data on breast milk composition and its relation with growth are sparse. We investigated whether short-chain fatty acids (SCFAs), known to be present in HM and linked to energy metabolism, are associated with infancy anthropometrics. In a prospective birth cohort, HM hindmilk samples were collected from 619 lactating mothers at 4-8 wk postnatally [median (IQR) age: 33.9 (31.3-36.5) y, body mass index (BMI) (kg/m2): 22.8 (20.9-25.2)]. Their offspring, born at 40.1 (39.1-41.0) wk gestation with weight 3.56 (3.22-3.87) kg and 51% male, were assessed with measurement of weight, length, and skinfold thickness at ages 3, 12, and 24 mo, and transformed to age- and sex-adjusted z scores. HM SCFAs were measured by 1H-nuclear magnetic resonance spectroscopy (NMR) and GC-MS. Multivariable linear regression models were conducted to analyze the relations between NMR HM SCFAs and infancy growth parameters with adjustment for potential confounders. NMR peaks for HM butyrate, acetate, and formic acid, but not propionate, were detected. Butyrate peaks were 17.8% higher in HM from exclusively breastfeeding mothers than mixed-feeding mothers (P = 0.003). HM butyrate peak values were negatively associated with changes in infant weight (standardized B = -0.10, P = 0.019) and BMI (B = -0.10, P = 0.018) between 3 and 12 mo, and negatively associated with BMI (B = -0.10, P = 0.018) and mean skinfold thickness (B = -0.10, P = 0.049) at age 12 mo. HM formic acid peak values showed a consistent negative association with infant BMI at all time points (B < = -0.10, P < = 0.014), whereas HM acetate was negatively associated with skinfold thickness at 3 mo (B = -0.10, P = 0.028) and 24 mo (B = -0.10, P = 0.036). These results suggest that HM SCFAs play a beneficial role in weight gain and adiposity during infancy. Further knowledge of HM SCFA function may inform future strategies to support healthy growth.


PrfA, the transcriptional activator of virulence genes, is upregulated during interaction of Listeria monocytogenes with mammalian cells and in eukaryotic cell extracts.
Most virulence genes of Listeria monocytogenes are activated by the transcriptional regulator PrfA. Previous studies have shown that environmental parameters, such as temperature, pH, stress conditions and medium composition, affect the expression of PrfA and PrfA-dependent proteins. In this report, we demonstrate a threefold increase in PrfA protein synthesis during infection of mammalian cells, which correlates with the increased activity of the plcA promoter, the major prfA promoter. Increased PrfA synthesis begins when L. monocytogenes adheres to host cells. In addition, we show that the observed induction of PrfA during the interaction of L. monocytogenes with mammalian cells can be reproduced in vitro using total cell extracts. Our data suggest a role for host proteinase K-sensitive protein(s) in PrfA upregulation.


Drug and chemical induced photosensitivity from a clinical perspective.
Drug photosensitivity is a relatively common occurrence and a range of mechanisms may be involved. Some of these mechanisms will be discussed, including the most common, that of drug phototoxicity. Different types of photosensitivity are addressed with respect to clinical presentation, mechanisms and additionally the contribution to our understanding through clinically directed investigations and regulatory requirements. Repeated controlled therapeutic use of drug phototoxicity, with psoralen-UVA (PUVA) photochemotherapy and photodynamic therapy (PDT) will also be discussed. Finally, the potential for drug-induced photocarcinogenesis will also be covered.


Characterization of wavelength-swept active mode locking fiber laser based on reflective semiconductor optical amplifier.
The static and dynamic characteristics of a wavelength-swept active mode locking (AML) fiber laser are presented in both the time-region and wavelength-region. This paper shows experimentally that the linewidth of a laser spectrum and the bandwidth of the sweeping wavelength are dependent directly on the length and dispersion of the fiber cavity as well as the modulation frequency and sweeping rate under the mode-locking condition. To achieve a narrower linewidth, a longer length and higher dispersion of the fiber cavity as well as a higher order mode locking condition are required simultaneously. For a broader bandwidth, a lower order of the mode locking condition is required using a lower modulation frequency. The dynamic sweeping performance is also analyzed experimentally to determine its applicability to optical coherence tomography imaging. It is shown that the maximum sweeping rate can be improved by the increased free spectral range from the shorter length of the fiber cavity. A reflective semiconductor optical amplifier (RSOA) was used to enhance the modulation and dispersion efficiency. Overall a triangular electrical signal can be used instead of the sinusoidal signal to sweep the lasing wavelength at a high sweeping rate due to the lack of mechanical restrictions in the wavelength sweeping mechanism.


Understanding the Experience of Cancer Pain From the Perspective of Patients and Family Caregivers to Inform Design of an In-Home Smart Health System: Multimethod Approach.
Inadequately managed pain is a serious problem for patients with cancer and those who care for them. Smart health systems can help with remote symptom monitoring and management, but they must be designed with meaningful end-user input. This study aims to understand the experience of managing cancer pain at home from the perspective of both patients and family caregivers to inform design of the Behavioral and Environmental Sensing and Intervention for Cancer (BESI-C) smart health system. This was a descriptive pilot study using a multimethod approach. Dyads of patients with cancer and difficult pain and their primary family caregivers were recruited from an outpatient oncology clinic. The participant interviews consisted of (1) open-ended questions to explore the overall experience of cancer pain at home, (2) ranking of variables on a Likert-type scale (0, no impact; 5, most impact) that may influence cancer pain at home, and (3) feedback regarding BESI-C system prototypes. Qualitative data were analyzed using a descriptive approach to identity patterns and key themes. Quantitative data were analyzed using SPSS; basic descriptive statistics and independent sample t tests were run. Our sample (n=22; 10 patient-caregiver dyads and 2 patients) uniformly described the experience of managing cancer pain at home as stressful and difficult. Key themes included (1) unpredictability of pain episodes; (2) impact of pain on daily life, especially the negative impact on sleep, activity, and social interactions; and (3) concerns regarding medications. Overall, taking pain medication was rated as the category with the highest impact on a patient's pain (=4.79), followed by the categories of wellness (=3.60; sleep quality and quantity, physical activity, mood and oral intake) and interaction (=2.69; busyness of home, social or interpersonal interactions, physical closeness or proximity to others, and emotional closeness and connection to others). The category related to environmental factors (temperature, humidity, noise, and light) was rated with the lowest overall impact (=2.51). Patients and family caregivers expressed receptivity to the concept of BESI-C and reported a preference for using a wearable sensor (smart watch) to capture data related to the abrupt onset of difficult cancer pain. Smart health systems to support cancer pain management should (1) account for the experience of both the patient and the caregiver, (2) prioritize passive monitoring of physiological and environmental variables to reduce burden, and (3) include functionality that can monitor and track medication intake and efficacy; wellness variables, such as sleep quality and quantity, physical activity, mood, and oral intake; and levels of social interaction and engagement. Systems must consider privacy and data sharing concerns and incorporate feasible strategies to capture and characterize rapid-onset symptoms.


Fruit Carts: A Domain and Corpus for Research in Dialogue Systems and Psycholinguistics.
We describe a novel domain, Fruit Carts, aimed at eliciting human language production for the twin purposes of (a) dialogue system research and development and (b) psycholinguistic research. Fruit Carts contains five tasks: choosing a cart, placing it on a map, painting the cart, rotating the cart, and filling the cart with fruit. Fruit Carts has been used for research in psycholinguistics and in dialogue systems. Based on these experiences, we discuss how well the Fruit Carts domain meets four desired features: unscripted, context-constrained, controllable difficulty, and separability into semi-independent subdialogues. We describe the domain in sufficient detail to allow others to replicate it; researchers interested in using the corpora themselves are encouraged to contact the authors directly.


The impact of modified mania assessment scale (MAS-M) implementation on the use of mechanical restraint in psychiatric units.
During recent years, there has been an increased focus on reducing use of mechanical restraint in psychiatric care. Studies show that implementing an assessment tool could potentially prevent or decrease the number of episodes of mechanical restraint. This study aims to examine the association between use of the Danish assessment tool for psychiatric inpatients diagnosed with mania (MAS-M) and mechanical restraint to highlight if number, type, and duration of restraint could be prevented or reduced by this procedure. This historical cohort study included psychiatric inpatients diagnosed with bipolar disorder and hospitalized with symptoms of mania at the departments of affective disorders during the years 2012-2015. Logistic regression was used in the statistical analyses. A total of 218 patients were included, 74 of whom were scored with MAS-M. Thirty-five episodes of mechanical restraint were recorded. A crude OR of 1.58 (95% CI: 0.75-3.30) of the association was estimated. The study showed a tendency toward patients scored with MAS-M being more frequently restrained with both belt and straps, however, in shorter duration, compared to the control group. This study reported relevant clinical information concerning staff's use of MAS-M, however, did not show a significant association between the use of MAS-M and mechanical restraint. Nevertheless, conflicting results about the impact of MAS-M on preventing and reducing these coercive measures have been highlighted, suggesting that more complex factors influence the use of mechanical restraint. No causal effect was examined thus further studies are needed.


The metagenomics RAST server - a public resource for the automatic phylogenetic and functional analysis of metagenomes.
Random community genomes (metagenomes) are now commonly used to study microbes in different environments. Over the past few years, the major challenge associated with metagenomics shifted from generating to analyzing sequences. High-throughput, low-cost next-generation sequencing has provided access to metagenomics to a wide range of researchers. A high-throughput pipeline has been constructed to provide high-performance computing to all researchers interested in using metagenomics. The pipeline produces automated functional assignments of sequences in the metagenome by comparing both protein and nucleotide databases. Phylogenetic and functional summaries of the metagenomes are generated, and tools for comparative metagenomics are incorporated into the standard views. User access is controlled to ensure data privacy, but the collaborative environment underpinning the service provides a framework for sharing datasets between multiple users. In the metagenomics RAST, all users retain full control of their data, and everything is available for download in a variety of formats. The open-source metagenomics RAST service provides a new paradigm for the annotation and analysis of metagenomes. With built-in support for multiple data sources and a back end that houses abstract data types, the metagenomics RAST is stable, extensible, and freely available to all researchers. This service has removed one of the primary bottlenecks in metagenome sequence analysis - the availability of high-performance computing for annotating the data. http://metagenomics.nmpdr.org.


Longitudinal auditory learning facilitates auditory cognition as revealed by microstate analysis.
The current study investigates cognitive processes as reflected in late auditory-evoked potentials as a function of longitudinal auditory learning. A normal hearing adult sample (n=15) performed an active oddball task at three consecutive time points (TPs) arranged at two week intervals, and during which EEG was recorded. The stimuli comprised of syllables consisting of a natural fricative (/sh/,/s/,/f/) embedded between two /a/ sounds, as well as morphed transitions of the two syllables that served as deviants. Perceptual and cognitive modulations as reflected in the onset and the mean global field power (GFP) of N2b- and P3b-related microstates across four weeks were investigated. We found that the onset of P3b-like microstates, but not N2b-like microstates decreased across TPs, more strongly for difficult deviants leading to similar onsets for difficult and easy stimuli after repeated exposure. The mean GFP of all N2b-like and P3b-like microstates increased more in spectrally strong deviants compared to weak deviants, leading to a distinctive activation for each stimulus after learning. Our results indicate that longitudinal training of auditory-related cognitive mechanisms such as stimulus categorization, attention and memory updating processes are an indispensable part of successful auditory learning. This suggests that future studies should focus on the potential benefits of cognitive processes in auditory training.


Conservation of the HBV RNA element epsilon in nackednaviruses reveals ancient origin of protein-primed reverse transcription.
Hepadnaviruses, with the human hepatitis B virus as prototype, are small, enveloped hepatotropic DNA viruses which replicate by reverse transcription of an RNA intermediate. Replication is initiated by a unique protein-priming mechanism whereby a hydroxy amino acid side chain of the terminal protein (TP) domain of the viral polymerase (P) is extended into a short DNA oligonucleotide, which subsequently serves as primer for first-strand synthesis. A key component in the priming of reverse transcription is the viral RNA element epsilon, which contains the replication origin and serves as a template for DNA primer synthesis. Here, we show that recently discovered non-enveloped fish viruses, termed nackednaviruses [C. Lauber et al., Cell Host Microbe 22, 387-399 (2017)], employ a fundamentally similar replication mechanism despite their huge phylogenetic distance and major differences in genome organization and viral lifestyle. In vitro cross-priming studies revealed that few strategic nucleotide substitutions in epsilon enable site-specific protein priming by heterologous P proteins, demonstrating that epsilon is functionally conserved since the two virus families diverged more than 400 Mya. In addition, other cis elements crucial for the hepadnavirus-typical replication of pregenomic RNA into relaxed circular double-stranded DNA were identified at conserved positions in the nackednavirus genomes. Hence, the replication mode of both hepadnaviruses and nackednaviruses was already established in their Paleozoic common ancestor, making it a truly ancient and evolutionary robust principle of genome replication that is more widespread than previously thought.


Increase in concentration of waking salivary cortisol in recovered patients with depression.
Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis with elevated plasma cortisol levels is characteristic of acute major depression. However, it is unclear whether HPA axis abnormalities are present in fully recovered patients. An increase in salivary cortisol levels after waking provides a simple, dynamic measure of HPA axis activity. The authors measured this increase in recovered depressed patients and in a healthy comparison group. Salivary cortisol levels were measured upon waking and at 15-minute intervals for the next hour in 31 medication-free, recovered depressed patients and in 31 matched healthy comparison subjects. The increase in salivary cortisol levels that followed waking was significantly higher in the patients. Greater secretion of cortisol may be present in depressed subjects after clinical recovery and withdrawal of medication. This may put patients at risk of further episodes of depression as well as comorbid medical conditions, such as coronary heart disease.


Analysis of genomic signatures in prokaryotes using multinomial regression and hierarchical clustering.
Recently there has been an explosion in the availability of bacterial genomic sequences, making possible now an analysis of genomic signatures across more than 800 hundred different bacterial chromosomes, from a wide variety of environments.Using genomic signatures, we pair-wise compared 867 different genomic DNA sequences, taken from chromosomes and plasmids more than 100,000 base-pairs in length. Hierarchical clustering was performed on the outcome of the comparisons before a multinomial regression model was fitted. The regression model included the cluster groups as the response variable with AT content, phyla, growth temperature, selective pressure, habitat, sequence size, oxygen requirement and pathogenicity as predictors. Many significant factors were associated with the genomic signature, most notably AT content. Phyla was also an important factor, although considerably less so than AT content. Small improvements to the regression model, although significant, were also obtained by factors such as sequence size, habitat, growth temperature, selective pressure measured as oligonucleotide usage variance, and oxygen requirement. The statistics obtained using hierarchical clustering and multinomial regression analysis indicate that the genomic signature is shaped by many factors, and this may explain the varying ability to classify prokaryotic organisms below genus level.


MicroRNA in pancreatic adenocarcinoma: predictive/prognostic biomarkers or therapeutic targets?
Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a poor prognosis, short overall survival and few chemotherapeutic choices. MicroRNAs (miRNAs) are non-coding, single-stranded RNAs of around 22 nucleotides involved in the pathogenic mechanisms of carcinogenesis and metastasis. They have been studied in many tumors in order to identify potential diagnostic, prognostic or therapeutic targets. In the current literature, many studies have analyzed the role of miRNAs in PDAC. In fact, the absence of appropriate biomarkers, the difficultly of early detection of this tumor, and the lack of effective chemotherapy in patients with unresectable disease have focused attention on miRNAs as new, interesting advance in this malignancy. In this review we analyzed the role of miRNAs in PDAC in order to understand the mechanisms of action and the difference between the onco-miRNA and the tumor suppressor miRNA. We also reviewed all the data related to the use of these molecules as predictive as well as prognostic biomarkers in the course of the disease. Finally, the possible therapeutic use of miRNAs or anti-miRNAs in PDAC is also discussed. In conclusion, although there is still no clinical application for these molecules in PDAC, it is our opinion that the preclinical evidence of the role of specific miRNAs in carcinogenesis, the possibility of using miRNAs as diagnostic or prognostic biomarkers, and their potential therapeutic role, warrant future studies in PDAC.


The case for low carbohydrate diets in diabetes management.
A low fat, high carbohydrate diet in combination with regular exercise is the traditional recommendation for treating diabetes. Compliance with these lifestyle modifications is less than satisfactory, however, and a high carbohydrate diet raises postprandial plasma glucose and insulin secretion, thereby increasing risk of CVD, hypertension, dyslipidemia, obesity and diabetes. Moreover, the current epidemic of diabetes and obesity has been, over the past three decades, accompanied by a significant decrease in fat consumption and an increase in carbohydrate consumption. This apparent failure of the traditional diet, from a public health point of view, indicates that alternative dietary approaches are needed. Because carbohydrate is the major secretagogue of insulin, some form of carbohydrate restriction is a prima facie candidate for dietary control of diabetes. Evidence from various randomized controlled trials in recent years has convinced us that such diets are safe and effective, at least in short-term. These data show low carbohydrate diets to be comparable or better than traditional low fat high carbohydrate diets for weight reduction, improvement in the dyslipidemia of diabetes and metabolic syndrome as well as control of blood pressure, postprandial glycemia and insulin secretion. Furthermore, the ability of low carbohydrate diets to reduce triglycerides and to increase HDL is of particular importance. Resistance to such strategies has been due, in part, to equating it with the popular Atkins diet. However, there are many variations and room for individual physician planning. Some form of low carbohydrate diet, in combination with exercise, is a viable option for patients with diabetes. However, the extreme reduction of carbohydrate of popular diets (<30 g/day) cannot be recommended for a diabetic population at this time without further study. On the other hand, the dire objections continually raised in the literature appear to have very little scientific basis. Whereas it is traditional to say that more work needs to be done, the same is true of the assumed standard low fat diets which have an ambiguous record at best. We see current trends in the national dietary recommendations as a positive sign and an appropriate move in the right direction.


Online empirical evaluation of tracking algorithms.
Evaluation of tracking algorithms in the absence of ground truth is a challenging problem. There exist a variety of approaches for this problem, ranging from formal model validation techniques to heuristics that look for mismatches between track properties and the observed data. However, few of these methods scale up to the task of visual tracking, where the models are usually nonlinear and complex and typically lie in a high-dimensional space. Further, scenarios that cause track failures and/or poor tracking performance are also quite diverse for the visual tracking problem. In this paper, we propose an online performance evaluation strategy for tracking systems based on particle filters using a time-reversed Markov chain. The key intuition of our proposed methodology relies on the time-reversible nature of physical motion exhibited by most objects, which in turn should be possessed by a good tracker. In the presence of tracking failures due to occlusion, low SNR, or modeling errors, this reversible nature of the tracker is violated. We use this property for detection of track failures. To evaluate the performance of the tracker at time instant t, we use the posterior of the tracking algorithm to initialize a time-reversed Markov chain. We compute the posterior density of track parameters at the starting time t=0 by filtering back in time to the initial time instant. The distance between the posterior density of the time-reversed chain (at t=0) and the prior density used to initialize the tracking algorithm forms the decision statistic for evaluation. It is observed that when the data are generated by the underlying models, the decision statistic takes a low value. We provide a thorough experimental analysis of the evaluation methodology. Specifically, we demonstrate the effectiveness of our approach for tackling common challenges such as occlusion, pose, and illumination changes and provide the Receiver Operating Characteristic (ROC) curves. Finally, we also show the applicability of the core ideas of the paper to other tracking algorithms such as the Kanade-Lucas-Tomasi (KLT) feature tracker and the mean-shift tracker.


A Systematic Review of Reminiscence Therapy for Older Adults in Taiwan.
Population aging is an increasing phenomenon in many countries around the world. It has been estimated that more than one quarter of all older adults experience a mental or neurological disorder or disease such as dementia, depression, anxiety, and substance abuse. Reminiscence is a popular treatment for enhancing well-being in older adults. Previous studies have shown that reminiscence therapy improves the cognitive functions, behaviors, and other psychosocial outcomes in older adult patients. The themes and materials that are used in reminiscence treatments for the older adults in Taiwan differ from those used in other countries because of Taiwan's unique historical background and culture. The main purpose of the current study was to review systematically the application and outcomes of reminiscence therapy in Taiwan. The terms "reminiscence," "dementia," "Alzheimer's disease," and "Taiwan" were used in an Integrated Resources Search that was conducted at National Taiwan Normal University. Sixteen articles were systematically reviewed using a synthesis of two matrices of experimental designs and intervention designs. Reminiscence group sizes ranged between 7 and 12 participants, session frequencies were all once a week for periods lasting between 4 and 16 weeks, and session durations ranged from 30 minutes to 2 hours. The memories of the participants were stimulated using materials dating from their youth such as Taiwanese folk songs, toys, photos, radio programs, newspapers, and food and drinks. In terms of research methodology, most of the studies that were reviewed used quasi-experimental designs without random assignment or control group due to sample size. A minority of the reviewed studies applied the randomized controlled treatment method. Only a few of the studies evaluated indicators in pretest, posttest, and follow-up periods. The results of these studies identified several benefits of reminiscence therapy in Taiwanese older adults, including improvements in cognitive function, anxiety, depressive symptoms, self-esteem, life satisfaction, and personal interaction. Reminiscence is a good noninvasive treatment for the prevention and treatment of mental diseases in Taiwanese older adults. Furthermore, reminiscence promotes mental health in older adults. Finally, this study provides recommendations for further study and clinical application of reminiscence therapy in Taiwan.


Affective compatibility between stimuli and response goals: a primer for a new implicit measure of attitudes.
We examined whether a voluntary response becomes associated with the (affective) meaning of intended response effects. Four experiments revealed that coupling a keypress with positive or negative consequences produces affective compatibility effects when the keypress has to be executed in response to positively or negatively evaluated stimulus categories. In Experiment 1, positive words were evaluated faster with a keypress that turned the words ON (versus OFF), whereas negative words were evaluated faster with a keypress that turned the words OFF (versus ON). Experiment 2 showed that this compatibility effect is reversed if an aversive tone is turned ON and OFF with keypresses. Experiment 3 revealed that keypresses acquire an affective meaning even when the association between the responses and their effects is variable and intentionally reconfigured before each trial. Experiment 4 used affective response effects to assess implicit in-group favoritism, showing that the measure is sensitive to the valence of categories and not to the valence of exemplars. Results support the hypothesis that behavioral reactions become associated with the affective meaning of the intended response goal, which has important implications for the understanding and construction of implicit attitude measures.


Spatial and seasonal variations in the composition of dissolved organic matter in a tropical catchment: the Lower Kinabatangan River, Sabah, Malaysia.
Dissolved organic matter (DOM) was characterised in water samples sampled in the Lower Kinabatangan River Catchment, Sabah, Malaysia between October 2009 and May 2010. This study aims at: (i) distinguishing between the quality of DOM in waters draining palm oil plantations (OP), secondary forests (SF) and coastal swamps (CS) and, (ii) identifying the seasonal variability of DOM quantity and quality. Surface waters were sampled during fieldwork campaigns that spanned the wet and dry seasons. DOM was characterised optically by using the fluorescence Excitation Emission Matrix (EEM), the absorption coefficient at 340 nm and the spectral slope coefficient (S). Parallel Factor Analysis (PARAFAC) was undertaken to assess the DOM composition from EEM spectra and five terrestrial derived components were identified: (C1, C2, C3, C4 and C5). Components C1 and C4 contributed the most to DOM fluorescence in all study areas during both the wet and dry seasons. The results suggest that component C4 could be a significant (and common) PARAFAC signal found in similar catchments. Peak M (C2 and C3) was dominant in all samples collected during wet and dry seasons, which could be anthropogenic in origin given the active land use change in the study area. In conclusion, there were significant seasonal and spatial variations in DOM which demonstrated the effects of land use cover and precipitation amounts in the Kinabatangan catchment.


Which Oxford Knee Score level represents a satisfactory symptom state after undergoing a total knee replacement?
Background and purpose - Meaningful interpretation of postoperative Oxford Knee Score (OKS) levels is challenging. We established Patient Acceptable Symptoms State (PASS) and Treatment Failure (TF) values for the OKS in patients undergoing primary total knee replacement (TKR) in Denmark.Patients and methods - Data from patients undergoing primary TKR between February 2015 and January 2019 was extracted from the arthroplasty registry at the Copenhagen University Hospital, Hvidovre in Denmark. Data included 3, 12, and 24 months postoperative responses to the OKS and 2 anchor questions asking whether they considered their symptom state to be satisfactory, and if not, whether they considered the treatment to have failed. PASS and TF threshold values were calculated using the adjusted predictive modeling method. Non-parametric bootstrapping was used to derive 95% confidence intervals (CI).Results - Complete 3, 12, and 24 months postoperative data was obtained for 187 of 209 (89%), 884 of 915 (97%), and 575 of 586 (98%) patients, with median ages from 68 to 70 years (59 to 64% female). 72%, 77%, and 79% considered as having satisfactory symptoms, while 6%, 11%, and 11% considered the treatment to have failed, at 3, 12, and 24 months postoperatively, respectively. OKS PASS values (CI) were 27 (26-28), 30 (29-31), and 30 (29-31) at 3, 12, and 24 months postoperatively. TF values were 27 (26-28) and 27 (26-29) at 12 and 24 months postoperatively.Interpretation - The OKS PASS values can be used to guide the interpretation of TKR outcome and support quality assessment in institutional and national registries.


Nitrogen positional scanning in tetramines active against HIV-1 as potential CXCR4 inhibitors.
The paradigm, derived from bicyclams and other cyclams, by which it is necessary to use the p-phenylene moiety as the central core in order to achieve high HIV-1 antiviral activities has been reexamined for the more flexible and less bulky structures 4, previously described by our group as potent HIV-1 inhibitors. The symmetrical compounds 7{x,x} and the non-symmetrical compounds 8{x,y} were designed, synthesized and biologically evaluated in order to explore the impact on the biological activity of the distance between the phenyl ring and the first nitrogen atom of the side chains. EC50 exactly followed the order 7{x,x} < 8{x,x} < 4{x,x} indicating that, for such flexible tetramines, the presence of two methylene units on each side of the central phenyl ring increases the biological activity contrary to AMD3100. A computational study of the interactions of 4{3,3}, 7{3,3} and 8{3,3} with CXCR4 revealed interactions in the same pocket region with similar binding modes for 4{3,3} and 7{3,3} but a different one for 8{3,3}.


Anatomic correlates of acoustic rhinometry as measured by rigid nasal endoscopy.
Acoustic rhinometry (AR) evaluates the cross-sectional areas and volume of the nasal cavity through acoustic reflections. Successive valleys displayed on an AR graph are believed to correspond to anatomic landmarks. To assess the anatomic accuracy of AR, we performed AR and endoscopic measurements with a rigid endoscope in 85 normal human subjects after topical decongestion. Endoscopic measurements were recorded for distances between the midcolumella and the nasal valve, the anterior end of the inferior turbinate, the anterior end of the middle turbinate, the midportion of the middle turbinate, and the posterior nasopharynx. The first AR valley most closely corresponded with endoscopic measurements of the nasal valve. The second valley had a mean value that corresponded with the anterior end of the inferior turbinate. The third valley matched best with the values of the anterior end of the middle turbinate. Nasopharyngeal measurements by each modality yielded a good agreement. AR appears to correspond to nasal anatomic landmarks but not in an exact point-to-point manner.


Methodologic issues in collecting data from debilitated patients with cancer near the end of life.
To report the experience of a group of researchers who have had a year of experience in a clinical trial with homecare hospice patients. 150 hospice patients with cancer and their primary caregivers who were accrued to a National Cancer Institute-funded clinical trial focusing on quality of life. The investigative team kept careful records of the numbers of patient/caregiver dyads accrued to the study and the reasons for nonaccrual as well as reasons for attrition. Data were analyzed using descriptive statistics. During a nine-month period, the hospice admitted 2,517 patients; 75% had cancer and 95% had caregivers, making them eligible for the study. However, after further screening, only 19% were eligible for contact and only 5% finally were accrued to the study. For the 125 patient/caregiver dyads actually accrued to the study, baseline data were obtained on only 50% and evaluable follow-up data on only 50%. Accruing patients to clinical trials and retaining them when they are critically ill and near death are extraordinarily difficult tasks. The inability to recruit and retain subjects for clinical trials has implications for integrity of data, data analysis, success of the project, and the cost of conducting such projects in the future.