Haemodynamic adaptation two months after transjugular intrahepatic portosystemic shunt (TIPS) in cirrhotic patients.
In portal hypertensive patients, transjugular intrahepatic portosystemic shunt (TIPS) acutely increases cardiac output and exaggerates peripheral vasodilatation. It has been suggested that the worsened hyperdynamic state may progress to high output heart failure. The aim was to evaluate the acute and short-term haemodynamic adaptation to this procedure. Systemic, splanchnic, and pulmonary haemodynamics were studied in 15 cirrhotic patients under stable haemodynamic conditions before placement of TIPS, then 15-30 minutes after and two months later. For inclusion in the final analysis, an uneventful post-TIPS at two months follow up and a stable portacaval gradient were required. The following variables were measured or calculated: portacaval gradient; cardiac index (thermodilution); systolic and diastolic mean arterial, atrial, pulmonary arterial, and wedged pulmonary capillary pressures; heart rate; and total peripheral and pulmonary vascular resistances. Blood flow in the shunt was measured using duplex Doppler ultrasound. The portacaval gradient decreased by 56% and remained stable thereafter. Shunt blood flow was unchanged when measured immediately after TIPS and two months later. Immediately after TIPS there was a pronounced increase in cardiac index (+32%; p < 0.05) in association with a decrease in peripheral and pulmonary vascular resistance (-21%; p < 0.05 and -14%; NS). Two months later, whereas the initial rise in cardiac index was attenuated, peripheral vascular resistances remained similar and pulmonary vascular resistances decreased further (-33%; p < 0.05) compared with immediate post-TIPS values. Hyperdynamic circulation worsened immediately after TIPS, with a progressive adaptation during follow up. The mechanisms of post-TIPS induced haemodynamic changes include an abrupt volume load resulting from splanchnic decompression and an increased delivery of gut derived vasodilators to the systemic circulation. The persistence of decreased peripheral and pulmonary vascular resistances despite the reduction in high cardiac output two months after TIPS suggests that vasodilatation is not solely a compensatory response to a TIPS induced increased preload. Vasodilatory substances shunted away from the liver probably play an important part in this phenomenon.


Thought Insertion Clarified.
'Thought insertion' in schizophrenia involves somehow experiencing one's own thoughts as someone else's. Some philosophers try to make sense of this by distinguishing between ownership and agency: one still experiences oneself as the owner of an inserted thought but attributes it to another agency. In this paper, we propose that thought insertion involves experiencing thought contents as alien, rather than episodes of thinking. To make our case, we compare thought insertion to certain experiences of 'verbal hallucination' and show that they amount to different descriptions of the same phenomenon: a quasi-perceptual experience of thought content. We add that the agency/ownership distinction is unhelpful here. What requires explanation is not why a person experiences a type of intentional state without the usual sense of agency, but why she experiences herself as the agent of one type of intentional state rather than another. We conclude by sketching an account of how this might happen.


Methods of international health technology assessment agencies for economic evaluations--a comparative analysis.
The number of Health Technology Assessment (HTA) agencies increases. One component of HTAs are economic aspects. To incorporate economic aspects commonly economic evaluations are performed. A convergence of recommendations for methods of health economic evaluations between international HTA agencies would facilitate the adaption of results to different settings and avoid unnecessary expense. A first step in this direction is a detailed analysis of existing similarities and differences in recommendations to identify potential for harmonization. The objective is to provide an overview and comparison of the methodological recommendations of international HTA agencies for economic evaluations. The webpages of 127 international HTA agencies were searched for guidelines containing recommendations on methods for the preparation of economic evaluations. Additionally, the HTA agencies were requested information on methods for economic evaluations. Recommendations of the included guidelines were extracted in standardized tables according to 13 methodological aspects. All process steps were performed independently by two reviewers. Finally 25 publications of 14 HTA agencies were included in the analysis. Methods for economic evaluations vary widely. The greatest accordance could be found for the type of analysis and comparator. Cost-utility-analyses or cost-effectiveness-analyses are recommended. The comparator should continuously be usual care. Again the greatest differences were shown in the recommendations on the measurement/sources of effects, discounting and in the analysis of sensitivity. The main difference regarding effects is the focus either on efficacy or effectiveness. Recommended discounting rates range from 1.5%-5% for effects and 3%-5% for costs whereby it is mostly recommended to use the same rate for costs and effects. With respect to the analysis of sensitivity the main difference is that oftentimes the probabilistic or deterministic approach is recommended exclusively. Methods for modeling are only described vaguely and mainly with the rational that the "appropriate model" depends on the decision problem. Considering all other aspects a comparison is challenging as recommendations vary regarding detailedness and addressed issues. There is a considerable unexplainable variance in recommendations. Further effort is needed to harmonize methods for preparing economic evaluations.


Determination of catechin isomers in human plasma subsequent to green tea ingestion using chiral capillary electrophoresis with a high-sensitivity cell.
A simple and reliable analytical electrophoretic method using chiral capillary electrophoresis (CCE) with a high-sensitivity cell of special design has been established for simultaneous determination of (+)-catechin (C) and (-)-epicatechin (EC) in aqueous and human plasma media. The application of a capillary with high-sensitivity cell has led to an improvement of 10-fold and 5-fold time-corrected peak area over a standard cell and a capillary with bubble cell, respectively. Analysis has involved the electrophoretic separation of C and EC in less than 4.0 min at 210 nm. The running buffer consist of 50.0 mmol L(-1) borate buffer with 1.0 mmol L(-1) beta-cyclodextrin at pH 8.5. CCE system has been proved for its intended use by applying procedure starting from calibration of CE instrument into validation of all experimental parameters. The resolution between catechin isomers under optimal conditions has been found to be more than 3.0. The detection limits of C and EC have been calculated to be 3.2 and 1.0 ng mL(-1), respectively. Good linearity has been obtained with correlation coefficient (r(2)) ranging between 0.995 and 0.996 at 99% confidence level (CL). Application of the proposed method to human plasma after ingestion of green tea has successfully been achieved and has statistically been proved. The unchanged amounts of C and EC in plasma were about 17.4 and 1.8% of the administered dose after 2 h of starting tea ingestion. The detection limits of C and EC in human plasma at 210 nm were 4.1 and 1.5 ng mL(-1), respectively.


Identifying Antibiotic Prescribing Patterns Through Multi-Level Latent Profile Analyses: A Cross-Sectional Survey of Primary Care Physicians.
Background: Overuse of antibiotics significantly fuels the development of Antimicrobial resistance, which threating the global population health. Great variations existed in antibiotic prescribing practices among physicians, indicating improvement potential for rational use of antibiotics. This study aims to identify antibiotic prescribing patterns of primary care physicians and potential determinants. Methods: A cross-sectional survey was conducted on 551 physicians from 67 primary care facilities in Hubei selected through random cluster sampling, tapping into their knowledge, attitudes and prescribing practices toward antibiotics. Prescriptions (n = 501,072) made by the participants from 1 January to March 31, 2018 were extracted from the medical records system. Seven indicators were calculated for each prescriber: average number of medicines per prescription, average number of antibiotics per prescription, percentage of prescriptions containing antibiotics, percentage of antibiotic prescriptions containing broad-spectrum antibiotics, percentage of antibiotic prescriptions containing parenteral administered antibiotics, percentage of antibiotic prescriptions containing restricted antibiotics, and percentage of antibiotic prescriptions containing antibiotics included in the WHO "Watch and Reserve" list. Two-level latent profile analyses were performed to identify the antibiotic prescribing patterns of physicians based on those indicators. Multi-nominal logistic regression models were established to identify determinants with the antibiotic prescribing patterns. Results: On average, each primary care physician issued 909 (ranging from 100 to 11,941 with a median of 474) prescriptions over the study period. The mean percentage of prescriptions containing antibiotics issued by the physicians reached 52.19% (SD = 17.20%). Of those antibiotic prescriptions, an average of 82.29% (SD = 15.83%) contained broad-spectrum antibiotics; 71.92% (SD = 21.42%) contained parenteral administered antibiotics; 23.52% (SD = 19.12%) contained antibiotics restricted by the regional government; and 67.74% (SD = 20.98%) contained antibiotics listed in the WHO "Watch and Reserve" list. About 28.49% of the prescribers were identified as low antibiotic users, compared with 51.18% medium users and 20.33% high users. Higher use of antibiotics was associated with insufficient knowledge, indifference to changes, complacency with satisfied patients, low household income and rural location of the prescribers. Conclusion: Great variation in antibiotic prescribing patterns exists among primary care physicians in Hubei of China. High use of antibiotics is not only associated with knowledge shortfalls but also low socioeconomic status of prescribers.


Trogocytosis-associated cell to cell spread of intracellular bacterial pathogens.
Macrophages are myeloid-derived phagocytic cells and one of the first immune cell types to respond to microbial infections. However, a number of bacterial pathogens are resistant to the antimicrobial activities of macrophages and can grow within these cells. Macrophages have other immune surveillance roles including the acquisition of cytosolic components from multiple types of cells. We hypothesized that intracellular pathogens that can replicate within macrophages could also exploit cytosolic transfer to facilitate bacterial spread. We found that viable Francisella tularensis, as well as Salmonella enterica bacteria transferred from infected cells to uninfected macrophages along with other cytosolic material through a transient, contact dependent mechanism. Bacterial transfer occurred when the host cells exchanged plasma membrane proteins and cytosol via a trogocytosis related process leaving both donor and recipient cells intact and viable. Trogocytosis was strongly associated with infection in mice, suggesting that direct bacterial transfer occurs by this process in vivo.


Investigating probation strategies with juvenile offenders: the influence of officers' attitudes and youth characteristics.
Probation officers are the focal point for most interventions with delinquent youths in the juvenile justice system. The present study examines probation strategies and interventions in a sample of 308 probation officers who completed the Probation Practices Assessment Survey (PPAS) in a web-based survey. The PPAS measures six probation approaches: deterrence, restorative justice, treatment, confrontation, counseling, and behavioral tactics. Structural equation models and latent class analyses showed that probation officers use multiple approaches with delinquent youths consistent with the balanced and restorative justice movement. Younger youths, high-risk youths, and youths with prior social service involvements are likely to receive more intensive interventions. The implications of these findings for improving probation practices with delinquent youth are discussed.


Water in cellulose: evidence and identification of immobile and mobile adsorbed phases by 2H MAS NMR.
The organization of water molecules adsorbed onto cellulose and the supramolecular hydrated structure of microfibril aggregates represents, still today, one of the open and complex questions in the physical chemistry of natural polymers. Here, we investigate by 2H MAS NMR the mobility of water molecules in carefully 2H-exchanged, and thereafter re-dried, microcrystalline cellulose. By subtracting the spectral contribution of deuteroxyls from the spectrum of hydrated cellulose, we demonstrate the existence of two distinct 2H2O spectral populations associated with mobile and immobile water environments, between which the water molecules do not exchange at the NMR observation time scale. We conclude that those two water phases are located at differently-accessible adsorption sites, here assigned to the cellulose surfaces between and within the microfibril aggregates, respectively. The superior performance of 2H MAS NMR encourages further applications of the same method to other complex systems that expose heterogeneous hygroscopic surfaces, like wood cell walls.


Salvage therapy for Chinese non-small cell lung cancer patients who failed previous chemotherapy.
Our aim was to determine the appropriate salvage regimen for Chinese non-small cell lung cancer (NSCLC) patients who failed previous chemotherapy. We retrospectively analyzed data from our seven clinical trials, including single-agent gemcitabine, gefitinib, docetaxel with a different schedule, vinorelbine plus cisplatin, vinorelbine plus gemcitabine, docetaxel plus gemcitabine, and docetaxel plus ifosfamide, with a total of 342 cases (including 314 patients, of which 28 entered two different trials due to different salvage line settings), and compared these data with those of other studies, addressing the efficacy and toxicity of salvage therapy in patients who failed previous chemotherapy to analyze choosing of an appropriate salvage regimen. Of the 342 cases receiving salvage treatment, 71.1% were in second-line treatment, and 28.9% in third-line or later treatment. The response rate to our salvage therapy ranged widely, from 6.1% to 36.1%. Median survival was between 5.7 and 8.4 months when different salvage chemotherapy regimens were used, whereas it was 9.3 months in those who received gefitinib treatment. Similarly, 1-year survival ranged between 19.7% and 40% in a chemotherapy setting, and 40.8% for gefitinib treatment. Those who received gefitinib had better toxicity profiles than those who received other regimens. Febrile neutropenia occurred in 19 patients who received a chemotherapy agent (6.2%), and four patients died despite granulocyte colony-stimulating factor and antibiotic treatment. Grade 3 or 4 interstitial pneumonitis occurred in 14 of 247 patients (5.7%) who received docetaxel with/without another agent, and 10 patients died. Grade 3 interstitial pneumonitis occurred in one patient who received gefitinib treatment and recovered. In conclusion, both chemotherapeutic agents, such as docetaxel alone or gemcitabine plus vinorelbine, and gefitinib, are probably appropriate salvage regimens for Chinese NSCLC patients who have failed previous chemotherapy. However, gefitinib has a better safety profile and probably better survival than the chemotherapeutic agents and would be an appropriate alternative choice for salvage chemotherapy, even in a second-line setting for Chinese patients.


Comparison of human menopausal gonadotropin, clomiphene citrate, and combined human menopausal gonadotropin-clomiphene citrate stimulation protocols for in vitro fertilization.
Human menopausal gonadotropins (hMG) and clomiphene citrate (CC), either alone or in combination, are frequently used for in vitro fertilization (IVF) in an attempt to maximize the number of oocytes recovered and the number of embryos transferred. However, direct comparison of the relative efficacy of these protocols in the same institution has been limited. To evaluate this question, the authors examined the outcome of 304 consecutive women attempting IVF. One hundred eighty-one women received hMG, 42 received CC, and 81 received combination hMG/CC. The percentages of women undergoing laparoscopy were not different among the groups (69%, 71%, and 74%, respectively), nor were the rates of oocyte recovery (94%, 100%, and 100%). However, the percentage of women achieving oocyte fertilization (77%, 83%, and 93%) and embryo transfer (73%, 83%, and 90%) were significantly greater among those who had received hMG/CC stimulation. A comparison of hMG/CC with hMG and CC cycles revealed a statistically significant increase in the total number of developing follicles (4.5 +/- 0.3, 3.3 +/- 0.2, and 3.1 +/- 0.3, respectively; P = 0.0137), total oocytes recovered (4.1 +/- 0.3, 3.2 +/- 0.2, and 2.5 +/- 0.2; P = 0.0011), and embryos transferred (2.2 +/- 0.2, 1.4 +/- 0.2, and 1.4 +/- 0.2; P = 0.0013). However, there was no significant difference in the occurrence of ongoing pregnancies. Thus, in terms of the per-patient number of follicles, oocytes, and embryo transfers, combined hMG/CC stimulation appears to be superior to either hMG or CC alone. However, to date the combined regimen has not improved pregnancy rates.


Incorporation of uncertainty in health economic modelling studies.
In a recent leading article in PharmacoEconomics, Nuijten described some methods for incorporating uncertainty into health economic models and for utilising the information on uncertainty regarding the cost effectiveness of a therapy in resource allocation decision-making. His proposals are found to suffer from serious flaws in statistical and health economic reasoning.Nuijten's suggestions for incorporating uncertainty: (a) wrongly interpret the p-value as the probability that the null hypothesis is true; (b) represent this probability wrongly by truncating the input distribution; and (c) in the specific example of an antiparkinsonian drug uses a completely inappropriate p-value of 0.05 when the null hypothesis would, in reality, be emphatically disproved by the data.His suggestions regarding minimum important differences in cost effectiveness: (a) introduce areas of indifference that suggest inappropriate reliance on cost minimisation while failing to recognise that decisions should be based on expected costs versus benefits; and (b) offer no guidance on how the probabilities associated with these areas could be used in decision-making. Furthermore, Nuijten's model for Parkinson's disease is over-simplified to the point of providing a bad example of modelling practice, which may mislead the readers of PharmacoEconomics. The rationale for this paper is to ensure that readers do not apply inappropriate analyses as a result of following the proposals contained in Nuijten's paper. In addition to a detailed critique of Nuijten's proposals, we provide brief summaries of the currently accepted best practice in cost-effectiveness decision-making under uncertainty.


Spin-state energies of heme-related models from spin-flip TDDFT calculations.
Spin-state energies of heme-related models are of vital importance in biochemistry. To compute the energies of different spin states, the traditional ΔSCF method based on the density functional theory (DFT) is usually employed. In this work, the spin-flip TDDFT (SF-TDDFT) approach is investigated to compute the spin-state energies, with six different exchange-correlation (XC) functionals. With the present protocol, the spin contamination is fully avoided by choosing appropriate reference states. Additionally, multiple excited states can be obtained with SF-TDDFT. Compared with the CCSD(T) results, it is shown that the SF-TDDFT calculations with the BHandHLYP functional provide better accuracy than ΔSCF for D-Q (doublet-quartet) and Q-S (quartet-sextet) gaps and agree well with the experimental results. A possible solution for the precise calculation of spin-state energies is proposed to improve the performance of SF-TDDFT, on account of that the excitation energies show highly linear dependence on the amount of Hartree-Fock (HF) exchange in the XC functionals.


Cyclo-oxygenase-2 inhibition and endothelium-dependent vasodilation in younger vs. older healthy adults.
A major feature of endothelial dysfunction is reduced endothelium-dependent vasodilation, which in ageing may be due to decreased production of endothelial prostacyclin, or nitric oxide (NO), or both. We tested this hypothesis in 12 younger (age 18-38 years, six women) and 12 older healthy adults (age 55-73 years, six post-menopausal women). Endothelium-dependent vasodilation was assessed by the forearm vascular conductance (FVC) response to intra-arterial acetylcholine (ACh) (0.5, 1.0, 2.0, 4.0 μg dl(-1) forearm tissue min(-1) ) before and 90 min after inhibition of the enzyme cyclo-oxygenase-2 (COX-2) with oral celecoxib (400 mg), followed by the addition of endothelial NO synthase inhibition with intra-arterial N(G) -monomethyl-l arginine acetate (L-NMMA). Ageing was associated with a significantly reduced FVC response to ACh (P = 0.009, age-by-dose interaction; highest dose FVC ± SEM in ageing: 11.2 ± 1.4 vs. younger: 17.7 ± 2.4 units, P = 0.02). Celecoxib did not reduce resting FVC or the responses to ACh in any group. L-NMMA significantly reduced resting FVC and the responses to ACh in all groups, and absolute FVC values following L-NMMA were similar between groups. In healthy normotensive younger and older adults, there is minimal contribution of prostacyclin to ACh-mediated vasodilation, yet the NO component of vasodilation is reduced with ageing. In the clinical context, these findings suggest that acute administration of medications that inhibit prostacyclin (i.e. COX-2 inhibitors) evoke modest vascular consequences in healthy persons. Additional studies are necessary to test whether chronic use of COX-2 medications reduces endothelium dependent vasodilation in older persons with or without cardiovascular risk factors.


Changes in striatal dopamine metabolism measured by in vivo voltammetry during transient brain ischemia in rats.
In vivo voltammetry was used in rats with brain ischemia induced by four-vessel occlusion to measure changes in dopamine metabolism via measurement of peak 2 (dopamine compounds) in the striatum. Changes in regional cerebral blood flow in the striatum were also assessed by means of a temperature-controlled thermoelectrical device. Peak 2 increased by 600-900% during 30 minutes of four-vessel occlusion, which may have reflected an ischemia-provoked increase in the release of dopamine and a disturbance in the outward transport of its metabolites. Following reperfusion by discontinuation of carotid occlusion, peak 2 rapidly decreased to below control values and then gradually increased, exceeding control values at 180-210 minutes after reperfusion. REgional cerebral blood flow in the striatum decreased to almost 0 ml/100 g/min during the ischemic period, transiently increased to greater than control values after reperfusion, then gradually decreased during the next 240 minutes. Since dopamine is known to have various effects on cerebral metabolism and blood flow, alterations in its behavior may contribute to changes in cerebral blood flow and to postischemic brain damage. In vivo voltammetry may be useful in the investigation of the pathophysiology of brain ischemia.


Sequence-based prediction of microRNA-binding residues in proteins using cost-sensitive Laplacian support vector machines.
The recognition of microRNA (miRNA)-binding residues in proteins is helpful to understand how miRNAs silence their target genes. It is difficult to use existing computational method to predict miRNA-binding residues in proteins due to the lack of training examples. To address this issue, unlabeled data may be exploited to help construct a computational model. Semisupervised learning deals with methods for exploiting unlabeled data in addition to labeled data automatically to improve learning performance, where no human intervention is assumed. In addition, miRNA-binding proteins almost always contain a much smaller number of binding than nonbinding residues, and cost-sensitive learning has been deemed as a good solution to the class imbalance problem. In this work, a novel model is proposed for recognizing miRNA-binding residues in proteins from sequences using a cost-sensitive extension of Laplacian support vector machines (CS-LapSVM) with a hybrid feature. The hybrid feature consists of evolutionary information of the amino acid sequence (position-specific scoring matrices), the conservation information about three biochemical properties (HKM) and mutual interaction propensities in protein-miRNA complex structures. The CS-LapSVM receives good performance with an F1 score of 26.23 ± 2.55% and an AUC value of 0.805 ± 0.020 superior to existing approaches for the recognition of RNA-binding residues. A web server called SARS is built and freely available for academic usage.


Visual Abstraction of Large Scale Geospatial Origin-Destination Movement Data.
A variety of human movement datasets are represented in an Origin-Destination(OD) form, such as taxi trips, mobile phone locations, etc. As a commonly-used method to visualize OD data, flow map always fails to discover patterns of human mobility, due to massive intersections and occlusions of lines on a 2D geographical map. A large number of techniques have been proposed to reduce visual clutter of flow maps, such as filtering, clustering and edge bundling, but the correlations of OD flows are often neglected, which makes the simplified OD flow map present little semantic information. In this paper, a characterization of OD flows is established based on an analogy between OD flows and natural language processing (NPL) terms. Then, an iterative multi-objective sampling scheme is designed to select OD flows in a vectorized representation space. To enhance the readability of sampled OD flows, a set of meaningful visual encodings are designed to present the interactions of OD flows. We design and implement a visual exploration system that supports visual inspection and quantitative evaluation from a variety of perspectives. Case studies based on real-world datasets and interviews with domain experts have demonstrated the effectiveness of our system in reducing the visual clutter and enhancing correlations of OD flows.


RCH1, a locus in Arabidopsis that confers resistance to the hemibiotrophic fungal pathogen Colletotrichum higginsianum.
When challenged with the crucifer pathogen Colletotrichum higginsianum, Arabidopsis thaliana ecotype Columbia (Col-0) was colonized by the fungus within 2 to 3 days, developing brown necrotic lesions surrounded by a yellow halo. Lesions spread from the inoculation site within 3 to 4 days, and subsequently continued to expand until they covered the entire leaf. Electron microscopy confirmed that C. higginsianum is a hemibiotroph on Arabidopsis, feeding initially on living cells as a biotroph before switching to a necrotrophic mode of growth. A collection of 37 ecotypes of Arabidopsis varied in their responses to infection by C. higginsianum. The ecotype Eil-0 was highly resistant, with symptoms limited to necrotic flecking and with only very limited fungal colonization. Analyses suggested that the hypersensitive response and reactive oxygen species may be important in this defense response. Expression analyses with cDNA microarrays indicated that the defense reaction depends primarily on the jasmonic acid- and ethylene-dependent signaling pathways and, to a lesser extent, on the salicylate-dependent pathway. Crosses between the Eil-0 and Col-0 ecotypes suggested that the resistance in Eil-0 was dominant and was conferred by a single locus, which we named RCH1. RCH1 is the first resistance locus to be identified from Arabidopsis against the hemibiotrophic fungus genus Colletotrichum.


Cost-effectiveness of bariatric surgery for severely obese adults with diabetes.
To analyze the cost-effectiveness of bariatric surgery in severely obese (BMI >or=35 kg/m(2)) adults who have diabetes, using a validated diabetes cost-effectiveness model. We expanded the Centers for Disease Control and Prevention-RTI Diabetes Cost-Effectiveness Model to incorporate bariatric surgery. In this simulation model, bariatric surgery may lead to diabetes remission and reductions in other risk factors, which then lead to fewer diabetes complications and increased quality of life (QoL). Surgery is also associated with perioperative mortality and subsequent complications, and patients in remission may relapse to diabetes. We separately estimate the costs, quality-adjusted life-years (QALYs), and cost-effectiveness of gastric bypass surgery relative to usual diabetes care and of gastric banding surgery relative to usual diabetes care. We examine the cost-effectiveness of each type of surgery for severely obese individuals who are newly diagnosed with diabetes and for severely obese individuals with established diabetes. In all analyses, bariatric surgery increased QALYs and increased costs. Bypass surgery had cost-effectiveness ratios of $7,000/QALY and $12,000/QALY for severely obese patients with newly diagnosed and established diabetes, respectively. Banding surgery had cost-effectiveness ratios of $11,000/QALY and $13,000/QALY for the respective groups. In sensitivity analyses, the cost-effectiveness ratios were most affected by assumptions about the direct gain in QoL from BMI loss following surgery. Our analysis indicates that gastric bypass and gastric banding are cost-effective methods of reducing mortality and diabetes complications in severely obese adults with diabetes.


Targeting the Ubiquitylation and ISGylation Machinery for the Treatment of COVID-19.
Ubiquitylation and ISGylation are protein post-translational modifications (PTMs) and two of the main events involved in the activation of pattern recognition receptor (PRRs) signals allowing the host defense response to viruses. As with similar viruses, SARS-CoV-2, the virus causing COVID-19, hijacks these pathways by removing ubiquitin and/or ISG15 from proteins using a protease called PLpro, but also by interacting with enzymes involved in ubiquitin/ISG15 machinery. These enable viral replication and avoidance of the host immune system. In this review, we highlight potential points of therapeutic intervention in ubiquitin/ISG15 pathways involved in key host-pathogen interactions, such as PLpro, USP18, TRIM25, CYLD, A20, and others that could be targeted for the treatment of COVID-19, and which may prove effective in combatting current and future vaccine-resistant variants of the disease.


Pattern matters: Snakes exhibiting triangular and diamond-shaped skin patterns modulate electrophysiological activity in human visual cortex.
The neural and perceptual mechanisms that support the efficient visual detection of snakes in humans are still not fully understood. According to the Snake Detection Theory, selection pressures posed by snakes on early primates have shaped the development of the visual system. Previous studies in humans have investigated early visual electrophysiological activity in response to snake images vs. various alternative dangerous or non-dangerous stimuli. These studies have shown that the Early Posterior Negativity (EPN) component is selectively elicited by snake or snake-like images. Recent findings yielded the complementary/alternative hypothesis that early humans (and possibly other primates) evolved an aversion especially for potentially harmful triangular shapes, such as teeth, claws or spikes. In the present study we investigated the effect of triangular and diamond-shaped patterns in snake skins on the ERP correlates of visual processing in humans. In the first experiment, we employed pictures of snakes displaying either triangular/diamond-shaped patterns or no particular pattern on their skins, and pictures of frogs as control. Participants observed a random visual presentation of these pictures. Consistent with previous studies, snakes elicited an enhanced negativity between 225 and 300 ms (EPN) compared to frogs. However, snakes featuring triangular/diamond-shaped patterns on their skin produced an enhanced EPN compared to the snakes that did not display such patterns. In a second experiment we used pictures displaying only skin patterns of snakes and frogs. Results from the second experiment confirmed the results of the first experiment, suggesting that triangular snake-skin patterns modulate the activity in human visual cortex. Taken together, our results constitute an important contribution to the snake detection theory.


Reasoning about social conflicts improves into old age.
It is well documented that aging is associated with cognitive declines in many domains. Yet it is a common lay belief that some aspects of thinking improve into old age. Specifically, older people are believed to show better competencies for reasoning about social dilemmas and conflicts. Moreover, the idea of aging-related gains in wisdom is consistent with views of the aging mind in developmental psychology. However, to date research has provided little evidence corroborating this assumption. We addressed this question in two studies, using a representative community sample. We asked participants to read stories about intergroup conflicts and interpersonal conflicts and predict how these conflicts would unfold. We show that relative to young and middle-aged people, older people make more use of higher-order reasoning schemes that emphasize the need for multiple perspectives, allow for compromise, and recognize the limits of knowledge. Our coding scheme was validated by a group of professional counselors and wisdom researchers. Social reasoning improves with age despite a decline in fluid intelligence. The results suggest that it might be advisable to assign older individuals to key social roles involving legal decisions, counseling, and intergroup negotiations. Furthermore, given the abundance of research on negative effects of aging, this study may help to encourage clinicians to emphasize the inherent strengths associated with aging.


Similarities and differences between human cyclophilin A and other beta-barrel structures. Structural refinement at 1.63 A resolution.
The structure of the unligated recombinant human cyclophilin A (CyP A) has been refined to an R-factor of 0.18 at 1.63 A resolution. The root-mean-squared deviations of the refined structure are 0.013 A and 2.50 degrees from ideal geometries of bond length and bond angle, respectively. Eight antiparallel beta-strands of CyP A form a right-handed beta-barrel. The structure of CyP A is compared with other members in the antiparallel eight-stranded beta-barrel family and with the parallel eight-stranded alpha/beta barrels. Although all known eight-stranded barrels are right-handed, the tilted angle of the strands against the barrel axis varies from 45 degrees for retinol binding protein and 49 degrees for CyP A to 70 degrees for superoxide dismutase. As a result, the beta-barrel of CyP A is not completely superimposable with other members of beta-barrels. The structure of CyP A has a unique topology, distinct from other members in the beta-barrel family. In addition, CyP A is a closed beta-barrel so that neither the immunosuppressive drug cyclosporin A (CsA) nor the proline-containing substrate can bind to the hydrophobic core of the CyP A barrel, while the hydrophobic core of most other barrels is open for ligation. These observations probably indicate that CyP A is neither functionally nor evolutionally related to other beta-barrel structures. Details of interactions between solvent molecules and the active site residues of CyP A are illustrated. A water-co-operated mechanism, where the cis<-->trans isomerization might possibly consist of (1) transition of the prolyl bond and (2) release of N or C-terminal residues of substrate from CyP, is addressed. The refined structure reveals no disulfide bridges in CyP A. Cys115 is near the CsA site, but unlikely to be directly involved in CsA binding because of steric hindrance from Thr119 and Leu122. This geometry probably rules out any mechanisms involving a tetrahedral intermediate formed between cysteine and substrate during cis<-->trans isomerization.


Antioxidant activities of honeybee products and their mixtures.
In this study, the total phenolic content (TPC), antioxidant activity, and free radical scavenging activities (FRSA) of 70 samples comprising honeybee products (honey, pollen, royal jelly, and propolis) and their mixtures were determined. The TPC was determined in accordance with the Folin-Ciocalteu method, antioxidant activity with phosphomolybdenum, and FRSA with the 1,1-diphenyl-2-picryl hydrazyl (DPPH) assays. Honeybee propolis showed the greatest TPC, antioxidant activity, and FRSA followed by pollen, honey, and royal jelly, respectively. A positive correlation was observed between TPC and antioxidant activity of honey, pollen and mixed samples (respectively, r=0.91, r=0.93 and r=0.92) (p<0.01). Similarly, honey and mixed samples exhibited positive correlations with TPC and FRSA (respectively, r=0.98 and r=0.92) (p<0.01). It was concluded that honeybee products and their mixtures have antioxidant activity and FRSA and these effects may be attributed to their phenolic content.


The hemoglobin A1c level as a progressive risk factor for cardiovascular death, hospitalization for heart failure, or death in patients with chronic heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program.
A progressive relationship between hemoglobin A(1c) (HbA(1c)) levels and cardiovascular (CV) events has been observed in persons with and without diabetes. To our knowledge, the nature of such a relationship in patients with symptomatic chronic heart failure (HF) has not been studied. A total of 2412 participants (907 with prior diabetes) in the Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program with at least 1 HbA(1c) level were followed up for a median of 34 months. The incidence of the primary outcome (CV death or HF hospitalization), CV death, and total mortality was calculated according to eighths of the usual HbA(1c) level ranging from 5.8% or less to greater than 8.6%. Adjusted and unadjusted hazard ratios per 1% rise in HbA(1c) levels were also calculated. A total of 99.6% of eligible participants were followed up until they developed an outcome or the study finished. The risk of the primary composite outcome, CV death, hospitalization for worsening HF, and total mortality rose progressively with higher levels of usual HbA(1c) (P for trend <.001). After age and sex were adjusted for, hazards of these outcomes per 1% higher HbA(1c) level were 1.25 (95% confidence interval [CI ], 1.20-1.31), 1.24 (95% CI, 1.17-1.31), 1.25 (95% CI, 1.19-1.31), and 1.22 (95% CI, 1.16-1.29), respectively. This relationship was evident in patients with and without diabetes and with reduced or preserved ejection fraction and persisted after adjustment for diabetes, other risk factors, and allocation to candesartan. In diabetic and nondiabetic patients with symptomatic chronic HF, the HbA(1c) level is an independent progressive risk factor for CV death, hospitalization for HF, and total mortality.


Dissociation Dynamics of XPC-RAD23B from Damaged DNA Is a Determining Factor of NER Efficiency.
XPC-RAD23B (XPC) plays a critical role in human nucleotide excision repair (hNER) as this complex recognizes DNA adducts to initiate NER. To determine the mutagenic potential of structurally different bulky DNA damages, various studies have been conducted to define the correlation of XPC-DNA damage equilibrium binding affinity with NER efficiency. However, little is known about the effects of XPC-DNA damage recognition kinetics on hNER. Although association of XPC is important, our current work shows that the XPC-DNA dissociation rate also plays a pivotal role in achieving NER efficiency. We characterized for the first time the binding of XPC to mono- versus di-AAF-modified sequences by using the real time monitoring surface plasmon resonance technique. Strikingly, the half-life (t1/2 or the retention time of XPC in association with damaged DNA) shares an inverse relationship with NER efficiency. This is particularly true when XPC remained bound to clustered adducts for a much longer period of time as compared to mono-adducts. Our results suggest that XPC dissociation from the damage site could become a rate-limiting step in NER of certain types of DNA adducts, leading to repression of NER.


Characterization of regulatory sequences in alternative promoters of hypermethylated genes associated with tumor resistance to cisplatin.
The development of cisplatin resistance in human cancers is controlled by multiple genes and leads to therapeutic failure. Hypermethylation of specific gene promoters is a key event in clinical resistance to cisplatin. Although the usage of multiple promoters is frequent in the transcription of human genes, the role of alternative promoters and their regulatory sequences have not yet been investigated in cisplatin resistance genes. In a new approach, we hypothesized that human cancers exploit the specific transcription factor-binding sites (TFBS) and CpG islands (CGIs) located in the alternative promoters of certain genes to acquire platinum drug resistance. To provide a useful resource of regulatory elements associated with cisplatin resistance, we investigated the TFBS and CGIs in 48 alternative promoters of 14 hypermethylated cisplatin resistance genes previously reported. CGIs prone to methylation were identified in 28 alternative promoters of 11 hypermethylated genes. The majority of alternative promoters harboring CGIs (93%) were clustered in one phylogenetic subclass, whereas the ones lacking CGIs were distributed in two unrelated subclasses. Regulatory sequences, initiator and TATA-532 prevailed over TATA-8 and were found in all the promoters. B recognition element (BRE) sequences were present only in alternative promoters harboring CGIs, but CCAAT and TAACC were found in both types of alternative promoters, whereas downstream promoter element sequences were significantly less frequent. Therefore, it was hypothesized that BRE and CGI sequences co-localized in alternative promoters of cisplatin resistance genes may be used to design molecular markers for drug resistance. A more extensive knowledge of alternative promoters and their regulatory elements in clinical resistance to cisplatin is likely to usher novel avenues for sensitizing human cancers to treatment.


Functional and physiological effects of yoga in women with rheumatoid arthritis: a pilot study.
Stress, both psychological and physiological, has been implicated as having a role in the onset and exacerbations of rheumatoid arthritis (RA). This study investigated whether neuroendocrine and physical function in women with RA can be altered through a yoga intervention. Exercise intervention. University research conducted at a medical clinic. Sixteen independently living, postmenopausal women with an RA classification of I, II, or III according to the American College of Rheumatology functional classification system served as either participants or controls. The study group participated in three 75-minute yoga classes a week over a 10-week period. At baseline and on completion of the 10-week intervention, diurnal cortisol patterns and resting heart rate were measured. Balance was measured using the Berg Balance Test. Participants completed the Health Assessment Questionnaire (HIQ), a visual analog pain scale, and the Beck Depression Inventory. Yoga resulted in a significantly decreased HAQ disability index, decreased perception of pain and depression, and improved balance. Yoga did not result in a significant change in awakening or diurnal cortisol patterns (P = .12).


Structure and mechanism of arylamine N-acetyltransferases.
Arylamine N-acetyltransferases (NATs) are a family of phase II drug-metabolising enzymes which are important in the biotransformation of various aromatic and heterocyclic amines and hydroxylamines, arylhydrazines and arylhydrazides. NATs are present in a wide range of eukaryotes and prokaryotes. Humans have two functional NAT isoforms, both of which are highly polymorphic. The pharmacogenetics of NATs is an area which has been extensively studied. The determination of the X-ray crystal structure of NAT from Salmonella typhimurium led to the identification of the catalytically essential triad of residues: Cys-His-Asp, which is present in all functional NAT enzymes. Recent co-crystallisation data and in silico docking studies of NAT from Mycobacterium smegmatis with substrates and inhibitors have aided the identification of important contact residues within the active site. The X-ray crystal structures of four prokaryotic NAT proteins have now been determined, and these have been used to generate structural models of eukaryotic NATs, providing valuable insight into their active-site architecture. In addition to aiding crystallographic experiments, recent progress in the production of recombinant prokaryotic and eukaryotic NATs has allowed comparative studies of the kinetics and activity profiles of these enzymes. In this review we present an overview of recent structural and activity studies on NAT enzymes, and we outline how in silico methods may be used to predict NAT protein-ligand interactions based on the current knowledge.


Size matters: The width and location of a ureteral stone accurately predict the chance of spontaneous passage.
To determine how to most accurately predict the chance of spontaneous passage of a ureteral stone using information in the diagnostic non-enhanced computed tomography (NECT) and to create predictive models with smaller stone size intervals than previously possible. Retrospectively 392 consecutive patients with ureteric stone on NECT were included. Three radiologists independently measured the stone size. Stone location, side, hydronephrosis, CRP, medical expulsion therapy (MET) and all follow-up radiology until stone expulsion or 26 weeks were recorded. Logistic regressions were performed with spontaneous stone passage in 4 weeks and 20 weeks as the dependent variable. The spontaneous passage rate in 20 weeks was 312 out of 392 stones, 98% in 0-2 mm, 98% in 3 mm, 81% in 4 mm, 65% in 5 mm, 33% in 6 mm and 9% in ≥6.5 mm wide stones. The stone size and location predicted spontaneous ureteric stone passage. The side and the grade of hydronephrosis only predicted stone passage in specific subgroups. Spontaneous passage of a ureteral stone can be predicted with high accuracy with the information available in the NECT. We present a prediction method based on stone size and location. • Non-enhanced computed tomography can predict the outcome of ureteral stones. • Stone size and location are the most important predictors of spontaneous passage. • Prediction models based on stone width or length and stone location are introduced. • The observed passage rates for stone size in mm-intervals are reported. • Clinicians can make better decisions about treatment.


Mepolizumab for urban children with exacerbation-prone eosinophilic asthma in the USA (MUPPITS-2): a randomised, double-blind, placebo-controlled, parallel-group trial.
Black and Hispanic children living in urban environments in the USA have an excess burden of morbidity and mortality from asthma. Therapies directed at the eosinophilic phenotype reduce asthma exacerbations in adults, but few data are available in children and diverse populations. Furthermore, the molecular mechanisms that underlie exacerbations either being prevented by, or persisting despite, immune-based therapies are not well understood. We aimed to determine whether mepolizumab, added to guidelines-based care, reduced the number of asthma exacerbations during a 52-week period compared with guidelines-based care alone. This is a randomised, double-blind, placebo-controlled, parallel-group trial done at nine urban medical centres in the USA. Children and adolescents aged 6-17 years, who lived in socioeconomically disadvantaged neighbourhoods and had exacerbation-prone asthma (defined as ≥two exacerbations in the previous year) and blood eosinophils of at least 150 cells per μL were randomly assigned 1:1 to mepolizumab (6-11 years: 40 mg; 12-17 years: 100 mg) or placebo injections once every 4 weeks, plus guideline-based care, for 52 weeks. Randomisation was done using a validated automated system. Participants, investigators, and the research staff who collected outcome measures remained masked to group assignments. The primary outcome was the number of asthma exacerbations that were treated with systemic corticosteroids during 52 weeks in the intention-to-treat population. The mechanisms of treatment response were assessed by study investigators using nasal transcriptomic modular analysis. Safety was assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03292588. Between Nov 1, 2017, and Mar 12, 2020, we recruited 585 children and adolescents. We screened 390 individuals, of whom 335 met the inclusion criteria and were enrolled. 290 met the randomisation criteria, were randomly assigned to mepolizumab (n=146) or placebo (n=144), and were included in the intention-to-treat analysis. 248 completed the study. The mean number of asthma exacerbations within the 52-week study period was 0·96 (95% CI 0·78-1·17) with mepolizumab and 1·30 (1·08-1·57) with placebo (rate ratio 0·73; 0·56-0·96; p=0·027). Treatment-emergent adverse events occurred in 42 (29%) of 146 participants in the mepolizumab group versus 16 (11%) of 144 participants in the placebo group. No deaths were attributed to mepolizumab. Phenotype-directed therapy with mepolizumab in urban children with exacerbation-prone eosinophilic asthma reduced the number of exacerbations. US National Institute of Allergy and Infectious Diseases and GlaxoSmithKline.


Elevation of the ACTH/cortisol ratio in female opioid dependent patients: A biomarker of aging and correlate of metabolic and immune activation.
Whilst the hypothalamic-pituitary-adrenal (HPA) Axis is a major stress axis, and is necessarily perturbed in opioid dependency, and stress is a major contributor to aging mechanisms, the HPA axis has not been studied in opioid dependency in an age-dependent manner. Hypothesis - Differences in age dependent levels of HPA components. Cross-sectional comparison of general medical and opioid dependent patients (ODP, GMP). Setting - Primary Care. Patients - 51 GMC, 233 ODP. Ages 37.92+1.95 v. 37.12+0.62 years (P - N.S.) and 33.33% v. 71.67% male (p<0.0001). Intervention(s) - Measurement ACTH, cortisol and their ratio (ACR). Main Outcome Measure(s) - Pre-planned analysis ACR. Impact of immune and metabolic markers. ACTH/cortisol was a negative biomarker for age in female patients. Whilst the mean ACR were not different, the (log) ACTH/cortisol showed a positive relationship with age:sex:status (p=0.0396) and age:status (p=0.0437). The effect of addictive status was confined to hepatitis C (HCV) positive female ODP (p=0.0355), and the age:status interaction was also stronger in female HCV+ (p=0.0075) compared to HCV - (p=0.0667) patients. Multiple regression of ACR against age, status, ALT, CRP, and Globulins confirmed many significant interactions. ACTH/cortisol ratio interacted significantly from p=0.0008 in males and p=0.0079 in females, and in both sexes four terms included addictive status. These data establish the ACTH/cortisol ratio as a negative biomarker of aging in females, and show that this decline is more pronounced in ODP an effect which is partly related to HCV seropositivity, immune and metabolic factors. Dementias are one of the most serious health and socioeconomic issues. Multi-infarct dementia (MID) and Alzheimer´s type dementia (AD) exhibit differences in cerebrovascular blood flow velocity profiles and in presence of microemboli, detected by transcranial Doppler sonography.


Infrared observations of the saturnian system from voyager 2.
During the passage of Voyager 2 through the Saturn system, infrared spectral and radiometric data were obtained for Saturn, Titan, Enceladus, Tethys, Iapetus, and the rings. Combined Voyager 1 and Voyager 2 observations of temperatures in the upper troposphere of Saturn indicate a seasonal asymmetry between the northern and southern hemispheres, with superposed small-scale meridional gradients. Comparison of high spatial resolution data from the two hemispheres poleward of 60 degrees latitude suggests an approximate symmetry in the small-scale structure, consistent with the extension of a symmetric system of zonal jets into the polar regions. Longitudinal variations of 1 to 2 K are observed. Disk- averaged infrared spectra of Titan show little change over the 9-month interval between Voyager encounters. By combining Voyager 2 temperature measurements with ground-based geometric albedo determinations, phase integrals of 0.91 +/- 0.13 and 0.89 +/- 0.09 were derived for Tethys and Enceladus, respectively. The subsolar point temperature of dark material on Iapetus must exceed 110 K. Temperatures (and infrared optical depths) for the A and C rings and for the Cassini division are 69 +/- 1 K (0.40 +/- 0.05), 85 +/- 1 K (0.10 +/- 0.03), and 85 +/- 2 K (0.07 +/- 0.04), respectively.


Effectiveness of theory-based educational interventions on breastfeeding self-efficacy and exclusive breastfeeding: A systematic review and meta-analysis.
Enhancing breastfeeding self-efficacy and intention is crucial for successful breastfeeding. Educational interventions highlighting breastfeeding self-efficacy and breastfeeding plans have been developed to help mothers initiate and sustain breastfeeding practices. This study aimed to determine whether the use of theory-based educational interventions, i.e., the theory of breastfeeding self-efficacy or theory of planned behavior, is associated with improved breastfeeding outcomes and to identify key factors of effective breastfeeding educational programs. We used electronic databases and reference lists of articles to identify published randomized controlled trials of educational programs that adopted the breastfeeding self-efficacy theory or theory of planned behavior. In total, 24 randomized controlled trials were identified, and 5678 mothers were included in those studies, with 4178 mothers in the breastfeeding self-efficacy group and 1500 mothers in the theory of planned behavior group. Mothers who received theory-based interventions had better breastfeeding outcomes for up to 6 months postpartum (standardized mean difference =0.63, 95% confidence interval: 0.34~0.92 for self-efficacy scores at 1~2 months; odds ratio =1.82, 95% confidence interval: 1.27~2.61 for the exclusive breastfeeding rate at 1~2 months; and odds ratio =2.19, 95% confidence interval: 1.24~3.89 for the exclusive breastfeeding rate at 3~6 months). Mothers who were from non-Organization for Economic Co-operation and Development countries, were of older age, had participated in an educational program in a hospital setting, or had used an integrative class format had higher levels of self-efficacy and longer breastfeeding durations to 6 months. Theory-based educational interventions are effective in improving breastfeeding self-efficacy and exclusive breastfeeding rates at 6 months. Future breastfeeding educational programs incorporating the theories of breastfeeding self-efficacy and planned behavior would be helpful in promoting sustained breastfeeding practices among mothers.


Nuclear magnetic resonance study of the Schiff base in bacteriorhodopsin: counterion effects on the 15N shift anisotropy.
High-resolution, solid-state 15N NMR has been used to study the chemical shift anisotropies of the Schiff bases in bacteriorhodopsin (bR) and in an extensive series of model compounds. Using slow-spinning techniques, we are able to obtain sufficient rotational sideband intensity to determine the full 15N chemical shift anisotropy for the Schiff base nitrogen in bR548 and bR568. Comparisons are made between all-trans-bR568 and N-all-trans-retinylidene butylimine salts with halide, phenolate, and carboxylate counterions. It is argued that for the model compounds the variation in 15N chemical shift reflects the variation in (hydrogen) bond strength with the various counterions. The results suggest that carboxylates and tyrosinates may form hydrogen bonds of comparable strength in a hydrophobic environment. Thus, the hydrogen bonding strength of a counterion depends on factors that are not completely reflected in the solution pKa of its conjugate acid. For the model compounds, the two most downfield principal values of the 15N chemical shift tensor, sigma 22 and sigma 33, vary dramatically with different counterions, whereas sigma 11 remains essentially unaffected. In addition, there exists a linear correlation between sigma 22 and sigma 33, which suggests that a single mechanism is responsible for the variation in chemical shifts present in all three classes of model compounds. The data for bR568 follow this trend, but the isotropic shift is 11 ppm further upfield than any of the model compounds. This extreme value suggests an unusually weak hydrogen bond in the protein.


Gene correction in the evolution of the T cell receptor beta chain.
Mutational mechanisms operating at the T cell receptor beta chain locus have been examined by comparison of the CT beta 1 and CT beta 2 gene sequences from Mus pahari, believed to be the oldest living species in the genus Mus, with those of inbred mice. Results indicate that a gene correction event independent of that suggested to have occurred in inbred mice has homogenized the M. pahari CT beta exon 1 sequences, minimizing diversity in this region of the molecule. These observations suggest that correction events such as gene conversion may occur frequently, even in pauci-gene families with as few as two members, and therefore play a significant role in gene diversification or homogenization of small as well as large gene families.


Proenzyme psa for the early detection of prostate cancer in the 2.5-4.0 ng/ml total psa range: preliminary analysis.
To determine the clinical utility of using proenzyme prostate-specific antigen (pPSA) for early detection of prostate cancer in the 2.5 to 4.0 ng/mL total PSA range. pPSA, the precursor form of PSA that contains a 7 amino acid leader peptide, and truncated forms such as [-2]pPSA and [-4]pPSA can be measured in serum by research immunoassay. Archival serum from 119 men (noncancer, 88; cancer, 31), obtained before biopsy and in the total PSA range of 2.5 to 4.0 ng/mL, were assayed for total PSA, free PSA (fPSA), and pPSA. pPSA was defined as the sum of the [-2], [-4], and [-7] forms, and the percent pPSA (%pPSA) was defined as pPSA/fPSA. pPSA averaged 4.6% +/- 0.4% (SEM) of total PSA and 39.3% +/- 3.5% of fPSA. PSA and %fPSA values were similar between the noncancer and cancer groups, and %pPSA tended to be higher in the cancer group (50.1% +/- 4.4%) compared with the noncancer group (35.5% +/- 6.7%; P = 0.07). Using receiver operating characteristic analysis to assess clinical utility, the area under the curve for %pPSA was 0.688 compared with 0.567 for %fPSA. At a fixed sensitivity of 75%, the specificity was significantly greater for %pPSA at 59% compared with %fPSA at 33% (P <0.0001). In the 2.5 to 4.0 ng/mL total PSA range, 75% of cancers can potentially be detected with 59% of unnecessary biopsies being spared using %pPSA; use of %fPSA would result in sparing only 33% of unnecessary biopsies. A large prospective clinical trial is needed to confirm these preliminary findings.


The psychological basis of problem-based learning: a review of the evidence.
Several potential advantages for students' learning are claimed for problem-based learning (PBL). Students in PBL curricula may be more highly motivated; they may be better problem solvers and self-directed learners; they may be better able to learn and recall information; and they may be better able to integrate basic science knowledge into the solutions of clinical problems. Although some of these claims find theoretical support from the literature on the psychology of learning, to date there has been no review of the experimental evidence supporting the possible differences in students' learning that can be attributed to PBL. In this review article, the authors examine each claim critically in light of that evidence. They conclude that (1) there is no evidence that PBL curricula result in any improvement in general, content-free problem-solving skills; (2) learning in a PBL format may initially reduce levels of learning but may foster, over periods up to several years, increased retention of knowledge; (3) some preliminary evidence suggests that PBL curricula may enhance both transfer of concepts to new problems and integration of basic science concepts into clinical problems; (4) PBL enhances intrinsic interest in the subject matter; and (5) PBL appears to enhance self-directed learning skills, and this enhancement may be maintained.


Evolution of SET-domain protein families in the unicellular and multicellular Ascomycota fungi.
The evolution of multicellularity is accompanied by the occurrence of differentiated tissues, of organismal developmental programs, and of mechanisms keeping the balance between proliferation and differentiation. Initially, the SET-domain proteins were associated exclusively with regulation of developmental genes in metazoa. However, finding of SET-domain genes in the unicellular yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe suggested that SET-domain proteins regulate a much broader variety of biological programs. Intuitively, it is expected that the numbers, types, and biochemical specificity of SET-domain proteins of multicellular versus unicellular forms would reflect the differences in their biology. However, comparisons across the unicellular and multicellular domains of life are complicated by the lack of knowledge of the ancestral SET-domain genes. Even within the crown group, different biological systems might use the epigenetic 'code' differently, adapting it to organism-specific needs. Simplifying the model, we undertook a systematic phylogenetic analysis of one monophyletic fungal group (Ascomycetes) containing unicellular yeasts, Saccharomycotina (hemiascomycetes), and a filamentous fungal group, Pezizomycotina (euascomycetes). Systematic analysis of the SET-domain genes across an entire eukaryotic phylum has outlined clear distinctions in the SET-domain gene collections in the unicellular and in the multicellular (filamentous) relatives; diversification of SET-domain gene families has increased further with the expansion and elaboration of multicellularity in animal and plant systems. We found several ascomycota-specific SET-domain gene groups; each was unique to either Saccharomycotina or Pezizomycotina fungi. Our analysis revealed that the numbers and types of SET-domain genes in the Saccharomycotina did not reflect the habitats, pathogenicity, mechanisms of sexuality, or the ability to undergo morphogenic transformations. However, novel genes have appeared for functions associated with the transition to multicellularity. Descendents of most of the SET-domain gene families found in the filamentous fungi could be traced in the genomes of extant animals and plants, albeit as more complex structural forms. SET-domain genes found in the filamentous species but absent from the unicellular sister group reflect two alternative evolutionary events: deletion from the yeast genomes or appearance of novel structures in filamentous fungal groups. There were no Ascomycota-specific SET-domain gene families (i.e., absent from animal and plant genomes); however, plants and animals share SET-domain gene subfamilies that do not exist in the fungi. Phylogenetic and gene-structure analyses defined several animal and plant SET-domain genes as sister groups while those of fungal origin were basal to them. Plants and animals also share SET-domain subfamilies that do not exist in fungi.


Giant viruses: conflicts in revisiting the virus concept.
The current paradigm on the nature of viruses is based on early work of the 'phage group' (the pro-phage concept) and molecular biologists working on tumour viruses (the proto-oncogene concept). It posits that viruses evolved from either prokaryotic or eukaryotic cellular genes that became infectious via their association with capsid genes. In this view, after their emergence viruses continued to evolve by stealing cellular genes (the escape model). This paradigm has been challenged recently by scientists who propose that viruses pre-dated modern cells. In particular, the discovery of Mimivirus has stimulated a lot of discussions on the nature of viruses. There are two major schools of thought, those who defend the escape model, suggesting that giant viruses are giant pickpockets (chimera), and those who emphasize their uniqueness and ancient origin. Comparative genomics of Mimivirus and related viruses (nucleo-cytoplasmic large DNA viruses) have produced a lot of data that have been interpreted according to the prejudices of the authors and thus failed until now to generate a consensus. I briefly review here the history of these debates and how they lead to new proposals, such as the definition of viruses as capsid-encoding organisms or else the recognition of their fundamentally cellular nature, the virocell concept.


Broad-Ranging Nutritional Deficiencies Predict Amputation in Diabetic Foot Ulcers.
Diabetic foot ulcers present across the spectrum of nonhealing wounds, be it acute or many months duration. There is developing literature highlighting that despite this group having high caloric intake, they often lack the micronutrients essential for wound healing. This study reports a retrospective cohort of patients' micro- and macro-nutritional state and its relationship to amputation. A retrospective cohort was observed over a 2-month period at one of Australia's largest tertiary referral centers for diabetic foot infection and vascular surgery. Patient information, duration of ulcer, various biochemical markers of nutrition and infection, and whether the patient required amputation were collected from scanned medical records. A cohort of 48 patients with a broad-spectrum of biochemical markers was established. Average hemoglobin A1c (HbA1c) was 8.6%. A total of 58.7% had vitamin C deficiency, including 30.4% with severe deficiency, average 22.6 Ł} 5.8 μmol/L; 61.5% had hypoalbuminemia, average albumin 28.7 Ł} 2.5 g/L. Average vitamin B12 was 294.6 Ł} 69.6 pmol/L; 57.9% had low vitamin D, average 46.3 Ł} 8.3 nmol/L. Basic screening scores for caloric intake failed to suggest this biochemical depletion. There was a 52.1% amputation rate; biochemical depletion was associated with risk of amputation with vitamin C (P < .01), albumin (P = .03), and hemoglobin (P = .01), markedly lower in patients managed with amputation than those managed conservatively. There was no relation between duration of ulceration and nutrient depletion. Patients with diabetic foot ulceration rely on multidisciplinary care to optimize their wound healing. An important but often overlooked aspect of this is nutritional state, with micronutrients being very important for the healing of complex wounds. General nutritional screening often fails to identify patients at risk of micronutrient deficiency. There is a high prevalence of vitamin deficiency in patients with diabetic foot ulcers. This presents an excellent avenue for future research to assess if aggressive nutrient replacement can improve outcomes in this cohort of patients.


The proteasomal inhibitor MG132 prevents muscular dystrophy in zebrafish.
Using sapje zebrafish which lack dystrophin, we have assessed both the quantitation of muscle damage in dystrophic fish, and the efficacy of the proteasomal inhibitor MG132 in reducing the dystrophic symptoms. Fourier analysis of birefringence patterns in normal and dystrophic fish was found to be a simple and reliable quantitative measure of muscle damage. MG132, as in mdx mouse, was found to be effective in reducing muscle damage with an EC50 of 0.4µM. This study adds further to the utility of zebrafish as a model of choice for testing muscular dystrophy therapeutics.


Two temporal functions of Glass: Ommatidium patterning and photoreceptor differentiation.
Much progress has been made in elucidating the molecular networks required for specifying retinal cells, including photoreceptors, but the downstream mechanisms that maintain identity and regulate differentiation remain poorly understood. Here, we report that the transcription factor Glass has a dual role in establishing a functional Drosophila eye. Utilizing conditional rescue approaches, we confirm that persistent defects in ommatidium patterning combined with cell death correlate with the overall disruption of eye morphology in glass mutants. In addition, we reveal that Glass exhibits a separable role in regulating photoreceptor differentiation. In particular, we demonstrate the apparent loss of glass mutant photoreceptors is not only due to cell death but also a failure of the surviving photoreceptors to complete differentiation. Moreover, the late reintroduction of Glass in these developmentally stalled photoreceptors is capable of restoring differentiation in the absence of correct ommatidium patterning. Mechanistically, transcription profiling at the time of differentiation reveals that Glass is necessary for the expression of many genes implicated in differentiation, i.e. rhabdomere morphogenesis, phototransduction, and synaptogenesis. Specifically, we show Glass directly regulates the expression of Pph13, which encodes a transcription factor necessary for opsin expression and rhabdomere morphogenesis. Finally, we demonstrate the ability of Glass to choreograph photoreceptor differentiation is conserved between Drosophila and Tribolium, two holometabolous insects. Altogether, our work identifies a fundamental regulatory mechanism to generate the full complement of cells required for a functional rhabdomeric visual system and provides a critical framework to investigate the basis of differentiation and maintenance of photoreceptor identity.


Articulated pose identification with sparse point features.
We propose a general algorithm for identifying an arbitrary pose of an articulated subject with sparse point features. The algorithm aims to identify a one-to-one correspondence between a model point-set and an observed point-set taken from freeform motion of the articulated subject. We avoid common assumptions such as pose similarity or small motions with respect to the model, and assume no prior knowledge from which to infer an initial or partial correspondence between the two point-sets. The algorithm integrates local segment-based correspondences under a set of affine transformations, and a global hierarchical search strategy. Experimental results, based on synthetic pose and real-world human motion data demonstrate the ability of the algorithm to perform the identification task. Reliability is increasingly compromised with increasing data noise and segmental distortion, but the algorithm can tolerate moderate levels. This work contributes to establishing a crucial self-initializing identification in model-based point-feature tracking for articulated motion.


Fetal growth velocity standards from the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project.
Human growth is susceptible to damage from insults, particularly during periods of rapid growth. Identifying those periods and the normative limits that are compatible with adequate growth and development are the first key steps toward preventing impaired growth. This study aimed to construct international fetal growth velocity increment and conditional velocity standards from 14 to 40 weeks' gestation based on the same cohort that contributed to the INTERGROWTH-21st Fetal Growth Standards. This study was a prospective, longitudinal study of 4321 low-risk pregnancies from 8 geographically diverse populations in the INTERGROWTH-21st Project with rigorous standardization of all study procedures, equipment, and measurements that were performed by trained ultrasonographers. Gestational age was accurately determined clinically and confirmed by ultrasound measurement of crown-rump length at <14 weeks' gestation. Thereafter, the ultrasonographers, who were masked to the values, measured the fetal head circumference, biparietal diameter, occipitofrontal diameter, abdominal circumference, and femur length in triplicate every 5 weeks (within 1 week either side) using identical ultrasound equipment at each site (4-7 scans per pregnancy). Velocity increments across a range of intervals between measures were modeled using fractional polynomial regression. Peak velocity was observed at a similar gestational age: 16 and 17 weeks' gestation for head circumference (12.2 mm/wk), and 16 weeks' gestation for abdominal circumference (11.8 mm/wk) and femur length (3.2 mm/wk). However, velocity growth slowed down rapidly for head circumference, biparietal diameter, occipitofrontal diameter, and femur length, with an almost linear reduction toward term that was more marked for femur length. Conversely, abdominal circumference velocity remained relatively steady throughout pregnancy. The change in velocity with gestational age was more evident for head circumference, biparietal diameter, occipitofrontal diameter, and femur length than for abdominal circumference when the change was expressed as a percentage of fetal size at 40 weeks' gestation. We have also shown how to obtain accurate conditional fetal velocity based on our previous methodological work. The fetal skeleton and abdomen have different velocity growth patterns during intrauterine life. Accordingly, we have produced international Fetal Growth Velocity Increment Standards to complement the INTERGROWTH-21st Fetal Growth Standards so as to monitor fetal well-being comprehensively worldwide. Fetal growth velocity curves may be valuable if one wants to study the pathophysiology of fetal growth. We provide an application that can be used easily in clinical practice to evaluate changes in fetal size as conditional velocity for a more refined assessment of fetal growth than is possible at present (https://lxiao5.shinyapps.io/fetal_growth/). The application is freely available with the other INTERGROWTH-21st tools at https://intergrowth21.tghn.org/standards-tools/.


Cannabidiol: A Brief Review of Its Therapeutic and Pharmacologic Efficacy in the Management of Joint Disease.
Cannabis use in the management of musculoskeletal diseases has gained advocacy since several states have legalized its recreational use. Cannabidiol (CBD), a commercially available, non-neurotropic marijuana constituent, has shown promise in arthritic animal models by attenuating pro-inflammatory immune responses. Additional research has demonstrated the benefit of CBD in decreasing the endogenous pain response in mice subjected to acute arthritic conditions, and further studies have highlighted improved fracture healing following CBD use in murine mid-femoral fractures. However, there is a lack of high-quality, novel research investigating the use of CBD in human musculoskeletal diseases aside from anecdotal accounts and retrospective reviews, perhaps due to legal ramifications limiting the enrollment of patients. The purpose of this review article is to highlight the extent of current research on CBD and its biochemical and pharmacologic efficacy in the treatment of joint disease, as well as the evidence for use of CBD and cannabis in patients undergoing joint arthroplasty. Based on available literature relying on retrospective data and case reports, it is challenging to propose a recommendation for CBD use in perioperative pain management. Additionally, a number of CBD products currently available as supplements with different methods of administration, and it is important to remember that these products are non-pharmaceuticals. However, given the increased social relevance of CBD and cannabis-based medicines, future, prospective controlled studies evaluating their efficacy are needed.


Informative SNPs selection based on two-locus and multilocus linkage disequilibrium: criteria of max-correlation and min-redundancy.
Currently, there are lots of methods to select informative SNPs for haplotype reconstruction. However, there are still some challenges that render them ineffective for large data sets. First, some traditional methods belong to wrappers which are of high computational complexity. Second, some methods ignore linkage disequilibrium that it is hard to interpret selection results. In this study, we innovatively derive optimization criteria by combining two-locus and multilocus LD measure to obtain the criteria of Max-Correlation and Min-Redundancy (MCMR). Then, we use a greedy algorithm to select the candidate set of informative SNPs constrained by the criteria. Finally, we use backward scheme to refine the candidate subset. We separately use small and middle (>1,000 SNPs) data sets to evaluate MCMR in terms of the reconstuction accuracy, the time complexity, and the compactness. Additionally, to demonstrate that MCMR is practical for large data sets, we design a parameter w to adapt to various platforms and introduce another replacement scheme for larger data sets, which sharply narrow down the computational complexity of evaluating the reconstruct ratio. Then, we first apply our method based on haplotype reconstruction for large size (>5,000 SNPs) data sets. The results confirm that MCMR leads to promising improvement in informative SNPs selection and prediction accuracy.


Integral-geometry characterization of photobiomodulation effects on retinal vessel morphology.
The morphological characterization of quasi-planar structures represented by gray-scale images is challenging when object identification is sub-optimal due to registration artifacts. We propose two alternative procedures that enhances object identification in the integral-geometry morphological image analysis (MIA) framework. The first variant streamlines the framework by introducing an active contours segmentation process whose time step is recycled as a multi-scale parameter. In the second variant, we used the refined object identification produced in the first variant to perform the standard MIA with exact dilation radius as multi-scale parameter. Using this enhanced MIA we quantify the extent of vaso-obliteration in oxygen-induced retinopathic vascular growth, the preventative effect (by photobiomodulation) of exposure during tissue development to near-infrared light (NIR, 670 nm), and the lack of adverse effects due to exposure to NIR light.


Influence of intramolecular vs. intermolecular phosphonium-borohydrides in catalytic hydrogen, hydride, and proton transfer reactions.
In this computational study, the thermodynamics of hydrogen, hydride, and proton transfer from 22 phosphonium-borohydride intramolecular and intermolecular frustrated Lewis pairs (FLPs) to eight probe substrates was investigated. The purpose of this study was to gain insight into the thermodynamics of H2 transfer with intramolecular phosphonium-borohydrides; to determine whether intramolecular or intermolecular FLPs are preferred in FLP-catalyzed hydrogenation reactions. Comparison of the computed thermodynamic values showed that by connecting a borohydride and phosphonium center through a linker, H2 loss from the respective intramolecular phosphonium-borohydride became less favorable by about five and seven kcal mol-1 in acetonitrile and toluene, respectively. Connecting the borohydride and phosphonium centers also resulted in both hydride and proton loss becoming less favorable, on average, by about 10.0 kcal mol-1 and about 4.6 pKa units, respectively. Analysis of hydrogen, proton, and hydride transfer to eight probe substrates showed that initial proton transfer is 49 and 20 kcal mol-1 more favorable than the initial hydride transfer in the reduction of nitrogen-containing and oxygen-containing unsaturated substrates, respectively. These results suggest that proton transfer, followed by hydride transfer occurs in the reduction of imines, ketones, aldehydes, and enamines. From the thermodynamic analysis of proton and hydride transfer, an intramolecular phosphonium-borohydride was the desired catalyst for the reduction of imines and enamines, while an intermolecular phosphonium-borohydride was the favored catalyst for the reduction of ketones and aldehydes.


Open-loop phase shifting for fast acquisition of interferograms in low light levels.
Phase shifting interferometry relies on sets of interferograms taken at multiple known phase offsets to deduce the instantaneous phase of a quasi-static fringe pattern. The traditional method for introducing these phase shifts has been either to step a mirror, and measure the fringe pattern at each step, or to scan a mirror, integrating the fringe pattern for discrete time intervals while the fringes "move" on the detector. A stepping mirror eliminates this fringe smear but has typically required a closed-loop controller to ensure that the optical path introduced is accurately known. Furthermore, implementing rapid stepping of a moderately sized optic can prove difficult if the fringe phase needs to be measured on a short time scale. We report results demonstrating very fast (>100 Hz) and precise phase shifting using a piezomodulated mirror operated in open-loop without any position feedback. Our method exploits the use of a synthetic driving waveform that is optimized to match the complex frequency response of the modulator and its supported optic. For phase measurements in the near-infrared at 2.15 μm, and with a time between steps as small as 0.2 ms, we report errors below λ/100 in the desired position of our optic, i.e., an effective optical path difference error of ~λ/55. For applications in near-infrared stellar interferometry, this implies an enhancement in the fringe-tracking sensitivity of roughly 20% (in the photon-limited regime) over that which is conventionally realized using a swept mirror.


Baccalaureate nursing studies: voyaging towards discovery.
Postregistration nursing courses are designed to enable registered nurses to convert their existing certificate or diploma qualifications to degree level. This paper presents the findings of a preliminary exploratory, descriptive investigation into the experience of nurses undertaking postregistration degree studies in Malaysian Borneo. The unique nature of this environment presents challenges for these students and these are examined using the metaphor of a ship's voyage. These experiences are explored within themes of setting sail, finding one's sea legs, all in the same boat and discovering the treasure. The findings indicate that, for most of the participants, completion of a baccalaureate postregistration course was a long-held goal. A number of challenges were faced during the course, including managing time, the stress of conflicting priorities and the adjustment to tertiary studies. Support from fellow students, faculty and family was crucial to successfully completing this course. Personal and professional changes were reported by all participants. These include an increased level of confidence and assertiveness, the development of critical thinking ability, and enhanced communication skills. Ultimately, participants reported a renewed attitude towards themselves and their profession.


Drosophila carrying pex3 or pex16 mutations are models of Zellweger syndrome that reflect its symptoms associated with the absence of peroxisomes.
The peroxisome biogenesis disorders (PBDs) are currently difficult-to-treat multiple-organ dysfunction disorders that result from the defective biogenesis of peroxisomes. Genes encoding Peroxins, which are required for peroxisome biogenesis or functions, are known causative genes of PBDs. The human peroxin genes PEX3 or PEX16 are required for peroxisomal membrane protein targeting, and their mutations cause Zellweger syndrome, a class of PBDs. Lack of understanding about the pathogenesis of Zellweger syndrome has hindered the development of effective treatments. Here, we developed potential Drosophila models for Zellweger syndrome, in which the Drosophila pex3 or pex16 gene was disrupted. As found in Zellweger syndrome patients, peroxisomes were not observed in the homozygous Drosophila pex3 mutant, which was larval lethal. However, the pex16 homozygote lacking its maternal contribution was viable and still maintained a small number of peroxisome-like granules, even though PEX16 is essential for the biosynthesis of peroxisomes in humans. These results suggest that the requirements for pex3 and pex16 in peroxisome biosynthesis in Drosophila are different, and the role of PEX16 orthologs may have diverged between mammals and Drosophila. The phenotypes of our Zellweger syndrome model flies, such as larval lethality in pex3, and reduced size, shortened longevity, locomotion defects, and abnormal lipid metabolisms in pex16, were reminiscent of symptoms of this disorder, although the Drosophila pex16 mutant does not recapitulate the infant death of Zellweger syndrome. Furthermore, pex16 mutants showed male-specific sterility that resulted from the arrest of spermatocyte maturation. pex16 expressed in somatic cyst cells but not germline cells had an essential role in the maturation of male germline cells, suggesting that peroxisome-dependent signals in somatic cyst cells could contribute to the progression of male germ-cell maturation. These potential Drosophila models for Zellweger syndrome should contribute to our understanding of its pathology.


Differential gene expression in human hepatocyte cell lines exposed to the antiretroviral agent zidovudine.
Zidovudine (3'-azido-3'-deoxythymidine; AZT) is the most widely used nucleoside reverse transcriptase inhibitor for the treatment of AIDS patients and prevention of mother-to-child transmission of HIV-1. Previously, we demonstrated that AZT had significantly greater growth inhibitory effects upon the human liver carcinoma cell line HepG2 as compared to the immortalized human liver cell line THLE2. We have now used gene expression profiling to determine the molecular pathways associated with toxicity in both cell lines. HepG2 cells were incubated with 0, 2, 20, or 100 μM AZT for 2 weeks; THLE2 cells were treated with 0, 50, 500, or 2,500 μM AZT, concentrations that were equi-toxic to those used in the HepG2 cells. After the treatment, total RNA was isolated and subjected to microarray analysis. Global analysis of gene expression, with a false discovery rate ≤0.01 and a fold change ≥1.5, indicated that 6- to 70-fold more genes were differentially expressed in a significant concentration-dependent manner in HepG2 cells when compared to THLE2 cells. Comparative analysis indicated that 7 % of these genes were common to both cell lines. Among the common differentially expressed genes, 70 % changed in the same direction, most of which were associated with cell death and survival, cell cycle, cell growth and proliferation, and DNA replication, recombination, and repair. As determined by the uptake of [methyl-(3)H]AZT, the intracellular levels of total AZT were approximately twofold higher in THLE2 cells than in HepG2 cells. The expression of thymidine kinase 1 (TK1) and UDP-glucuronosyltransferase 2B7 (UGT2B7) genes that regulate the metabolic activation and deactivation of AZT, respectively, was increased in HepG2 cells but decreased in THLE2 cells after treatment with AZT. This differential response in AZT metabolism was confirmed by real-time PCR, western blotting, and/or enzymatic assays. These data indicate that molecular pathways involved with cell death and survival, cell cycle, cell growth and proliferation, and DNA replication, recombination, and repair are involved in the toxicities associated with AZT in both human cell lines, and that the difference in expression of TK1 and UGT2B7 in response to AZT treatment in HepG2 cells and THLE2 cells might explain why HepG2 cells are more sensitive than THLE2 cells to the toxicity of AZT.


Cross-sectional and Prospective Associations of Rest-Activity Rhythms With Metabolic Markers and Type 2 Diabetes in Older Men.
Disruption of rest-activity rhythms is cross-sectionally associated with metabolic disorders, including type 2 diabetes, yet it remains unclear whether it predicts impaired glucose metabolism and homeostasis. The aim of this study is to examine the cross-sectional and prospective associations between rest-activity rhythm characteristics and glycemic measures in a cohort of older men. Baseline rest-activity rhythms were derived from actigraphy with use of extended cosine model analysis. With subjects fasting, glucose, insulin, and HOMA of insulin resistance (HOMA-IR) were measured from blood at baseline and after ∼3.5 years. Type 2 diabetes was defined based on self-report, medication use, and fasting glucose. In the cross-sectional analysis (n = 2,450), lower 24-h amplitude-to-mesor ratio (i.e., mean activity-adjusted rhythm amplitude) and reduced overall rhythmicity were associated with higher fasting insulin and HOMA-IR (all P trend < 0.0001), indicating increased insulin resistance. The odds of baseline type 2 diabetes were significantly higher among those in the lowest quartile of amplitude (Q1) (odds ratio [OR]Q1 vs. Q4 1.63 [95% CI 1.14, 2.30]) and late acrophase group (ORlate vs. normal 1.46 [95% CI 1.04, 2.04]). In the prospective analysis (n = 861), multiple rest-activity characteristics predicted a two- to threefold increase in type 2 diabetes risk, including a lower amplitude (ORQ1 vs. Q4 3.81 [95% CI 1.45, 10.00]) and amplitude-to-mesor ratio (OR 2.79 [95% CI 1.10, 7.07]), reduced overall rhythmicity (OR 3.49 [95% CI 1.34, 9.10]), and a late acrophase (OR 2.44 [1.09, 5.47]). Rest-activity rhythm characteristics are associated with impaired glycemic metabolism and homeostasis and higher risk of incident type 2 diabetes.


Specific electron transport chain abnormalities in amyotrophic lateral sclerosis.
In an amyotrophic lateral sclerosis (ALS) patient who also had an IgA gammopathy, autopsy studies identified the IgA in the surviving motor neurons. Further, the IgA bound the surface of isolated bovine motor neurons and inhibited neuronal proliferation in culture. To determine the pathologic basis of this IgA interaction with motor neurons, a neuroblastoma cDNA library was generated and screened with the IgA monoclonal antibody. Reactive clones were identified as flavin adenine dinucleotide (FAD) synthetase. To extend this finding to ALS in general, quantitative RT-PCRs were performed on blood samples from 26 ALS and 30 control blood samples to determine mRNA expression levels of FAD synthetase and other electron transport chain proteins, specifically riboflavin kinase (RFK), cytochrome C1 (CYC1), and succinate dehydrogenase complex subunit B (SDHB). All expression levels were measured against a control enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Expression levels for a non-respiratory chain protein (beta-actin) were also measured. We found that FAD synthetase expression levels were decreased in ALS samples compared to expression levels in controls (P = 0.0151). Expression levels for RFK, CYC1, and SDHB were also significantly decreased in the ALS group (P = 0.0025, P = 0.0002, and P < 0.0001, respectively). As control, expression levels for beta-actin did not show a significant difference between ALS and control groups (P = 0.2118). Our data show that a reduction in electron transport proteins, namely FAD synthetase, RFK, CYC1, and SDHB, is seen in patients with ALS. It is possible that this may have an effect on oxygen-dependent metabolic pathways. Human motor neurons may be particularly susceptible to injury if there is sub-optimal oxidative metabolism.


Efficacy of N-Butylphthalide and Hyperbaric Oxygen Therapy on Cognitive Dysfunction in Patients with Delayed Encephalopathy After Acute Carbon Monoxide Poisoning.
BACKGROUND Delayed encephalopathy after acute carbon monoxide (CO) poisoning (DEACMP) is one of the most serious complications after CO poisoning. This study was conducted to explore the efficacy of the combined application of N-Butylphthalide and hyperbaric oxygenation therapy (HBO) on cognitive dysfunction in patients with DEACMP. MATERIAL AND METHODS A total of 184 patients with DEACMP were randomly assigned to either receive HBO or N-Butylphthalide and HBO. Meanwhile, all patients received conventional treatment. The total remission rate (RR) was used to assess the clinical efficacy. The Mini-Mental State Examination (MMSE) was used to assess the cognitive function, and the National Institutes of Health Stroke Scale (NIHSS) was used to assess the neurological function. RESULTS Finally, there were 90 and 94 patients in the control and experimental groups, respectively. After eight weeks of treatment, the total RR in the experimental group (47.9%) was significantly higher than that in the control group (33.3%). Compared to the control group, significantly more patients in the experimental group had MMSE scores of 24-30. The lower NIHSS score in the experimental group showed that N-Butylphthalide had the effect of preservation and restoration of neurological function. No obvious drug toxicity or liver and kidney dysfunction was observed, and there was no significant change in the level of blood glucose and blood lipids. CONCLUSIONS These results indicated that the combined application of N-Butylphthalide and HBO could significantly improve the cognitive dysfunction of patients with DEACMP and have great clinical efficacy, which should be further studied.


The impact of a new public health approach to end-of-life care: A systematic review.
Communities play an increasingly significant role in their own health and social care, and evidence demonstrates the positive impact of this work on a range of health outcomes. Interest is building regarding the application of the principles of the new public health approach to those facing the end of life and their families and communities. To review the evidence relating to the impact of a new public health approach to end-of-life care, specifically as this applies to efforts to strengthen community action. A systematic review employing narrative synthesis. Both meta-ethnography and the use of descriptive statistics supported analysis. Eight databases (AMED, ASSIA, BiblioMap, CINAHL, Cochrane Reviews, EMBASE, MEDLINE and PsycINFO) were searched from the earliest record to March 2015 using set eligibility criteria. Eight articles were included in the analysis. Three main themes emerged from the meta-ethnography: making a practical difference, individual learning and personal growth and developing community capacity. The quantitative findings mapped to the meta-ethnography and demonstrated that engaging communities can lead to improved outcomes for carers such as decreased fatigue or isolation, increase in size of caring networks and that wider social networks can influence factors such as place of death and involvement of palliative care services. Evidence exists for the impact of community engagement in end-of-life care. Impact assessment should be an integral part of future initiatives and policy makers should recognise that these approaches can influence complex issues such as carer support, community capacity, wellbeing and social isolation.


Individualized dynamic prediction of survival with the presence of intermediate events.
Often, in follow-up studies, patients experience intermediate events, such as reinterventions or adverse events, which directly affect the shapes of their longitudinal profiles. Our work is motivated by two studies in which such intermediate events have been recorded during follow-up. In both studies, we are interested in the change of the longitudinal evolutions after the occurrence of the intermediate event and in utilizing this information to improve the accuracy of dynamic prediction of their risk. To achieve so, we propose a flexible joint modeling framework for longitudinal and time-to-event data, which includes features of the intermediate event as time-varying covariates in both the longitudinal and survival submodels. We consider a set of joint models that postulate different effects of the intermediate event in the longitudinal profile and the risk of the clinical endpoint, with different formulations for the association structure while allowing its functional form to change after the occurrence of the intermediate event. Based on these models, we derive dynamic predictions of conditional survival probabilities which are adaptive to different scenarios with respect to the occurrence of the intermediate event. We evaluate the predictive accuracy of these predictions with a simulation study using the time-dependent area under the receiver operating characteristic curve and the expected prediction error adjusted to our setting. The results suggest that accounting for the changes in the longitudinal profiles and the instantaneous risk for the clinical endpoint is important, and improves the accuracy of the dynamic predictions.