Bioavailability of Sulforaphane from two broccoli sprout beverages: results of a short-term, cross-over clinical trial in Qidong, China.
One of several challenges in design of clinical chemoprevention trials is the selection of the dose, formulation, and dose schedule of the intervention agent. Therefore, a cross-over clinical trial was undertaken to compare the bioavailability and tolerability of sulforaphane from two of broccoli sprout-derived beverages: one glucoraphanin-rich (GRR) and the other sulforaphane-rich (SFR). Sulforaphane was generated from glucoraphanin contained in GRR by gut microflora or formed by treatment of GRR with myrosinase from daikon (Raphanus sativus) sprouts to provide SFR. Fifty healthy, eligible participants were requested to refrain from crucifer consumption and randomized into two treatment arms. The study design was as follows: 5-day run-in period, 7-day administration of beverages, 5-day washout period, and 7-day administration of the opposite intervention. Isotope dilution mass spectrometry was used to measure levels of glucoraphanin, sulforaphane, and sulforaphane thiol conjugates in urine samples collected daily throughout the study. Bioavailability, as measured by urinary excretion of sulforaphane and its metabolites (in approximately 12-hour collections after dosing), was substantially greater with the SFR (mean = 70%) than with GRR (mean = 5%) beverages. Interindividual variability in excretion was considerably lower with SFR than with GRR beverage. Elimination rates were considerably slower with GRR, allowing for achievement of steady-state dosing as opposed to bolus dosing with SFR. Optimal dosing formulations in future studies should consider blends of sulforaphane and glucoraphanin as SFR and GRR mixtures to achieve peak concentrations for activation of some targets and prolonged inhibition of others implicated in the protective actions of sulforaphane. Cancer Prev Res; 4(3); 384-95. ©2011 AACR.


Employing Extracellular Volume Cardiovascular Magnetic Resonance Measures of Myocardial Fibrosis to Foster Novel Therapeutics.
Quantifying myocardial fibrosis (MF) with myocardial extracellular volume measures acquired during cardiovascular magnetic resonance promises to transform clinical care by advancing pathophysiologic understanding and fostering novel therapeutics. Extracellular volume quantifies MF by measuring the extracellular compartment depicted by the myocardial uptake of contrast relative to plasma. MF is a key domain of dysfunctional but viable myocardium among others (eg, microvascular dysfunction and cardiomyocyte/mitochondrial dysfunction). Although anatomically distinct, these domains may functionally interact. MF represents pathological remodeling in the heart associated with cardiac dysfunction and adverse outcomes likely mediated by interactions with the microvasculature and the cardiomyocyte. Reversal of MF improves key measures of cardiac dysfunction, so reversal of MF represents a likely mechanism for improved outcomes. Instead of characterizing the myocardium as homogenous tissue and using important yet still generic descriptors, such as thickness (hypertrophy) and function (diastolic or systolic), which lack mechanistic specificity, paradigms of cardiac disease have evolved to conceptualize myocardial disease and patient vulnerability based on the extent of disease involving its various compartments. Specifying myocardial compartmental involvement may then implicate cellular/molecular disease pathways for treatment and targeted pharmaceutical development and above all highlight the role of the cardiac-specific pathology in heart failure among myriad other changes in the heart and beyond. The cardiology community now requires phase 2 and 3 clinical trials to examine strategies for the regression/prevention of MF and eventually biomarkers to identify MF without reliance on cardiovascular magnetic resonance. It seems likely that efficacious antifibrotic therapy will improve outcomes, but definitive data are needed.


Genetic research in autism spectrum disorders.
The recent explosion of genetic findings in autism spectrum disorder (ASD) research has improved knowledge of the disorder's underlying biology and etiologic architecture. This review introduces concepts and results from recent genetic studies and discusses the manner in which those findings can influence the trajectory of ASD research. Large consortium studies have associated ASDs with many types of genetic risk factors, including common polygenic risk, de novo single nucleotide variants, copy number variants, and rare inherited variants. In aggregate, these results confirm the heterogeneity and complexity of ASDs. The rare variant findings in particular point to genes and pathways that begin to bridge the gap between behavior and biology. Genetic studies have the potential to identify the biological underpinnings of ASDs and other neuropsychiatric disorders. The data they generate are already being used to examine disease pathways and pathogenesis. The results also speak to ASD heterogeneity and, in the future, may be used to stratify research studies and treatment trials.


Shifting from the perceptual brain to the logical brain: the neural impact of cognitive inhibition training.
What happens in the human brain when the mind has to inhibit a perceptual process in order to activate a logical reasoning process? Here, we use functional imaging to show the networks of brain areas involved in a deductive logic task performed twice by the same subjects, first with a perceptual bias and then with a logical response following bias-inhibition training. The main finding is a striking shift in the cortical anatomy of reasoning from the posterior part of the brain (the ventral and dorsal pathways) to a left-prefrontal network including the middle-frontal gyrus, Broca's area, the anterior insula, and the pre-SMA. This result indicates that such brain shifting is an essential element for human access to logical thinking.


Helicobacter pylori and cardiovascular disease.
Helicobacter pylori (H. pylori) is one of the most common infections in human. The association between H. pylori and gastrointestinal diseases including peptic ulcer, chronic gastritis, mucosa associated tissue lymphoma (MALT) and gastric cancer is well known. However it was also suggested that H. pylori was linked to various extra-gastrointestinal disorders such as diabetes mellitus and coronary artery disease. In this review we summarized the association between H. pylori and cardiovascular disease.


Association Between Unruptured Intracranial Aneurysms and Downstream Stroke.
Background and Purpose- Case reports suggest that unruptured intracranial aneurysms may serve as a nidus for thrombus formation and downstream embolic stroke. However, few data exist to support an association between unruptured aneurysms and ischemic stroke. Methods- We conducted a within-subjects case-control study of acute ischemic stroke patients prospectively enrolled in the Cornell Acute Stroke Academic Registry who had magnetic resonance imaging of the brain and arterial imaging of the head within 14 days of admission. Reviewers blinded to the study hypothesis ascertained the presence of aneurysms from the neuroradiologist's clinical report of the arterial imaging findings. McNemar test for paired data was used to compare the prevalence of unruptured aneurysms ipsilateral versus contralateral to the side of anterior circulation infarcts. Aneurysms of the anterior communicating artery or in the posterior circulation were not counted in the analysis. Results- Among 2116 patients registered in the Cornell Acute Stroke Academic Registry during 2011 to 2016, 1541 met our inclusion criteria, of whom 176 (11.4%; 95% CI, 9.8-13.0%) had an intracranial aneurysm. The prevalence of aneurysms did not differ on the side ipsilateral versus contralateral to the infarction (risk ratio [RR], 1.2; 95% CI, 0.9-1.5). There was no significant association between aneurysms and ipsilateral stroke in secondary analyses of the 1244 patients with stroke in a single anterior circulation territory (RR, 1.2; 95% CI, 0.8-1.9), the 619 patients with cryptogenic stroke (RR, 1.4; 95% CI, 0.9-2.0), or the 485 patients with cryptogenic stroke in a single anterior circulation territory (RR, 1.7; 95% CI, 0.8-3.3). Results were unchanged when counting only aneurysms >3 mm (RR, 1.2; 95% CI, 0.8-1.9) or 5 mm in diameter (RR, 1.2; 95% CI, 0.9-1.5). Conclusions- Contrary to our hypothesis, we found no significant association between unruptured intracranial aneurysms and ipsilateral ischemic stroke.


Socioeconomic status and risk of cardiovascular disease in 20 low-income, middle-income, and high-income countries: the Prospective Urban Rural Epidemiologic (PURE) study.
Socioeconomic status is associated with differences in risk factors for cardiovascular disease incidence and outcomes, including mortality. However, it is unclear whether the associations between cardiovascular disease and common measures of socioeconomic status-wealth and education-differ among high-income, middle-income, and low-income countries, and, if so, why these differences exist. We explored the association between education and household wealth and cardiovascular disease and mortality to assess which marker is the stronger predictor of outcomes, and examined whether any differences in cardiovascular disease by socioeconomic status parallel differences in risk factor levels or differences in management. In this large-scale prospective cohort study, we recruited adults aged between 35 years and 70 years from 367 urban and 302 rural communities in 20 countries. We collected data on families and households in two questionnaires, and data on cardiovascular risk factors in a third questionnaire, which was supplemented with physical examination. We assessed socioeconomic status using education and a household wealth index. Education was categorised as no or primary school education only, secondary school education, or higher education, defined as completion of trade school, college, or university. Household wealth, calculated at the household level and with household data, was defined by an index on the basis of ownership of assets and housing characteristics. Primary outcomes were major cardiovascular disease (a composite of cardiovascular deaths, strokes, myocardial infarction, and heart failure), cardiovascular mortality, and all-cause mortality. Information on specific events was obtained from participants or their family. Recruitment to the study began on Jan 12, 2001, with most participants enrolled between Jan 6, 2005, and Dec 4, 2014. 160 299 (87·9%) of 182 375 participants with baseline data had available follow-up event data and were eligible for inclusion. After exclusion of 6130 (3·8%) participants without complete baseline or follow-up data, 154 169 individuals remained for analysis, from five low-income, 11 middle-income, and four high-income countries. Participants were followed-up for a mean of 7·5 years. Major cardiovascular events were more common among those with low levels of education in all types of country studied, but much more so in low-income countries. After adjustment for wealth and other factors, the HR (low level of education vs high level of education) was 1·23 (95% CI 0·96-1·58) for high-income countries, 1·59 (1·42-1·78) in middle-income countries, and 2·23 (1·79-2·77) in low-income countries (pinteraction<0·0001). We observed similar results for all-cause mortality, with HRs of 1·50 (1·14-1·98) for high-income countries, 1·80 (1·58-2·06) in middle-income countries, and 2·76 (2·29-3·31) in low-income countries (pinteraction<0·0001). By contrast, we found no or weak associations between wealth and these two outcomes. Differences in outcomes between educational groups were not explained by differences in risk factors, which decreased as the level of education increased in high-income countries, but increased as the level of education increased in low-income countries (pinteraction<0·0001). Medical care (eg, management of hypertension, diabetes, and secondary prevention) seemed to play an important part in adverse cardiovascular disease outcomes because such care is likely to be poorer in people with the lowest levels of education compared to those with higher levels of education in low-income countries; however, we observed less marked differences in care based on level of education in middle-income countries and no or minor differences in high-income countries. Although people with a lower level of education in low-income and middle-income countries have higher incidence of and mortality from cardiovascular disease, they have better overall risk factor profiles. However, these individuals have markedly poorer health care. Policies to reduce health inequities globally must include strategies to overcome barriers to care, especially for those with lower levels of education. Full funding sources are listed at the end of the paper (see Acknowledgments).


Skin conditions in epileptics.
The prevalence of skin and mucous membrane conditions occurring in 173 epileptics between the ages of 6 and 19 years was compared with that of an age-matched group of 211 non-epileptics. The most frequently used anticonvulants, singly or in combination, were carbamazepine in 54.9%, phenytoin in 47.8%, barbiturates in 36.6% and ethosuximide in 11.2% of epileptics. The most frequent combination was phenytoin and carbamazepine in 14% of the males and 18.4% of the females. An increased prevalence of acne was found in epileptic females; 80.3% compared to 30.2% in non-epileptic females. Hirsutism was found in 43.9% of the female epileptics compared to 7.5% of the non-epileptic females. Of interest was the finding of punctate and linear scars on the dorsum of the hands of 27.7% epileptics compared to 3.8% non-epileptics. Both ephilides and naevocellular naevi occurred in 12.7% of the epileptics compared to 29.4% and 52.1% respectively of the non-epileptics. Leukonychia was also found more frequently in epileptics than in non-epileptics; 52% and 28.9% respectively.


Radiotherapy and breast reconstruction: oncology, cosmesis and complications.
Breast reconstruction plays a highly important role in the management of patients with breast cancer, from a psycho-social and sexual stand-point. Given that immediate breast reconstruction does not impair the oncologic safety of breast cancer management, with no increase in local recurrence rates, and no delays in the initiation of adjuvant chemotherapy or radiotherapy, the need to balance cosmesis in reconstruction with the oncologic needs of breast cancer patients is no more evident than in the discussion of radiotherapy. Radiotherapy is essential adjuvant therapy in the treatment of breast cancer, with the use of adjuvant radiotherapy widely shown to reduce local recurrence after both partial and total mastectomy and shown to prolong both disease-free and overall survival in patients with nodal disease. In the setting of breast reconstruction, the effects of radiotherapy are potentially two-fold, with consideration required of the impact of breast reconstruction on the administration of and the initiation of radiotherapy, as well as the effects of radiotherapy on operative complications and cosmetic outcome following immediate breast reconstruction. The current editorial piece aims to analyze this balance, contrasting both autologous and implant-based reconstruction. The literature is still evolving as to the relative role of autologous vs. alloplastic reconstruction in the setting of radiotherapy, and the more recent introduction of acellular dermal matrix and other compounds further complicate the evidence. Fat grafting and evolving techniques in breast reconstruction will herald new discussions on this front.


Cecal ligation and puncture followed by methicillin-resistant Staphylococcus aureus pneumonia increases mortality in mice and blunts production of local and systemic cytokines.
Mortality in the intensive care unit frequently results from the synergistic effect of two temporally distinct infections. This study examined the pathophysiology of a new model of intra-abdominal sepsis followed by methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. Mice underwent cecal ligation and puncture (CLP) or sham laparotomy followed 3 days later by an intratracheal injection of MRSA or saline. Both CLP/saline and sham/MRSA mice had 100% survival, whereas animals with CLP followed by MRSA pneumonia had 67% 7-day survival. Animals subjected to CLP/MRSA had increased bronchoalveolar lavage concentrations of MRSA compared with sham/MRSA animals. Animals subjected to sham/MRSA pneumonia had increased bronchoalveolar lavage levels of interleukin 6 (IL-6), tumor necrosis factor α, and granulocyte colony-stimulating factor compared with those given intratracheal saline, whereas CLP/MRSA mice had a blunted local inflammatory response with markedly decreased cytokine levels. Similarly, animals subjected to CLP/saline had increased peritoneal lavage levels of IL-6 and IL-1β compared with those subjected to sham laparotomy, whereas this response was blunted in CLP/MRSA mice. Systemic cytokines were upregulated in both CLP/saline and sham/MRSA mice, and this was blunted by the combination of CLP/MRSA. In contrast, no synergistic effect on pneumonia severity, white blood cell count, or lymphocyte apoptosis was identified in CLP/MRSA mice compared with animals with either insult in isolation. These results indicate that a clinically relevant model of CLP followed by MRSA pneumonia causes higher mortality than could have been predicted from studying either infection in isolation, and this was associated with a blunted local (pulmonary and peritoneal) and systemic inflammatory response and decreased ability to clear infection.


Quantification of muscle fat in patients with low back pain: comparison of multi-echo MR imaging with single-voxel MR spectroscopy.
To compare lumbar muscle fat-signal fractions derived from three-dimensional dual gradient-echo magnetic resonance (MR) imaging and multiple gradient-echo MR imaging with fractions from single-voxel MR spectroscopy in patients with low back pain. This prospective study had institutional review board approval, and written informed consent was obtained from all study participants. Fifty-six patients (32 women; mean age, 52 years ± 15 [standard deviation]; age range, 20-79 years) with low back pain underwent standard 1.5-T MR imaging, which was supplemented by dual-echo MR imaging, multi-echo MR imaging, and MR spectroscopy to quantify fatty degeneration of bilateral lumbar multifidus muscles in a region of interest at the intervertebral level of L4 through L5. Fat-signal fractions were determined from signal intensities on fat- and water-only images from both imaging data sets (dual-echo and multi-echo fat-signal fractions without T2* correction) or directly obtained, with additional T2* correction, from multi-echo MR imaging. The results were compared with MR spectroscopic fractions. The Student t test and Bland-Altman plots were used to quantify agreement between fat-signal fractions derived from imaging and from spectroscopy. In total, 102 spectroscopic measurements were obtained bilaterally (46 of 56) or unilaterally (10 of 56). Mean spectroscopic fat-signal fraction was 19.6 ± 11.4 (range, 5.4-63.5). Correlation between spectroscopic and all imaging-based fat-signal fractions was statistically significant (R(2) = 0.87-0.92; all P < .001). Mean dual-echo fat-signal fractions not corrected for T2* and multi-echo fat-signal fractions corrected for T2* significantly differed from spectroscopic fractions (both P < .01), but mean multi-echo fractions not corrected for T2* did not (P = .11). There was a small measurement bias of 0.5% (95% limits of agreement: -6.0%, 7.2%) compared with spectroscopic fractions. Large-volume image-based (dual-echo and multi-echo MR imaging) and spectroscopic fat-signal fractions agree well, thus allowing fast and accurate quantification of muscle fat content in patients with low back pain.


Effects of initial solute distribution on contaminant availability, desorption modeling, and subsurface remediation.
Low permeability regions in which solute movement is governed by diffusion reduce the availability of pollutants for remediation and can function as long-term sources of groundwater contamination. The inherent difficulty in understanding mass transfer from these regions of sequestered contamination is further complicated by unknown solute distributions within the low-permeability regions (sequestering regions). When models are calibrated to reproduce temporal histories of solute release from a sequestering region (desorption), the fitted parameter values are used to infer the physical or chemical characteristics of the media; however, the calibrated parameters also reflect the case-specific initial conditions (i.e., the solute distribution within the sequestering region domain at the onset of desorption). This phenomenon is demonstrated using model simulations of solute diffusion from hypothetical solids with characteristics similar to those of the well studied Borden, Ontario aquifer system. Solute release from the solids is simulated using a batch diffusion model under different initial solute distributions within the solids. The results of these model simulations are used to calibrate parameters of a multiple first-order rate desorption model (MRM) to illustrate how the fitted MRM parameters increase or decrease depending on the initial "aging" of the solids. Further numerical simulations are conducted for a one-dimensional flow system under steady-state and variable-rate hydraulic flushing. These simulations show that although aging reduces desorptive mass flux during early stages of flushing, aged sites have greater desorptive mass flux (greater solute availability) than "freshly" contaminated media during the later stages of remediation. Overall, the results demonstrate why the physicochemical meaning of observed desorption rates cannot be accurately deduced without first understanding the initial solute distribution within the media.


An in situ spectroelectrochemical study on the orientation changes of an [FeiiiLN2O3] metallosurfactant deposited as LB Films on gold electrode surfaces.
In this paper we analyze the changes in molecular orientation triggered by electrochemical reduction of an iron-containing surfactant in Langmuir-Blodgett films deposited onto gold electrodes. The metallosurfactant [Feiii(LN2O3)] (1) is an established molecular rectifier capable of unidirectional electron transfer between two electrodes. A gradual decrease in the activity is observed in sequential current vs. potential curves upon repeated cycles. Here we evaluate the redox response associated with the reduction of the Feiii/Feii couple in a single monolayer, as well as in a 5-layer LB film of 1. We use polarization modulation infrared reflection absorption spectroscopy (PM IRRAS) to follow structural and orientation changes associated with such applied potential scans. We observe that the reduction of the Fe center becomes increasingly irreversible because an Fe-Ophenolate bond is cleaved. This transformation is accompanied by an almost vertical change in the orientation of metallosurfactant molecules in LB films.


Natural kinds in evolution and systematics: metaphysical and epistemological considerations.
Despite the traditional focus on metaphysical issues in discussions of natural kinds in biology, epistemological considerations are at least as important. By revisiting the debate as to whether taxa are kinds or individuals, I argue that both accounts are metaphysically compatible, but that one or the other approach can be pragmatically preferable depending on the epistemic context. Recent objections against construing species as homeostatic property cluster kinds are also addressed. The second part of the paper broadens the perspective by considering homologues as another example of natural kinds, comparing them with analogues as functionally defined kinds. Given that there are various types of natural kinds, I discuss the different theoretical purposes served by diverse kind concepts, suggesting that there is no clear-cut distinction between natural kinds and other kinds, such as functional kinds. Rather than attempting to offer a unique metaphysical account of 'natural' kind, a more fruitful approach consists in the epistemological study of how different natural kind concepts are employed in scientific reasoning.


Hydrogen water consumption prevents osteopenia in ovariectomized rats.
Accumulating evidence indicates an important role of oxidative stress in the progression of osteoporosis. Recently, it was demonstrated that hydrogen gas, as a novel antioxidant, could selectively reduce hydroxyl radicals and peroxynitrite anion to exert potent therapeutic antioxidant activity. The aim of the present work was to investigate the effect of hydrogen water (HW) consumption on ovariectomy-induced osteoporosis. Ovariectomized rats were fed with HW (1.3 ± 0.2 mg·L⁻¹) for 3 months. Then, blood was collected and femur and vertebrae were removed for evaluation of the effect of HW on bone. HW consumption in ovariectomized rats had no significant effect on oestrogen production, but prevented the reduction of bone mass including bone mineral content and bone mineral density in femur and vertebrae, and preserved mechanical strength including ultimate load, stiffness, and energy, and bone structure including trabecular bone volume fraction, trabecular number, and trabecular thickness in femur, and preserved mechanical strength including ultimate load and stiffness, and bone structure including trabecular bone volume fraction and trabecular number in vertebrae. In addition, treatment with HW abated oxidative stress and suppressed IL-6 and TNF-α mRNA expressions in femur of ovariectomized rats; treatment with HW increased femur endothelial NOS activity and enhanced circulating NO level in ovariectomized rats. HW consumption prevents osteopenia in ovariectomized rats possibly through the ablation of oxidative stress induced by oestrogen withdrawal.


The application of a recently isolated strain of Bacteroides (GB-124) to identify human sources of faecal pollution in a temperate river catchment.
Recent work has suggested that bacteriophages infecting Bacteroides are a potential tool for faecal source tracking, but that different host strains may be needed for different geographic areas. This study used a recently identified strain of Bacteroides (GB-124) to detect human sources of faecal pollution in a river catchment in southeast England (UK). A total of 306 river water, municipal wastewater and animal samples were obtained over a 16-month period. Bacteriophages capable of infecting GB-124 were present in all municipal wastewaters but were not detected in faecal samples from animals, and were detected at significantly lower levels (P< 0.001) in river waters directly downstream of a dairy farm. This last observation was despite the presence of high levels of faecal indicator bacteria at this site. The study suggests that GB-124 appears to be specific to human faeces. As such it may represent an effective and low-cost method of faecal source identification.


Fractal feature of sEMG from Flexor digitorum superficialis muscle correlated with levels of contraction during low-level finger flexions.
This research paper reports an experimental study on identification of the changes in fractal properties of surface Electromyogram (sEMG) with the changes in the force levels during low-level finger flexions. In the previous study, the authors have identified a novel fractal feature, Maximum fractal length (MFL) as a measure of strength of low-level contractions and has used this feature to identify various wrist and finger movements. This study has tested the relationship between the MFL and force of contraction. The results suggest that changes in MFL is correlated with the changes in contraction levels (20%, 50% and 80% maximum voluntary contraction (MVC)) during low-level muscle activation such as finger flexions. From the statistical analysis and by visualisation using box-plot, it is observed that MFL (p ≈ 0.001) is a more correlated to force of contraction compared to RMS (p≈0.05), even when the muscle contraction is less than 50% MVC during low-level finger flexions. This work has established that this fractal feature will be useful in providing information about changes in levels of force during low-level finger movements for prosthetic control or human computer interface.


Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses.
Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex. In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10-8) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study. The associations between circulating UCB levels and CRC risk differed by sex (Pheterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (Pheterogeneity ≥ 0.2). Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.


Interaction of 4-arylcoumarin analogues of combretastatins with microtubule network of HBL100 cells and binding to tubulin.
The synthesis of different 4-arylcoumarin analogues of combretastatin A-4 led to the identification of two new compounds (1 and 2) with potent cytotoxic activity on a CEM leukemia cell line and a third one completely inactive (compound 3). It was suggested that the cytotoxicity of compounds 1 and 2 may be related to their interaction with microtubules and tubulin, since these compounds inhibit microtubule formation from purified tubulin in vitro [Bailly et al. (2003) J. Med. Chem. 46 (25), 5437-5444]. In the present study, tubulin was identified as the main target of these molecules. We studied structure-activity relationships of these compounds using biological experiments specific for tubulin binding. The modification of cell cycle progression induced by compounds 1 and 2 was characterized by an apoptotic induction on human breast cells (HBL100). In addition, these two molecules disturbed cell survival by depolymerizing the microtubule network, leading to a mitotic block. We then determined the thermodynamic parameters of their interaction with purified tubulin by fluorescence spectroscopy and isothermal microcalorimetry. These results, together with a superimposition of the molecule on colchicine in the X-ray-determined three-dimensional structure model of tubulin-colchicine complex, allowed us to identify the pharmacophore of the combretastatin A-4 analogues responsible for their biological activity.


Learning from Heterogeneous Data Sources: An Application in Spatial Proteomics.
Sub-cellular localisation of proteins is an essential post-translational regulatory mechanism that can be assayed using high-throughput mass spectrometry (MS). These MS-based spatial proteomics experiments enable us to pinpoint the sub-cellular distribution of thousands of proteins in a specific system under controlled conditions. Recent advances in high-throughput MS methods have yielded a plethora of experimental spatial proteomics data for the cell biology community. Yet, there are many third-party data sources, such as immunofluorescence microscopy or protein annotations and sequences, which represent a rich and vast source of complementary information. We present a unique transfer learning classification framework that utilises a nearest-neighbour or support vector machine system, to integrate heterogeneous data sources to considerably improve on the quantity and quality of sub-cellular protein assignment. We demonstrate the utility of our algorithms through evaluation of five experimental datasets, from four different species in conjunction with four different auxiliary data sources to classify proteins to tens of sub-cellular compartments with high generalisation accuracy. We further apply the method to an experiment on pluripotent mouse embryonic stem cells to classify a set of previously unknown proteins, and validate our findings against a recent high resolution map of the mouse stem cell proteome. The methodology is distributed as part of the open-source Bioconductor pRoloc suite for spatial proteomics data analysis.


Stakeholder perceptions of curriculum design, development and delivery for continuing e-learning for nurses.
This paper reports the qualitative findings from stage 5 of an action research project which involved the redesign of continuing professional education (CPE) courses in one organisation. The aim of this study was to explore key stakeholders perceptions of the teaching, learning and outcomes of a new curriculum design for CPE involving e-learning. This project used participatory action research, involving stakeholders as participants in a process of inquiry about the change. The study took place in an academic teaching hospital and consisted of three focus group interviews with a total of 20 nurses. Participants included stakeholders who had developed curricula and managers from clinical areas where CPE courses had been undertaken. Four main themes emerged, revealing staff perceptions on the process of change and their own 'lightbulb moments' experienced during this process. Results also indicate that the change has resulted in learner-focused CPE, with a range of opportunities for continued educational development in future. Key stakeholders' experience is seldom reported in studies related to CPE. This study provides an insight into the experiences of key stakeholders in relation to the development and delivery of CPE courses. Stakeholders indicated that they were able to see the benefits of implementing new CPE curricula they had contributed to. They also commented that clinical-pertinent and competence-based courses were more learner focused as a result of combining online content with supported workshops.


Preparation and Isolation of siRNA-Loaded Extracellular Vesicles.
RNA interference (RNAi) has tremendous potential for specific silencing of disease-causing genes. Its clinical usage however critically depends on the development of carrier systems that can transport the RNAi-mediating small interfering RNA (siRNA) molecules to the cytosol of target cells. Recent reports have suggested that extracellular vesicles (EVs) form a natural transport system through which biomolecules, including RNA, is exchanged between cells. Therefore, EVs are increasingly being considered as potential therapeutic siRNA delivery systems.In this chapter we describe a method for preparing siRNA-loaded EVs, including a robust, scalable method to isolate them from cell culture supernatants.


NodeTrix: a hybrid visualization of social networks.
The need to visualize large social networks is growing as hardware capabilities make analyzing large networks feasible and many new data sets become available. Unfortunately, the visualizations in existing systems do not satisfactorily resolve the basic dilemma of being readable both for the global structure of the network and also for detailed analysis of local communities. To address this problem, we present NodeTrix, a hybrid representation for networks that combines the advantages of two traditional representations: node-link diagrams are used to show the global structure of a network, while arbitrary portions of the network can be shown as adjacency matrices to better support the analysis of communities. A key contribution is a set of interaction techniques. These allow analysts to create a NodeTrix visualization by dragging selections to and from node-link and matrix forms, and to flexibly manipulate the NodeTrix representation to explore the dataset and create meaningful summary visualizations of their findings. Finally, we present a case study applying NodeTrix to the analysis of the InfoVis 2004 coauthorship dataset to illustrate the capabilities of NodeTrix as both an exploration tool and an effective means of communicating results.


Using pulse transit delay in Z-scan to discriminate between excited-state absorption and other nonlinear processes in ZnO nanocones.
We report a new approach that uses the single beam Z-scan technique, to discriminate between excited state absorption (ESA) and two and three photon nonlinear absorption. By measuring the apparent delay or advance of the pulse in reaching the detector, the nonlinear absorption can be unambiguously identified as either instantaneous or transient. The simple method does not require a large range of input fluences or sophisticated pulse-probe experimental apparatus. The technique is easily extended to any absorption process dependent on pulse width and to nonlinear refraction measurements. We demonstrate in particular, that the large nonlinear absorption in ZnO nanocones when exposed to nanosecond 532 nm pulses, is due mostly to ESA, not pure two-photon absorption.


Mechanisms of ertapenem resistance in Enterobacteriaceae isolates in a tertiary university hospital.
The aim of this study was to investigate the molecular mechanisms of ertapenem resistance among Enterobacteriaceae isolates in a clinical microbiology laboratory at a tertiary university hospital. A total of 40 clinical isolates including 20 resistant and 20 intermediate isolates were collected from August 2012 to July 2013. Ertapenem susceptibility was confirmed by the broth microdilution method. PCR and sequencing analysis of carbapenemase, AmpC β-lactamase, and extended-spectrum β-lactamase (ESBL) genes were performed. Outer membrane proteins (OMPs) were examined by urea-sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Molecular epidemiology studies were performed by pulsed-field gel electrophoresis (PFGE). AmpC β-lactamases and ESBLs were found in 32 (80.0%) and 20 (50.0%) of the 40 isolates with ertapenem non-susceptibility, respectively. Distributions of β-lactamase genes differed among the species. One Citrobacter freundii isolate among the 40 isolates with ertapenem non-susceptibility carrying the blaIMP-1 associated class 1 integron was detected. SDS-PAGE of OMPs showed altered or greatly diminished expression of porins in all isolates of Klebsiella pneumoniae (n=5) and Enterobacter cloacae (n=11) with ertapenem resistance. Porin alterations were less common among the isolates with intermediate susceptibility (4/19). Integration of the results of molecular analysis of β-lactamases and OMP analysis revealed that most of the isolates with ertapenem resistance exhibited β-lactamase activity and porin alteration. PFGE revealed that most isolates were epidemiologically unrelated. Ertapenem resistance in clinical Enterobacteriaceae isolates was associated with β-lactamase activity and porin alteration. Even though carbapenemase-producing Enterobacteriaceae are still rare, continuous monitoring and infection control for carbapenem-resistant Enterobacteriaceae are necessary.


Opportunities and Challenges in Interpreting and Sharing Personal Genomes.
The 2019 "Personal Genomes: Accessing, Sharing and Interpretation" conference (Hinxton, UK, 11-12 April 2019) brought together geneticists, bioinformaticians, clinicians and ethicists to promote openness and ethical sharing of personal genome data while protecting the privacy of individuals. The talks at the conference focused on two main topic areas: (1) Technologies and Applications, with emphasis on personal genomics in the context of healthcare. The issues discussed ranged from new technologies impacting and enabling the field, to the interpretation of personal genomes and their integration with other data types. There was particular emphasis and wide discussion on the use of polygenic risk scores to inform precision medicine. (2) Ethical, Legal, and Social Implications, with emphasis on genetic privacy: How to maintain it, how much privacy is possible, and how much privacy do people want? Talks covered the full range of genomic data visibility, from open access to tight control, and diverse aspects of balancing benefits and risks, data ownership, working with individuals and with populations, and promoting citizen science. Both topic areas were illustrated and informed by reports from a wide variety of ongoing projects, which highlighted the need to diversify global databases by increasing representation of understudied populations.


Serum 25-Hydroxyvitamin D Levels and Stress Fractures in Military Personnel: A Systematic Review and Meta-analysis.
Low serum 25-hydroxyvitamin D (25(OH)D) levels have been associated with stress fractures in various physically active populations such as the military. To examine the association between serum 25(OH)D levels and stress fractures in the military. Systematic review and meta-analysis. Relevant studies were identified through searching multiple databases and manually screening reference lists. Two reviewers independently selected the included studies by applying the eligibility criteria to the title, abstract, and/or full text of the articles yielded in the search. Two reviewers also independently conducted the methodological quality assessment and data extraction. A random-effects model was used to calculate the mean difference (MD) with 95% CI in serum 25(OH)D levels between stress fracture cases and controls. Nine observational studies on lower extremity stress fractures were eligible, and 1 was excluded due to inadequate data. A total of 2634 military personnel (age, 18-30 years; 44% male) with 761 cases (16% male) and 1873 controls (61% male) from 8 studies were included in the analysis. Three of the 8 studies measured serum 25(OH)D levels at the time of stress fracture diagnosis, and the 5 remaining studies measured serum 25(OH)D levels at the time of entry into basic training. The mean serum 25(OH)D level was lower in stress fracture cases than in controls at the time of entry into basic training (MD, -2.63 ng/mL; 95% CI, -5.80 to 0.54; P = .10; I(2) = 65%) and at the time of stress fracture diagnosis (MD, -2.26 ng/mL; 95% CI, -3.89 to -0.63; P = .007; I(2) = 42%). Despite the inherent limitations of the included studies, the study results suggest some association between low serum 25(OH)D levels and lower extremity stress fractures in military personnel. Given the rigorous training of military personnel, implementing strategies to ensure sufficient 25(OH)D levels may be beneficial for reducing the risk of stress fractures.


Pleth variability index and fluid responsiveness of hemodynamically stable patients after cardiothoracic surgery.
Fluid responsiveness is a measure of preload dependence and is defined as an increase in cardiac output due to volume expansion. Recent publications have suggested that variation in amplitude of the pulse oximetry waveform may be predictive of fluid responsiveness. The pleth variability index (PVI) was developed as a noninvasive bedside measurement of this variation in the pulse oximetry waveform. To measure the discriminatory value of PVI for predicting fluid responsiveness as measured by pulmonary artery catheter thermodilution in patients after cardiothoracic surgery. A prospective observational study of hemodynamically stable postoperative cardiac surgery patients with pulmonary artery catheters. A fingertip sensor was used to measure PVI. Vital signs, PVI, and cardiac index were measured before, during, and after passive leg raise. Fluid responsiveness was defined by increase in cardiac index of greater than 15% during passive leg raise. The discriminatory value of PVI was assessed by using the Wilcoxon method to measure the area under the receiver operating curve. In 13 months, 47 patients (24 receiving mechanical ventilation, 23 spontaneously breathing) were enrolled. Fluid responsiveness was noted in 42% of intubated patients and 48% of spontaneously breathing patients. PVI was not adequate to discriminate fluid responsiveness in intubated patients (area under curve, 0.63; P = .16) or spontaneously breathing patients (area under curve, 0.41; P = .75). Among postoperative cardiac surgery patients, PVI is not reliable for predicting fluid responsiveness as measured by pulmonary artery catheter thermodilution, regardless of ventilatory status.


Genome analysis of methicillin-resistant Staphylococcus aureus isolated from pigs: Detection of the clonal lineage ST398 in Cameroon and South Africa.
Food animals are considered reservoirs of methicillin-resistant Staphylococcus aureus (MRSA) and are implicated in their zoonotic transmission in the farm-to-plate continuum. LA-MRSA has been reported as a zoonotic agent that has the potential to spread to humans and may cause infections in at-risk groups. In this study, whole genome sequencing was used to describe the genetic environment (resistance mechanisms, virulence factors and mobile genetic elements) and investigate the genetic lineages of MRSA isolates from pigs in Cameroonian and South African abattoirs. During March-October 2016, 288 nasal and rectal pooled samples from 432 pigs as well as nasal and hand swabs from 82 humans were collected. Genomic DNA was sequenced using an Illumina MiSeq platform. Generated reads were de novo-assembled using the Qiagen CLC Genomics Workbench and SPAdes. The assembled contigs were annotated, and antibiotic resistance genes, virulence factors, plasmids, SCCmec and phage elements were identified with ResFinder, Virulence Finder, PlasmidFinder, SCCmec Finder and PHAST, respectively. Core genome single nucleotide analysis was undertaken to assess clonal relatedness among isolates. A lower MRSA prevalence was observed in pigs in Cameroon (n = 1/13; 0.07%) compared with South Africa (n = 4/22; 18.18%), and none of the workers were colonized by MRSA. Genome analysis identified various antibiotic resistance genes along with six virulence factors in all isolates. All MRSA isolates belonged to the clonal lineage ST398 (spa-type t011) and harboured the type Vc SCCmec and several plasmids. Our study shows that the livestock-associated MRSA clonal lineage ST398 is already present in both Cameroon and South Africa and is probably underestimated in the absence of molecular epidemiological studies. It reveals the serious food safety and public health threat associated with this animal strain and underscores the need for interventions to contain this resistant clone.


Baseline Religion Involvement Predicts Subsequent Salivary Cortisol Levels Among Male But not Female Black Youth.
Compared to Whites, Blacks are exposed to higher levels of chronic stress in the United States. As a result, major Black-White differences exist in the baseline and response of cortisol. Yet, the potential association between baseline religiosity and subsequent cortisol levels of Blacks are not known. In the current study we aimed to determine the association between baseline religious behaviors and daytime salivary cortisol level among male and female Black youth. With a longitudinal design, data came from wave 1 (1994) and wave 6 (2000) of a cohort from an urban area in the Midwest of the United States. The study followed 227 Black adolescents (109 males and 118 females) for six years. Socio-demographics and religious behaviors (frequency of participation in religious activities) were measured at baseline. Base morning cortisol level at wave 6 was the outcome. We fitted a linear regression model to test the association between baseline religiosity at wave 1 and cortisol level at wave 6, while baseline age, socio-economics, and psychological symptoms were controlled. In the pooled sample, frequency of participation in religious activities at baseline was negatively associated with mean cortisol level at follow up (r = -0.29, P > 0.01) among all, males (r = -0.38, P > 0.01), but not females (r = -.20, P > 0.05). Frequency of participation in religious activities remained a significant predictor of subsequent cortisol level (b = -0.283, 95% CI = -.107 - -0.022) while the effect of age, socioeconomics, and psychological symptoms were controlled. We could only find such an association among male Black youth (b = -0.368, 95% CI = -0.148 - -0.024) but not female Black youth (b = -0.229, 95% CI = -.113 - 0.011). Religiosity has been used as a coping mechanism among Blacks. Religiosity may also be related to stress regulation among Black youth. Future studies need to test complex associations between race, sex, religiosity, chronic stress, coping, and function of hypothalamo-pituitary-adrenal (HPA). It is not known whether male Black youth who are and those who are not religious differently cope with stress associated with daily discrimination and living in disadvantaged neighborhoods.


Rscreenorm: normalization of CRISPR and siRNA screen data for more reproducible hit selection.
Reproducibility of hits from independent CRISPR or siRNA screens is poor. This is partly due to data normalization primarily addressing technical variability within independent screens, and not the technical differences between them. We present "rscreenorm", a method that standardizes the functional data ranges between screens using assay controls, and subsequently performs a piecewise-linear normalization to make data distributions across all screens comparable. In simulation studies, rscreenorm reduces false positives. Using two multiple-cell lines siRNA screens, rscreenorm increased reproducibility between 27 and 62% for hits, and up to 5-fold for non-hits. Using publicly available CRISPR-Cas screen data, application of commonly used median centering yields merely 34% of overlapping hits, in contrast with rscreenorm yielding 84% of overlapping hits. Furthermore, rscreenorm yielded at most 8% discordant results, whilst median-centering yielded as much as 55%. Rscreenorm yields more consistent results and keeps false positive rates under control, improving reproducibility of genetic screens data analysis from multiple cell lines.


Does load position affect gait and subjective responses of females during load carriage?
Recreational hikers carry heavy loads while often walking long distances over uneven terrain. Previous studies have suggested that not only the load mass but also the position of the load may influence load carriage. The purpose of this study was to determine the effect of vertical load position on gait and subjective responses of female recreational hikers. Fifteen experienced female hikers walked for 2 km over a simulated hiking trail carrying 30% BW in three vertical load positions (high, medium and low). Lower limb and trunk kinematic, electromyography (EMG) and ground reaction force (GRF) data were collected together with heart rate (HR), ratings of perceived exertion (RPE) and discomfort measures. Although HR, RPE and discomfort measures were not able to discern statistical differences between load positions, the high load position was the most preferred by participants. The high load position also resulted in a more upright posture (p < 0.001), decreased gastrocnemius integrated EMG compared to the medium (p = 0.005) and low load positions (p = 0.02) and a higher first peak deceleration vertical GRF compared to the low load position (p = 0.011). However, the absolute differences were small and unlikely to be functionally relevant in load carriage studies. Based on the findings of this study, a high, medium or low load position cannot be preferentially recommended for healthy, experienced, female hikers carrying 30% BW.


Biophysical properties of gap junction channels formed by mouse connexin40 in induced pairs of transfected human HeLa cells.
A clone of human HeLa cells stably transfected with mouse connexin40 DNA was used to examine gap junctions. Two separate cells were brought into physical contact with each other ("induced cell pair") to allow insertion of gap junction channels and, hence, formation of a gap junction. The intercellular current flow was measured with a dual voltage-clamp method. This approach enabled us to study the electrical properties of gap junction channels (cell pairs with a single channel) and gap junctions (cell pairs with many channels). We found that single channels exhibited multiple conductances, a main state (gamma j(main state)), several substates (gamma j(substates)), a residual state (gamma j (residual state)), and a closed state (gamma j(closed state)). The gamma j(main state) was 198 pS, and gamma j(residual state) was 36 pS (temperature, 36-37 degrees C; pipette solution, potassium aspartate). Both properties were insensitive to transjunctional voltage, Vj. The transitions between the closed state and an open state (i.e., residual state, substate, or main state) were slow (15-45 ms); those between the residual state and a substate or the main state were fast (1-2 ms). Under steady-state conditions, the open channel probability, Po, decreased in a sigmoidal manner from 1 to 0 (Boltzmann fit: Vj,o = -44 mV; z = 6). The temperature coefficient, Q10, for gamma j(main state) and gamma j(residual state) was 1.2 and 1.3, respectively (p < 0.001; range 15-40 degrees C). This difference suggests interactions between ions and channel structure in case of gamma j(residual state). In cell pairs with many channels, the gap junction conductance at steady state, gj, exhibited a bell-shaped dependency from Vj (Boltzmann fit, negative Vj, Vj,o = -45 mV, gj(min) = 0.24; positive Vj, Vj,o = 49 mV, gj(min) = 0.26; z = 6). We conclude that each channel is controlled by two types of gates, a fast one responsible for Vj gating and involving transitions between open states (i.e., residual state, substates, main state), and a slow one involving transitions between the closed state and an open state.


Development of an Open-Source Thermal Image Processing Software for Improving Irrigation Management in Potato Crops (Solanum tuberosum L.).
Accurate determination of plant water status is mandatory to optimize irrigation scheduling and thus maximize yield. Infrared thermography (IRT) can be used as a proxy for detecting stomatal closure as a measure of plant water stress. In this study, an open-source software (Thermal Image Processor (TIPCIP)) that includes image processing techniques such as thermal-visible image segmentation and morphological operations was developed to estimate the crop water stress index (CWSI) in potato crops. Results were compared to the CWSI derived from thermocouples where a high correlation was found ( r P e a r s o n = 0.84). To evaluate the effectiveness of the software, two experiments were implemented. TIPCIP-based canopy temperature was used to estimate CWSI throughout the growing season, in a humid environment. Two treatments with different irrigation timings were established based on CWSI thresholds: 0.4 (T2) and 0.7 (T3), and compared against a control (T1, irrigated when soil moisture achieved 70% of field capacity). As a result, T2 showed no significant reduction in fresh tuber yield (34.5 ± 3.72 and 44.3 ± 2.66 t ha - 1 ), allowing a total water saving of 341.6 ± 63.65 and 515.7 ± 37.73 m 3 ha - 1 in the first and second experiment, respectively. The findings have encouraged the initiation of experiments to automate the use of the CWSI for precision irrigation using either UAVs in large settings or by adapting TIPCIP to process data from smartphone-based IRT sensors for applications in smallholder settings.


An epidemiological study of dengue in Delhi, India.
Delhi, the capital of India, is an important metropolitan hub for major financial and sociocultural exchanges, offering challenging threats to current public health infrastructure. In recent past, an upsurge of dengue cases in Delhi posed a significant menace to the existing dengue control policies. To reform the control strategies and take timely intervention to prevent future epidemics, an epidemiological study on the proportion of both asymptomatic and symptomatic dengue infections in selected population was conducted. The aim of the study was to investigate and assess the epidemiology of dengue infection and to estimate the proportion of asymptomatic and symptomatic dengue infections in Delhi. In this study, around 50 confirmed dengue cases, a total of 2125 individuals as household and neighbourhood contacts, with or without dengue febrile illness, were finger pricked and serologically detected as dengue positive or negative using SD Duo Bioline Rapid Diagnostic Test (SD Inc, Korea) with NS1, IgM & IgG combo test, which detected dengue virus antigen and antibodies to dengue virus in human blood. Out of 2125 individuals, 768 (36.1%) individuals showed positive dengue test with past (25.5%), primary (1.88%) or secondary (8.8%) dengue infections. Higher percentage of IgG was found in age groups 15-24 years and 25-50 years (36% each). Infants (<1 year) presented higher incidence of new infections (22% of NS1+IgM positives) as compared to adults. Further analysis revealed that out of the 226 newly infected cases (including NS1 and IgM positives), 142 (63%) were asymptomatic and 84 (37%) were symptomatic, as per WHO guidelines. Our findings also suggest that out of the total population screened, 10.6% dengue infection was either primary or secondary. On the basis of these results, it may be hypothesized that there are large number of asymptomatic dengue infections in the community as compared to reported symptomatic cases in Delhi. For the effective control of dengue transmission in such community like Delhi where dengue epidemics have frequently been encountered, it is essential to ascertain the proportion of asymptomatic dengue infections which may act as a reservoir for dengue transmission, as well as threat for developing dengue haemorrhagic fever (DHF).


Glycolytic inhibitor 2-deoxyglucose prevents cortical hyperexcitability after traumatic brain injury.
Traumatic brain injury (TBI) causes cortical dysfunction and can lead to post-traumatic epilepsy. Multiple studies demonstrate that GABAergic inhibitory network function is compromised following TBI, which may contribute to hyperexcitability and motor, behavioral, and cognitive deficits. Preserving the function of GABAergic interneurons, therefore, is a rational therapeutic strategy to preserve cortical function after TBI and prevent long-term clinical complications. Here, we explored an approach based on the ketogenic diet, a neuroprotective and anticonvulsant dietary therapy which results in reduced glycolysis and increased ketosis. Utilizing a pharmacologic inhibitor of glycolysis (2-deoxyglucose, or 2-DG), we found that acute in vitro application of 2-DG decreased the excitability of excitatory neurons, but not inhibitory interneurons, in cortical slices from naïve mice. Employing the controlled cortical impact (CCI) model of TBI in mice, we found that in vitro 2-DG treatment rapidly attenuated epileptiform activity seen in acute cortical slices 3 to 5 weeks after TBI. One week of in vivo 2-DG treatment immediately after TBI prevented the development of epileptiform activity, restored excitatory and inhibitory synaptic activity, and attenuated the loss of parvalbumin-expressing inhibitory interneurons. In summary, 2-DG may have therapeutic potential to restore network function following TBI.


Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies.
Single nucleotide polymorphism arrays (SNP-As) have emerged as an important tool in the identification of chromosomal defects undetected by metaphase cytogenetics (MC) in hematologic cancers, offering superior resolution of unbalanced chromosomal defects and acquired copy-neutral loss of heterozygosity. Myelodysplastic syndromes (MDSs) and related cancers share recurrent chromosomal defects and molecular lesions that predict outcomes. We hypothesized that combining SNP-A and MC could improve diagnosis/prognosis and further the molecular characterization of myeloid malignancies. We analyzed MC/SNP-A results from 430 patients (MDS = 250, MDS/myeloproliferative overlap neoplasm = 95, acute myeloid leukemia from MDS = 85). The frequency and clinical significance of genomic aberrations was compared between MC and MC plus SNP-A. Combined MC/SNP-A karyotyping lead to higher diagnostic yield of chromosomal defects (74% vs 44%, P < .0001), compared with MC alone, often through detection of novel lesions in patients with normal/noninformative (54%) and abnormal (62%) MC results. Newly detected SNP-A defects contributed to poorer prognosis for patients stratified by current morphologic and clinical risk schemes. The presence and number of new SNP-A detected lesions are independent predictors of overall and event-free survival. The significant diagnostic and prognostic contributions of SNP-A-detected defects in MDS and related diseases underscore the utility of SNP-A when combined with MC in hematologic malignancies.


Durability of ChAdOx1 nCoV-19 vaccination in people living with HIV.
Duration of protection from SARS-CoV-2 infection in people living with HIV (PWH) following vaccination is unclear. In a substudy of the phase II/III the COV002 trial (NCT04400838), 54 HIV+ male participants on antiretroviral therapy (undetectable viral loads, CD4+ T cells > 350 cells/μL) received 2 doses of ChAdOx1 nCoV-19 (AZD1222) 4-6 weeks apart and were followed for 6 months. Responses to vaccination were determined by serology (IgG ELISA and Meso Scale Discovery [MSD]), neutralization, ACE-2 inhibition, IFN-γ ELISpot, activation-induced marker (AIM) assay and T cell proliferation. We show that, 6 months after vaccination, the majority of measurable immune responses were greater than prevaccination baseline but with evidence of a decline in both humoral and cell-mediated immunity. There was, however, no significant difference compared with a cohort of HIV-uninfected individuals vaccinated with the same regimen. Responses to the variants of concern were detectable, although they were lower than WT. Preexisting cross-reactive T cell responses to SARS-CoV-2 spike were associated with greater postvaccine immunity and correlated with prior exposure to beta coronaviruses. These data support the ongoing policy to vaccinate PWH against SARS-CoV-2, and they underpin the need for long-term monitoring of responses after vaccination.


Optical data encryption using time-dependent dynamics of refractive index changes in LiNbO3.
We present a method for optical encryption of information, based on the time-dependent dynamics of writing and erasure of refractive index changes in a bulk lithium niobate medium. Information is written into the photorefractive crystal with a spatially amplitude-modulated laser beam which when overexposed significantly degrades the stored data making it unrecognizable. We show that the degradation can be reversed and that a one-to-one relationship exists between the degradation and recovery rates. It is shown that this simple relationship can be used to determine the erasure time required for decrypting the scrambled index patterns. In addition, this method could be used as a straightforward general technique for determining characteristic writing and erasure rates in photorefractive media.


Pediatric Moyamoya disease.
Moyamoya disease (MMD) is a progressive cerebrovascular occlusive disease of the bilateral internal carotid arteries that leads to a compensatory abnormal vascular network at the base of the brain. Its average annual incidence 0.54 per 100,000 population but it is the most common pediatric cerebrovascular disease in East Asia. The reported incidence in USA is approximately 0.086 per 100,000 patients. We present a case of Moyamoya disease that was to detected in a 7-year-old female who presented with transient altered mental status. Moyamoya disease can be diagnosed if history, physical exam and brain imaging is highly suspicious. Conventional angiography remains the gold standard for diagnosis and aids in surgical planning for patients with suspected Moyamoya disease.


Update on Acinetobacter species: mechanisms of antimicrobial resistance and contemporary in vitro activity of minocycline and other treatment options.
Among Acinetobacter species, A. baumannii and other closely related species are commonly implicated in nosocomial infections. These organisms are usually multidrug resistant (MDR), and therapeutic options to treat A. baumannii infections are very limited. Clinicians have been resorting to older antimicrobial agents to treat infections caused by MDR A. baumannii, and some of these agents have documented toxicity and/or are not optimized for the infection type to be treated. Recent clinical experience supported by antimicrobial susceptibility data suggests that minocycline has greater activity than other tetracyclines and glycylcyclines against various MDR pathogens that have limited therapeutic options available, including Acinetobacter species. An intravenous formulation of minocycline has recently become available for clinical use, and in contrast to most older tetracyclines, minocycline has high activity against Acinetobacter species. In this report, we summarized some of the characteristics of the tetracycline class, and quantified the minocycline activity against contemporary (2007-2011) isolates and its potential therapeutic role against a collection of 5477 A. baumannii and other relevant gram-negative organisms when compared directly with tetracycline, doxycycline, and other broad-spectrum antimicrobial agents. Acinetobacter baumannii strains were highly resistant to all agents tested, with the exception of minocycline (79.1% susceptible) and colistin (98.8% susceptible). Minocycline (minimum inhibitory concentration that inhibits 50% and 90% of the isolates [MIC(50/90)]: 1/8 µg/mL) displayed greater activity than doxycycline (MIC(50/90): 2/>8 µg/mL) and tetracycline hydrochloride (HCL) (only 30.2% susceptible) against A. baumannii isolates, and was significantly more active than other tetracyclines against Burkholderia cepacia, Escherichia coli, Serratia marcescens, and Stenotrophomonas maltophilia isolates. In vitro susceptibility testing using tetracycline HCL as a surrogate for the susceptibility other tetracyclines fails to detect minocycline-susceptible isolates and the potential utility of minocycline for the treatment of many MDR A. baumannii infections and other difficult-to-treat species, where there are often limited choices of antimicrobials.


Identification of a major determinant for serine-threonine kinase phosphoacceptor specificity.
Eukaryotic protein kinases are generally classified as being either tyrosine or serine-threonine specific. Though not evident from inspection of their primary sequences, many serine-threonine kinases display a significant preference for serine or threonine as the phosphoacceptor residue. Here we show that a residue located in the kinase activation segment, which we term the "DFG+1" residue, acts as a major determinant for serine-threonine phosphorylation site specificity. Mutation of this residue was sufficient to switch the phosphorylation site preference for multiple kinases, including the serine-specific kinase PAK4 and the threonine-specific kinase MST4. Kinetic analysis of peptide substrate phosphorylation and crystal structures of PAK4-peptide complexes suggested that phosphoacceptor residue preference is not mediated by stronger binding of the favored substrate. Rather, favored kinase-phosphoacceptor combinations likely promote a conformation optimal for catalysis. Understanding the rules governing kinase phosphoacceptor preference allows kinases to be classified as serine or threonine specific based on their sequence.


Health assessment of patients with achondroplasia, pseudoachondroplasia, and rickets based on 3D non-linear diagnostics.
The goal of this study was to analyze diminishment of the functional status of the skeleton, parts of organs, regions of the brain, connective tissues, and chondrocytes in patients with achondroplasia (ACH), pseudoachondroplasia (PSACH), and rickets. Three-dimensional non-linear scanning (3D-NLS) was used to analyze the functional status of patients with genetic bone disorders, including 7 patients with ACH, 3 patients with PSACH, and 3 patients with rickets. Results indicated that the percentage of patients with long bones in the decompensatory phase did not differ depending on whether they had ACH, PSACH, or rickets. Joints in the decompensatory phase did not differ in patients with ACH except for the right hip (16.67%). Various joints were in the decompensatory phase (16.7-33.3%) in patients with rickets. The thoracic vertebrae, lumbar vertebrae, and liver were in the decompensatory phase in all 3 groups of patients. Connective tissues were in the decompensatory phase in 33.33% of patients with ACH. None of the patients with PSACH had chondrocytes in the decompensatory phase but 66.67% of patients with ACH or rickets did. Regions of the brain in the decompensatory phase were most prevalent in patients with rickets or ACH but not in patients with PSACH. In conclusion, diagnosis based on 3D-NLS was able to identify the functional status of genetic bone disorders. Some areas of decompensation were common to the 3 diseases studied but other areas were specific to a given disease.


Efficacy of second-line treatment and importance of comorbidity scores and clinical parameters affecting prognosis in elderly patients with non-small cell lung cancer without epidermal growth factor receptor mutations.
The present study investigated the importance of comorbidity scores and clinical parameters in elderly patients with non-small cell lung cancer (NSCLC) not harboring epidermal growth factor receptor (EGFR) mutations who received second-line chemotherapy. The present study also compared the efficacy of tyrosine kinase inhibitor and cytotoxic chemotherapy as second-line treatment in elderly patients. The present study retrospectively reviewed the treatment of elderly patients with NSCLC (≥70 years old) who received second-line chemotherapy at Korea University Guro Hospital. Patients who had an EGFR mutation were excluded from the analysis. Between 2005 and 2013, 126 patients were included in the present study. The median progression-free survival (PFS) and overall survival (OS) for all patients who received second-line treatment were 2.47 months [95% confidence interval (CI), 2.08-2.86] and 8.63 months (95% CI, 5.99-11.28), respectively. A total of 52 patients (41.3%) were treated with tyrosine kinase inhibitor (TKI) and 74 (58.7%) were treated with chemotherapy. No difference was observed in the median PFS and OS between the TKI and chemotherapy groups (P=0.287 for PFS and P=0.374 for OS). The Charlson comorbidity index was not associated with survival, whereas a simplified comorbidity score and clinical factors, including poor performance status, short PFS of first-line chemotherapy, presence of brain metastasis and low serum albumin and sodium levels were significant prognostic factors in these elderly patients. Second-line chemotherapy was not beneficial to patients who had at least 3 of these factors and a median OS of 1.73 months, whereas patients who had less than 2 of these factors had a median OS of 11.50 months. For elderly lung cancer patients without EGFR mutations, clinical parameters were the most important factors affecting survival, rather than the types of drugs.


Replication of individual DNA molecules under electronic control using a protein nanopore.
Nanopores can be used to analyse DNA by monitoring ion currents as individual strands are captured and driven through the pore in single file by an applied voltage. Here, we show that serial replication of individual DNA templates can be achieved by DNA polymerases held at the α-haemolysin nanopore orifice. Replication is blocked in the bulk phase, and is initiated only after the DNA is captured by the nanopore. We used this method, in concert with active voltage control, to observe DNA replication catalysed by bacteriophage T7 DNA polymerase (T7DNAP) and by the Klenow fragment of DNA polymerase I (KF). T7DNAP advanced on a DNA template against an 80-mV load applied across the nanopore, and single nucleotide additions were measured on the millisecond timescale for hundreds of individual DNA molecules in series. Replication by KF was not observed when this enzyme was held on top of the nanopore orifice at an applied potential of 80 mV. Sequential nucleotide additions by KF were observed upon applying controlled voltage reversals.


Cranial myology and bite force performance of Erlikosaurus andrewsi: a novel approach for digital muscle reconstructions.
The estimation of bite force and bite performance in fossil and extinct animals is a challenging subject in palaeontology and is highly dependent on the reconstruction of the cranial myology. Furthermore, the morphology and arrangement of the adductor muscles considerably affect feeding processes and mastication and thus also have important dietary and ecological ramifications. However, in the past, the reconstruction of the (cranial) muscles was restricted to the identification of muscle attachment sites or simplified computer models. This study presents a detailed reconstruction of the adductor musculature of the Cretaceous therizinosaur Erlikosaurus andrewsi based on a stepwise and iterative approach. The detailed, three-dimensional models of the individual muscles allow for more accurate measurements of the muscle properties (length, cross-section, attachment angle and volume), from which muscle and bite force estimates are calculated. Bite force estimations are found to be the lowest at the tip of the snout (43-65 N) and respectively higher at the first (59-88 N) and last tooth (90-134 N) position. Nevertheless, bite forces are comparatively low for E. andrewsi, both in actual numbers as well as in comparison with other theropod dinosaurs. The results further indicate that the low bite performance was mainly used for leaf-stripping and plant cropping, rather than active mastication or chewing processes. Muscle and thus bite force in E. andrewsi (and most likely all therizinosaurs) is considerably constrained by the cranial anatomy and declines in derived taxa of this clade. This trend is reflected in the changes of dietary preferences from carnivory to herbivory in therizinosaurs.


In situ observation of oscillatory growth of bismuth nanoparticles.
We study the growth of Bi nanoparticles in an engineered precursor-scarce environment in a liquid cell at an elevated temperature (180 °C) using transmission electron microscopy. Observation reveals dynamics of oscillatory growth of individual nanoparticles, pairwise Ostwald ripening and anti-Ostwald ripening and a global collective oscillation. The experimental results suggest a mass-transport zone is present around each particle, which couples to the observed growth kinetics. This study shed light on a new route for system engineering to reverse particle coursing by Ostwald ripening.


HOXA1 is overexpressed in oral squamous cell carcinomas and its expression is correlated with poor prognosis.
HOX genes encode homeodomain-containing transcription factors involved in the regulation of cellular proliferation and differentiation during embryogenesis. However, members of this family demonstrated oncogenic properties in some malignancies. The present study investigated whether genes of the HOXA cluster play a role in oral cancer. In order to identify differentially expressed HOXA genes, duplex RT-PCR in oral samples from healthy mucosa and squamous cell carcinoma was used. The effects of HOXA1 on proliferation, apoptosis, adhesion, invasion, epithelial-mesenchymal transition (EMT) and anchorage-independent growth were assessed in cells with up- and down-regulation of HOXA1. Immunohistochemical analysis using a tissue microarray (TMA) containing 127 oral squamous cell carcinomas (OSCC) was performed to determine the prognostic role of HOXA1 expression. We showed that transcripts of HOXA genes are more abundant in OSCC than in healthy oral mucosa. In particular, HOXA1, which has been described as one of the HOX members that plays an important role in tumorigenesis, was significantly more expressed in OSCCs compared to healthy oral mucosas. Further analysis demonstrated that overexpression of HOXA1 in HaCAT human epithelial cells promotes proliferation, whereas downregulation of HOXA1 in human OSCC cells (SCC9 cells) decreases it. Enforced HOXA1 expression in HaCAT cells was not capable of modulating other events related to tumorigenesis, including apoptosis, adhesion, invasion, EMT and anchorage-independent growth. A high number of HOXA1-positive cells was significantly associated with T stage, N stage, tumor differentiation and proliferative potential of the tumors, and was predictive of poor survival. In multivariate analysis, HOXA1 was an independent prognostic factor for OSCC patients (HR: 2.68; 95% CI: 1.59-2.97; p = 0.026). Our findings indicate that HOXA1 may contribute to oral carcinogenesis by increasing tumor cell proliferation, and suggest that HOXA1 expression might be helpful as a prognostic marker for patients with OSCC.


Extraction behaviour and mechanism of Pt(iv) and Pd(ii) by liquid-liquid extraction with an ionic liquid [HBBIm]Br.
In this study, a method of one-step separation and recycling of high purity Pd(ii) and Pt(iv) using an ionic liquid, 1-butyl-3-benzimidazolium bromate ([HBBIm]Br), was investigated. The effects of [HBBIm]Br concentration, initial metal concentration, and loading capacity of [HBBIm]Br were examined in detail. It was observed that [HBBIm]Br was a very effective extractant for selectively extracting Pd(ii) and precipitating Pt(iv). Through selectively extracting Pd(ii) and precipitating Pt(iv), each metal with high purity was separately obtained from mixed Pd(ii) and Pt(iv) multi-metal solution. The method of one-step separation of Pd(ii) and Pt(iv) is simple and convenient. The anion exchange mechanism between [HBBIm]Br and Pt(iv) was proven through Job's method and FTIR and 1H NMR spectroscopies. The coordination mechanism between [HBBIm]Br and Pd(ii) was demonstrated via single X-ray diffraction and was found to be robust and distinct, as supported by the ab initio quantum-chemical studies. The crystals of the [PdBr2 ·2BBIm] complex were formed first. Moreover, the influence of the concentrations of hydrochloric acid, sodium chloride, and sodium nitrate on the precipitation of Pt(iv) and extraction of Pd(ii) was studied herein. It was found that only the concentration of H+ could inhibit the separation of Pt(iv) because H+ could attract the anion PtCl62-; thus, the exchange (anion exchange mechanism) between the anions PtCl62- and Br- was prevented. However, both the concentration of H+ and Cl- can obviously inhibit the extraction of Pd(ii) because H+ and Cl- are the reaction products and increasing their concentration can inhibit the progress of the reaction (coordination mechanism).


Safety and efficacy of chloral hydrate for procedural sedation in paediatric ophthalmology: a systematic review and meta-analysis.
Although chloral hydrate (CH) has been used as a sedative for decades, it is not widely accepted as a valid choice for ophthalmic examinations in uncooperative children. This study aimed to systematically review the literature on the drug's safety and efficacy. We searched PubMed, EMBASE, ISI Web of Science, Scopus, CENTRAL, Google Scholar and Trip database to 1 October 2015, using the keywords 'chloral hydrate', 'paediatric' and 'procedural sedation OR diagnostic sedation'. A meta-analysis of randomised controlled trials (RCTs) was performed. A total of 6961 articles were screened and 104 were included in the review. Thirteen of these concerned paediatric ophthalmic examination, while 13 others were RCTs and were meta-analysed. CH was reported to have been administered in a total of 24 265 sedation episodes in children aged from <1 month to 18 years. The meta-analysis showed CH had a higher OR (2.95, 95% CI 1.09 to 7.99) for successful sedation compared to other sedatives, but significant limitations apply. The commonest reported adverse events (AE) were not serious (eg, paradoxical reaction or transient vomiting) and required no intervention. Severe AE, including two deaths, were related to comorbidity, overdose or aspiration. Despite the paucity of high quality evidence, the existing literature suggests that the use of CH for procedural sedation in children appears to be an effective alternative to general anaesthesia, and it can be safe when administered in the hospital setting with appropriate monitoring and vigilance for intervention.


The health care crisis: impact on surgery in the community hospital setting.
Hospitals and health systems across the United States are in crisis. The causes of this crisis are multiple, and they reflect the interplay among reduced operating margins, workforce issues, the technology explosion, consumerism, and leadership. They affect hospitals of every type and location. In aggregate, they profoundly influence our trifold mission of patient care, education, and research. Departments of surgery have a disproportionate effect on hospital financial viability, and therefore, surgical leaders must work with other clinical and administrative leaders to manage these issues. This article is a personal view of how this crisis has affected our community-based academic medical center, William Beaumont Hospital, Royal Oak, Mich.


GISS-E2.1: Configurations and Climatology.
This paper describes the GISS-E2.1 contribution to the Coupled Model Intercomparison Project, Phase 6 (CMIP6). This model version differs from the predecessor model (GISS-E2) chiefly due to parameterization improvements to the atmospheric and ocean model components, while keeping atmospheric resolution the same. Model skill when compared to modern era climatologies is significantly higher than in previous versions. Additionally, updates in forcings have a material impact on the results. In particular, there have been specific improvements in representations of modes of variability (such as the Madden-Julian Oscillation and other modes in the Pacific) and significant improvements in the simulation of the climate of the Southern Oceans, including sea ice. The effective climate sensitivity to 2 × CO2 is slightly higher than previously at 2.7-3.1°C (depending on version) and is a result of lower CO2 radiative forcing and stronger positive feedbacks.


RACBVHs: random-accessible compressed bounding volume hierarchies.
We present a novel compressed bounding volume hierarchy (BVH) representation, random-accessible compressed bounding volume hierarchies (RACBVHs), for various applications requiring random access on BVHs of massive models. Our RACBVH representation is compact and transparently supports random access on the compressed BVHs without decompressing the whole BVH. To support random access on our compressed BVHs, we decompose a BVH into a set of clusters. Each cluster contains consecutive bounding volume (BV) nodes in the original layout of the BVH. Also, each cluster is compressed separately from other clusters and serves as an access point to the RACBVH representation. We provide the general BVH access API to transparently access our RACBVH representation. At runtime, our decompression framework is guaranteed to provide correct BV nodes without decompressing the whole BVH. Also, our method is extended to support parallel random access that can utilize the multicore CPU architecture. Our method can achieve up to a 12:1 compression ratio, and more importantly, can decompress 4.2 M BV nodes ({=}135 {\rm MB}) per second by using a single CPU-core. To highlight the benefits of our approach, we apply our method to two different applications: ray tracing and collision detection. We can improve the runtime performance by more than a factor of 4 as compared to using the uncompressed original data. This improvement is a result of the fast decompression performance and reduced data access time by selectively fetching and decompressing small regions of the compressed BVHs requested by applications.


Lyb-2 system of mouse B cells. Evidence for a role in the generation of antibody-forming cells.
The Lyb-2 cell-surface alloantigens of the mouse are selectively and perhaps exclusively expressed in the B lymphocyte lineage, but not on antibody- forming cells. Thus if the Lyb-2 molecule is concerned in specific B cell function, it must participate in the generative phase of the antibody response. Accordingly, monoclonal Lyb-2 antibody was found to depress the plaque- forming cell (PFC) response to sheep erythrocytes in 5-d Mishell-Dutton assays when added within the first 3 d of culture, but not later. The rate of PFC generation was not affected, signifying an absolute reduction in the number of PFC generated. Because reduction of PFC counts by Lyb-2 antibody was not affected by exclusion of Lyt-2(+) T cells, it is unlikely that the reduction depends on augmented suppression by T cells. Augmented B cell- mediated suppression is also unlikely, because the PFC response of serial combinations of congenic Lyb-2.1 and Lyb-2.2 cells, in the presence of monoclonal Lyb-2.1 antibody, was reduced only in direct proportion to the number of Lyb-2.1 cells present. The PFC response of Lyb-2.1/Lyb-2.2 heterozygous cells was not reduced by Lyb-2.1 antibody, presumably because generation of PFC is impeded only if most Lyb-2 sites are blocked. Further evidence that the molecule identified by Lyb-2 plays a critical role in the generation of antibody-forming cells (AFC) in response to T-dependent antigen comes from the finding that Lyb-2 antibody does not reduce the PFC response to the T-independent antigens trinitrophenylated (TNP) Brucella abortus and TNP-FicolI, although elimination of Lyb-2(+) cells from the starting population by Lyb-2 antibody and complement reduces the PFC response to T- dependent and T-independent antigens alike.


miR-34 is associated with poor prognosis of patients with gallbladder cancer through regulating telomere length in tumor stem cells.
miR-34a has been identified as a tumor suppressor in several tumors, but its involvement in gallbladder cancer (GBC) has not been reported. In this study, the miR-34a level and telomere length were measured in 77 gallbladder adenocarcinomas and 36 peritumoral tissues by real-time PCR. Forced miR-34a expression was established by an adenovirus carrying a miR-34a expression cassette. The colony-forming ability of isolated CD44+CD133+ GBC tumor stem-like cells was measured by matrigel colony assay. The xenograft tumor models were established by inoculating nude mice with CD44+CD133+cells. Results showed that significantly lower miR-34a expression and longer telomere length were observed in gallbladder adenocarcinoma tissues, which correlated with poor prognosis of GBC patients. Forced overexpression of miR-34a inhibited the colony-forming ability of CD44+CD133+ GBC tumor stem-like cells in vitro and xenograft tumor growth in vivo. Injection of Ad-miR-34a downregulated PNUTS expression and reduced telomere length in xenograft GBC tumor cells. In conclusion, miR-34a is a tumor suppressor in gallbladder cancer. Both low miR-34a expression and long telomere length are markers for poor prognosis of patients with gallbladder adenocarcinoma. Our study also suggests that the miR-34a gene could be a target for targeting therapy of GBC.


Immunosuppressive drug therapy for preventing rejection following lung transplantation in cystic fibrosis.
For patients with cystic fibrosis and advanced pulmonary damage, lung transplantation is an available and viable option. However, graft rejection is an important potential consequence after lung transplantation. Immunosuppressive therapy is needed to prevent episodes of graft rejection and thus subsequently reduce morbidity and mortality in this population. There are a number of classes of immunosuppressive drugs which act on different components of the immune system. There is considerable variability in the use of immunosuppressive agents after lung transplantation in cystic fibrosis. While much of the research in immunosuppressive drug therapy has focused on the general population of lung transplant recipients, little is known about the comparative effectiveness and safety of these agents in patients with cystic fibrosis. To assess the effects of individual drugs or combinations of drugs compared to placebo or other individual drugs or combinations of drugs in preventing rejection following lung transplantation in patients with cystic fibrosis. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register and scanned references of the potentially eligible study. We also searched the www.clinicaltrials.gov trials registry to obtain information on unpublished and ongoing studies.Date of latest search: 22 August 2013. Randomised and quasi-randomised studies. We independently assessed the studies identified from our searches for inclusion in the review. Should eligible studies be identified and included in future updates of the review, we will independently extract data and assess the risk of bias. While two studies met our inclusion criteria, we did not include them in the review because the investigators of the studies did not report any information specific to patients with cystic fibrosis. Our attempts to obtain this information have not yet been successful. We will include any provided data in future updates of the review. The lack of currently available evidence makes it impossible to make conclusions about the comparative efficacy and safety of the various immunosuppressive drugs among patients with cystic fibrosis after lung transplantation. A recent Cochrane review comparing tacrolimus with cyclosporine in all patients with lung transplantation (not restricted to patients with cystic fibrosis) reported no significant difference in mortality and risk of acute rejection. However, tacrolimus use was associated with lower risk of broncholitis obliterans syndrome and arterial hypertension and higher risk of diabetes mellitus. It should be noted that this review contained only a small number of included studies (n = 3) with a high risk of bias. Additional randomised studies are required to provide evidence for the benefit and safety of the use of immunosuppressive therapy among patients with cystic fibrosis after lung transplantation.


Objectively quantified physical activity in persons with multiple sclerosis.
To investigate levels of moderate-to-vigorous physical activity (MVPA) in a large sample of persons with multiple sclerosis (MS) and controls using accelerometry as a measure of physical activity, and to compare the rates of meeting public health guidelines for MVPA (ie, 30min/d) between persons with MS and controls. Secondary analysis of a combined data set of persons with MS and healthy controls from 13 previous investigations of physical activity over a 8-year period (2005-2013). University. Participants with MS (n=800) were recruited primarily within Illinois through multiple sources, including print and e-mail flyers and an online advertisement on the National Multiple Sclerosis Society website. Healthy controls (n=137) were recruited via public e-mail postings delivered across the university community. Not applicable. Levels of MVPA and meeting public health guidelines for MVPA between persons with MS and controls. After controlling for covariates (ie, age, sex, education, race, income), there was a moderate (d=.68) and statistically significant (F=47.2, P<.001) difference of 13.1 minutes of MVPA per day (95% confidence interval, 9.4-16.8) between MS and controls. There was a difference in the rates of meeting public health guidelines for MVPA (χ(2)=50.7, P<.001) between MS patients (20%) and controls (47%). Among those with MS, minutes of MVPA significantly differed as a function of education, employment status, clinical course, disease duration, and disability status. We provide data using an objective physical activity measure and a large sample to indicate that only a small proportion of persons with MS are achieving adequate amounts of daily MVPA.


A seven-year epidemiology study of 12,381 admitted burn patients in Taiwan--using the Internet registration system of the Childhood Burn Foundation.
This study described the epidemiological characteristics of the 12,381 admitted burn patients in Taiwan. The data was from 43 contracted hospitals of the Childhood Burn Foundation, in the years from 1997 to 2003. This descriptive study included 8172 males and 4206 females, with a male to female ratio of 1.94 and an average age of 29.3 years. There were 3993 (33.4%) patients under 18 years old; and 26.4% of the patients were children under 7 years old. First and second years of life were the peak of incidence. The mean extent of burn was 14.0% total body surface area with 950 patients (7.7%) suffering from a burn extent >/=40% TBSA. Scalds resulted in 5085 admissions (43.2%) and flame burns accounted for 3825 admissions (32.5%). In patient group under 18 years old, 76.8% were scald burn and 14.1% were flame burn. The majority of the burn injuries (53.3%) occurred in the dwelling place; 1122 patients had inhalation injuries and required admission to the burn center for pulmonary support. In addition, suicide attempts were recorded in 2.4% (300 cases) of all burn patients with a mean burn size of 40.7% total body surface and mortality rate of 29.3%. The overall mortality rate is 381 out of 12,381 patients (3.1%). The LA(50) was around 80% TBSA. The significant effects of risk factors, such as old age, large burn extent, combined inhalation injury and suicide were demonstrated. Adequate first aid by water cooling affected the outcome of the patient group with burn extent less than 30% TBSA, which was shown by the decrease of length of stay. These results showed some unique distributions that reflected certain socio-economic and cultural background of Taiwan.


Participants' experiences of music, mindful music, and audiobook listening interventions for people recovering from stroke.
Existing research evidence suggests that both music listening and mindfulness interventions may have beneficial effects on mood and cognition poststroke. This mixed-methods study, nested within a pilot randomized controlled trial investigating the feasibility and acceptability of combining music listening and brief mindfulness training poststroke, explored study participants' experiences of engaging in the interventions. Fifty-six stroke survivors who were randomized to receive an 8-week intervention of mindful music listening (n = 15), music listening (n = 21), or audiobook listening (n = 20, control) using self-selected material participated in a postintervention individual semistructured interview with a researcher not involved in their intervention delivery. Interview questions focused on affective, cognitive, and physical experiences. Data were coded and analyzed using thematic analysis. Across groups, listening was associated with positive distraction from thoughts and worries. Mindful music listening was most strongly associated with relaxation and concentration, improved attentional control, and emotion regulation, as well as enjoyment. Music listening was most strongly associated with increased activity, memory reminiscence, and improved mood. In addition, participants provided valuable feedback on intervention feasibility and acceptability. The findings suggest that the interventions were feasible and enjoyable for people recovering from stroke.