Temperature- and solvation-dependent dynamics of liquid sulfur dioxide studied through the ultrafast optical Kerr effect.
The ultrafast dynamics of liquid sulphur dioxide have been studied over a wide temperature range and in solution. The optically heterodyne-detected and spatially masked optical Kerr effect (OKE) has been used to record the anisotropic and isotropic third-order responses, respectively. Analysis of the anisotropic response reveals two components, an ultrafast nonexponential relaxation and a slower exponential relaxation. The slower component is well described by the Stokes-Einstein-Debye equation for diffusive orientational relaxation. The simple form of the temperature dependence and the agreement between collective (OKE) and single molecule (e.g., NMR) measurements of the orientational relaxation time suggests that orientational pair correlation is not significant in this liquid. The relative contributions of intermolecular interaction-induced and single-molecule orientational dynamics to the ultrafast part of the spectral density are discussed. Single-molecule librational-orientational dynamics appear to dominate the ultrafast OKE response of liquid SO2. The temperature-dependent OKE data are transformed to the frequency domain to yield the Raman spectral density for the low-frequency intermolecular modes. These are bimodal with the lowest-frequency component arising from diffusive orientational relaxation and a higher-frequency component connected with the ultrafast time-domain response. This component is characterized by a shift to higher frequency at lower temperature. This result is analyzed in terms of a harmonic librational oscillator model, which describes the data accurately. The observed spectral shifts with temperature are ascribed to increasing intermolecular interactions with increasing liquid density. Overall, the dynamics of liquid SO2 are found to be well described in terms of molecular orientational relaxation which is controlled over every relevant time range by intermolecular interactions.


Brain-computer interface research comes of age: traditional assumptions meet emerging realities.
Brain-computer interfaces (BCIs) could provide important new communication and control options for people with severe motor disabilities. Most BCI research to date has been based on 4 assumptions that: (a) intended actions are fully represented in the cerebral cortex; (b) neuronal action potentials can provide the best picture of an intended action; (c) the best BCI is one that records action potentials and decodes them; and (d) ongoing mutual adaptation by the BCI user and the BCI system is not very important. In reality, none of these assumptions is presently defensible. Intended actions are the products of many areas, from the cortex to the spinal cord, and the contributions of each area change continually as the CNS adapts to optimize performance. BCIs must track and guide these adaptations if they are to achieve and maintain good performance. Furthermore, it is not yet clear which category of brain signals will prove most effective for BCI applications. In human studies to date, low-resolution electroencephalography-based BCIs perform as well as high-resolution cortical neuron-based BCIs. In sum, BCIs allow their users to develop new skills in which the users control brain signals rather than muscles. Thus, the central task of BCI research is to determine which brain signals users can best control, to maximize that control, and to translate it accurately and reliably into actions that accomplish the users' intentions.


Spatial assessment of attitudes toward tigers in Nepal.
In many regions around the world, wildlife impacts on people (e.g., crop raiding, attacks on people) engender negative attitudes toward wildlife. Negative attitudes predict behaviors that undermine wildlife management and conservation efforts (e.g., by exacerbating retaliatory killing of wildlife). Our study (1) evaluated attitudes of local people toward the globally endangered tiger (Panthera tigris) in Nepal's Chitwan National Park; and (2) modeled and mapped spatial clusters of attitudes toward tigers. Factors characterizing a person's position in society (i.e., socioeconomic and cultural factors) influenced attitudes toward tigers more than past experiences with tigers (e.g., livestock attacks). A spatial cluster of negative attitudes toward tigers was associated with concentrations of people with less formal education, people from marginalized ethnic groups, and tiger attacks on people. Our study provides insights and descriptions of techniques to improve attitudes toward wildlife in Chitwan and many regions around the world with similar conservation challenges.


Effect of 3-nitrooxypropanol on methane and hydrogen emissions, methane isotopic signature, and ruminal fermentation in dairy cows.
The objective of this crossover experiment was to investigate the effect of a methane inhibitor, 3-nitrooxypropanol (3NOP), on enteric methane emission, methane isotopic composition, and rumen fermentation and microbial profile in lactating dairy cows. The experiment involved 6 ruminally cannulated late-lactation Holstein cows assigned to 2 treatments: control and 3NOP (60 mg/kg of feed dry matter). Compared with the control, 3NOP decreased methane emission by 31% and increased hydrogen emission from undetectable to 1.33 g/d. Methane emissions per kilogram of dry matter intake and milk yield were also decreased 34% by 3NOP. Milk production and composition were not affected by 3NOP, except milk fat concentration was increased compared with the control. Concentrations of total VFA and propionate in ruminal fluid were not affected by treatment, but acetate concentration tended to be lower and acetate-to-propionate ratio was lower for 3NOP compared with the control. The 3NOP decreased the molar proportion of acetate and increase those of propionate, butyrate, valerate, and isovalerate. Deuterium-to-hydrogen ratios of methane and the abundance of (13)CH3D were similar between treatments. Compared with the control, minor (4‰) depletion in the (13)C/(12)C ratio was observed for 3NOP. Genus composition of methanogenic archaea (Methanobrevibacter, Methanosphaera, and Methanomicrobium) was not affected by 3NOP, but the proportion of methanogens in the total cell counts tended to be decreased by 3NOP. Prevotella spp., the predominant bacterial genus in ruminal contents in this experiment, was also not affected by 3NOP. Compared with the control, Ruminococcus and Clostridium spp. were decreased and Butyrivibrio spp. was increased by 3NOP. This experiment demonstrated that a substantial inhibition of enteric methane emission by 3NOP in dairy cows was accompanied with increased hydrogen emission and decreased acetate-to-propionate ratio; however, neither an effect on rumen archaeal community composition nor a significant change in the isotope composition of methane was observed.


The C-terminal extension landscape of naturally presented HLA-I ligands.
HLA-I molecules play a central role in antigen presentation. They typically bind 9- to 12-mer peptides, and their canonical binding mode involves anchor residues at the second and last positions of their ligands. To investigate potential noncanonical binding modes, we collected in-depth and accurate HLA peptidomics datasets covering 54 HLA-I alleles and developed algorithms to analyze these data. Our results reveal frequent (442 unique peptides) and statistically significant C-terminal extensions for at least eight alleles, including the common HLA-A03:01, HLA-A31:01, and HLA-A68:01. High resolution crystal structure of HLA-A68:01 with such a ligand uncovers structural changes taking place to accommodate C-terminal extensions and helps unraveling sequence and structural properties predictive of the presence of these extensions. Scanning viral proteomes with the C-terminal extension motifs identifies many putative epitopes and we demonstrate direct recognition by human CD8+ T cells of a 10-mer epitope from cytomegalovirus predicted to follow the C-terminal extension binding mode.


Protein feeding pattern, casein feeding, or milk-soluble protein feeding did not change the evolution of body composition during a short-term weight loss program.
Studies have shown that timing of protein intake, leucine content, and speed of digestion significantly affect postprandial protein utilization. Our aim was to determine if one can spare lean body mass during energy restriction by varying the quality and the timing of protein intake. Obese volunteers followed a 6-wk restricted energy diet. Four groups were compared: casein pulse, casein spread, milk-soluble protein (MSP, = whey) pulse, and MSP spread (n = 10-11 per group). In casein groups, caseins were the only protein source; it was MSP in MSP groups. Proteins were distributed in four meals per day in the proportion 8:80:4:8% in the pulse groups; it was 25:25:25:25% in the spread groups. We measured weight, body composition, nitrogen balance, 3-methylhistidine excretion, perception of hunger, plasma parameters, adipose tissue metabolism, and whole body protein metabolism. Volunteers lost 7.5 ± 0.4 kg of weight, 5.1 ± 0.2 kg of fat, and 2.2 ± 0.2 kg of lean mass, with no difference between groups. In adipose tissue, cell size and mRNA expression of various genes were reduced with no difference between groups. Hunger perception was also never different between groups. In the last week, due to a higher inhibition of protein degradation and despite a lower stimulation of protein synthesis, postprandial balance between whole body protein synthesis and degradation was better with caseins than with MSP. It seems likely that the positive effect of caseins on protein balance occurred only at the end of the experiment.


SABRE is required for stabilization of root hair patterning in Arabidopsis thaliana.
Patterned differentiation of distinct cell types is essential for the development of multicellular organisms. The root epidermis of Arabidopsis thaliana is composed of alternating files of root hair and non-hair cells and represents a model system for studying the control of cell-fate acquisition. Epidermal cell fate is regulated by a network of genes that translate positional information from the underlying cortical cell layer into a specific pattern of differentiated cells. While much is known about the genes of this network, new players continue to be discovered. Here we show that the SABRE (SAB) gene, known to mediate microtubule organization, anisotropic cell growth and planar polarity, has an effect on root epidermal hair cell patterning. Loss of SAB function results in ectopic root hair formation and destabilizes the expression of cell fate and differentiation markers in the root epidermis, including expression of the WEREWOLF (WER) and GLABRA2 (GL2) genes. Double mutant analysis reveal that wer and caprice (cpc) mutants, defective in core components of the epidermal patterning pathway, genetically interact with sab. This suggests that SAB may act on epidermal patterning upstream of WER and CPC. Hence, we provide evidence for a role of SAB in root epidermal patterning by affecting cell-fate stabilization. Our work opens the door for future studies addressing SAB-dependent functions of the cytoskeleton during root epidermal patterning.


Transcriptomic signatures of schizophrenia revealed by dopamine perturbation in an ex vivo model.
The dopaminergic hypothesis of schizophrenia (SZ) postulates that dopaminergic over activity causes psychosis, a central feature of SZ, based on the observation that blocking dopamine (DA) improves psychotic symptoms. DA is known to have both receptor- and non-receptor-mediated effects, including oxidative mechanisms that lead to apoptosis. The role of DA-mediated oxidative processes in SZ has been little studied. Here, we have used a cell perturbation approach and measured transcriptomic profiles by RNAseq to study the effect of DA exposure on transcription in B-cell transformed lymphoblastoid cell lines (LCLs) from 514 SZ cases and 690 controls. We found that DA had widespread effects on both cell growth and gene expression in LCLs. Overall, 1455 genes showed statistically significant differential DA response in SZ cases and controls. This set of differentially expressed genes is enriched for brain expression and for functions related to immune processes and apoptosis, suggesting that DA may play a role in SZ pathogenesis through modulating those systems. Moreover, we observed a non-significant enrichment of genes near genome-wide significant SZ loci and with genes spanned by SZ-associated copy number variants (CNVs), which suggests convergent pathogenic mechanisms detected by both genetic association and gene expression. The study suggests a novel role of DA in the biological processes of immune and apoptosis that may be relevant to SZ pathogenesis. Furthermore, our results show the utility of pathophysiologically relevant perturbation experiments to investigate the biology of complex mental disorders.


Differentiation impairs low pH-induced Ca2+ signaling and ERK phosphorylation in granule precursor tumour cells.
Extracellular acidification is a hallmark of a number of debilitating pathologies including cancer, ischemia and inflammation. We have recently shown that in human granule precursor tumour cells a fall in extracellular pH triggers increases in intracellular Ca(2+) concentration through activation of G-protein coupled proton-sensing receptors coupling to phospholipase C. This pH-dependent rise in cytosolic Ca(2+) led to activation of the extracellular signal-regulated kinase ERK, providing a mechanistic explanation of how extracellular acidification can promote tumour growth. We now find that differentiation of granule precursor tumour cells profoundly affects their ability to respond to extracellular acidification with gene transcription. Differentiating cells have a lower Ca(2+) release probability from intracellular Ca(2+) stores upon acidification and cells that respond have a significantly smaller and slower Ca(2+) signal than proliferating cells. Importantly, Ca(2+) release in differentiating cells fails to evoke ERK phosphorylation. This altered responsiveness of differentiating cells is not due to reduced proton-sensing receptor expression or diminished Ca(2+) store content. Rather, our results suggest that in differentiating cells, the proton-sensing receptor couples less effectively to phospholipase C activation and IP(3) formation. Hence, the ability of human granule cells to respond to extracellular acidification by generating Ca(2+) signals and ERK activation is state-dependent, being lost upon differentiation.


A Framework to Prioritize the Public Expectations from Water Treatment Plants based on Trapezoidal Type-2 Fuzzy Ahp Method.
Water treatment plants play a major role in the cycle of water recovery and reuse. Besides the benefits of water treatment plants, they have a great impact on the environment, social life, economy, and natural habitats. In this sense, decision-makers should effectively plan the construction and operational activities of plants, taking into account the expectations of users. Growing public expectations about water treatment plants increase the pressures on investors and government managers. In this study, we focus on defining and determining the weights of public expectations from water treatment plants and handle as a multi-criteria decision-making problem. A two-level hierarchical model is structured to evaluate public expectations from water treatment plants as model criteria. For the problem, a literature review is performed to search the main criteria. The most suitable criteria for the problem are determined using experts' opinions. Then, the sub-criteria are determined. Experts' evaluations are collected by face to face interviews. These evaluations are consolidated and finalized via the modified Delphi method. Trapezoidal Type-2 Fuzzy Analytic Hierarchy Process (T2F-AHP) is employed to determine criteria weights using results obtained by the modified Delphi method. A sensitivity analysis is performed to show the reliability of the proposed methodology. A comparison is also performed between the Analytic Hierarchy Process (AHP) and the proposed methodology. The results of this study can be used as a guide to develop public strategies about water treatment plants. Finally, conclusions and future directions of this work are given.


Treating muscular dystrophy with stem cells?
There is currently no effective treatment for the devastating muscle-wasting disease Duchenne muscular dystrophy (DMD). Cossu and colleagues report in a recent Nature paper that transplantation of mesoangioblast stem cells may hold promise for treating DMD. Further studies are required to fully evaluate the clinical potential of these blood-vessel-associated stem cells.


Congestive gastropathy in cirrhotic patients: correlation between endoscopic and histological findings.
Congestive gastropathy is a common cause of gastrointestinal bleeding in cirrhotic patients. Forty-six patients with cirrhosis of the liver and 225 control subjects matched in age and sex without cirrhosis of the liver entered the study. We studied the prevalence of congestive gastropathy in cirrhotic patients, and the relationship between endoscopic and histological findings. Congestive gastropathy seen endoscopically was found to be more common in the cirrhotic group than in the control (85% vs. 5%, P < 0.05). The sensitivity, specificity and positive predictive value were 85%, 95% and 76%, respectively. The presence of endoscopic congestive gastropathy was correlated with the severity of liver disease (P < 0.05), but not to the etiology of cirrhosis and the size of esophageal varices with or without red color sign. Endoscopic congestive gastropathy showed no correlation with the histological features including gastritis, interstitial edema, vessel ectasia/congestion and hemosiderin in endoscopic biopsy specimens. In conclusion, congestive gastropathy is a common finding in cirrhotic patients. Its appearance is closely correlated with the severity of liver disease. There is no good correlation between endoscopic congestive gastropathy and mucosal histology.


Allomermis solenopsi n. sp. (Nematoda: Mermithidae) parasitising the fire ant Solenopsis invicta Buren (Hymenoptera: Formicidae) in Argentina.
Allomermis solenopsi n. sp. (Mermithidae: Nematoda) is described from the fire ant Solenopsis invicta Buren (Hymenoptera: Formicidae) in Argentina. Diagnostic characters of the new species include stiff and erect processes on the surface of the mature egg, small female amphids, extension of the latero-medial rows of male genital papillae beyond the middle rows, an obliquely truncate spicule tip and a ventrally swollen male terminus. This is the first record of Allomermis Steiner, 1924 from South America and the first host record for members of this genus. Previous records of mermithids from Solenopsis spp. are summarised. The placement in Allomermis was confirmed by molecular analyses based on nuclear 18S ribosomal DNA sequences, the first such molecular framework for the Mermithidae. The possible life-cycle of the parasite is discussed, with the aim of using A. solenopsi as a biological control agent for fire ants in the United States.


Metabolic fate of fructose ingested with and without glucose in a mixed meal.
Ingestion of pure fructose stimulates de novo lipogenesis and gluconeogenesis. This may however not be relevant to typical nutritional situations, where fructose is invariably ingested with glucose. We therefore assessed the metabolic fate of fructose incorporated in a mixed meal without or with glucose in eight healthy volunteers. Each participant was studied over six hours after the ingestion of liquid meals containing either 13C-labelled fructose, unlabeled glucose, lipids and protein (Fr + G) or 13C-labelled fructose, lipids and protein, but without glucose (Fr), or protein and lipids alone (ProLip). After Fr + G, plasma 13C-glucose production accounted for 19.0% ± 1.5% and 13CO2 production for 32.2% ± 1.3% of 13C-fructose carbons. After Fr, 13C-glucose production (26.5% ± 1.4%) and 13CO2 production (36.6% ± 1.9%) were higher (p < 0.05) than with Fr + G. 13C-lactate concentration and very low density lipoprotein VLDL 13C-palmitate concentrations increased to the same extent with Fr + G and Fr, while chylomicron 13C-palmitate tended to increase more with Fr + G. These data indicate that gluconeogenesis, lactic acid production and both intestinal and hepatic de novo lipogenesis contributed to the disposal of fructose carbons ingested together with a mixed meal. Co-ingestion of glucose decreased fructose oxidation and gluconeogenesis and tended to increase 13C-pamitate concentration in gut-derived chylomicrons, but not in hepatic-borne VLDL-triacylglycerol (TG). This trial was approved by clinicaltrial. gov. Identifier is NCT01792089.


Grape seed proanthocyanidin extract (GSPE) attenuates collagen-induced arthritis.
To examine whether grape seed proanthocyanidin extract (GSPE) which is known to act as an antioxidant has therapeutic effect on collagen-induced arthritis (CIA) in mice, an animal model of rheumatoid arthritis. Mice were treated with an intraperitoneal injection of GSPE (10, 50, or 100 mg/kg) or saline. Clinical, histological, and biochemical parameters were assessed. The effects of GSPE on osteoclastogenesis were determined by tartrate-resistant acid phosphatase (TRAP) staining of the inflamed joints and bone-marrow cells cultured with the receptor activator of nuclear factor B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Intracellular levels of hydrogen peroxide were determined using carboxy-dichlorodihydrofluorescein diacetate. GSPE treatment significantly attenuated the severity of CIA in a dose-dependent manner and reduced the histology scores for synovial inflammation, cartilage erosion, bone erosion, and the number of TRAP+ osteoclasts. GSPE treatment significantly reduced the numbers of tumor necrosis factor alpha (TNF-alpha)- or interleukin 17 (IL-17)-producing cells in the synovial tissue and the spontaneous production of TNF-alpha and IL-17 by splenocytes compared with those in the control mice. The serum levels of type-II-collagen-specific IgG2a and plasma levels of 8-isoprostane in the GSPE-treated mice were significantly lower than those in the control mice. GSPE dose-dependently suppressed osteoclastogenesis in vitro. GSPE significantly reduced hydrogen peroxide production by anti-CD3-monoclonal-antibody-stimulated CD4+ splenocytes. These results indicate that intraperitoneal injection of GSPE attenuated CIA in mice. GSPE may be useful in the treatment of rheumatoid arthritis.


Comparison of Laughter Yoga and Anti-Anxiety Medication on Anxiety and Gastrointestinal Symptoms of Patients with Irritable Bowel Syndrome.
BACKGROUND Irritable bowel syndrome (IBS) is the most common chronic gastrointestinal (GI) disorder. Patients with IBS usually suffer from anxiety and depression. A combination of psychological approaches and pharmacological treatments can be a significantly effective treatment for IBS. The main objective of the present study was to provide a therapeutic plan based on laughter yoga and anti-anxiety medication, employed for the very first time, and to determine the effectiveness of these treatments on the anxiety and GI symptoms of patients with IBS. METHODS In this randomized, controlled, clinical trial, the participants were 60 patients selected from those who referred to the GI clinic of Vali-asr Hospital (Birjand, Iran) during the study period (April 2017 to March 2017) and were diagnosed as having IBS based on ROME III criteria. The participants were randomly assigned to either the laughter yoga group, the anti-anxiety medication group, or the symptomatic treatment (control) group. Severity levels of anxiety and GI symptoms before and after intervention were determined and compared among these three groups according to approved protocols. RESULTS The severity of IBS symptoms after the interventions was more greatly reduced in the laughter yoga group than in the anti-anxiety medication and control groups (p = 0.006). The severity of anxiety after interventions decreased in all three groups, especially in the yoga treatment group, but the difference was not statistically significant (p = 0.1). CONCLUSION Laughter yoga is more effective than anti-anxiety medication in reducing the GI symptoms of patients with IBS. Therefore, applying laughter yoga along with common pharmacological therapies for patients with IBS might be strongly advised.


Bioavailability of pharmaceuticals in waters close to wastewater treatment plants: use of fish bile for exposure assessment.
Pharmaceuticals are ubiquitous in surface waters as a consequence of discharges from municipal wastewater treatment plants. However, few studies have assessed the bioavailability of pharmaceuticals to fish in natural waters. In the present study, passive samplers and rainbow trout were experimentally deployed next to three municipal wastewater treatment plants in Finland to evaluate the degree of animal exposure. Pharmaceuticals from several therapeutic classes (in total 15) were analyzed by liquid chromatography-tandem mass spectrometry in extracts of passive samplers and in bile and blood plasma of rainbow trout held at polluted sites for 10 d. Each approach indicated the highest exposure near wastewater treatment plant A and the lowest near that of plant C. Diclofenac, naproxen, and ibuprofen were found in rainbow trout, and their concentrations in bile were 10 to 400 times higher than in plasma. The phase I metabolite hydroxydiclofenac was also detected in bile. Hence, bile proved to be an excellent sample matrix for the exposure assessment of fish. Most of the monitored pharmaceuticals were found in passive samplers, implying that they may overestimate the actual exposure of fish in receiving waters. Two biomarkers, hepatic vitellogenin and cytochrome P4501A, did not reveal clear effects on fish, although a small induction of vitellogenin mRNA was observed in trout caged near wastewater treatment plants B and C.


The impact of Medicaid managed care on pregnant women in Ohio: a cohort analysis.
To examine the impact of mandatory HMO enrollment for Medicaid-covered pregnant women on prenatal care use, smoking, Cesarean section (C-section) use, and birth weight. Linked birth certificate and Medicaid enrollment data from July 1993 to June 1998 in 10 Ohio counties, 6 that implemented mandatory HMO enrollment, and 4 with low levels of voluntary enrollment (under 15 percent). Cuyahoga County (Cleveland) is analyzed separately; the other mandatory counties and the voluntary counties are grouped for analysis, due to small sample sizes. Study Design. Women serve as their own controls, which helps to overcome the bias from unmeasured variables such as health beliefs and behavior. Changes in key outcomes between the first and second birth are compared between women who reside in mandatory HMO enrollment counties and those in voluntary enrollment counties. County of residence is the primary indicator of managed care status, since, in Ohio, women are allowed to "opt out" of HMO enrollment in mandatory counties in certain circumstances, leading to selection. As a secondary analysis, we compare women according to their HMO enrollment status at the first and second birth. Linked birth certificate/enrollment data were used to identify 4,917 women with two deliveries covered by Medicaid, one prior to the implementation of mandatory HMO enrollment (mid-1996) and one following implementation. Data for individual births were linked over time using a scrambled maternal Medicaid identification number. The effects of HMO enrollment on prenatal care use and smoking were confined to Cuyahoga County, Ohio's largest county. In Cuyahoga, the implementation of mandatory enrollment was related to a significant deterioration in the timing of initiation of care, but an improvement in the number of prenatal visits. In that county also, women who smoked in their first pregnancy were less likely to smoke during the second pregnancy, compared to women in voluntary counties. Women residing in all the mandatory counties were less likely to have a repeat C-section. There were no effects on infant birth weight. The effects of women's own managed care status were inconsistent depending on the outcome examined; an interpretation of these results is hampered by selection issues. Changes over time in outcomes, both positive and negative, were more pronounced for African American women. With careful implementation and attention to women's individual differences as in Ohio, outcomes for pregnant women may improve with Medicaid managed care implementation. Quality monitoring should continue as Medicaid managed care becomes more widespread. More research is needed to identify the types of health maintenance organization activities that lead to improved outcomes.


Reading Aloud, Play, and Social-Emotional Development.
To determine impacts on social-emotional development at school entry of a pediatric primary care intervention (Video Interaction Project [VIP]) promoting positive parenting through reading aloud and play, delivered in 2 phases: infant through toddler (VIP birth to 3 years [VIP 0-3]) and preschool-age (VIP 3 to 5 years [VIP 3-5]). Factorial randomized controlled trial with postpartum enrollment and random assignment to VIP 0-3, control 0 to 3 years, and a third group without school entry follow-up (Building Blocks) and 3-year second random assignment of VIP 0-3 and control 0 to 3 years to VIP 3-5 or control 3 to 5 years. In the VIP, a bilingual facilitator video recorded the parent and child reading and/or playing using provided learning materials and reviewed videos to reinforce positive interactions. Social-emotional development at 4.5 years was assessed by parent-report Behavior Assessment System for Children, Second Edition (Social Skills, Attention Problems, Hyperactivity, Aggression, Externalizing Problems). VIP 0-3 and VIP 3-5 were independently associated with improved 4.5-year Behavior Assessment System for Children, Second Edition T-scores, with effect sizes (Cohen's d) ∼-0.25 to -0.30. Receipt of combined VIP 0-3 and VIP 3-5 was associated with d = -0.63 reduction in Hyperactivity (P = .001). VIP 0-3 resulted in reduced "Clinically Significant" Hyperactivity (relative risk reduction for overall sample: 69.2%; P = .03; relative risk reduction for increased psychosocial risk: 100%; P = .006). Multilevel models revealed significant VIP 0-3 linear effects and age × VIP 3-5 interactions. Phase VIP 0-3 resulted in sustained impacts on behavior problems 1.5 years after program completion. VIP 3-5 had additional, independent impacts. With our findings, we support the use of pediatric primary care to promote reading aloud and play from birth to 5 years, and the potential for such programs to enhance social-emotional development.


Spatial disorientation in Alzheimer's disease.
Spatial disorientation was investigated in 28 ambulatory patients meeting the National Institute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association Work Group criteria for "probable" Alzheimer's disease. Based on caregivers' reports, 39% of subjects engaged in at least three of four behavioral measures of spatial disorientation three or more times a week; these patients did not significantly differ from other Alzheimer's disease subjects with regard to age, sex, education, or symptom duration. Using stepwise regression analysis, we found that neuropsychologic measures of memory and visuoconstructive functions, but not disease severity, attention, or language impairment, emerged as significant predictors of spatial disorientation. In the setting of impaired memory, the tendency of some patients with Alzheimer's disease to wander or to get lost may implicate particularly severe dysfunction of right hemisphere neocortical areas concerned with visuospatial processes.


An Introduction to Principal Surrogate Evaluation with the pseval Package.
We describe a new package called pseval that implements the core methods for the evaluation of principal surrogates in a single clinical trial. It provides a flexible interface for defining models for the risk given treatment and the surrogate, the models for integration over the missing counterfactual surrogate responses, and the estimation methods. Estimated maximum likelihood and pseudo-score can be used for estimation, and the bootstrap for inference. A variety of post-estimation methods are provided, including print, summary, plot, and testing. We summarize the main statistical methods that are implemented in the package and illustrate its use from the perspective of a novice R user.


Increasing the Number of Outpatients Receiving Spiritual Assessment: A Pain and Palliative Care Service Quality Improvement Project.
Spirituality is a patient need that requires special attention from the Pain and Palliative Care Service team. This quality improvement project aimed to provide spiritual assessment for all new outpatients with serious life-altering illnesses. Percentage of new outpatients receiving spiritual assessment (Faith, Importance/Influence, Community, Address/Action in care, psychosocial evaluation, chaplain consults) at baseline and postinterventions. Interventions included encouraging clinicians to incorporate adequate spiritual assessment into patient care and implementing chaplain covisits for all initial outpatient visits. The quality improvement interventions increased spiritual assessment (baseline vs. postinterventions): chaplain covisits (25.5% vs. 50%), Faith, Importance/Influence, Community, Address/Action in care completion (49% vs. 72%), and psychosocial evaluation (89% vs. 94%). Improved spiritual assessment in an outpatient palliative care clinic setting can occur with a multidisciplinary approach. This project also identifies data collection and documentation processes that can be targeted for improvement.


A Multi-institutional International Analysis of Textbook Outcomes Among Patients Undergoing Curative-Intent Resection of Intrahepatic Cholangiocarcinoma.
Composite measures may be superior to individual measures for the analysis of hospital performance and quality of surgical care. To determine the incidence of a so-called textbook outcome, a composite measure of the quality of surgical care, among patients undergoing curative-intent resection of intrahepatic cholangiocarcinoma. This cohort study involved an analysis of a multinational, multi-institutional cohort of patient from 15 major hepatobiliary centers in North America, Europe, Australia, and Asia who underwent curative-intent resection of intrahepatic cholangiocarcinoma between 1993 and 2015. Data analysis was conducted from April 2018 to May 2018. Hospital variation in the composite end point of textbook outcome, defined as negative margins, no perioperative transfusion, no postoperative surgical complications, no prolonged length of stay, no 30-day readmissions, and no 30-day mortality. Secondary end points were factors associated with achieving textbook outcomes. Among 687 patients (of whom 370 [53.9%] were men; median patient age, 61 [range, 18-86] years) undergoing curative-intent resection of intrahepatic cholangiocarcinoma, a textbook outcome was achieved in 175 patients (25.5%). Being 60 years or younger (odds ratio [OR], 1.61 [95% CI, 1.04-2.49]; P = .03), absence of preoperative jaundice (OR, 4.40 [95% CI, 1.28-15.15]; P = .02), no neoadjuvant chemotherapy (OR, 2.57 [95% CI, 1.05-6.29]; P = .04), T1a/T1b-stage disease (OR, 1.58 [95% CI, 1.01-2.49]; P = .049), N0 status (OR, 3.89 [95% CI, 1.77-8.54]; P = .001), and no bile duct resection (OR, 2.46 [95% CI, 1.25-4.84]; P = .009) were independently associated with achieving a textbook outcome after resection. A prolonged length of stay had the greatest negative association with a textbook outcome. A nomogram to assess the probability of textbook outcome was developed and had good accuracy in both the training data set (area under the curve, 0.755) and validation data set (area under the curve, 0.763). In this study, while hepatic resection for intrahepatic cholangiocarcinoma was performed with less than 5% mortality in specialized centers, a textbook outcome was achieved in only approximately 26% of patients. A textbook outcome may be useful for the reporting of patient-level hospital performance and hospital variation, leading to quality improvement efforts after resection of intrahepatic cholangiocarcinoma.


Inflammation in dry eye associated with rheumatoid arthritis: cytokine and in vivo confocal microscopy study.
The purpose of this research was to study ocular surface inflammation in relation to systemic disease activity in rheumatoid arthritis (RA) patients with or without secondary Sjögren's syndrome (SSII and non-SSII respectively). The study was conducted in two phases. In phase I, 12 patients with active RA SSII and 12 with active RA non-SSII were consecutively enrolled. Each completed an Ocular Surface Disease Index (OSDI) questionnaire and underwent a full eye exam and in vivo confocal microscopy examination of the cornea. Tear fluid samples were collected in sponges and analyzed for IL-1α, -6, and -8, and TNF-α. When RA activity was suppressed by systemic treatment the patients entered phase II of the study in which all of the phase I examinations were repeated. In RA SSII patients, OSDI, fluorescein staining dendritic cell density, and concentrations of IL-1α and IL-6 decreased significantly (P < 0.01) between phases I and II. Tear breakup time scores increased significantly. For RA non-SSII patients, there were no significant differences between phases I and II. Differences in the clinical, cellular and cytokine responsiveness to systemic RA treatments show that the ocular surface pathology is dissimilar for RA SSII and RA non-SSII patients.


Fingerprints of topological defects in a metasurface.
Singularity, representing a structurally stable topological defect (TD), plays a pivotal role in various physical systems. Here we theoretically present the fingerprints of TDs and uncover the resulting exotic optical properties in a tailored metasurface system. The presence of the TDs results in coherent perfect absorption, and dramatic optical property transition from slow to superluminal light behavior when the parameters cross the TD. Our investigation provides a new route to explore many phenomena of the TDs, extends the capabilities of metasurface, and offers benefits to develop potential nanophotonic applications based on the design of the metasurface.


Usefulness of glycated hemoglobin A1c-based adjusted glycemic variables in diabetic patients presenting with acute ischemic stroke.
Acute hyperglycemia is a common condition among patients with diabetes who are admitted to the emergency department (ED) for acute ischemic stroke (AIS). Previous findings regarding the association between hyperglycemia at admission and adverse outcomes among patients with diabetes and AIS have been inconsistent. When investigating this association, it is necessary to consider premorbid blood glucose control. The objective of the current study was to assess whether HbA1c-based adjusted glycemic variables were associated with unfavorable outcomes among patients admitted to the hospital for AIS. We retrospectively analyzed data from 309 patients who were hospitalized for AIS at a single medical center in Taiwan between January 1, 2013, and October 31, 2015. We found that 1) HbA1c-based adjusted glycemic variables, including the glycemic gap and stress hyperglycemia ratio, were associated with both AIS severity and neurological status at discharge; additionally, 2) HbA1c-based adjusted glycemic variables showed superior discriminative power compared with acute hyperglycemia regarding the development of severe AIS. We conclude that both the glycemic gap and stress hyperglycemia ratio might be useful in assessing the disease severity and prognosis of patients presenting with AIS. Further prospective long-term follow-up studies should be performed to validate these findings.


Expression, purification and characterization of methyl DNA binding protein from Bombyx mori.
A cDNA clone encoding methyl DNA binding domain-containing protein (bMBD2/3) was obtained by homology searches using a Bombyx mori fat body cDNA library. The cDNA encoded a polypeptide with 249 amino acids sharing 54% similarity with the methyl DNA binding protein from Drosophila melanogaster. To characterize the biochemical properties of bMBD2/3, the clone was expressed in Escherichia coli as His-tagged protein. The recombinant protein was purified to homogeneity using Ni-NTA superflow resin and heparin agarose. The protein showed specific methyl DNA binding activity and was phosphorylated by protein kinase in vitro. Immunoblotting using the purified antibody indicated that bMBD2/3 was expressed in almost all tissues. Using west-western blotting analysis, some proteins that interact with bMBD2/3 were identified in the brain. This is the first report that insect MBD is phosphorylated and is present in adult tissues. These results suggest that bMBD2/3 plays important roles in the DNA methylation-specific transcription of Bombyx mori.


Clozapine-Induced Myocarditis or Acute Coronary Syndrome? Optical Coherence Tomography to the Rescue.
Chest pain and troponin elevation may be due to an acute coronary syndrome, myocarditis, acute cardiomyopathy, or other less common conditions. Management differs depending on the aetiology, and the pathophysiologic diagnosis has direct implications on treatment and patient outcomes. History and clinical examination is supplemented by selected investigations including the electrocardiogram, chest X-ray, echocardiography, coronary angiography, and even myocardial perfusion scintigraphy or cardiac magnetic resonance imaging. Intravascular imaging can provide important insights into the underlying mechanism of acute coronary syndromes, especially when angiography is ambiguous.


Likelihoods and simulation methods for a class of nonneutral population genetics models.
Methods for simulating samples and sample statistics, under mutation-selection-drift equilibrium for a class of nonneutral population genetics models, and for evaluating the likelihood surface, in selection and mutation parameters, are developed and applied for observed data. The methods apply to large populations in settings in which selection is weak, in the sense that selection intensities, like mutation rates, are of the order of the inverse of the population size. General diploid selection is allowed, but the approach is currently restricted to models, such as the infinite alleles model and certain K-models, in which the type of a mutant allele does not depend on the type of its progenitor allele. The simulation methods have considerable advantages over available alternatives. No other methods currently seem practicable for approximating likelihood surfaces.


Final overall survival results and effect of prolonged (≥ 1 year) first-line bevacizumab-containing therapy for metastatic breast cancer in the ATHENA trial.
The ATHENA study expanded on the safety and efficacy data derived from first-line trials of bevacizumab combined with standard chemotherapy for locally recurrent/metastatic breast cancer (LR/mBC). In ATHENA, 2,264 patients received first-line bevacizumab-containing therapy in routine oncology practice. Overall survival (OS) data are now mature; additional analyses from this large data set can provide insights into treatment duration and the effect of prolonged bevacizumab exposure, where data are currently limited. Patients with HER2-negative LR/mBC received first-line bevacizumab with standard chemotherapy until disease progression, unacceptable toxicity, or physician/patient decision. We performed subgroup analyses on data from patients treated for ≥12 months and those who continued single-agent bevacizumab after stopping chemotherapy. After median follow-up of 20.1 months, median OS was 25.2 months (95% confidence interval [CI] 24.0-26.3 months) in the entire population. Median OS was 30.0 months (95% CI 28.5-32.7 months) in 1,205 patients who continued bevacizumab after discontinuation of chemotherapy and 18.4 months (95% CI 17.2-19.7 months) in 1,058 patients who discontinued bevacizumab before or at the same time as stopping chemotherapy. Bevacizumab treatment was continued for ≥12 months in 473 patients (21%). In most, bevacizumab was administered as monotherapy for extended periods after stopping chemotherapy. In the subgroup of patients treated for ≥12 months, the median time to onset of grade 3-5 adverse events was 5.0 months. There was no evidence that first onset of adverse events of special interest, except for proteinuria, was more common in later than earlier cycles. No relationship was detected between development of hypertension and OS. Findings from these analyses suggest that patients with LR/mBC can receive bevacizumab for prolonged periods without major toxicity or progression of disease. In the absence of progression, continuation of single-agent bevacizumab appears to be a reasonable approach, with minimal toxicity and the possibility of long-term disease control.


Gut microbiota and Covid-19- possible link and implications.
Covid-19 is a major pandemic facing the world today caused by SARS-CoV-2 which has implications on our understanding of infectious diseases. Although, SARS-Cov-2 primarily causes lung infection through binding of ACE2 receptors present on the alveolar epithelial cells, yet it was recently reported that SARS-CoV-2 RNA was found in the faeces of infected patients. Interestingly, the intestinal epithelial cells particularly the enterocytes of the small intestine also express ACE2 receptors. Role of the gut microbiota in influencing lung diseases has been well articulated. It is also known that respiratory virus infection causes perturbations in the gut microbiota. Diet, environmental factors and genetics play an important role in shaping gut microbiota which can influence immunity. Gut microbiota diversity is decreased in old age and Covid-19 has been mainly fatal in elderly patients which again points to the role the gut microbiota may play in this disease. Improving gut microbiota profile by personalized nutrition and supplementation known to improve immunity can be one of the prophylactic ways by which the impact of this disease can be minimized in old people and immune-compromised patients. More trials may be initiated to see the effect of co-supplementation of personalized functional food including prebiotics/probiotics along with current therapies.


Future water resources for food production in five South Asian river basins and potential for adaptation--a modeling study.
The Indian subcontinent faces a population increase from 1.6 billion in 2000 towards 2 billion around 2050. Therefore, expansion of agricultural area combined with increases in productivity will be necessary to produce the food needed in the future. However, with pressure on water resources already being high, and potential effects of climate change still uncertain, the question rises whether there will be enough water resources available to sustain this production. The objective of this study is to make a spatially explicit quantitative analysis of water requirements and availability for current and future food production in five South Asian basins (Indus, Ganges, Brahmaputra, Godavari and Krishna), in the absence or presence of two different adaptation strategies: an overall improvement in irrigation efficiency, and an increase of reservoir storage capacity. The analysis is performed by using the coupled hydrology and crop production model LPJmL. It is found that the Godavari and Krishna basins will benefit most from an increased storage capacity, whereas in the Ganges and the Indus water scarcity mainly takes place in areas where this additional storage would not provide additional utility. Increasing the irrigation efficiency will be beneficial in all basins, but most in the Indus and Ganges, as it decreases the pressure on groundwater resources and decreases the fraction of food production that would become at risk because of water shortage. A combination of both options seems to be the best strategy in all basins. The large-scale model used in this study is suitable to identify hotspot areas and support the first step in the policy process, but the final design and implementation of adaptation options requires supporting studies at finer scales.


Reproductive and developmental health effects of prenatal exposure to tetrachloroethylene-contaminated drinking water.
Tetrachloroethylene (PCE) is a common contaminant in both occupational and community settings. High exposure levels in the workplace have been shown to have adverse impacts on reproduction and development but few epidemiological studies have examined these effects at the lower levels commonly seen in community settings. We were presented with a unique opportunity to examine the reproductive and developmental effects of prenatal exposure to PCE-contaminated drinking water resulting from the installation of vinyl-lined water pipes in Massachusetts and Rhode Island from the late 1960s through 1980. This review describes the methods and findings of two community-based epidemiological studies, places their results in the context of the existing literature, and describes the strengths and challenges of conducting epidemiological research on a historical pollution episode. Our studies found that prenatal exposure to PCE-contaminated drinking water is associated with delayed time-to-pregnancy, and increased risks of placental abruption, stillbirths stemming from placental dysfunction, and certain birth defects. No associations were observed with pregnancy loss, birth weight, and gestational duration. Important strengths of this research included the availability of historical data on the affected water systems, a relatively high exposure prevalence and wide range of exposure levels, and little opportunity for recall bias and confounding. Challenges arose mainly from the retrospective nature of the exposure assessments. This research highlights the importance of considering pregnant women and their developing fetuses when monitoring, regulating, and remediating drinking water contaminants.


Regulation of nitrate reductase of Neurospora at the level of transcription and translation.
The presence of nitrate is required for the induced synthesis of NADPH-nitrate reductase and its related partial activity Benzyl Viologen-nitrate reductase in a wild-type strain of Neurospora. In nit-3, a mutant lacking complete NADPH-nitrate reductase activity but retaining the partial activity Benzyl Viologen-nitrate reductase, the presence of nitrate ions is not required for the de-repressed synthesis of the latter enzyme. The accumulation of the capacity to synthesize nitrate reductase, and the related Benzyl Viologen-nitrate reductase, in the absence of protein synthesis does not require nitrate in the normal strain or in strain nit-3. Ammonia antagonizes the accumulation of this capacity in both strains. Nitrate is required for the synthesis of nitrate reductase and related activities from presumedly preformed mRNA in the wild-type strain. Nitrate is not required for the comparable function in strain nit-3. Ammonia appears to stop the synthesis of nitrate reductase and related activities from presumedly preformed mRNA in the wild-type strain and in strain nit-3. The effects of nitrate, or ammonia and of no nitrogen source on the induced synthesis of nitrate reductase cannot be explained on the basis of the effects of the different nitrogen sources on general synthesis of RNA or of protein.


Alignment of a three-mirror anastigmat using the sine condition test.
Continuing to develop the sine condition test (SCTest), we show how violations of the generalized sine condition can be used to align a three-mirror anastigmat (TMA). This paper shows how the linear aberrations measured using the sine condition, along with aberrations that have constant field dependence, can be used to align a system. We discuss the design of the test hardware needed to align a TMA and the procedure for alignment. Using simulation, we then investigate the behavior of the alignment SCTest for various levels of mirror misalignment, mirror fabrication errors, and misalignment of the test equipment. All of these tests show that the alignment SCTest can successfully align an optical system.


Prediction of peak flow values followed by feedback improves perception of lung function and adherence to inhaled corticosteroids in children with asthma.
Failure to detect respiratory compromise can lead to emergency healthcare use and fatal asthma attacks. The purpose of this study was to examine the effect of predicting peak expiratory flow (PEF) and receiving feedback on perception of pulmonary function and adherence to inhaled corticosteroids (ICS). The sample consisted of 192 ethnic minority, inner-city children (100 Puerto Rican, 54 African-American, 38 Afro-Caribbean) with asthma and their primary caregivers recruited from outpatient clinics in Bronx, New York. Children's PEF predictions were entered into an electronic spirometer and compared with actual PEF across 6 weeks. Children in one study were blinded to PEF (n=88; no feedback) and children in a separate study were able to see PEF (n=104; feedback) after predictions were locked in. Dosers were attached to asthma medications to monitor use. Children in the feedback condition displayed greater accuracy (p<0.001), less under-perception (p<0.001) and greater over-perception (p<0.001) of respiratory compromise than children in the no feedback condition. This between-group difference was evident soon after baseline training and maintained across 6 weeks. The feedback condition displayed greater adherence to ICS (p<0.01) and greater quick-relief medication use (p<0.01) than the no feedback condition. Feedback on PEF predictions for ethnic minority, inner-city children may decrease under-perception of respiratory compromise and increase adherence to controller medications. Children and their families may shift their attention to asthma perception and management as a result of this intervention.


Polarity controls forces governing asymmetric spindle positioning in the Caenorhabditis elegans embryo.
Cell divisions that create daughter cells of different sizes are crucial for the generation of cell diversity during animal development. In such asymmetric divisions, the mitotic spindle must be asymmetrically positioned at the end of anaphase. The mechanisms by which cell polarity translates to asymmetric spindle positioning remain unclear. Here we examine the nature of the forces governing asymmetric spindle positioning in the single-cell-stage Caenorhabditis elegans embryo. To reveal the forces that act on each spindle pole, we removed the central spindle in living embryos either physically with an ultraviolet laser microbeam, or genetically by RNA-mediated interference of a kinesin. We show that pulling forces external to the spindle act on the two spindle poles. A stronger net force acts on the posterior pole, thereby explaining the overall posterior displacement seen in wild-type embryos. We also show that the net force acting on each spindle pole is under control of the par genes that are required for cell polarity along the anterior-posterior embryonic axis. Finally, we discuss simple mathematical models that describe the main features of spindle pole behaviour. Our work suggests a mechanism for generating asymmetry in spindle positioning by varying the net pulling force that acts on each spindle pole, thus allowing for the generation of daughter cells with different sizes.


Detection of anti-pertussis toxin IgG in oral fluids for use in diagnosis and surveillance of Bordetella pertussis infection in children and young adults.
Bordetella pertussis infection is being increasingly recognized as a cause of prolonged, distressing cough (without whooping symptoms) in children and young adults. Diagnosis of infection in this population is important for treatment and surveillance purposes, and may also prove useful in reducing transmission to unvaccinated babies, for whom disease can be fatal. Serum IgG titres against pertussis toxin (PT) are routinely used as a marker of recent or persisting B. pertussis infection. However, collection of serum from young children is difficult, and compliance amongst these subjects to give samples is low. To circumvent these problems, an IgG-capture ELISA capable of detecting anti-PT IgG in oral fluid was devised. The assay was evaluated by comparison to a serum ELISA, using 187 matched serum and oral fluid samples from children (aged 5-16 years) with a history of prolonged coughing, whose serum anti-PT titre had already been determined (69 seropositive, 118 seronegative). The results showed that, using a cutoff of 70 arbitrary units (AU), the oral fluid assay detected seropositive subjects with a sensitivity of 79.7% [95% confidence interval (CI) 68.3-88.4] and a specificity of 96.6% (95% CI 91.5-99.1). Thus, oral fluid titres of >or=70 AU would possess a positive predictive value of 76.2-93.2% for pertussis amongst children with chronic coughs when used as a surrogate for the serum ELISA (assuming disease prevalence of 12-37%). This oral fluid ELISA will greatly assist in the convenience of B. pertussis disease diagnosis and surveillance.


Household survey of injuries in a Kenyan district.
To determine the pattern and burden of injuries, their causes and action taken in a rural and urban community in Kenya. Household interview survey and focus group discussions. Four rural villages and five urban clusters in Kiambu District, Kenya. A total of 1,980 members of 200 rural and 230 urban households. The number of reported injuries was 495, corresponding to 300,000 injuries per 100,000 people per year. Most common were cut or piercing (38.4%), followed by fall (16.2%), burn or scald (14.3%), animal bite or kick (10.1%), hit by moving object (5.9%) and road traffic accident (3.6%). Poisoning, sub-mersion/drowning and explosion were uncommon, each below three per cent. Of all reported injuries, 149 (30.1%) sought care from traditional healers, 91 (18.4%) were subject to self-care, 76 (15.4%) obtained service from drug shops, 22 (4.4%) were brought to a health facility for attention and 17 (3.4%) took no action at all. Additional information was obtained through focus group discussions with students, teachers and members of women groups. These generated detailed information about cases of sexual assault within and outside households which had not been captured during the previous household interviews. Injuries are very common but most of them are mild, prompting only home care or no action at all. Only one out of 25 injuries were brought to a health facility for attention. Some types of injury, such as domestic violence and sexual assault, are more likely to be captured through focus group discussions than during household interviews. A combination of methods is likely to best reflect the pattern of injury at community level.


97 percent light absorption in an ultrabroadband frequency range utilizing an ultrathin metal layer: randomly oriented, densely packed dielectric nanowires as an excellent light trapping scaffold.
In this paper, we propose a facile and large scale compatible design to obtain perfect ultrabroadband light absorption using metal-dielectric core-shell nanowires. The design consists of atomic layer deposited (ALD) Pt metal uniformly wrapped around hydrothermally grown titanium dioxide (TiO2) nanowires. It is found that the randomly oriented dense TiO2 nanowires can impose excellent light trapping properties where the existence of an ultrathin Pt layer (with a thickness of 10 nm) can absorb the light in an ultrabroadband frequency range with an amount near unity. Throughout this study, we first investigate the formation of resonant modes in the metallic nanowires. Our findings prove that a nanowire structure can support multiple longitudinal localized surface plasmons (LSPs) along its axis together with transverse resonance modes. Our investigations showed that the spectral position of these resonance peaks can be tuned with the length, radius, and orientation of the nanowire. Therefore, TiO2 random nanowires can contain all of these features simultaneously in which the superposition of responses for these different geometries leads to a flat perfect light absorption. The obtained results demonstrate that taking unique advantages of the ALD method, together with excellent light trapping of chemically synthesized nanowires, a perfect, bifacial, wide angle, and large scale compatible absorber can be made where an excellent performance is achieved while using less materials.


Evaluation of ultrasound-guided femoral nerve block in endoluminal laser ablation of the greater saphenous vein.
Endoluminal laser ablation has emerged as a new method for treating greater saphenous vein insufficiency. However, the procedure is not completely painless and requires applying tumescent anesthesia. The aim of this study was to evaluate the safety and efficacy of ultrasound-guided femoral nerve block in patients subjected to endoluminal laser ablation of the greater saphenous vein. Two consecutive groups of 25 patients subjected to ambulatory endoluminal laser ablation of the greater saphenous vein were analyzed in this study. Tumescent anesthesia only was applied in the first group. In the second group, before applying tumescent anesthesia, ultrasound-guided femoral nerve block was performed with 20 mL of 1% lidocaine. The pain during the application of tumescent anesthesia and vein ablation was evaluated by the patients using a 5-point scale. The heart rate and blood pressure was monitored during the procedures. The duration of the postprocedure stay in the recovery area was also recorded. The results were analyzed using statistical methods. No complications associated with performing the femoral nerve block were observed. The pain associated with applying the tumescent anesthesia and that of performing the ablation was more intense in group 1 (p > 0.001). The volume of tumescent anesthesia solution was lower in group 2, 240 (±73) mL, compared to 399 (±137) mL in group 1, (p < 0.001). The group 2 patients had less hemodynamic changes during the procedure (p = 0.01). In conclusion, ultrasound-guided femoral nerve block was shown to be a safe and effective option to decrease intraoperative discomforts associated with tumescent anesthesia and endoluminal laser ablation of the greater saphenous vein.


Concentrations of dopamine and noradrenaline in hypophysial portal blood in the sheep and the rat.
The concentrations of dopamine, noradrenaline and their respective primary neuronal metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylethyleneglycol (DHPG) were measured in the hypophysial portal and peripheral plasma of sheep and rats by combined gas chromatography-mass spectrometry. Hypophysial portal and jugular blood samples were taken at 5- to 10-min intervals for 3-7 h from six conscious ovariectomized ewes. Blood was also collected for 30 min under urethane anaesthesia from the cut pituitary stalk from 16 pro-oestrous female and five intact male rats. In ovariectomized ewes, noradrenaline concentrations were higher in hypophysial portal plasma than in peripheral plasma (6.6 +/- 0.8 vs 2.2 +/- 0.4 nmol/l). In contrast, dopamine was undetectable (less than 1 nmol/l) in the portal and peripheral plasma of all ewes. Plasma levels of DOPAC and DHPG in portal and jugular samples were similar. In all pro-oestrous female rats, plasma concentrations of dopamine were higher in portal blood than in jugular blood (8.0 +/- 1.4 vs 4.8 +/- 0.6 nmol/l). Detectable concentrations of dopamine were measured in the portal plasma of two out of five male rats. Noradrenaline concentrations were higher in portal plasma than in peripheral plasma of both female (8.3 +/- 1.7 vs 3.7 +/- 0.6 nmol/l) and male (14.8 +/- 2.7 vs 6.1 +/- 1.2 nmol/l) rats. These data show that noradrenaline, but not dopamine, is secreted into the long portal vessels in sheep. The results suggest that there are species differences in the secretion of hypothalamic dopamine into hypophysial portal blood.


[Aa DICOM based PACS for nuclear medicine].
The installation of a Radiology Information System (RIS) connected to a Hospital Information System (HIS) and a Picture Archiving and Communications System (PACS) seems mandatory for a nuclear medicine department in order to guarantee a high patient throughput. With these systems a fast transmission of reports, images to the in- and out-patients' wards and private practitioners is realized. Therefore, since April 2000, at the department of nuclear medicine of the university of Würzburg a completely DICOM based PACS has been implemented in addition to the RIS. With this system a DICOM based workflow is realized throughout the department of nuclear medicine for reporting and archiving. The PACS is connected to six gamma-cameras, a PET scanner, a bone densitometry system and an ultrasound device. The volume of image data archived per month is 4 GByte. Patient demographics are provided to the modalities via DICOM-Worklist. With these PACS components a department specific archive purely based on DICOM can be realized. During the installation process problems occurred mainly because of the complex DICOM standard for nuclear medicine. Related to that is the problem that most of the software implementations still contain bugs or are not adopted to the needs of a nuclear medicine department (particularly for PET). A communication software for the distribution of nuclear medicine reports and images based on techniques used for the worldwide web is currently tested.


Treatment of the elderly colorectal cancer patient: SIOG expert recommendations.
Colorectal cancer (CRC) is one of the commonest malignancies of Western countries, with approximately half the incidence occurring in patients >70 years of age. Elderly CRC patients, however, are understaged, undertreated and underrepresented in clinical trials. The International Society of Geriatric Oncology created a task force with a view to assessing the potential for developing guidelines for the treatment of elderly (geriatric) CRC patients. A review of the evidence presented by the task force members confirmed the paucity of clinical trial data in elderly people and the lack of evidence-based guidelines. However, recommendations have been proposed on the basis of the available data and on the emerging evidence that treatment outcomes for fit, elderly CRC patients can be similar to those of younger patients. It is hoped that these will pave the way for formal treatment guidelines based upon solid scientific evidence in the future.


Efficacy and safety of vedolizumab in Crohn's disease in patients from Asian countries in the GEMINI 2 study.
The efficacy and safety of vedolizumab in moderate-to-severely active Crohn's disease (CD) were demonstrated in the GEMINI 2 study (NCT00783692). This post-hoc exploratory analysis aimed to assess the efficacy and safety of vedolizumab in the subgroup of patients from Asian countries. During the induction phase (doses at day 1, 15), clinical remission, enhanced clinical response, and change in C-reactive protein at 6 weeks; during the maintenance phase, clinical remission, enhanced clinical response, glucocorticoid-free remission and durable clinical remission at 52 weeks, were the efficacy outcomes of interest. Efficacy and safety of vedolizumab compared to placebo were assessed in Asian countries (Hong Kong, India, Malaysia, Singapore, South Korea, and Taiwan) using descriptive analyses. During the induction phase, in Asian countries (n = 51), 14.7% of the vedolizumab-treated patients achieved clinical remission at week 6 compared to none with placebo (difference, 14.7%; 95% confidence interval, 15.8%-43.5%). In non-Asian countries (n = 317), the remission rate at week 6 with vedolizumab was 14.5%. During maintenance, in Asian countries, clinical remission rates at 52 weeks with vedolizumab administered every 4 weeks, vedolizumab administered every 8 weeks and placebo were 41.7%, 36.4%, and 0%, respectively; while enhanced clinical response rates were 41.7%, 63.6%, and 42.9%, respectively. During induction, 39.7% of patients with vedolizumab experienced an adverse event compared to 58.8% of patients with placebo, and vedolizumab was generally well-tolerated. This post-hoc analysis demonstrates the treatment effect and safety of vedolizumab in moderateto-severely active CD in patients from Asian countries.


The Effect of Positive End-Expiratory Pressure on Lung Micromechanics Assessed by Synchrotron Radiation Computed Tomography in an Animal Model of ARDS.
Modern ventilatory strategies are based on the assumption that lung terminal airspaces act as isotropic balloons that progressively accommodate gas. Phase contrast synchrotron radiation computed tomography (PCSRCT) has recently challenged this concept, showing that in healthy lungs, deflation mechanisms are based on the sequential de-recruitment of airspaces. Using PCSRCT scans in an animal model of acute respiratory distress syndrome (ARDS), this study examined whether the numerosity (ASnum) and dimension (ASdim) of lung airspaces change during a deflation maneuver at decreasing levels of positive end-expiratory pressure (PEEP) at 12, 9, 6, 3, and 0 cmH2O. Deflation was associated with significant reduction of ASdim both in the whole lung section (passing from from 13.1 ± 2.0 at PEEP 12 to 7.6 ± 4.2 voxels at PEEP 0) and in single concentric regions of interest (ROIs). However, the regression between applied PEEP and ASnum was significant in the whole slice (ranging from 188 ± 52 at PEEP 12 to 146.4 ± 96.7 at PEEP 0) but not in the single ROIs. This mechanism of deflation in which reduction of ASdim is predominant, differs from the one observed in healthy conditions, suggesting that the peculiar alveolar micromechanics of ARDS might play a role in the deflation process.


Mechanical properties of cross-linked collagen meshes after human adipose derived stromal cells seeding.
The main goal of this study was to evaluate the potential of collagen meshes derived from porcine dermis as scaffolds for repairing pelvic organ prolapses. Mechanical properties of collagen meshes with different cross-linking percentages before and after Adipose Derived Stromal Cells (ADSC) seeding were studied as well as the cell-scaffold interaction. Uniaxial tensile tests of the collagen meshes with three different cross-linking percentages (full-, partial-, and noncross-linked) were carried out along orthogonal directions. Their mechanical properties were studied with the same tests before and after seeding with human derived adipose stem cells (ADSC) after 1 and 7 days. Histological analyses were performed to determine adhesion and proliferation of ADSC. Significant differences in mechanical properties of the unseeded meshes were observed between each orthogonal direction independently of the cross-linking percentage. A better cell adhesion rate was observed in the cross-linked meshes. An increase in the mechanical properties after cell seeding was observed with a direct relation with the degree of cross-linking. All meshes analyzed showed a marked anisotropy that should be taken into account during the surgical procedure. The cross-linking treatment increased cell adhesion and the mechanical properties of the collagen meshes after seeding. These results suggest that the mechanical properties of this type of collagen mesh could be useful as scaffolds for repair of pelvic organ prolapse.


Acupuncture for Diarrhoea-Predominant Irritable Bowel Syndrome: A Network Meta-Analysis.
The objective of this study was to compare the efficacy and side effects of acupuncture, sham acupuncture, and drugs in the treatment of diarrhoea-predominant irritable bowel syndrome. Randomized controlled trials (RCTs) assessing the effects of acupuncture and drugs were comprehensively retrieved from electronic databases (such as PubMed, Cochrane Library, Embase, CNKI, Wanfang Database, VIP Database, and CBM) up to December 2017. Additional references were obtained from review articles. With document quality evaluations and data extraction, Network Meta-Analysis was performed using a random-effects model under a frequentist framework. A total of 29 studies (n = 9369) were included; 19 were high-quality studies, and 10 were low-quality studies. NMA showed the following: (1) the ranking of treatments in terms of efficacy in diarrhoea-predominant irritable bowel syndrome is acupuncture, sham acupuncture, pinaverium bromide, alosetron = eluxadoline, ramosetron, and rifaximin; (2) the ranking of treatments in terms of severity of side effects in diarrhoea-predominant irritable bowel syndrome is rifaximin, alosetron, ramosetron = pinaverium bromide, sham acupuncture, and acupuncture; and (3) the treatment of diarrhoea-predominant irritable bowel syndrome includes common acupoints such as ST25, ST36, ST37, SP6, GV20, and EX-HN3. Acupuncture may improve diarrhoea-predominant irritable bowel syndrome better than drugs and has the fewest side effects. Sham acupuncture may have curative effect except for placebo effect. In the future, it is necessary to perform highly qualified research to prove this result. Pinaverium bromide also has good curative effects with fewer side effects than other drugs.


Implementation of a Blood Management Program at a Tertiary Care Hospital: Effect on Transfusion Practices and Clinical Outcomes Among Patients Undergoing Surgery.
Patient blood management (PBM) programs represent a perioperative bundle of care that aim to reduce or eliminate unnecessary transfusions. To evaluate the impact of a PBM program on transfusion practices and clinical outcomes at a single surgical department at a tertiary care hospital in the United States. This pre-post, cross-sectional study was performed using data from 17,114 patients undergoing gastrointestinal surgery between 2010 and 2013. Multivariable regression analysis was used to evaluate the impact of implementing a PBM program on transfusion practices and perioperative clinical outcomes. Implementation of the PBM program was associated with a reduction in the proportion of patients receiving packed red blood cell (PRBC) using a liberal trigger hemoglobin concentration (pre-PBM vs post-PBM: trigger ≥8.0 g/dL: 20.2% vs 15.3%, P < 0.001), as well as an increase in the proportion of patients receiving PRBC using a restrictive trigger hemoglobin concentration (trigger <7.0 g/dL: 37.1% vs 46.4%, P < 0.001). The proportion of patients overtransfused to a target hemoglobin concentration of 9.0 g/dL (54.8% vs 43.9%, P < 0.001) or 10.0 g/dL (22.3% vs 15.8%, P < 0.001) also decreased following implementation of the PBM program. On multivariable analysis, implementation of the PBM program was associated with 23% lower odds of receiving PRBC transfusion (odds ratio = 0.77, 95% confidence interval 0.657-0.896, P = 0.001); hospital length-of-stay, postoperative morbidity, and postoperative mortality were unchanged (all P > 0.05). Implementation of a PBM program was associated with fewer patients receiving PRBC transfusion using a liberal trigger hemoglobin concentration and fewer patients being "overtransfused," without any detectable change in length-of-stay, morbidity or mortality. PBM programs can be safely implemented across hospitals and should be used to improve quality and reduce unnecessary transfusions.


Embedding the quality agenda into tissue viability and wound care.
The vision for the NHS over the next 5 years is to go from 'good to great', with the government's 5-year plan mapping the journey for the NHS while focusing on improving quality and productivity, using innovation and prevention to drive and connect them. The Department of Health's 2010 report Frontline Care. Report of the Prime Minister's Commission on the Future of Nursing and Midwifery in England identified the need to develop national nursing indicators that measure nurse quality and their impact on patient outcomes and satisfaction. This article explores the impact that the quality agenda will have on tissue viability and wound care, and discusses the development of effective and achievable metrics. The importance of the multidisciplinary team working together to develop metrics and achieve quality outcomes for patients is further identified and discussed.


Detection of Suppressiveness against Rotylenchulus reniformis in Soil from Cotton (Gossypium hirsutum) Fields in Texas and Louisiana.
Rotylenchulus reniformis is a major problem confronting cotton production in the central part of the cotton belt of the United States of America. In this study, the hypothesis that natural antagonists in some cases are responsible for unusually low densities of the nematode in certain fields was tested by assaying soils from 22 selected fields for the presence of transferable agents in pots containing cotton plants. In one field, soil from four different depth ranges was tested. In the first of two types of assays, 1 part nematode infested soil was added to 9 parts test soil that was left untreated or autoclaved before mixing; this mixture was used to fill pots. In the second type of assay, 1 part test soil was added to 9 or 19 parts pasteurized fine sand, and nematodes were introduced in aqueous suspension. In three experiments representing both types of assay, transferable or autoclavable agent(s) from four fields in South Texas suppressed nematode populations by 48, 78, 90 and 95%. In one experiment, transferable agents in five fields in Louisiana suppressed populations from 37 to 66%. Identification and evaluation of these agents for biological control of R. reniformis merits further study.


Connection domain mutations in treatment-experienced patients in the OPTIMA trial.
To determine the frequency of mutations in the connection domain (CD) of HIV reverse transcriptase in treatment-experienced patients in the Options in Management with Antiretrovirals trial, their impact on susceptibility to antiretroviral (ARV) drugs, and their impact on virologic outcomes. Baseline plasma ARV genotypes and inferred resistance phenotypes were obtained. Frequencies of E312Q, Y318F, G333D, G333E, G335C, G335D, N348I, A360I, A360V, V365I, A371V, A376S, and E399G were compared with a treatment-naive population. The association of CD mutations with inferred IC50 fold changes to nucleos(t)ide reverse transcriptase inhibitors was evaluated. Univariate and multivariate analyses examined the association of CD mutations with a >1 log10 per milliliter decrease in HIV viral load after 24 weeks on a new ARV regimen. Higher CD mutation rates were seen in Options in Management with Antiretrovirals patients (n = 345) compared with a treatment-naive population. CD mutations were associated with increased inferred IC50 fold changes to abacavir, stavudine, tenofovir, and zidovudine. On univariate analysis, A371V was associated with lack of virologic response, as was having any CD mutation on multivariate analysis. CD mutations are frequent in treatment-experienced populations. They are associated with reduced susceptibility to some nucleos(t)ide reverse transcriptase inhibitors and with a diminished response to ARV therapy.


Adverse effects of Gulf War Illness (GWI) serum on neural cultures and their prevention by healthy serum.
Gulf War Illness (GWI) is a chronic debilitating disease of unknown etiology that affects the brain and has afflicted many veterans of the 1990-91 Gulf War (GW). Here we tested the hypothesis that brain damage may be caused by circulating harmful substances to which GW veterans were exposed but which could not be eliminated due to lack of specific immunity. We assessed the effects of serum from GWI patients on function and morphology of brain cultures in vitro, including cultures of embryonic mouse brain and neuroblastoma N2A line. Blood serum from GWI and healthy GW veterans was added, alone and in combination, to the culture and its effects on the function and morphology of the culture assessed. Neural network function was assessed using electrophysiological recordings from multielectrode arrays in mouse brain cultures, whereas morphological assessments (neural growth and cell apoptosis) were done in neuroblastoma cultures. In contrast to healthy serum, the addition of GWI serum disrupted neural network communication and caused reduced cell growth and increased apoptosis. All of these detrimental effects were prevented or ameliorated by the concomitant addition of serum from healthy GW veterans. These findings indicate that GWI serum contains neuropathogenic factors that can be neutralized by healthy serum. We hypothesize that these factors are persistent antigens circulating in GWI blood that can be neutralized, possibly by specific antibodies present in the healthy serum, as proposed earlier1.


Survival in ventricular fibrillation with emphasis on the number of defibrillations in relation to other factors at resuscitation.
Mortality after out of hospital cardiac arrest (OHCA) is high and a shockable rhythm is a key predictor of survival. A concomitant need for repeated shocks appears to be associated with less favorable outcome. To, among patients found in ventricular fibrillation (VF) or pulseless ventricular tachycardia (pVT) describe: (a) factors associated with 30-day survival with emphasis on the number of defibrillatory shocks delivered; (b) the distribution of and the characteristics of patients in relation to the number of defibrillatory shocks that were delivered. Patients who were reported to The Swedish Register for Cardiopulmonary Resuscitation (SRCR) between January 1 1990 and December 31 2015 and who were found in VF/pVT took part in the survey. In all there were 19,519 patients found in VF/pVT. The 30-day survival decreased with an increasing number of shocks among all patients regardless of witnessed status and regardless of time period in the survey. In a multivariate analysis there were 12 factors that were associated with the chance of 30-day survival one of which was the number of shocks that was delivered. For each shock that was added the chance of survival decreased. Factors associated with an increased 30-day survival included CPR before arrival of EMS, female sex, cardiac etiology and year of OHCA (increasing survival over years). Factors associated with a decreased chance of 30-day survival included: increasing age, OHCA at home, the use of adrenaline and intubation and an increased delay to CPR, defibrillation and EMS arrival. Among patients found in VF/pVT, 7.5% required more than 10 shocks. For each shock that was added the chance of 30-day survival decreased. There was an increase in 30-day survival over time regardless of the number of shocks. On top of the number of defibrillations, eleven further factors were associated with 30-day survival.


The cerebellum in children with spina bifida and Chiari II malformation: Quantitative volumetrics by region.
Few volumetric MRI studies of the entire cerebellum have been published; even less quantitative information is available in patients with hindbrain malformations, including the Chiari II malformation which is ubiquitous in patients with spina bifida meningomyelocele (SBM). In the present study, regional volumetric analyses of the cerebellum were conducted in children with SBM/Chiari II and typically developing (TD) children. Total cerebellar volume was significantly reduced in the SBM group relative to the TD group. After correcting for total cerebellum volume, and relative to the TD group, the posterior lobe was significantly reduced in SBM, the corpus medullare was not different, and the anterior lobe was significantly enlarged. Children with thoracic level lesions had smaller cerebellar volumes relative to those with lumbar/sacral lesions, who had smaller volumes compared to TD children. The reduction in cerebellar volume in the group with SBM represents not a change in linear scaling but rather a reconfiguration involving anterior lobe enlargement and posterior lobe reduction.


Memory and cognitive control in task switching.
Cognitive control and memory are fundamentally intertwined, but interactions between the two have only recently received sustained research interest. In the study reported here, we used a novel paradigm to investigate how control influences memory encoding and, conversely, how memory measures can provide new insight into flexible cognitive control. Participants switched between classifying objects and words, then were tested for their recognition memory of items presented in this task-switching phase. Task switching impaired memory for task-relevant information but actually improved memory for task-irrelevant information, which indicates that control demands reduced the selectivity of memory encoding rather than causing a general memory decline. Recognition memory strength provided a robust trial-by-trial measure of the effectiveness of cognitive control that "predicted" earlier task-switching performance. It also revealed a substantial influence of bottom-up factors on between-task competition, but only on trials in which participants had to switch from one type of classification to the other. Collectively, our findings illustrate how cognitive control and bottom-up factors interact to simultaneously influence both current performance and future memory.


Paradoxical results of adaptive false discovery rate procedures in neuroimaging studies.
Adaptive false discovery rate (FDR) procedures, which offer greater power than the original FDR procedure of Benjamini and Hochberg, are often applied to statistical maps of the brain. When a large proportion of the null hypotheses are false, as in the case of widespread effects such as cortical thinning throughout much of the brain, adaptive FDR methods can surprisingly reject more null hypotheses than not accounting for multiple testing at all-i.e., using uncorrected p-values. A straightforward mathematical argument is presented to explain why this can occur with the q-value method of Storey and colleagues, and a simulation study shows that it can also occur, to a lesser extent, with a two-stage FDR procedure due to Benjamini and colleagues. We demonstrate the phenomenon with reference to a published data set documenting cortical thinning in attention deficit/hyperactivity disorder. The paper concludes with recommendations for how to proceed when adaptive FDR results of this kind are encountered in practice.


Use of Atomized Intranasal Tranexamic Acid as an Adjunctive Therapy in Difficult-to-Treat Epistaxis.
There is a growing body of literature on the safe, effective use of tranexamic acid (TXA) for hemostasis in a variety of clinical settings. We present a case series of three patients with difficult-to-treat epistaxis where standard treatment methods were not effective. Using atomized intranasal TXA (ATXA) as part of a stepwise treatment approach, we were able to achieve hemostasis and manage all three cases independently, and we did so without major complications in our emergency department (ED). Given recent literature showing the underuse of TXA in combat casualties, ATXA, if formulated and delivered properly, may be of benefit for epistaxis and other significant hemorrhage cases. Further work must be done to elucidate the mechanism of action, specific dose, delivery method, use indications, and safety profile of ATXA.


Validation study of medicare claims to identify older US adults with CKD using the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study.
Health care claims data may provide a cost-efficient approach for studying chronic kidney disease (CKD). Prospective cohort study. We compared characteristics and outcomes for individuals with CKD defined using laboratory measurements versus claims data from 6,982 REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study participants who had Medicare fee-for-service coverage. Presence of CKD as defined by both the REGARDS Study (CKDREGARDS) and Medicare data (CKDMedicare), presence of CKDREGARDS but not CKDMedicare, and presence of CKDMedicare but not CKDREGARDS, and absence of both CKDREGARDS and CKDMedicare. Mortality and incident end-stage renal disease (ESRD). The research study definition of CKD (CKDREGARDS) included estimated glomerular filtration rate (eGFR) < 60mL/min/1.73m(2) or albumin-creatinine ratio > 30mg/g at the REGARDS Study visit. CKD in Medicare (CKDMedicare) was identified during the 2 years before each participant's REGARDS visit using a claims-based algorithm. Overall, 32% of participants had CKDREGARDS and 6% had CKDMedicare. Sensitivity, specificity, and positive and negative predictive values of CKDMedicare for identifying CKDREGARDS were 15.5% (95% CI, 14.0%-17.1%), 97.7% (95% CI, 97.2%-98.1%), 75.6% (95% CI, 71.4%-79.5%), and 71.5% (95% CI, 70.4%-72.6%), respectively. Mortality and ESRD incidence rates, expressed per 1,000 person-years, were higher for participants with versus without CKDMedicare (mortality: 72.5 [95% CI, 61.3-83.7] vs 33.3 [95% CI, 31.5-35.2]; ESRD: 16.4 [95% CI, 11.2-21.6] vs 1.3 [95% CI, 0.9-1.6]) and with versus without CKDREGARDS (mortality: 59.9 [95% CI, 55.4-64.4] vs 25.5 [95% CI, 23.6-27.4]; ESRD: 6.8 [95% CI, 5.4-8.3] vs 0.1 [95% CI, 0.0-0.3]). Among participants with CKDREGARDS, those with abdominal obesity, diabetes, anemia, lower eGFR, more outpatient visits, hospitalization, and a nephrologist visit in the 2 years before their REGARDS visit were more likely to have CKDMedicare. CKDREGARDS relied on eGFR and albuminuria assessed at a single visit. CKD, whether defined in claims or through research study measurements, was associated with increased mortality and ESRD. However, individuals with CKD identified in claims may represent a select high-risk population.


Identification and characterization of 20 novel pathogenic variants in 60 unrelated Indian patients with mucopolysaccharidoses type I and type II.
Mucopolysaccharidoses (MPS), a subgroup of lysosomal storage disorders, are caused due to deficiency of specific lysosomal enzyme involved in catabolism of glycosaminoglycans. To date more than 200 pathogenic variants in the alpha-l-iduronidase (IDUA) for MPS I and ∼500 pathogenic variants in the iduronate-2-sulphatase (IDS) for MPS II have been reported worldwide. The mutation spectrum of MPS type I and MPS type II disorders in Indian population is not characterized yet. In this study, we carried out clinical, biochemical, molecular and in silico analyses to establish the mutation spectrum of MPS I and MPS II in the Indian population. We conducted molecular analysis for 60 MPS-affected patients [MPS I (n = 30) (Hurler syndrome = 17, Hurler-Scheie syndrome = 13), and MPS II (n = 30) (severe = 18, attenuated = 12)] and identified a total of 44 [MPS I (n = 22) and MPS II (n = 22)] different pathogenic variants comprising missense, nonsense, frameshift, gross deletions and splice site variants. A total of 20 [MPS I (n = 14), and MPS II (n = 6)] novel pathogenic sequence variants were identified in our patient cohort. We found that 32% of pathogenic variants detected in IDUA were recurrent and 25% in MPS II. This is the first study revealing the mutation spectrum of MPS I and MPS II patients in the Indian population.


Spondylocheiro dysplastic form of the Ehlers-Danlos syndrome--an autosomal-recessive entity caused by mutations in the zinc transporter gene SLC39A13.
We present clinical, radiological, biochemical, and genetic findings on six patients from two consanguineous families that show EDS-like features and radiological findings of a mild skeletal dysplasia. The EDS-like findings comprise hyperelastic, thin, and bruisable skin, hypermobility of the small joints with a tendency to contractures, protuberant eyes with bluish sclerae, hands with finely wrinkled palms, atrophy of the thenar muscles, and tapering fingers. The skeletal dysplasia comprises platyspondyly with moderate short stature, osteopenia, and widened metaphyses. Patients have an increased ratio of total urinary pyridinolines, lysyl pyridinoline/hydroxylysyl pyridinoline (LP/HP), of approximately 1 as opposed to approximately 6 in EDS VI or approximately 0.2 in controls. Lysyl and prolyl residues of collagens were underhydroxylated despite normal lysyl hydroxylase and prolyl 4-hydroxylase activities; underhydroxylation was a generalized process as shown by mass spectrometry of the alpha1(I)- and alpha2(I)-chain-derived peptides of collagen type I and involved at least collagen types I and II. A genome-wide SNP scan and sequence analyses identified in all patients a homozygous c.483_491 del9 SLC39A13 mutation that encodes for a membrane-bound zinc transporter SLC39A13. We hypothesize that an increased Zn(2+) content inside the endoplasmic reticulum competes with Fe(2+), a cofactor that is necessary for hydroxylation of lysyl and prolyl residues, and thus explains the biochemical findings. These data suggest an entity that we have designated "spondylocheiro dysplastic form of EDS (SCD-EDS)" to indicate a generalized skeletal dysplasia involving mainly the spine (spondylo) and striking clinical abnormalities of the hands (cheiro) in addition to the EDS-like features.


Developments in pharmacotherapy for tobacco dependence: past, present and future.
In the mid-1970s there were no effective pharmacological treatments for tobacco dependence. The invention of nicotine gum was a major treatment advance and also greatly helped our understanding of the nature of tobacco dependence. There are now eight effective pharmacotherapies (nicotine gum, patch, nasal spray, inhaler, lozenge/tablet, bupropion, nortriptyline and clonidine) available to aid smoking cessation. Other non-nicotine agents that show promise are under investigation, including glucose, rimonabant, selegiline and varenicline. Greater knowledge of the mechanisms of action of the effective non-nicotine agents should lead to better understanding of the nature of tobacco dependence. Future research into optimal treatments should examine long-term combination pharmacotherapy combined with improved psychosocial support that is partly designed to enhance medication compliance. In addition, there is a need for studies designed to evaluate the efficacy of pharmacotherapies in populations such as youth, pregnant smokers and smokers with co-occurring mental health problems.


Solution-Processable BODIPY-Based Small Molecules for Semiconducting Microfibers in Organic Thin-Film Transistors.
Electron-deficient π-conjugated small molecules can function as electron-transporting semiconductors in various optoelectronic applications. Despite their unique structural, optical, and electronic properties, the development of BODIPY-based organic semiconductors has lagged behind that of other π-deficient units. Here, we report the design and synthesis of two novel solution-proccessable BODIPY-based small molecules (BDY-3T-BDY and BDY-4T-BDY) for organic thin-film transistors (OTFTs). The new semiconductors were fully characterized by (1)H/(13)C NMR, mass spectrometry, cyclic voltammetry, UV-vis spectroscopy, photoluminescence, differential scanning calorimetry, and thermogravimetric analysis. The single-crystal X-ray diffraction (XRD) characterization of a key intermediate reveals crucial structural properties. Solution-sheared top-contact/bottom-gate OTFTs exhibited electron mobilities up to 0.01 cm(2)/V·s and current on/off ratios of >10(8). Film microstructural and morphological characterizations indicate the formation of relatively long (∼0.1 mm) and micrometer-sized (1-2 μm) crystalline fibers for BDY-4T-BDY-based films along the shearing direction. Fiber-alignment-induced charge-transport anisotropy (μ∥/μ⊥ ≈ 10) was observed, and higher mobilities were achieved when the microfibers were aligned along the conduction channel, which allows for efficient long-range charge-transport between source and drain electrodes. These OTFT performances are the highest reported to date for a BODIPY-based molecular semiconductor, and demonstrate that BODIPY is a promising building block for enabling solution-processed, electron-transporting semiconductor films.


Characterization of calretinin-immunoreactive structures in the striatum of the rat.
Previous observations have shown that the striatum contains a population of neurones that display immunoreactivity for calretinin. In order to morphologically characterize these neurones, sections of the rat striatum were immunostained to reveal calretinin and examined at both light and electron microscopic levels. The striatum contained a small population of calretinin-immunoreactive neurones, which were of medium-size (9-17 microns) and possessed few aspiny, infrequently branching dendrites which tapered to become very thin processes in their most distal portions. Although the calretinin-immunoreactive neurones were homogeneously distributed in the frontal plane, there was a marked rostrocaudal gradient with a much greater density of cells in the rostral than in the caudal parts of the striatum. At the ultrastructural level, calretinin-immunoreactive neurones were seen to possess an indented nucleus and to receive synaptic input from at least three types of boutons. In addition to the calretinin-immunoreactive neurones, the striatum also contained axons and terminal boutons that displayed immunoreactivity for calretinin. At least two types of immunoreactive terminals were identified, those forming symmetrical synaptic specialisations and those forming asymmetrical synaptic specialisations. Approximately 50% formed asymmetrical contacts with spines and 30% formed symmetrical synaptic contact with dendritic shafts. In an attempt to further chemically characterize the calretinin-containing neurones, double pre-embedding immunocytochemistry for calretinin and parvalbumin or choline acetyltransferase was carried out and calretinin immunocytochemistry was combined with histochemistry for NADPH-diaphorase. Analysis of these double-stained sections revealed that the population of calretinin-immunoreactive neurones was distinct from the populations of neurones containing parvalbumin, choline acetyltransferase or NADPH-diaphorase. It is concluded that: (1) on the basis of distribution, morphology, chemistry, ultrastructure and afferent synaptic input, the calretinin-immunoreactive neurones are distinct from the major classes of neurones that have been previously recognised in the striatum; (2) calretinin-immunoreactive terminals are heterogeneous and are probably derived from local calretinin-containing neurones and possibly other sources.