Knowledge and Outcome Measure of HbA1c Testing in Asian Indian Patients with Type 2 Diabetes from a Tertiary Care Center.
HbA1c test is considered to be the reliable measure for evaluating long-term glycemic control in type 2 diabetes. The purpose of this study was to evaluate whether knowledge about HbA1c test is associated with a better glycemic control. We conducted a cross-sectional survey of 480 (M:F; 287:193) adults with type 2 diabetes attending a tertiary care center during a period of four months. Baseline demographic and clinical data of all the subjects was obtained. Subject's knowledge about HbA1c test and their target goal was assessed using a questionnaire. Recent HbA1c results were obtained from medical records. Seventy four per cent of the subjects had awareness about HbA1c test and about 43% of those who knew HbA1c test also knew their target goal. 33% remember their last HbA1c result. The mean A1C of Group A was significantly lower when compared with Group B (8.1 ± 1.7 vs 9.2 ± 1.9, P<0.0001). Group C had lower A1C levels compared to Group D (7.7 ± 1.4 vs 8.5 ± 1.9, p<0.0001). Patients who kept their HbA1c less than 7% were significantly higher in Group C than in Group D. (37.8 vs 12.7%, p<0.00001). Subjects had good glycemic control with increasing levels of awareness about HbA1c. Majority of the diabetic patients who attended the tertiary care center for diabetes care knew HbA1c test and half of them were aware about their target goal. Awareness about HbA1c had a positive impact on maintenance of better glycemic control.


Single terrace growth of graphene on a metal surface.
The epitaxial growth of graphene by chemical vapor deposition of ethylene on a Ru(0001) surface was monitored by high-temperature scanning tunneling microscopy. The in situ data show that at low pressures and high temperatures the metal surface facets into large terraces, leading to much better ordered graphene layers than resulting from the known growth mode. Density functional theory calculations show that the single terrace growth mode can be understood from the energetics of the graphene-metal interaction.


Drinking or Smoking While Breastfeeding and Later Cognition in Children.
Although prenatal alcohol and nicotine exposure are associated with reduced cognition in children, associations between consumption of alcohol during lactation and cognition have not been examined. We aimed to examine whether drinking or smoking while breastfeeding lowers children's cognitive scores. We hypothesized that increased drinking or smoking would be associated with dose-dependent cognitive reductions. Data were sourced from Growing Up in Australia: The Longitudinal Study of Australian Children. Participants were 5107 Australian infants recruited in 2004 and assessed every 2 years. Multivariable linear regression analyses assessed relationships between drinking and smoking habits of breastfeeding mothers and children's Matrix Reasoning, Peabody Picture Vocabulary Test-Third Edition and Who Am I? scores at later waves. Increased or riskier wave 1 maternal alcohol consumption was associated with reductions in Matrix Reasoning scores at age 6 to 7 years in children who had been breastfed (B = -0.11; SE = 0.03; 95% confidence interval: -0.18 to -0.04; P = .01). This relationship was not evident in infants who had never breastfed (B = -0.02; SE = 0.10; 95% confidence interval = -0.20 to 0.17; P = .87). Smoking during lactation was not associated with any outcome variable. Exposing infants to alcohol through breastmilk may cause dose-dependent reductions in their cognitive abilities. This reduction was observed at age 6 to 7 years but was not sustained at age 10 to 11 years. Although the relationship is small, it may be clinically significant when mothers consume alcohol regularly or binge drink. Further analyses will assess relationships between alcohol consumption or tobacco smoking during lactation and academic, developmental, physical, and behavioral outcomes in children.


Analysis of the asymmetrically expressed Ablim1 locus reveals existence of a lateral plate Nodal-independent left sided signal and an early, left-right independent role for nodal flow.
Vertebrates show clear asymmetry in left-right (L-R) patterning of their organs and associated vasculature. During mammalian development a cilia driven leftwards flow of liquid leads to the left-sided expression of Nodal, which in turn activates asymmetric expression of the transcription factor Pitx2. While Pitx2 asymmetry drives many aspects of asymmetric morphogenesis, it is clear from published data that additional asymmetrically expressed loci must exist. A L-R expression screen identified the cytoskeletally-associated gene, actin binding lim protein 1 (Ablim1), as asymmetrically expressed in both the node and left lateral plate mesoderm (LPM). LPM expression closely mirrors that of Nodal. Significantly, Ablim1 LPM asymmetry was detected in the absence of detectable Nodal. In the node, Ablim1 was initially expressed symmetrically across the entire structure, resolving to give a peri-nodal ring at the headfold stage in a flow and Pkd2-dependent manner. The peri-nodal ring of Ablim1 expression became asymmetric by the mid-headfold stage, showing stronger right than left-sided expression. Node asymmetry became more apparent as development proceeded; expression retreated in an anticlockwise direction, disappearing first from the left anterior node. Indeed, at early somite stages Ablim1 shows a unique asymmetric expression pattern, in the left lateral plate and to the right side of the node. Left LPM Ablim1 is expressed in the absence of detectable LPM Nodal, clearly revealing existence of a Pitx2 and Nodal-independent left-sided signal in mammals. At the node, a previously unrecognised action of early nodal flow and Pkd2 activity, within the pit of the node, influences gene expression in a symmetric manner. Subsequent Ablim1 expression in the peri-nodal ring reveals a very early indication of L-R asymmetry. Ablim1 expression analysis at the node acts as an indicator of nodal flow. Together these results make Ablim1 a candidate for controlling aspects of L-R identity and patterning.


Introduced and native congeners use different resource allocation strategies to maintain performance during infection.
Abstract Hosts can manage parasitic infections using an array of tactics, which are likely to vary contingent on coevolutionary history between the host and the parasite. Here we asked whether coping ability of congeners that differ in host-parasite coevolutionary history differed in response to experimental infections with a coccidian parasite. House sparrows (Passer domesticus) and gray-headed sparrows (Passer griseus) are sympatric and ecologically similar, but house sparrows are recent colonizers of Kenya, the site of our comparison, whereas gray-headed sparrows are native. We evaluated three variables as barometers of infection coping ability: vertical flight, pectoral muscle size, and fat score. We also measured routing of a dose of (13)C-labeled leucine, an essential amino acid, among tissues to compare resource allocation strategies in response to infection. We found that burden effects on performance were minimal in both species, but house sparrows maintained considerably higher burdens than gray-headed sparrows regardless of exposure. House sparrows also had more exogeneous leucine tracer in all tissues after 24 h, demonstrating a difference in the way the two species allocate or distribute resources. We argue that house sparrows may be maintaining larger resource reserves to mitigate costs associated with exposure and infection. Additionally, in response to increased parasite exposure, gray-headed sparrows had less leucine tracer in their spleens and more in their gonads, whereas house sparrows did not change allocation, perhaps indicating a trade-off that is not experienced by the introduced species.


Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: systematic review and meta-analysis of randomized trials.
To evaluate the outcomes with use of renin angiotensin system (RAS) blockers compared with other antihypertensive agents in people with diabetes. Meta-analysis. PubMed, Embase, and the Cochrane central register of controlled trials databases for randomized trials of RAS blockers versus other antihypertensive agents in people with diabetes mellitus. Outcomes were death, cardiovascular death, myocardial infarction, angina, stroke, heart failure, revascularization, and end stage renal disease. The search yielded 19 randomized controlled trials that enrolled 25,414 participants with diabetes for a total of 95,910 patient years of follow-up. When compared with other antihypertensive agents, RAS blockers were associated with a similar risk of death (relative risk 0.99, 95% confidence interval 0.93 to 1.05), cardiovascular death (1.02, 0.83 to 1.24), myocardial infarction (0.87, 0.64 to 1.18), angina pectoris (0.80, 0.58 to 1.11), stroke (1.04, 0.92 to 1.17), heart failure (0.90, 0.76 to 1.07), and revascularization (0.97, 0.77 to 1.22). There was also no difference in the hard renal outcome of end stage renal disease (0.99, 0.78 to 1.28) (power of 94% to show a 23% reduction in end stage renal disease). In people with diabetes, RAS blockers are not superior to other antihypertensive drug classes such as thiazides, calcium channel blockers, and β blockers at reducing the risk of hard cardiovascular and renal endpoints. These findings support the recommendations of the guidelines of the European Society of Cardiology/European Society of Hypertension and eighth Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure to also use other antihypertensive agents in people with diabetes but without kidney disease.


Role of calcium in the fade of the potassium release response in the rat parotid gland.
1. The 86Rb release response in the parotid due to alpha-adrenergic (epinephrine), muscarinic (carbachol) or peptide (Substance P) receptor activation exhibited 'fade': a return of efflux to control levels despite the continuing presence of agonist. 2. The time course of fade of the response to all three agonists was independent of the concentration of the agonist. 3. After fade was fully developed to one agonist, the response to an agonist acting on a different receptor was either absent or greatly diminished. 4. Removal of carbachol from muscarinic receptors with atropine 10 min prior to Substance P partially restored the ability of Substance P to produce a response. 5. Fade of the response with all three agonists was greatly retarded by the omission of Ca. 6. release of alpha-amylase did not appear to fade following exposure to carbachol or Substance P. 7. It is concluded that the K+ release response may be inactivated with time due to diminution in responsiveness of the K+ channel to an increase in internal Ca2+.


Puf1p acts in combination with other yeast Puf proteins to control mRNA stability.
The eukaryotic Puf proteins bind 3' untranslated region (UTR) sequence elements to regulate the stability and translation of their target transcripts, and such regulatory events are critical for cell growth and development. Several global genome analyses have identified hundreds of potential mRNA targets of the Saccharomyces cerevisiae Puf proteins; however, only three mRNA targets for these proteins have been characterized thus far. After direct testing of nearly 40 candidate mRNAs, we established two of these as true mRNA targets of Puf-mediated decay in yeast, HXK1 and TIF1. In a novel finding, multiple Puf proteins, including Puf1p, regulate both of these mRNAs in combination. TIF1 mRNA decay can be stimulated individually by Puf1p and Puf5p, but the combination of both proteins is required for full regulation. This Puf-mediated decay requires the presence of two UGUA binding sites within the TIF1 3' UTR, with one site regulated by Puf5p and the other by both Puf1p and Puf5p. Alteration of the UGUA site in the tif1 3' UTR to more closely resemble the Puf3p binding site broadens the specificity to include regulation by Puf3p. The stability of the endogenously transcribed HXK1 mRNA, cellular levels of Hxk1 protein activity, and HXK1 3' UTR-directed decay are affected by Puf1p and Puf5p as well as Puf4p. Together these results identify the first mRNA targets of Puf1p-mediated decay, describe similar yet distinct combinatorial control of two new target mRNAs by the yeast Puf proteins, and suggest the importance of direct testing to evaluate RNA-regulatory mechanisms.


Acellular Dermal Matrix as a Core Strut for Projection in Nipple Reconstruction: Approaches for Three Different Methods of Breast Reconstruction.
The objective of this paper was to describe a novel technique for improving the maintenance of nipple projection in primary nipple reconstruction by using acellular dermal matrix as a strut in one of three different configurations, according to the method of prior breast reconstruction. The struts were designed to best fill the different types of dead spaces in nipple reconstruction depending on the breast reconstruction method. A total of 50 primary nipple reconstructions were performed between May 2012 and May 2015. The prior breast reconstruction methods were latissimus dorsi (LD) flap (28 cases), transverse rectus abdominis myocutaneous (TRAM) flap (10 cases), or tissue expander/implant (12 cases). The nipple reconstruction technique involved the use of local flaps, including the C-V flap or star flap. A 1×2-cm acellular dermal matrix was placed into the core with O-, I-, and L-shaped struts for prior LD, TRAM, and expander/implant methods, respectively. The projection of the reconstructed nipple was measured at the time of surgery and at 3, 6, and 9 months postoperatively. The nine-month average maintenance of nipple projection was 73.0%±9.67% for the LD flap group using an O-strut, 72.0%±11.53% for the TRAM flap group using an I-strut, and 69.0%±10.82% for the tissue expander/implant group using an L-strut. There were no cases of infection, wound dehiscence, or flap necrosis. The application of an acellular dermal matrix with a different kind of strut for each of 3 breast reconstruction methods is an effective addition to current techniques for improving the maintenance of long-term projection in primary nipple reconstruction.


Wavefront-Guided Versus Wavefront-Optimized Photorefractive Keratectomy: Visual and Military Task Performance.
To compare visual performance, marksmanship performance, and threshold target identification following wavefront-guided (WFG) versus wavefront-optimized (WFO) photorefractive keratectomy (PRK). In this prospective, randomized clinical trial, active duty U.S. military Soldiers, age 21 or over, electing to undergo PRK were randomized to undergo WFG (n = 27) or WFO (n = 27) PRK for myopia or myopic astigmatism. Binocular visual performance was assessed preoperatively and 1, 3, and 6 months postoperatively: Super Vision Test high contrast, Super Vision Test contrast sensitivity (CS), and 25% contrast acuity with night vision goggle filter. CS function was generated testing at five spatial frequencies. Marksmanship performance in low light conditions was evaluated in a firing tunnel. Target detection and identification performance was tested for probability of identification of varying target sets and probability of detection of humans in cluttered environments. Visual performance, CS function, marksmanship, and threshold target identification demonstrated no statistically significant differences over time between the two treatments. Exploratory regression analysis of firing range tasks at 6 months showed no significant differences or correlations between procedures. Regression analysis of vehicle and handheld probability of identification showed a significant association with pretreatment performance. Both WFG and WFO PRK results translate to excellent and comparable visual and military performance.


Atrazine concentrations, gonadal gross morphology and histology in ranid frogs collected in Michigan agricultural areas.
The triazine herbicide atrazine has been suggested to be a potential disruptor of normal sexual development in male frogs. The goals of this study were to collect native ranid frogs from sites in agricultural and non-agricultural areas and determine whether hypothesised atrazine effects on the gonads could be observed at the gross morphological and histological levels. Juvenile and adult green frogs (Rana clamitans), bullfrogs (R. catesbeiana) and leopard frogs (R. pipiens) were collected in the summers of 2002 and 2003. Atrazine concentrations were below the limit of quantification at non-agricultural sites, and concentrations did not exceed 2 microg/L at most agricultural sites. One concentration greater than 200 microg atrazine/L was measured once at one site in 2002. Hermaphroditic individuals with both male and female gonad tissue in either one or both gonads, were found at a low incidence at both non-agricultural and agricultural sites, and in both adults and juveniles. Testicular oocytes (TO) were found in male frogs at most of the sites, with the greatest incidence occurring in juvenile leopard frogs. TO incidence was not significantly different between agricultural and non-agricultural sites with the exception of juveniles collected in 2003. Atrazine concentrations were not significantly correlated with the incidence of hermaphroditism, but maximum atrazine concentrations were correlated with TO incidence in juvenile frogs in 2003. However, given the lack of a consistent relationship between atrazine concentrations and TO incidence, it is more likely the TOs observed in this study result from natural processes in development rather than atrazine exposure.


A new inborn error of glycosylation due to a Cog8 deficiency reveals a critical role for the Cog1-Cog8 interaction in COG complex formation.
The hetero-octameric conserved oligomeric Golgi (COG) complex is essential for the structure/function of the Golgi apparatus through regulation of membrane trafficking. Here, we describe a patient with a mild form of a congenital disorder of glycosylation type II (CDG-II), which is caused by a homozygous nonsense mutation in the hCOG8 gene. This leads to a premature stop codon resulting in a truncated Cog8 subunit lacking the 76 C-terminal amino acids. Mass spectrometric analysis of the N- and O-glycan structures identified a mild sialylation deficiency. We showed that the molecular basis of this defect in N- and O-glycosylation is caused by the disruption of the Cog1-Cog8 interaction due to truncation. As a result, Cog1 deficiency accompanies the Cog8 deficiency, preventing assembly of the intact, stable complex and resulting in the appearance of smaller subcomplexes. Moreover, levels of beta1,4-galactosytransferase were significantly reduced. The defects in O-glycosylation could be fully restored by transfecting the patient's fibroblasts with full-length Cog8. The Cog8 defect described here represents a novel type of CDG-II, which we propose to name as CDG-IIh or CDG caused by Cog8 deficiency (CDG-II/Cog8).


Mitogen-Activated Protein Kinases (MAPKs) and Cholangiocarcinoma: The Missing Link.
In recent years, the incidence of both liver and biliary tract cancer has increased. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the two most common types of hepatic malignancies. Whereas HCC is the fifth most common malignant tumor in Western countries, the prevalence of CCA has taken an alarming increase from 0.3 to 2.1 cases per 100,000 people. The lack of specific biomarkers makes diagnosis very difficult in the early stages of this fatal cancer. Thus, the prognosis of CCA is dismal and surgery is the only effective treatment, whilst recurrence after resection is common. Even though chemotherapy and radiotherapy may prolong survival in patients with CCA, the 5-year survival rate is still very low-a significant global problem in clinical diagnosis and therapy. The mitogen-activated protein kinase (MAPK) pathway plays an important role in signal transduction by converting extracellular stimuli into a wide range of cellular responses including inflammatory response, stress response, differentiation, survival, and tumorigenesis. Dysregulation of the MAPK cascade involves key signaling components and phosphorylation events that play an important role in tumorigenesis. In this review, we discuss the pathophysiological role of MAPK, current therapeutic options, and the current situation of MAPK-targeted therapies in CCA.


Towards an in vitro model mimicking the foreign body response: tailoring the surface properties of biomaterials to modulate extracellular matrix.
Despite various studies to minimize host reaction following a biomaterial implantation, an appealing strategy in regenerative medicine is to actively use such an immune response to trigger and control tissue regeneration. We have developed an in vitro model to modulate the host response by tuning biomaterials' surface properties through surface modifications techniques as a new strategy for tissue regeneration applications. Results showed tunable surface topography, roughness, wettability, and chemistry by varying treatment type and exposure, allowing for the first time to correlate the effect of these surface properties on cell attachment, morphology, strength and proliferation, as well as proinflammatory (IL-1β, IL-6) and antiinflammatory cytokines (TGF-β1, IL-10) secreted in medium, and protein expression of collagen and elastin. Surface microstructuring, derived from chloroform partial etching, increased surface roughness and oxygen content. This resulted in enhanced cell adhesion, strength and proliferation as well as a balance of soluble factors for optimum collagen and elastin synthesis for tissue regeneration. By linking surface parameters to cell activity, we could determine the fate of the regenerated tissue to create successful soft tissue-engineered replacement.


Applicability of Dynamic Facilitation Theory to Binary Hard Disk Systems.
We numerically investigate the applicability of dynamic facilitation (DF) theory for glass-forming binary hard disk systems where supercompression is controlled by pressure. By using novel efficient algorithms for hard disks, we are able to generate equilibrium supercompressed states in an additive nonequimolar binary mixture, where microcrystallization and size segregation do not emerge at high average packing fractions. Above an onset pressure where collective heterogeneous relaxation sets in, we find that relaxation times are well described by a "parabolic law" with pressure. We identify excitations, or soft spots, that give rise to structural relaxation and find that they are spatially localized, their average concentration decays exponentially with pressure, and their associated energy scale is logarithmic in the excitation size. These observations are consistent with the predictions of DF generalized to systems controlled by pressure rather than temperature.


Design of high-activity mutants of human butyrylcholinesterase against (-)-cocaine: structural and energetic factors affecting the catalytic efficiency.
The present study was aimed to explore the correlation between the protein structure and catalytic efficiency of butyrylcholinesterase (BChE) mutants against (-)-cocaine by modeling the rate-determining transition state (TS1), i.e., the transition state for the first step of chemical reaction process, of (-)-cocaine hydrolysis catalyzed by various mutants of human BChE in comparison with the wild type. Molecular modeling of the TS1 structures revealed that mutations on certain nonactive site residues can indirectly affect the catalytic efficiency of the enzyme against (-)-cocaine through enhancing or weakening the overall hydrogen bonding between the carbonyl oxygen of (-)-cocaine benzoyl ester and the oxyanion hole of the enzyme. Computational insights and predictions were supported by the catalytic activity data obtained from wet experimental tests on the mutants of human BChE, including five new mutants reported for the first time. The BChE mutants with at least ∼1000-fold improved catalytic efficiency against (-)-cocaine compared to the wild-type BChE are all associated with the TS1 structures having stronger overall hydrogen bonding between the carbonyl oxygen of (-)-cocaine benzoyl ester and the oxyanion hole of the enzyme. The combined computational and experimental data demonstrate a reasonable correlation relationship between the hydrogen-bonding distances in the TS1 structure and the catalytic efficiency of the enzyme against (-)-cocaine.


Executive function and memory in relation to olfactory deficits in alcohol-dependent patients.
Prior research indicates that chronic alcoholism is accompanied by olfactory deficits. These have been suggested to reflect dysfunctions in olfactory brain regions. The present study investigated the role of neurocognitive functioning in tests (executive function and memory) sensitive to the functional integrity of brain areas that are crucial to olfactory processing in patients with alcohol dependence. Performance on olfactory functions (detection threshold, quality discrimination, identification), executive function (Wisconsin Card Sorting Test), and memory (German version of the California Verbal Learning Test) was assessed in 32 alcohol-dependent patients and 30 healthy comparison subjects, comparable in age, gender, and smoking status. Compared with controls, alcohol-dependent patients were impaired in all 3 domains, olfactory functions, executive function, and memory. In patients, olfactory discrimination ability was positively correlated with executive function performance. Regression analyses conducted to clarify the relation between group (patients vs controls), executive function, memory, and olfactory functions indicated that group was the only significant predictor of olfactory detection threshold and identification, and both group and executive function were found to be the significant predictors of olfactory discrimination. Olfactory deficits in alcohol dependence appear to be associated with prefrontal cognitive dysfunction. Results indicate that olfactory quality discrimination deficits are related to executive function impairment. These findings add to the available research on frontal lobe dysfunction in alcoholism, suggesting that alcohol-related olfactory discrimination deficits may be associated with impairment in the functional integrity of the prefrontal lobe.


Health Care Supervision for Children With Williams Syndrome.
This set of recommendations is designed to assist the pediatrician in caring for children with Williams syndrome (WS) who were diagnosed by using clinical features and with chromosome 7 microdeletion confirmed by fluorescence in situ hybridization, chromosome microarray, or multiplex ligation-dependent probe amplification. The recommendations in this report reflect review of the current literature, including previously peer-reviewed and published management suggestions for WS, as well as the consensus of physicians and psychologists with expertise in the care of individuals with WS. These general recommendations for the syndrome do not replace individualized medical assessment and treatment.


Correlation between the clinic and the index of cervical myelopathy Torg.
Cervical myelopathy is a spinal cord dysfunction related to degeneration typical of aging. Its primary pathology is related to ischemia and spinal cord compression. Patients with myelopathy present many clinical problems; more severe cases may lead to quadriplegia if not treated in a timely manner. Because the primary pathology of this disease is caused by compression, thus generating spinal cord ischemia, we believed there must be a correlation between the degree of compression and the clinical assessment of patients with cervical myelopathy, but we did not find any study in the literature that made this correlation. Because there is doubt the literature we aimed, in our study, to analyze the correlation between the degree of clinical impairment of patients with cervical myelopathy and the Torg index. A prospective, descriptive study, evaluating 46 patients, in which radiographic measurements of the Torg index were performed, with clinical analysis through the Nurick and JOA scale. Of the 46 study patients included in the study, 100% presented a Torg score <0.8. The decrease in Torg values was directly proportional to clinical worsening on the Nurick and JOA scale. The degree of clinical impairment in patients with cervical myelopathy is directly related to the degree of spinal canal stenosis. Level of Evidence I, Prognostic Studies - Investigating the effect of the characteristics of a patient on the outcome of the disease.


Anterior Urethra Reconstruction With Lateral Lingual Mucosa Harvesting Technique.
To describe a new technique for harvesting the long lingual mucosal graft (LMG) to repair the long-segment urethral strictures. We performed a retrospective observational study of patients from whom LMGs were harvested from the lateral lining of the tongue for the long-segment anterior urethral strictures repair from 2012 to 2014 at the Shanghai Sixth People's Hospital. Patients who had 12 months minimum follow-up were included. Patients with incomplete clinical records were excluded. The LMG was applied on the urethra according to the dorsal onlay technique. The primary outcome of the study was the postoperative failure-free survival rate. The secondary outcome was the rate of early and late complications at the harvesting site. Success was defined as Qmax >12 ml/s and no postoperative procedures. One hundred and one patients were included. Median stricture length was 7.1 ± 3.6 cm; median LMG length was 7.2 ± 3.6 cm. The success rate was 81.2% with a median follow-up of 23 months. Complications at the donor site had occurred in 41 patients at 6-months follow-up, and persisted in 18 patients at the 12-months follow-up. A bilateral harvest and harvest length were the main factors influencing complication rate (P = .0038 for 6 months and P = .1112 for 12 months). Almost half of donor site complications subsided within 12 months (P = .0018). In patients requiring long oral grafts >7 cm to repair anterior strictures, a valid option is to harvest the graft from the lateral lining of the tongue.


Costimulator deficient antigen presentation by an endothelial cell line induces a nonproliferative T cell activation response without anergy.
The ability of endothelial cells to activate helper T (Th) cells by antigen presentation was studied using the murine endothelial cell line SVEC4-10 and antigen-specific murine T cell clones. SEVEC4-10 cells constitutively express vascular cell adhesion molecule 1 but not intercellular adhesion molecule 1. Interferon gamma (IFN-gamma) treatment of these cells induced class II major histocompatibility complex (MHC) expression and antigen-presenting capabilities, but did not alter surface integrin expression. IFN-gamma-treated SVEC4-10 cells were competent at mediating antigen-dependent cytokine production and proliferation of a Th2 clone. In contrast, endothelial antigen presentation to Th1 cells did not stimulate T cell proliferation. The addition of MHC mismatched spleen cells as a source of costimulatory molecules resulted in the ability of the endothelial cells to stimulate Th1 cell proliferation in an antigen-specific manner. The failure of the endothelial cell line alone to support Th1 cell proliferation correlated with the failure to stimulate interleukin 2 (IL-2) gene expression. T cell exposure to the endothelial cells plus antigen resulted in upregulation of IL-2 receptors and an enhanced response to subsequent antigen presentation by splenic antigen-presenting cells. Despite the lack of functional costimulators for IL-2 expression, antigen presentation by the endothelial cell line did not induce Th1 cell anergy, indicating that costimulator deficiency for IL-2 expression is not obligatorily linked to anergy induction. Thus, endothelial cells are capable of presenting antigens to helper T lymphocytes, but stimulate only partial T cell responses. These partial responses may serve to selectively stimulate transmigration of antigen-specific T cells and may enhance functional responses upon subsequent, extravascular antigen exposure.


A novel combined biomarker including plasma carotenoids, vitamin C, and ferric reducing antioxidant power is more strongly associated with fruit and vegetable intake than the individual components.
Monitoring of fruit and vegetable (F&V) intake is fraught with difficulties. Available dietary assessment methods are associated with considerable error, and the use of biomarkers offers an attractive alternative. Few studies to date have examined the use of plasma biomarkers to monitor or predict the F&V intake of volunteers consuming a wide range of intakes from both habitual F&V and manipulated diets. This study tested the hypothesis that an integrated biomarker calculated from a combination of plasma vitamin C, cholesterol-adjusted carotenoid concentration and Ferric Reducing Antioxidant Power (FRAP) had more power to predict F&V intake than each individual biomarker. Data from a randomized controlled dietary intervention study [FLAVURS (Flavonoids University of Reading Study); n = 154] in which the test groups observed sequential increases of 2.3, 3.2, and 4.2 portions of F&Vs every 6 wk across an 18-wk period were used in this study. An integrated plasma biomarker was devised that included plasma vitamin C, total cholesterol-adjusted carotenoids, and FRAP values, which better correlated with F&V intake (r = 0.47, P < 0.001) than the individual biomarkers (r = 0.33, P < 0.01; r = 0.37, P < 0.001; and r = 0.14, respectively; P = 0.099). Inclusion of urinary potassium concentration did not significantly improve the correlation. The integrated plasma biomarker predicted F&V intake more accurately than did plasma total cholesterol-adjusted carotenoid concentration, with the difference being significant at visit 2 (P < 0.001) and with a tendency to be significant at visit 1 (P = 0.07). Either plasma total cholesterol-adjusted carotenoid concentration or the integrated biomarker could be used to distinguish between high- and moderate-F&V consumers. This trial was registered at www.controlled-trials.com as ISRCTN47748735.


National AIDS incidence trends and the extent of zidovudine therapy in selected demographic and transmission groups.
After mid-1987 fewer than the expected number of cases of AIDS were reported in the United States in some demographic and transmission groups but not in others. Gay men (regardless of intravenous drug use), adults with hemophilia, and transfusion recipients exhibited fewer cases than expected based on previously reliable models. These favorable trends could not be explained by assuming earlier cessation of human immunodeficiency virus (HIV) infection. Favorable AIDS incidence trends were not found in heterosexual intravenous drug users or in persons infected through heterosexual contact. White gay men from New York City, Los Angeles, and San Francisco experienced markedly favorable trends, whereas little changes was observed for nonwhite gay men from nonurban areas. AIDS incidence trends were quantitatively consistent with the fraction of AIDS-free persons with severe immunodeficiency who received zidovudine in three cohorts. Gay men in San Francisco used zidovudine more frequently than did adults with hemophilia, while little was used by intravenous drug users in New York City. Data describing the initial national distribution of zidovudine (March 31-September 18, 1987) indicated relatively high use by patients with severe immunodeficiency in those groups, such as urban white gay men, that subsequently experienced fewer cases of AIDS than expected. Available data suggest that zidovudine, perhaps in combination with other therapies, has been one factor contributing to favorable AIDS incidence trends in some groups. Broader application of therapy might further retard the incidence of AIDS, especially in intravenous drug users, persons infected through heterosexual contact, minorities, women, and persons diagnosed outside major metropolitan areas.


Metabolic Flexibility in Cancer: Targeting the Pyruvate Dehydrogenase Kinase:Pyruvate Dehydrogenase Axis.
Cancer cells use alterations of normal metabolic processes to sustain proliferation indefinitely. Transcriptional and posttranscriptional control of the pyruvate dehydrogenase kinase (PDK) family is one way in which cancer cells alter normal pyruvate metabolism to fuel proliferation. PDKs can phosphorylate and inactivate the pyruvate dehydrogenase complex (PDHC), which blocks oxidative metabolism of pyruvate by the mitochondria. This process is thought to enhance cancer cell growth by promoting anabolic pathways. Inhibition of PDKs induces cell death through increased PDH activity and subsequent increases in ROS production. The use of PDK inhibitors has seen widespread success as a potential therapeutic in laboratory models of multiple cancers; however, gaps still exist in our understanding of the biology of PDK regulation and function, especially in the context of individual PDKs. Efforts are currently underway to generate PDK-specific inhibitors and delineate the roles of individual PDK isozymes in specific cancers. The goal of this review is to understand the regulation of the PDK isozyme family, their role in cancer proliferation, and how to target this pathway therapeutically to specifically and effectively reduce cancer growth.


Minimal angle horizontal strabismus detectable by lay observers.
Patients with socially significant strabismus may be at risk for certain psychosocial consequences. However, the magnitude at which strabismus becomes socially significant is ill defined. Suggested criteria for socially significant strabismus can be found in the literature, but they are rarely, if ever, referenced. The purpose of this study is to further define the magnitude at which strabismus becomes socially significant according to lay observers. Strabismus was simulated using photo manipulation and off-center fixation. Horizontal deviations were created in 3Delta steps up to 24Delta. One model was used for all photos. The photos were presented in random order to non-health care professionals (N = 58). Participants were instructed to view each picture and determine: "yes, this person has an eye turn" or "no, this person does not have an eye turn." A chi test was used for analysis. RESULTS.: There was an increase in the likelihood of strabismus detection as the size of the angle increased for exotropia and esotropia. Overall, exotropia was easier to identify than esotropia. For esotropia, a dramatic increase in detectability occurred between 9Delta (47.41% detection; p = 0.001) and 12Delta (67.24% detection; p = 0.001), with 70% detection being achieved at 14.5Delta. A significant increase in detection of exotropia occurred between 6Delta (60.34% detection; p = 0.001) and 9Delta (77.59% detection; p = 0.001), with 70% detection achieved at 8Delta. Our results suggest that exotropia is easier for lay observers to detect than esotropia, with the critical magnitude (70% detection) being 14.5Delta for esotropia and 8Delta for exotropia. This refutes generally accepted beliefs that esotropia is easier to detect than exotropia. Additional studies are needed to look at the effect of ethnicity, sex, and age. Multiple models should be used to reduce the possible influence of distinct facial characteristics and increase the generalizability of the results.


Susceptibility mapping in the human brain using threshold-based k-space division.
A method for calculating quantitative three-dimensional susceptibility maps from field measurements acquired using gradient echo imaging at high field is presented. This method is based on division of the three-dimensional Fourier transforms of high-pass-filtered field maps by a simple function that is the Fourier transform of the convolution kernel linking field and susceptibility, and uses k-space masking to avoid noise enhancement in regions where this function is small. Simulations were used to show that the method can be applied to data acquired from objects that are oriented at one angle or multiple angles with respect to the applied field and that the use of multiple orientations improves the quality of the calculated susceptibility maps. As part of this work, we developed an improved approach for high-pass filtering of field maps, based on using an arrangement of dipoles to model the fields generated by external structures. This approach was tested on simulated field maps from the substantia nigra and red nuclei. Susceptibility mapping was successfully applied to experimental measurements on a structured phantom and then used to make measurements of the susceptibility of the red nuclei and substantia nigra in healthy subjects at 3 and 7 T.


Segmental processing in the human auditory dorsal stream.
In the present study we investigated the functional organization of sublexical auditory perception with specific respect to auditory spectro-temporal processing in speech and non-speech sounds. Participants discriminated verbal and nonverbal auditory stimuli according to either spectral or temporal acoustic features in the context of a sparse event-related functional magnetic resonance imaging (fMRI) study. Based on recent models of speech processing, we hypothesized that auditory segmental processing, as is required in the discrimination of speech and non-speech sound according to its temporal features, will lead to a specific involvement of a left-hemispheric dorsal processing network comprising the posterior portion of the inferior frontal cortex and the inferior parietal lobe. In agreement with our hypothesis results revealed significant responses in the posterior part of the inferior frontal gyrus and the parietal operculum of the left hemisphere when participants had to discriminate speech and non-speech stimuli based on subtle temporal acoustic features. In contrast, when participants had to discriminate speech and non-speech stimuli on the basis of changes in the frequency content, we observed bilateral activations along the middle temporal gyrus and superior temporal sulcus. The results of the present study demonstrate an involvement of the dorsal pathway in the segmental sublexical analysis of speech sounds as well as in the segmental acoustic analysis of non-speech sounds with analogous spectro-temporal characteristics.


Animal handling and stress-related behaviour at mobile slaughter of cattle.
By avoiding animal transportation, mobile slaughter may have the potential to reduce animal stress. In a cross-sectional study with elements of cohort design, we investigated relationships between animal handling and stress-related animal behaviours in connection with slaughter at two Swedish slaughter plants: a newly started small-scale on-farm mobile abattoir and a relatively large-scale stationary slaughterhouse. To the stationary plant, the animals were transported on average 99 km from farms, and one third of these animals spent one night in lairage before slaughter. Data were collected during processing of 298 animals at both plants during one year. Stockperson actions and animal behaviours were observed in the driveways (2.4-7.3 m long) to the stun box. Data on season, hour of day, air temperature, animal breed, animal category, animal age, carcass weight and stockperson category (plant or farm) were also collected. We used Spearman rank correlation, principal-component analysis and confirmatory factor analysis to develop a final generalised structural equation model, which contained six variables that represented observed animal backing; turning; slipping; eliminating; vocalising; and violent behaviour, regressed on a latent variable representing animal stress level. Stress level and animal behaviours were also regressed on five variables representing observed stockperson actions (touching, patting or hitting with hand; touching, patting or hitting with a tool; pushing; tail-twisting; and prodding with an electric goad) and on background variables including plant identity. The animal behaviours were modelled as counts per driveway length, clustered on farm identity. Marginal effects of stockperson actions and predictive margins of plants were calculated. The animals displayed backing and violent behaviour (kicking, goring or violent fighting) at significantly lower frequencies at the mobile plant than at the stationary one. In general, stockperson actions were significantly positively associated with animal behaviours, i.e. increased actions were associated with more frequent behaviours. Stockperson moving with tool, pushing and using electric goad were indirectly significantly associated with all animal behaviours via animal stress level. This study shows the importance of adequate cattle handling to limit pre-slaughter stress.


Use of Cyanoacrylate Glue Casting for Stabilization of Periocular Skin Grafts and Flaps.
To examine a novel technique for periocular skin graft and flap stabilization using cyanoacrylate glue applied to the host bed around the perimeter of the graft or flap to create an immobile cast in the immediate postoperative period to promote successful graft take and stable anatomic position. Retrospective review was performed of a single surgeon's patients who underwent periocular skin graft or flap between August 1, 2011, and February 29, 2016, in which cyanoacrylate glue was applied postoperatively for graft stabilization. Data examined included indication for procedure, location and size of graft, postoperative complications, and length of follow up postoperatively. Of 164 cases reviewed, 9 cases were identified in which cyanoacrylate glue was used as the sole means of graft or flap stabilization. Indications for surgery included repair of cicatricial ectropion (3 cases) and repair of Mohs defect status after excision of basal or squamous cell carcinoma (6 cases). All cases involved reformation of the lower eyelid. Five cases employed full-thickness skin grafts and 4 cases employed adjacent tissue rearrangement. Size of defect repaired ranged from 8 mm to 35 mm when largest diameter was measured. Complications included mild residual ectropion or mild punctal ectropion in 2 patients who was asymptomatic and did not require further surgery. No cases were complicated by hematoma, infection, or graft necrosis. Cyanoacrylate glue can be used to successfully stabilize skin grafts and flaps in the immediate postoperative period.


The mucosal invasion model: a novel in vitro model for evaluating the invasive behavior of mucocutaneous malignancies.
Prevention of regional and metastatic spread of cutaneous malignancies requires understanding the physiologic mechanism of tumor cell invasion. In vitro models are convenient for studying the in vitro invasive phenotype of normal cells, tumor cell lines, or genetically altered cells in a 3-dimensional matrix, but they should attempt to recapitulate the complex in vivo submucosal environment. A new acellular extracellular matrix, porcine submucosal matrix (PSM), is thought to accurately recapitulate the submucosal matrix. A novel in vitro model using PSM to assess mucocutaneous tumor cell invasion was studied. The morphologic characteristics, growth, and invasive behavior of human head and neck squamous cell carcinoma (UM-SCC-1, UM-SCC-5, UM-SCC-17B, and OSC-19) cell lines were assessed on the PSM gel and compared with commonly used in vitro invasion models (type I collagen and Matrigel matrices). The invasive phenotype of canine kidney cells was also assessed on each matrix, because this cell line is known to demonstrate a characteristic in vitro invasive phenotype. The PSM-supported head and neck squamous cell carcinoma tumor cell line growth and single cell invasion were seen under stimulated conditions, similar to type I collagen gels. The invasive phenotype of canine kidney cells behaved similarly on PSM and collagen. Matrigel did not support growth well, and invasion occurred only superficially in isolated areas. The PSM is a good in vitro model for assessment of pharmacologic and genetic manipulations of head and neck squamous cell carcinoma tumor cell lines and has several advantages over other commonly used matrices.


Designing proteins to crystallize through beta-strand pairing.
Inherent difficulties in growing protein crystals are major concerns within structural biology and particularly in structural proteomics. Here, we describe a novel approach of engineering target proteins by surface mutagenesis to increase the odds of crystallizing the molecules. To this end, we have exploited our recent triad-hypothesis using proteins with crystallographically defined beta-structures as the principal models. Crystal packing analyses of 182 protein structures belonging to 21 different superfamilies implied that the propensities to crystallize could be engineered into target proteins by replacing short segments, 5-6 residues, of their beta-strands with 'cassettes' of suitable packing motifs. These packing motifs will generate specific crystal packing interactions that promote crystallization. Key features of the primary and tertiary structures of such packing motifs have been identified for immunoglobulins. Further, packing motifs have been engineered successfully into six model antibodies without disturbing their capabilities to be produced, their immunoreactivity and their overall structure. Preliminary crystallization analyses have also been performed. Taken together, the procedures outline a rational protocol for crystallizing proteins by surface mutagenesis. The importance of these findings is discussed in relation to the crystallization of proteins in general.


Chimeric L2-Based Virus-Like Particle (VLP) Vaccines Targeting Cutaneous Human Papillomaviruses (HPV).
Common cutaneous human papillomavirus (HPV) types induce skin warts, whereas species beta HPV are implicated, together with UV-radiation, in the development of non-melanoma skin cancer (NMSC) in immunosuppressed patients. Licensed HPV vaccines contain virus-like particles (VLP) self-assembled from L1 major capsid proteins that provide type-restricted protection against mucosal HPV infections causing cervical and other ano-genital and oro-pharyngeal carcinomas and warts (condylomas), but do not target heterologous HPV. Experimental papillomavirus vaccines have been designed based on L2 minor capsid proteins that contain type-common neutralization epitopes, to broaden protection to heterologous mucosal and cutaneous HPV types. Repetitive display of the HPV16 L2 cross-neutralization epitope RG1 (amino acids (aa) 17-36) on the surface of HPV16 L1 VLP has greatly enhanced immunogenicity of the L2 peptide. To more directly target cutaneous HPV, L1 fusion proteins were designed that incorporate the RG1 homolog of beta HPV17, the beta HPV5 L2 peptide aa53-72, or the common cutaneous HPV4 RG1 homolog, inserted into DE surface loops of HPV1, 5, 16 or 18 L1 VLP scaffolds. Baculovirus expressed chimeric proteins self-assembled into VLP and VLP-raised NZW rabbit immune sera were evaluated by ELISA and L1- and L2-based pseudovirion (PsV) neutralizing assays, including 12 novel beta PsV types. Chimeric VLP displaying the HPV17 RG1 epitope, but not the HPV5L2 aa53-72 epitope, induced cross-neutralizing humoral immune responses to beta HPV. In vivo cross-protection was evaluated by passive serum transfer in a murine PsV challenge model. Immune sera to HPV16L1-17RG1 VLP (cross-) protected against beta HPV5/20/24/38/96/16 (but not type 76), while antisera to HPV5L1-17RG1 VLP cross-protected against HPV20/24/96 only, and sera to HPV1L1-4RG1 VLP cross-protected against HPV4 challenge. In conclusion, RG1-based VLP are promising next generation vaccine candidates to target cutaneous HPV infections.


Genetic architecture of plasma Alzheimer disease biomarkers.
Genome-wide association studies (GWAS) of cerebrospinal fluid (CSF) Alzheimer's Disease (AD) biomarker levels have identified novel genes implicated in disease risk, onset and progression. However, lumbar punctures have limited availability and may be perceived as invasive. Blood collection is readily available and well accepted, but it is not clear whether plasma biomarkers will be informative for genetic studies. Here we perform genetic analyses on concentrations of plasma amyloid-β peptides Aβ40 (n = 1,467) and Aβ42 (n = 1,484), Aβ42/40 (n = 1467) total tau (n = 504), tau phosphorylated (p-tau181; n = 1079) and neurofilament light (NfL; n = 2,058). GWAS and gene-based analysis was used to identify single variant and genes associated with plasma levels. Finally, polygenic risk score and summary statistics were used to investigate overlapping genetic architecture between plasma biomarkers, CSF biomarkers and AD risk. We found a total of six genome-wide significant signals. APOE was associated with plasma Aβ42, Aβ42/40, tau, p-tau181 and NfL. We proposed 10 candidate functional genes on the basis of 12 single nucleotide polymorphism-biomarker pairs and brain differential gene expression analysis. We found a significant genetic overlap between CSF and plasma biomarkers. We also demonstrate that it is possible to improve the specificity and sensitivity of these biomarkers, when genetic variants regulating protein levels are included in the model. This current study using plasma biomarker levels as quantitative traits can be critical to identification of novel genes that impact AD and more accurate interpretation of plasma biomarker levels.


Respiratory complications from acute corrosive poisonings in adults.
Acute corrosive poisonings are caused by ingestion of corrosive chemicals which are most commonly used as household agents. Intoxications with these kind of agents produce numerous and severe post-corrosive complications of the upper gastrointestinal tract. On the other hand, our experience showed that corrosive agents may also cause injuries of the respiratory system, which makes the treatment very hard and additionally complicates the severe clinical condition of the patient. The aim of the study is to show the incidence of respiratory complications in acute corrosive poisonings, the need of various clinical investigations and also the treatment and final outcome of these kind of poisoning. We retrospectively analyzed clinical records of 415 patients hospitalized and treated at the University clinic for toxicology and urgent internal medicine, in Skopje, Republic of Macedonia, in the period between 2007 and 2011. The protocol consisted of methods for analyzing the systemic complications, with an accent on the post-corrosive respiratory complications. From the total number of patients even 98 (23.61%) exhibited systemic complications, from which 51 (52.04%) are respiratory complications. The majority of patients are female (n=40, 78.43%) and the most common complication is pneumonia (n=47). The youngest patient in this study was 14 and the oldest was 87 years old. Besides the gastrointestinal complications in the acute corrosive poisonings respiratory complications are also very often. They complicate the clinical state of patient and very often lead to fatal endings.


Probability of thrombosis of vascular access among hemodialysis patients treated with recombinant human erythropoietin.
The objective was to evaluate the effect of the treatment of anemia with recombinant human erythropoietin (EPO) on thrombosis of the vascular access used for hemodialysis. The research design was a prospective cohort study comparing EPO-treated hemodialysis patients with a comparison group matched for type of vascular access, clinical center, and age. All patients commencing hemodialysis in the study centers between March 1988 and July 1991 were eligible if either a graft or fistula had been used as a first permanent vascular access. There were 64 matched fistula pairs and 38 matched graft pairs. There were more patients with a history of cardiovascular disease in the EPO group than in the comparison group for both fistulae and grafts, 34 versus 14% for the former and 37 versus 5% for the latter. There was no difference between EPO and comparison groups with respect to time to first thrombosis of fistula, 11.3 versus 10.6%, respectively, by thrombosis of grafts among those treated with EPO--33.6 versus 11.2% (P = 0.02). EPO treatment does not increase the probability of fistula thrombosis, but there is an association with an increased probability of graft thrombosis.


Inpatient care intensity and patients' ratings of their hospital experiences.
The intensity of hospital care provided to chronically ill Medicare patients varies greatly among regions, independent of illness. We examined the associations among hospital care intensity, the technical quality of hospital care, and patients' ratings of their hospital experiences. Greater inpatient care intensity was associated with lower quality scores and lower patient ratings; lower quality scores were associated with lower patient ratings. The common thread linking greater care intensity with lower quality and less favorable patient experiences may be poorly coordinated care.


Dynamic relationship between SIPA1 gene and protein expression and the development of gastric cancer.
Association of signal-induced proliferation-associated 1 (SIPA) gene and protein expression with gastric cancer development was examined. SIPA1 mRNA and protein levels were determined by real-time quantitative polymerase chain reaction and western blot, respectively, in 40 gastric tumor and tumor-adjacent normal tissues. SIPA1, VEGF-A, and FVIII levels in 60 gastric tumor and 40 tumor-adjacent normal tissues were examined by immunohistochemical staining. Correlations between SIPA1, VEGF-A, and microvessel density (MVD) were analyzed. SIPA1 mRNA levels were significantly lower in tumor tissues than in tumor-adjacent normal tissues (P < 0.05). Similarly, protein levels were significantly lower in tumor tissues (0.3043 ± 0.1062) than in tumor-adjacent normal tissues (0.5423 ± 0.0682, P < 0.05). Positive staining rates of SIPA1 (48.3%) and VEGF-A (36.7%) were lower and higher, respectively, in tumor tissues than in tumor-adjacent normal tissues (65.0 and 2.5%, P < 0.05). Positive protein staining rates in tumor tissues correlated with the degree of differentiation, lymph node metastases, and clinical grading (P < 0.05) and not with sex, age, or tumor size (P > 0.05). Significantly higher MVD (57.4 ± 9.3) was observed in tumor tissues displaying positive SIPA1 staining than in tumor-adjacent normal tissues (41.2 ± 5.7, P < 0.05). SIPA1 and VEGF-A expression in tumor tissues were negatively correlated (r = -0.736, P < 0.05). SIPA1 and its protein may play important roles in gastric cancer invasion, metastasis, and biological behavior. Low SIPA1 levels in gastric cancer may accelerate tumor development and progression by promoting VEGF-A expression to increase vascular density.


The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis.
The Surviving Sepsis Campaign (SSC or "the Campaign") developed guidelines for management of severe sepsis and septic shock. A performance improvement initiative targeted changing clinical behavior (process improvement) via bundles based on key SSC guideline recommendations on process improvement and patient outcomes. A multifaceted intervention to facilitate compliance with selected guideline recommendations in the ICU, ED, and wards of individual hospitals and regional hospital networks was implemented voluntarily in the US, Europe, and South America. Elements of the guidelines were "bundled" into two sets of targets to be completed within 6 h and within 24 h. An analysis was conducted on data submitted from January 2005 through March 2008. Data from 15,022 subjects at 165 sites were analyzed to determine the compliance with bundle targets and association with hospital mortality. Compliance with the entire resuscitation bundle increased linearly from 10.9% in the first site quarter to 31.3% by the end of 2 years (P<0.0001). Compliance with the entire management bundle started at 18.4% in the first quarter and increased to 36.1% by the end of 2 years (P = 0.008). Compliance with all bundle elements increased significantly, except for inspiratory plateau pressure, which was high at baseline. Unadjusted hospital mortality decreased from 37 to 30.8% over 2 years (P = 0.001). The adjusted odds ratio for mortality improved the longer a site was in the Campaign, resulting in an adjusted absolute drop of 0.8% per quarter and 5.4% over 2 years (95% CI, 2.5-8.4%). The Campaign was associated with sustained, continuous quality improvement in sepsis care. Although not necessarily cause and effect, a reduction in reported hospital mortality rates was associated with participation. The implications of this study may serve as an impetus for similar improvement efforts.


Distribution of microcrack lengths in bone in vivo and in vitro.
It is well known that bone contains small cracks; in vivo these microcracks are constantly growing and being repaired. Too rapid crack growth leads to stress fractures or fragility fractures. In vitro, changes occur in this population of microcracks when subjected to cyclic loading up to and including failure. Normally, the only parameters reported from such investigations are the number density of cracks and their average length. In the present work we examined the microcrack population in more detail. We analysed ten different sets of experimental data including in vivo and in vitro microcracks, plus two theoretical simulations. We showed for the first time that the distribution of crack lengths can be described using the two-parameter Weibull equation. The values of the two constants in the equation varied depending on bone type/species and showed consistent trends during in vitro testing. This is the most detailed study to be conducted on microcrack populations in bone; the results will be useful in future studies including the development of theoretical models and computer simulations of bone damage and failure.


Nurses' Establishment of Health Promoting Relationships: A Descriptive Synthesis of Anorexia Nervosa Research.
Qualitative values that address personal and interpersonal dimensions are often overlooked in research that examines mental well-being among young patients with anorexia nervosa. The aim of this review was to identify and describe factors that promote and impede the relationships between nurses and the children, adolescents and young adults who are diagnosed with anorexia nervosa and also to explore and describe how those relationships benefit the patients' processes toward increased health and well-being. A descriptive literature synthesis was conducted following the four steps as described by Evans. The three databases CINAHL, PsycINFO and PubMed were used to search for qualitative articles. Fourteen articles met the criteria for inclusion and were analysed. Key findings were identified, and categories and themes were formulated and compared across the studies. Four themes are presented in the results: (1) The essentials in a relationship; (2) The person at the centre; (3) The nurses' attitudes; and (4) Knowledge. In addition to the contribution to the knowledge of how anorexia is manifested, our findings demonstrate the necessity for nurses to be person-centred in their relationships with patients and to have attitudes characterised by presence, genuine commitment and motivation. Nurses are more likely to convey a sense of trust and safety when they communicate with openness and honesty. Our review suggests that the motivation for patients to adhere to treatment is likely to increase when nurses approach patients with these characteristics and attitudes. We argue that the findings are relevant for nurses in their everyday practices.


Characteristics of elderly tuberculosis patients in Recife, Brazil: a contribution to the tuberculosis control program.
To describe the demographic characteristics, everyday habits, socio-economic conditions, clinico-epidemiological profiles and access to health care services among the elderly patients with tuberculosis diagnosed and treated in the city of Recife, Brazil, comparing them to those observed in young adults with tuberculosis. A case-control type strategy was used to evaluate a cohort of patients with tuberculosis, all of whom were treated in public health care facilities in Recife between May of 2001 and July of 2003. The final cohort consisted of 1127 patients: 136 elderly patients (cases) and 991 young adults (controls). In both groups, males predominated, and the most common form of tuberculosis was the pulmonary form. Alcoholism was more common in the control group, whereas illiteracy was more common in the case group. There were fewer complaints of cough, sweats and chest pain among the patients in the case group than among those in the control group. Serological testing for the human immunodeficiency virus was performed in only 29 patients (2.6%). The percentage of positive sputum smear microscopy results, as well as that of positive cultures, was higher in the controls. Prior to being diagnosed with the disease, patients in both groups had sought treatment at more than two health care facilities and had waited more than two months (after first seeking treatment). The elderly patients presented higher indices of cure and were more often compliant with the treatment regimen, yet presented higher mortality rates. In the population studied, the elderly presented less cough, fewer episodes of night sweats and less chest pain, as well as less often presenting positivity on complementary exams. Nevertheless, the mortality rate was higher among the elderly patients than among the young adult patients. Elderly patients with tuberculosis constitute a population that should be given special attention in public health care facilities.


Perivascular adipose tissue and coronary atherosclerosis.
Adipose tissue (AT) is no longer viewed as a passive, energy-storing depot, and a growing body of evidence supports the concept that both quantitative and qualitative aspects of AT are critical in determining an individual's cardiometabolic risk profile. Among all AT sites, perivascular AT (PVAT) has emerged as a depot with a distinctive biological significance in cardiovascular disease given its close anatomical proximity to the vasculature. Recent studies have suggested the presence of complex, bidirectional paracrine and vasocrine signalling pathways between the vascular wall and its PVAT, with far-reaching implications in cardiovascular diagnostics and therapeutics. In this review, we first discuss the biological role of PVAT in both cardiovascular health and disease, highlighting its dual pro-atherogenic and anti-atherogenic roles, as well as potential therapeutic targets in cardiovascular disease. We then review current evidence and promising new modalities on the non-invasive imaging of epicardial AT and PVAT. Specifically, we present how our expanding knowledge on the bidirectional interplay between the vascular wall and its PVAT can be translated into novel clinical diagnostics tools to assess coronary inflammation. To this end, we present the example of a new CT-based method that tracks spatial changes in PVAT phenotype to extract information about the inflammatory status of the adjacent vasculature, highlighting the numerous diagnostic and therapeutic opportunities that arise from our increased understanding of PVAT biology.


Prediction of Cardiovascular Disease Risk by Cardiac Biomarkers in 2 United Kingdom Cohort Studies: Does Utility Depend on Risk Thresholds For Treatment?
We tested the predictive ability of cardiac biomarkers N-terminal pro B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T, and midregional pro adrenomedullin for cardiovascular disease (CVD) events using the British Regional Heart Study (BRHS) of men aged 60 to 79 years, and the MIDSPAN Family Study (MFS) of men and women aged 30 to 59 years. They included 3757 and 2226 participants, respectively, and during median 13.0 and 17.3 years follow-up the primary CVD event rates were 16.6 and 5.3 per 1000 patient-years, respectively. In Cox models adjusted for basic classical risk factors, 1 SD increases in log-transformed NT-proBNP, high-sensitivity troponin T, and midregional pro adrenomedullin were generally associated with increased primary CVD risk in both the studies (P<0.006) except midregional pro adrenomedullin in MFS (P=0.10). In BRHS, QRISK2 risk factors yielded a C-index of 0.657, which was improved by 0.017 (P=0.005) by NT-proBNP, but not by other biomarkers. Using 28% 14-year risk as a proxy for 20% 10-year risk, NT-proBNP improved risk classification for primary CVD cases (case net reclassification index, 5.9%; 95% confidence interval, 2.8%-9.2%), but only improved classification of noncases at a 14% 14-year risk threshold (4.6%; 2.9%-6.3%). In MFS, ASSIGN risk factors yielded a C-index of 0.752 for primary CVD; none of the cardiac biomarkers improved the C-index. Improvements in risk classification were only seen using NT-proBNP and high-sensitivity troponin T among cases using the 28% 14-year risk threshold (4.7%; 1.0%-9.2% and 2.6%; 0.0%-5.8%, respectively). In conclusion, the improvement in treatment allocation gained by adding cardiac biomarkers to risk scores seems to depend on the risk threshold chosen for commencing preventative treatments.


Biomaterials modulate interleukin-8 and other inflammatory proteins during reepithelialization in cutaneous partial-thickness wounds in pigs.
Acute and chronic cutaneous wounds remain a clinical challenge that require a mechanistic understanding to advance treatment options. For example, the role of inflammatory mediators during wound healing is not completely understood. Biomimetic materials, such as an in situ photopolymerizable semi-interpenetrating network (sIPN) derived from extracellular matrix components, show great potential in improving healing through the delivery of therapeutic agents and the function as a temporary tissue scaffold. In this study, we characterized the temporal profile of porcine cutaneous partial-thickness wound healing in response to Xeroform and sIPN treatment via histological and inflammatory protein analyses in epidermal, remodeling dermal, and dermal regions. Generally, interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-10, IL-12p70, interferon-γ, and tumor necrosis factor-α, but not IL-8, were expressed in the epidermis and remodeling dermis in a time course that followed the progression of epidermal maturation in response to both treatments. Differences in cellularity and protein expression were observed between treatments in a time- and region-dependent manner. In particular, the healing response to sIPN exemplified a potentially key relationship between IL-8 expression and reepithelialization. These results provide insights into the expression of inflammatory mediators and the time course of cutaneous healing and the capacity for biomaterials to further modulate this relationship.


LIBERTI: A SMART study in plastic surgery.
Laser treatment of burns scars is considered by some providers to be standard of care. However, there is little evidence-based research as to the true benefit. A number of factors hinder evaluation of the benefit of laser treatment. These include significant heterogeneity in patient response and possible delayed effects from the laser treatment. Moreover, laser treatments are often provided sequentially using different types of equipment and settings, so there are effectively a large number of overall treatment options that need to be compared. We propose a trial capable of coping with these issues and that also attempts to take advantage of the heterogeneous response in order to estimate optimal treatment plans personalized to each individual patient. It will be the first large-scale randomized trial to compare the effectiveness of laser treatments for burns scars and, to our knowledge, the very first example of the utility of a Sequential Multiple Assignment Randomized Trial in plastic surgery. We propose using a Sequential Multiple Assignment Randomized Trial design to investigate the effect of various permutations of laser treatment on hypertrophic burn scars. We will compare and test hypotheses regarding laser treatment effects at a general population level. Simultaneously, we hope to use the data generated to discover possible beneficial personalized treatment plans, tailored to individual patient characteristics. We show that the proposed trial has good power to detect laser treatment effect at the overall population level, despite comparing a large number of treatment combinations. The trial will simultaneously provide high-quality data appropriate for estimating precision-medicine treatment rules. We detail population-level comparisons of interest and corresponding sample size calculations. We provide simulations to suggest the power of the trial to detect laser effect and also the possible benefits of personalization of laser treatment to individual characteristics. We propose, to our knowledge, the first use of a Sequential Multiple Assignment Randomized Trial in surgery. The trial is rigorously designed so that it is reasonably straightforward to implement and powered to answer general overall questions of interest. The trial is also designed to provide data that are suitable for the estimation of beneficial precision-medicine treatment rules that depend both on individual patient characteristics and on-going real-time patient response to treatment.


The Phylogeny and Evolutionary Timescale of Muscoidea (Diptera: Brachycera: Calyptratae) Inferred from Mitochondrial Genomes.
Muscoidea is a significant dipteran clade that includes house flies (Family Muscidae), latrine flies (F. Fannidae), dung flies (F. Scathophagidae) and root maggot flies (F. Anthomyiidae). It is comprised of approximately 7000 described species. The monophyly of the Muscoidea and the precise relationships of muscoids to the closest superfamily the Oestroidea (blow flies, flesh flies etc) are both unresolved. Until now mitochondrial (mt) genomes were available for only two of the four muscoid families precluding a thorough test of phylogenetic relationships using this data source. Here we present the first two mt genomes for the families Fanniidae (Euryomma sp.) (family Fanniidae) and Anthomyiidae (Delia platura (Meigen, 1826)). We also conducted phylogenetic analyses containing of these newly sequenced mt genomes plus 15 other species representative of dipteran diversity to address the internal relationship of Muscoidea and its systematic position. Both maximum-likelihood and Bayesian analyses suggested that Muscoidea was not a monophyletic group with the relationship: (Fanniidae + Muscidae) + ((Anthomyiidae + Scathophagidae) + (Calliphoridae + Sarcophagidae)), supported by the majority of analysed datasets. This also infers that Oestroidea was paraphyletic in the majority of analyses. Divergence time estimation suggested that the earliest split within the Calyptratae, separating (Tachinidae + Oestridae) from the remaining families, occurred in the Early Eocene. The main divergence within the paraphyletic muscoidea grade was between Fanniidae + Muscidae and the lineage ((Anthomyiidae + Scathophagidae) + (Calliphoridae + Sarcophagidae)) which occurred in the Late Eocene.


The Walch type B humerus: glenoid retroversion is associated with torsional differences in the humerus.
The Walch type B glenoid has the hallmark features of retroversion, joint subluxation, and bony erosion. Although the type B glenoid has been well described, the morphology of the corresponding type B humerus is poorly understood. As such, the aim of this imaging-based anthropometric study was to investigate humeral torsion in Walch type B shoulders. Three-dimensional models of the full-length humerus were generated from computed tomography data for the Walch type B group (n = 59) and for a control group of normal nonarthritic shoulders (n = 59). An anatomic humeral head-neck plane was created and used to determine humeral torsion relative to the epicondylar axis. Measurements were repeated, and intraclass correlation coefficients were calculated. The type B humeri had significantly (P < .001) less retrotorsion (14° ± 9°) than the control group (36° ± 12°) relative to the epicondylar axis. Male and female individuals within the control group showed statistically significant differences in humeral torsion (P = .043), which were not found in the type B group. Inter-rater reliability showed excellent agreement for humeral torsion (intraclass correlation coefficient, 0.962). A subgroup analysis between Walch type B2 and B3 shoulders showed no significant differences in any of the humeral or glenoid parameters. The Walch type B humerus has significantly less retrotorsion than non-osteoarthritic shoulders. At present, it is unknown whether the altered humeral retrotorsion is a cause or effect of the type B glenoid. In addition, it is unknown whether surgeons should be reconstructing type B2 humeral component version to pathologic torsion or to nonpathologic population means to optimize arthroplasty survivorship.


The Internet of Things in Health Care in Oxford: Protocol for Proof-of-Concept Projects.
Demands on health services across are increasing because of the combined challenges of an expanding and aging population, alongside complex comorbidities that transcend the classical boundaries of modern health care. Continuing to provide and coordinate care in the current manner is not a viable route to sustain the improvements in health outcomes observed in recent history. To ensure that there continues to be improvement in patient care, prevention of disease, and reduced burden on health systems, it is essential that we adapt our models of delivery. Providers of health and social care are evolving to face these pressures by changing the way they think about the care system and, importantly, how to involve patients in the planning and delivery of services. The objective of this paper is to provide (1) an overview of the current state of Internet of Things (IoT) and key implementation considerations, (2) key use cases demonstrating technology capabilities, (3) an overview of the landscape for health care IoT use in Oxford, and (4) recommendations for promoting the IoT via collaborations between higher education institutions and industry proof-of-concept (PoC) projects. This study describes the PoC projects that will be created to explore cost-effectiveness, clinical efficacy, and user adoption of Internet of Medical Things systems. The projects will focus on 3 areas: (1) bring your own device integration, (2) chronic disease management, and (3) personal health records. This study is funded by Research England's Connecting Capability Fund. The study started in March 2018, and results are expected by the end of 2019. Embracing digital solutions to support the evolution and transformation of health services is essential. Importantly, this should not simply be undertaken by providers in isolation. It must embrace and exploit the advances being seen in the consumer devices, national rollout of high-speed broadband services, and the rapidly expanding medical device industry centered on mobile and wearable technologies. Oxford University Hospitals and its partner providers, patients, and stakeholders are building on their leading position as an exemplar site for digital maturity in the National Health Service to implement and evaluate technologies and solutions that will capitalize on the IoT. Although early in the application to health, the IoT and the potential it provides to make the patient a partner at the center of decisions about care represent an exciting opportunity. If achieved, a fully connected and interoperable health care environment will enable continuous acquisition and real-time analysis of patient data, offering unprecedented ability to monitor patients, manage disease, and potentially deliver early diagnosis. The clinical benefit of this is clear, but additional patient benefit and value will be gained from being able to provide expert care at home or close to home. DERR1-10.2196/12077.


AHNAK Loss in Mice Promotes Type II Pneumocyte Hyperplasia and Lung Tumor Development.
AHNAK is known to be a tumor suppressor in breast cancer due to its ability to activate the TGFβ signaling pathway. However, the role of AHNAK in lung tumor development and progression remains unknown. Here, the Ahnak gene was disrupted to determine its effect on lung tumorigenesis and the mechanism by which it triggers lung tumor development was investigated. First, AHNAK protein expression was determined to be decreased in human lung adenocarcinomas compared with matched nonneoplastic lung tissues. Then, Ahnak -/- mice were used to investigate the role of AHNAK in pulmonary tumorigenesis. Ahnak -/- mice showed increased lung volume and thicker alveolar walls with type II pneumocyte hyperplasia. Most importantly, approximately 20% of aged Ahnak -/- mice developed lung tumors, and Ahnak -/- mice were more susceptible to urethane-induced pulmonary carcinogenesis than wild-type mice. Mechanistically, Ahnak deficiency promotes the cell growth of lung epithelial cells by suppressing the TGFβ signaling pathway. In addition, increased numbers of M2-like alveolar macrophages (AM) were observed in Ahnak -/- lungs, and the depletion of AMs in Ahnak -/- lungs alleviated lung hyperplastic lesions, suggesting that M2-like AMs promoted the progression of lung hyperplastic lesions in Ahnak-null mice. Collectively, AHNAK suppresses type II pneumocyte proliferation and inhibits tumor-promoting M2 alternative activation of macrophages in mouse lung tissue. These results suggest that AHNAK functions as a novel tumor suppressor in lung cancer.Implications: The tumor suppressor function of AHNAK, in murine lungs, occurs by suppressing alveolar epithelial cell proliferation and modulating lung microenvironment. Mol Cancer Res; 16(8); 1287-98. ©2018 AACR.


The Construction and Analysis of ceRNA Network and Patterns of Immune Infiltration in Mesothelioma With Bone Metastasis.
Background: Mesothelioma is a rare and aggressive tumor. Bone metastasis often occurs in the later stages of this disease along with poor quality of life. Thus, it is important to explore the tumorigenesis and bone metastasis mechanism of invasive mesothelioma. For this purpose, we established two nomograms based on tumor-infiltrating immune cells and ceRNA networks to describe the molecular immunity and the clinical prediction of mesothelioma patients with bone metastasis. Method: The expression profiles of mRNAs, lncRNAs, and miRNAs of 87 primary mesotheliomas were obtained from the TCGA database; there were four patients with bone metastasis and 83 patients without. We constructed a ceRNAs network based on the differentially expressed RNAs between mesothelioma and bone metastasis. CIBERSORT was used to distinguish 22 immune cell types from the tumor transcriptomes. Kaplan-Meier survival analysis and the Cox proportional hazards model were used to evaluate the prognostic value of each factor. Prognosis-associated immune cells and ceRNAs were applied to establish prediction nomograms. The receiver operating characteristic curves (ROC) and calibration curves were utilized to assess the discrimination and accuracy of the nomogram. Results: Differential analysis revealed that 20 lncRNAs, 15 miRNAs, and 230 mRNAs were significantly different in mesothelioma samples vs. bone metastasis samples. We constructed the ceRNA network to include 10 protein-coding mRNAs, 8 lncRNAs, and 10 miRNAs. Nine of 28 ceRNAs were found to be significant in the Kaplan-Meier analysis. Out of the 22 cell types, the fraction of dendritic cells resting (P = 0.018) was significantly different between the bone metastasis group and the non-bone metastasis group. The ROC and the calibration curves, based on ceRNA networks and tumor-infiltrating immune cells, respectively, suggested acceptable accuracy (AUC of 3-year survival: 0.827, AUC of 5-year survival: 0.840; AUC of 3-year survival: 0.730; AUC of 5-year survival: 0.753). Notably, based on the co-expression patterns between ceRNAs and Immune cells, we found that the hsa-miR-582-5p, CASP9, dendritic cells resting, ANIX2, T cells CD8, and T cells CD4 memory resting might be associated with the mesothelioma bone metastasis. Conclusion: Based on ceRNA networks and patterns of immune infiltration, our study provided a valid bioinformatics basis in order to explore the molecular mechanism and predict the possibility of mesothelioma bone metastasis.


Ground reaction forces and lower-limb joint kinetics of turning gait in typically developing children.
Turning is a common locomotor task essential to daily activity; however, very little is known about the forces and moments responsible for the kinematic adaptations occurring relative to straight-line gait in typically developing children. Thus, the aims of this study were to analyse ground reaction forces (GRFs), ground reaction free vertical torque (TZ), and the lower-limb joint kinetics of 90° outside (step) and inside (spin) limb turns. Step, spin, and straight walking trials from fifty-four typically developing children were analysed. All children were fit with the Plug-in Gait and Oxford Foot Model marker sets while walking over force plates embedded in the walkway. Net internal joint moments and power were computed via a standard inverse dynamics approach. All dependent variables were statistically analysed over the entire curves using the mean difference 95% bootstrap confidence band approach. GRFs were directed medially for step turns and laterally for spin turns during the turning phase. Directions were reversed and magnitudes decreased during the approach phase. Step turns showed reduced ankle power generation, while spin turns showed large TZ. Both strategies required large knee and hip coronal and transverse plane moments during swing. These kinetic differences highlight adaptations required to maintain stability and reorient the body towards the new walking direction during turning. From a clinical perspective, turning gait may better reveal weaknesses and motor control deficits than straight walking in pathological populations, such as children with cerebral palsy, and could potentially be implemented in standard gait analysis sessions.


The neural substrates of recognition memory for verbal information: spanning the divide between short- and long-term memory.
One of the classic categorical divisions in the history of memory research is that between short-term and long-term memory. Indeed, because memory for the immediate past (a few seconds) and memory for the relatively more remote past (several seconds and beyond) are assumed to rely on distinct neural systems, more often than not, memory research has focused either on short- (or "working memory") or on long-term memory. Using an auditory-verbal continuous recognition paradigm designed for fMRI, we examined how the neural signatures of recognition memory change across an interval of time (from 2.5 to 30 sec) that spans this hypothetical division between short- and long-term memory. The results revealed that activity during successful auditory-verbal item recognition in inferior parietal cortex and the posterior superior temporal lobe was maximal for early lags, whereas, conversely, activity in the left inferior frontal gyrus increased as a function of lag. Taken together, the results reveal that as the interval between item repetitions increases, there is a shift in the distribution of memory-related activity that moves from posterior temporo-parietal cortex (lags 1-4) to inferior frontal regions (lags 5-10), indicating that as time advances, the burden of recognition memory is increasingly placed on top-down retrieval mechanisms that are mediated by structures in inferior frontal cortex.


Relationships between language impairment, temperament, behavioural adjustment and maternal factors in a community sample of preschool children.
Relationships between child language development and temperament have been little studied in young children, although it is known that children with language impairment are at risk in a number of domains of psychosocial development involving temperamental influences. To investigate the relationships between temperament and language development, along with child behavioural adjustment and maternal psychosocial factors. A sample of 4-year-old children with language impairment was compared with typically developing children, from a large community cohort in a longitudinal study, on three temperament dimensions, behavioural and emotional problems, and maternal factors. Participants were part of a large community cohort involved in a longitudinal study. While the groups did not differ significantly on temperamental shyness/sociability, children with language impairment showed more negative dispositions on the persistence/self-regulation factor, and on overall temperamental difficultness. Behavioural problems were elevated in the language impairment group and were associated with temperament in both groups. Maternal measures of education level, reading and vocabulary skills were significantly lower in the language impairment group. Generally the language impairment group showed a constellation of developmental disadvantages which add to the existing developmental vulnerability conferred by the presence of language impairment. Poorer child temperament self-regulation and behavioural adjustment are strong risk factors for school learning, while lower mother education and literacy contribute further disadvantage. Clinicians managing language impairment in children need to be aware of the whole package of risk factors which are common in this population.


In-hospital mortality among incident hemodialysis older patients in Peru.
Understanding the pattern of mortality linked to end stage renal disease (ESRD) is important given the increasing ageing population in low- and middle-income countries. We analyzed older patients with ESRD with incident hemodialysis, from January 2012 to August 2017 in one large general hospital in Peru. Individual and health system-related variables were analyzed using Generalized Linear Models (GLM) to estimate their association with in-hospital all-cause mortality. Relative risk (RR) with their 95% confidence intervals (95% CI) were calculated. We evaluated 312 patients; mean age 69 years, 93.6% started hemodialysis with a transient central venous catheter, 1.7% had previous hemodialysis indication and 24.7% died during hospital stay. The mean length of stay was 16.1 days (SD 13.5). In the adjusted multivariate models, we found higher in-hospital mortality among those with encephalopathy (aRR 1.85, 95% CI 1.21-2.82 vs. without encephalopathy) and a lower in-hospital mortality among those with eGFR ≤7 mL/min (aRR 0.45, 95% CI 0.31-0.67 vs. eGFR>7 mL/min). There is a high in-hospital mortality among older hemodialysis patients in Peru. The presence of uremic encephalopathy was associated with higher mortality and a lower estimated glomerular filtration rate with lower mortality.


Global relevance of literature on trauma.
The trauma pandemic disproportionately kills and maims citizens of low-income countries although the immediate cause of the trauma is often an industrial export of a high-income country, such as a motor vehicle. Addressing the trauma pandemic in low-income countries requires access to relevant research information regarding prevention and treatment of injuries. Such information is also generally produced in high-income countries. We reviewed two years' worth of articles from leading orthopaedic and general medical journals to determine whether the scientific literature appropriately reflects the global burden of musculoskeletal disease, particularly that due to trauma. General medical journals underrepresented musculoskeletal disease, but within musculoskeletal disease an appropriate majority of papers were regarding trauma, in particular the epidemiology and prevention of injury. Orthopaedic journals, while focusing on musculoskeletal conditions, substantially underrepresented the global burden of disease due to trauma and hardly consider injury epidemiology and prevention. If orthopaedic surgeons want to maximize their global impact, they should focus on writing about trauma questions relevant to their colleagues in low-income countries and ensuring these same colleagues have access to the literature.


Intrinsic expression of transcortin in neural cells of the mouse brain: a histochemical and molecular study.
Corticosteroid binding globulin (CBG, transcortin) has been shown to be expressed in the brain of rat and human species. In this study, we examined the CBG brain expression and cDNA structure in mice, comparing wild-type (Cbg(+/+)) and Cbg knockout mice (Cbg(-/-), obtained by genetic disruption of the SerpinA6 alias Cbg gene). We used double immunofluorescence labeling with specific neuronal and glial markers to analyze the cellular localization of CBG in various regions of the mouse brain. In wild-type (Cbg(+/+)) mice, we found CBG immunoreactivity in neuronal perikarya of the magnocellular hypothalamic nuclei, amygdala, hippocampus, cerebral cortex, cerebellum and pituitary. A portion of glial cells (astrocytes, oligodendrocytes) contained CBG immunoreactivity, including some of the ependymal cells and choroid plexus cells. No CBG immunoreactivity was detected in Cbg(-/-) brain tissues. Using RT-PCR, we showed that the full-length Cbg mRNA is present in those regions, indicating an intrinsic expression of the steroid-binding globulin. Furthermore, sequencing analysis showed that Cbg cDNA obtained from the mouse hypothalamus was homologous to Cbg cDNA obtained from the liver. Finally, we have evaluated the relative levels of CBG expression in various brain regions and in the liver by quantitative PCR. We found that brain levels of Cbg mRNA are low compared with the liver but significantly higher than in CBG-deficient mice. Although derived from the same gene as liver CBG, brain CBG protein may play a specific or complementary role that requires the production and analysis of brain-specific Cbg knockout models.


Staff perspectives on facilitating the implementation of hepatitis C services at drug treatment programs.
Drug users are at risk of acquiring the hepatitis C virus (HCV). Although ancillary services available to clients at drug treatment programs are often limited, some of these programs are providing HCV services. Presenting qualitative data, the authors describe the HCV education and/or support services available at four drug treatment programs and examine staff and client perspectives on factors that facilitated the implementation of these services. Major findings include participants' perceptions that their programs had: (1) at least one change agent on staff who promoted the innovation and delivery of HCV services; (2) at least one administrator or director who encouraged and supported the adoption of these services; and (3) a treatment team that tended to collectively "buy into" and value the HCV service. Ultimately, we found that some drug treatment programs are finding creative and nonresource-intensive ways of delivering HCV services despite the existence of significant barriers. While programs need more funding and resources to overcome these barriers, these findings may prove helpful to other drug treatment programs that would like to offer HCV services to at least some of their clients.


Spatial heterogeneity in climate change effects decouples the long-term dynamics of wild reindeer populations in the high Arctic.
The 'Moran effect' predicts that dynamics of populations of a species are synchronized over similar distances as their environmental drivers. Strong population synchrony reduces species viability, but spatial heterogeneity in density dependence, the environment, or its ecological responses may decouple dynamics in space, preventing extinctions. How such heterogeneity buffers impacts of global change on large-scale population dynamics is not well studied. Here, we show that spatially autocorrelated fluctuations in annual winter weather synchronize wild reindeer dynamics across high-Arctic Svalbard, while, paradoxically, spatial variation in winter climate trends contribute to diverging local population trajectories. Warmer summers have improved the carrying capacity and apparently led to increased total reindeer abundance. However, fluctuations in population size seem mainly driven by negative effects of stochastic winter rain-on-snow (ROS) events causing icing, with strongest effects at high densities. Count data for 10 reindeer populations 8-324 km apart suggested that density-dependent ROS effects contributed to synchrony in population dynamics, mainly through spatially autocorrelated mortality. By comparing one coastal and one 'continental' reindeer population over four decades, we show that locally contrasting abundance trends can arise from spatial differences in climate change and responses to weather. The coastal population experienced a larger increase in ROS, and a stronger density-dependent ROS effect on population growth rates, than the continental population. In contrast, the latter experienced stronger summer warming and showed the strongest positive response to summer temperatures. Accordingly, contrasting net effects of a recent climate regime shift-with increased ROS and harsher winters, yet higher summer temperatures and improved carrying capacity-led to negative and positive abundance trends in the coastal and continental population respectively. Thus, synchronized population fluctuations by climatic drivers can be buffered by spatial heterogeneity in the same drivers, as well as in the ecological responses, averaging out climate change effects at larger spatial scales.