Comparative morphometric analyses of the deciduous molars of Homo naledi from the Dinaledi Chamber, South Africa.
The purpose of this study is to help elucidate the taxonomic relationship between Homo naledi and other hominins. Homo naledi deciduous maxillary and mandibular molars from the Dinaledi Chamber, South Africa were compared to those of Australopithecus africanus, Australopithecus afarensis, Paranthropus robustus, Paranthropus boisei, early Homo sp., Homo erectus, early Homo sapiens, Upper Paleolithic H. sapiens, recent southern African H. sapiens, and Neanderthals by means of morphometric analyses of crown outlines and relative cusp areas. The crown shapes were analyzed using elliptical Fourier analyses followed by principal component analyses (PCA). The absolute and relative cusp areas were obtained in ImageJ and compared using PCA and cluster analyses. PCA suggests that the crown shapes and relative cusp areas of mandibular molars are more diagnostic than the maxillary molars. The H. naledi deciduous mandibular first and second molar (dm1 and dm2 ) do not have a strong affinity to any taxon in the comparative sample in all analyses. While the H. naledi dm2 plots as an outlier in the relative cusp analysis, the H. naledi specimen fall closest to Australopithecus due to their relatively large metaconid, a primitive trait for the genus Homo. Although useful for differentiating Neanderthals from recent southern African H. sapiens and UP H. sapiens, the PCA of the relative cusp areas suggests that the deciduous maxillary second molars (dm2 ) do not differentiate other groups. The three H. naledi dm2 cuspal areas are variable and fall within the ranges of other Homo, as well as Australopithecus, and Paranthropus suggesting weak diagnostic utility. This research provides another perspective on the morphology of, and variation within, H. naledi. The H. naledi deciduous molars do not consistently align with any genus or species in the comparative sample in either the crown shape or relative cusp analyses. This line of inquiry is consistent with other cranial and postcranial studies suggesting that H. naledi is unique.


The legacy of minimum legal drinking age law changes: long-term effects on suicide and homicide deaths among women.
Prior to the establishment of the uniform drinking age of 21 in the United States, many states permitted legal purchase of alcohol at younger ages. Lower drinking ages were associated with several adverse outcomes, including elevated rates of suicide and homicide among youth. The objective of this study is to examine whether individuals who were legally permitted to drink prior to age 21 remained at elevated risk in adulthood. Analysis of data from the U.S. Multiple Cause of Death files, 1990 to 2004, combined with data on the living population from the U.S. Census and American Community Survey. The assembled data contained records on over 200,000 suicides and 130,000 homicides for individuals born between 1949 and 1972, the years during which the drinking age was in flux. Logistic regression models were used to evaluate whether adults who were legally permitted to drink prior to age 21 were at elevated risk for death by these causes. A quasi-experimental analytical approach was employed, which incorporated state and birth-year fixed effects to account for unobserved covariates associated with policy exposure. In the population as a whole, we found no association between minimum drinking age and homicide or suicide. However, significant policy-by-sex interactions were observed for both outcomes, such that women exposed to permissive drinking age laws were at higher risk for both suicide (OR = 1.12, 95% CI: 1.05, 1.18, p = 0.0003) and homicide (OR = 1.15, 95% CI: 1.04, 1.25, p = 0.0028). Effect sizes were stronger for the portion of the cohort born after 1960, whereas no significant effects were observed for women born prior to 1960. Lower drinking ages may result in persistent elevated risk for suicide and homicide among women born after 1960. The national drinking age of 21 may be preventing about 600 suicides and 600 homicides annually.


Disorders of phospholipid metabolism: an emerging class of mitochondrial disease due to defects in nuclear genes.
The human nuclear and mitochondrial genomes co-exist within each cell. While the mitochondrial genome encodes for a limited number of proteins, transfer RNAs, and ribosomal RNAs, the vast majority of mitochondrial proteins are encoded in the nuclear genome. Of the multitude of mitochondrial disorders known to date, only a fifth are maternally inherited. The recent characterization of the mitochondrial proteome therefore serves as an important step toward delineating the nosology of a large spectrum of phenotypically heterogeneous diseases. Following the identification of the first nuclear gene defect to underlie a mitochondrial disorder, a plenitude of genetic variants that provoke mitochondrial pathophysiology have been molecularly elucidated and classified into six categories that impact: (1) oxidative phosphorylation (subunits and assembly factors); (2) mitochondrial DNA maintenance and expression; (3) mitochondrial protein import and assembly; (4) mitochondrial quality control (chaperones and proteases); (5) iron-sulfur cluster homeostasis; and (6) mitochondrial dynamics (fission and fusion). Here, we propose that an additional class of genetic variant be included in the classification schema to acknowledge the role of genetic defects in phospholipid biosynthesis, remodeling, and metabolism in mitochondrial pathophysiology. This seventh class includes a small but notable group of nuclear-encoded proteins whose dysfunction impacts normal mitochondrial phospholipid metabolism. The resulting human disorders present with a diverse array of pathologic consequences that reflect the variety of functions that phospholipids have in mitochondria and highlight the important role of proper membrane homeostasis in mitochondrial biology.


[Relationship between depression and resilience among children with nephrotic syndrome].
The purposes of this study were to describe the relationship between depression and resilience and to identify variables associated with depression among children with nephrotic syndrome. Data was collected from 45 children who were registered at one hospital in Seoul. The criteria for sample selection were 10 to 15 year-old children who were diagnosed at least 6 month prior. The instruments included a self-reported questionnaire on resilience by Kim, CDI by Beck, and MBRI by Kwak. Descriptive, Pearson correlation and multiple regression analyses were done. The mean score of depression was 11.44 (range:0-54) and resilience was 97.47 (range:32-128). There were significant positive relationships between depression and age (r=0.302, p<.005) and academic achievement (r=-0.318, p<.005). In addition, negative relationships between depression and maternal attitude (r=-0.412, p<.001) and resilience (r=-0.649, p<.001) occurred. The results of multiple regression analysis showed that maternal behavior (beta=-0.421, p<.005) and resilience (beta=-0.639, p<.001) were related to depression. Children with higher resilience and with an affectionate mother were less depressed. Thus, it is important to identify strengths of children and help them to increase resilience and implement parenting and counseling programs for parents' of these children. Similar studies with children with other chronic illnesses are needed.


Ischaemic infarction masking aortic dissection: a pitfall to be avoided before thrombolysis.
Acute aortic dissection complicated by stroke is not uncommon but may be difficult to evaluate, especially in patients with impaired mental status. We report a patient who had evidence of an ischaemic stroke but was fortuitously not given thrombolytic treatment. She was subsequently found to have an extensive aortic dissection involving both carotid arteries. The decision of whether to give thrombolytic treatment is understandably an urgent one, but careful attention should be paid to subtle signs and symptoms such as atypical chest pain and carotid bruits that might suggest aortic dissection, especially involving the carotid arteries. There should be a high index of suspicion for acute aortic dissection in such cases and a low threshold for performing carotid ultrasound.


Direct immunoassay on a polyester microwell plate for colorimetric detection of the spike protein in swab and saliva samples.
This study presents the development of a polyester microplate for detecting the S-protein of the SARS-CoV-2 virus in saliva and nasopharyngeal swab samples using direct enzyme-linked immunosorbent assay (ELISA) technology. The polyester microplate was designed to contain 96 zones with a 3 mm diameter each, and a volume of 2-3 μL. The experimental conditions including reagent concentration and reaction time were optimized. The microplate image was digitized and analyzed using graphical software. The linear range obtained between protein S concentrations and pixel intensity was 0-10 μg mL-1, with a correlation coefficient of 0.99 and a limit of detection of 0.44 μg mL-1. The developed methodology showed satisfactory intraplate and interplate repeatability with RSD values lower than 7.8%. The results achieved through immunoassay performed on polyester microplates were consistent with those of the RT-PCR method and showed a sensitivity of 100% and 90% and specificity of 85.71% and 100% for saliva and nasopharyngeal samples, respectively. The proposed direct immunoassay on polyester microplates emerges as an alternative to conventional immunoassays performed on commercial polystyrene plates, given the low cost of the device, low consumption of samples and reagents, lower waste generation, and shorter analysis time. Moreover, the immunoassay has shown great potential for diagnosing COVID-19 with precision and accuracy.


Opposing effects of low versus high concentrations of water soluble vitamins/dietary ingredients Vitamin C and niacin on colon cancer stem cells (CSCs).
Colorectal cancer is one of the global causes of cancer deaths. Cancer stem cells (CSCs) inside the tumour niche responsible for metastasis and relapses, and hence need to be targeted for cancer therapeutics. Although dietary fibre and lifestyle changes have been recommended as measures for colorectal cancer prevention, no such recommendations are available for using water soluble vitamins as prophylaxis measure for colorectal cancers. High dose of Vitamin C has been proven to selectively kill colon cancer cells having BRAF and KRAS mutations by inducing oxidative stress. In this study, we show for the first time the opposing effects of the low and high dose of Vitamin C and vitamin B3 on colon CSCs isolated from HT-29 and HCT-15 colorectal carcinoma cell lines. At small doses, both of these vitamins exerted a cell proliferative effect only on CSCs, while there was no change in the proliferation status of non-stem cancer cells and wild-type (WT) populations. On the other hand, the death effects induced by high doses of Vitamin C and B3 were of the order of 50-60% and ∼30% on CSCs from HT-29 and HCT15, respectively. Interestingly, the control fibroblast cell line (NIH3T3) was highly refractory all the tested concentrations of Vitamin C and B3, except for the highest dose - 10,000 μg of Vitamin C that induced only 15% of cell death. Hence, these results indicate the future scope of use of therapeutic doses of Vitamin C and B3 especially in patients with advanced colorectal cancer.


Circulating tumor DNA profiling reveals clonal evolution and real-time disease progression in advanced hepatocellular carcinoma.
Circulating tumor DNA (ctDNA) provides a potential non-invasive biomarker for cancer diagnosis and prognosis, but whether it could reflect tumor heterogeneity and monitor therapeutic responses in hepatocellular carcinoma (HCC) is unclear. Focusing on 574 cancer genes known to harbor actionable mutations, we identified the mutation repertoire of HCC tissues, and monitored the corresponding ctDNA features in blood samples to evaluate its clinical significance. Analysis of 3 HCC patients' mutation profiles revealed that ctDNA could overcome tumor heterogeneity and provide information of tumor burden and prognosis. Further analysis was conducted on the 4th HCC case with multiple lesion samples and sequential plasma samples. We identified 160 subclonal SNVs in tumor tissues as well as matched peritumor tissues with PBMC as control. 96.9% of this patient's tissue mutations could be also detected in plasma samples. These subclonal SNVs were grouped into 9 clusters according to their trends of cellular prevalence shift in tumor tissues. Two clusters constituted of tumor stem somatic mutations showed circulating levels relating with cancer progression. Analysis of tumor somatic mutations revealed that circulating level of such tumor stem somatic mutations could reflect tumor burden and even predict prognosis earlier than traditional strategies. Furthermore, HCK (p.V174M), identified as a recurrent/metastatic related mutation site, could promote migration and invasion of HCC cells. Taken together, study of mutation profiles in biopsy and plasma samples in HCC patients showed that ctDNA could overcome tumor heterogeneity and real-time track the therapeutic responses in the longitudinal monitoring.


Investigation of the Impact of Neutron Irradiation on SiC Power MOSFETs Lifetime by Reliability Tests.
High temperature reverse-bias (HTRB), High temperature gate-bias (HTGB) tests and electrical DC characterization were performed on planar-SiC power MOSFETs which survived to accelerated neutron irradiation tests carried out at ChipIr-ISIS (Didcot, UK) facility, with terrestrial neutrons. The neutron test campaigns on the SiC power MOSFETs (manufactered by ST) were conducted on the same wafer lot devices by STMicroelectronics and Airbus, with different neutron tester systems. HTGB and HTRB tests, which characterise gate-oxide integrity and junction robustness, show no difference between the non irradiated devices and those which survived to the neutron irradiation tests, with neutron fluence up to 2× 1011 (n/cm2). Electrical characterization performed pre and post-irradiation on different part number of power devices (Si, SiC MOSFETs and IGBTs) which survived to neutron irradiation tests does not show alteration of the data-sheet electrical parameters due to neutron interaction with the device.


Could Medicare readmission policy exacerbate health care system inequity?
The Centers for Medicare & Medicaid Services recently started publicly reporting hospital readmission rates. Health care reform proposals include readmission provisions as vehicles to promote care coordination and achieve savings. Current approaches ascribe variability in hospital readmission primarily to differences in patient medical risk and hospital performance. These approaches do not adequately account for the effect of patient sociodemographic and community factors that influence health care utilization and outcomes. The evidence base on cost-effective and generalizable care management techniques to reduce readmission is still evolving. Although readmission-related policies may prove to be a transformational force in health care reform, their incorrect application in facilities serving vulnerable communities may increase health care system inequity. Policy options can mitigate this potential.


Hypnotic drug risks of mortality, infection, depression, and cancer: but lack of benefit.
This is a review of hypnotic drug risks and benefits. Almost every month, new information appears about the risks of hypnotics (sleeping pills). The most important risks of hypnotics include excess mortality (especially overdose deaths, quiet deaths at night, and suicides), infections, cancer, depression, automobile crashes, falls, other accidents, and hypnotic-withdrawal insomnia. Short-term use of one-two prescriptions is associated with even greater risk per dose than long-term use. Hypnotics have usually been prescribed without approved indication, most often with specific contraindications, but even when indicated, there is little or no benefit. The recommended doses objectively increase sleep little if at all, daytime performance is often made worse (not better) and the lack of general health benefits is commonly misrepresented in advertising. Treatments such as the cognitive behavioral treatment of insomnia and bright light treatment of circadian rhythm disorders offer safer and more effective alternative approaches to insomnia.


Spatial variability of 2H and 18O composition of meteoric freshwater lakes in Scotland.
Coastal regions, and in particular islands where precipitation from clouds formed out at sea occurs for the first time, are prime candidates for regions where 2H and 18O composition of precipitation will deviate significantly from the global mean geographic and physiographic trends of vapour-transport patterns. The results reported here are the outcome of a study that aimed to test this hypothesis by 'isotopographically' mapping the characteristic δ2H and δ18O signatures of Scottish freshwaters. The resulting isotope abundance landscapes or 'isoscapes' will underpin studies aiming to authenticate origin of Scottish produce but may also offer a baseline against which environmental changes could be assessed. Between April 2011 and May 2012 freshwater samples were collected from 127 different freshwater lochs and reservoirs across Scotland, and analysis results were compared to precipitation data provided by the British Geological Survey. Here we present the results of the 2H and 18O analyses of these water samples as well as the first detailed Scotland freshwater isoscapes with a grid resolution of about 5 × 5 km (0.05 degrees).


Simultaneous determination of paracetamol and lornoxicam by RP-HPLC in bulk and tablet formulation.
The objective of the study was to develop simple RP-HPLC method for the simultaneous determination of paracetamol and lornoxicam without prior separation. In this method, Kromasil C8 (250 mm, 4.6 mm, 5 μm) column was used. The mobile phase used was methanol:phosphate buffer (60:40, v/v, pH 6.4), at flow rate of 1 ml min(-1). UV detection was monitored at 302 nm. Calibration graphs were established in the range of 1-150 μg ml(-1) and 0.5-100 μg ml(-1) for paracetamol and lornoxicam, respectively. The average retention time for paracetamol and lornoxicam was found to be 3.15 ± 0.03 min and 5.25 ± 0.06 min, respectively. The detection limit and quantitation limit for paracetamol are 0.19 μg ml(-1) and 0.59 μg ml(-1) and for lornoxicam 0.10 μg ml(-1) and 0.31 μg mL(-1), respectively. The intraday and interday precision expressed as percent relative standard deviation were below 2%. The mean recovery of paracetamol and lornoxicam was found to be in the range of 99.03-101.2%. The validated HPLC method was found to be rapid, precise and accurate and can be readily utilized for analysis of paracetamol and lornoxicam in bulk and in pharmaceutical formulations.


Effect of the esters of gallic acid on model and human blood platelet membranes studied by Fourier transform infrared spectroscopy.
Gallic acid is one of the components of Chinese herbal drug Radix paeoniae used for promoting blood circulation to remove blood stasis. This paper studied the effects of gallic acid and its esters (e.g. ethyl, propyl, isobutyl and butyl gallate) on model and human blood platelet membranes by FTIR which was used for monitoring the physical state of the acyl chain, interfacial and head group region of the membrane lipid bilayer. From the experimental results it can be seen that the gallic acid and its esters have the modifying function on the pure and cholesterol-containing DPPC model membranes, and have the quantity-effective and structural-effective relationships. In addition, it is discovered that these esters have the modifying effect on the structure of human blood platelet membrane and can reverse the effect of ADP. That the effect of the esters of gallic acid counteracts the effect of cholesterol and ADP on human blood platelet perhaps provides a new explanation of the mechanism of Chinese herbal drugs used for promoting blood circulation to remove blood stasis.


Heterojunction oxide thin-film transistors with unprecedented electron mobility grown from solution.
Thin-film transistors made of solution-processed metal oxide semiconductors hold great promise for application in the emerging sector of large-area electronics. However, further advancement of the technology is hindered by limitations associated with the extrinsic electron transport properties of the often defect-prone oxides. We overcome this limitation by replacing the single-layer semiconductor channel with a low-dimensional, solution-grown In2O3/ZnO heterojunction. We find that In2O3/ZnO transistors exhibit band-like electron transport, with mobility values significantly higher than single-layer In2O3 and ZnO devices by a factor of 2 to 100. This marked improvement is shown to originate from the presence of free electrons confined on the plane of the atomically sharp heterointerface induced by the large conduction band offset between In2O3 and ZnO. Our finding underscores engineering of solution-grown metal oxide heterointerfaces as an alternative strategy to thin-film transistor development and has the potential for widespread technological applications.


Calcium and phosphate metabolism in tumoral calcinosis.
We have recently seen a patient with tumoral calcinosis, a syndrome comprising hyperphosphatemia, normocalcemia, normal glomerular filtration rate (GFR), and extensive periarticular calcific masses. Parathyroid hormone (PTH) deficiency or target organ resistance was ruled out by demonstration of normal serum PTH and urinary 3'5'cyclic AMP excretion and normal response to exogenous PTH and to endogenous stimulation by ethylenediaminetetraacetate. An intrinsic proximal tubular defect allowing enhanced renal PO4 reabsorption was probably present because there was no phosphaturic response to acetazolamine and renal PO4 threshold remained abnormally elevated even after PTH infusion. We then studied the mechanism by which serum calcium level is maintained in the normal range despite hyperphosphatemia and absence of secondary hyperparathyroidism. Normal 1,25-(OH)2 vitamin D was found, suggesting normal gastrointestinal calcium absorption. This, combined with markedly reduced urinary calcium excretion, perhaps a direct effect of hyperphosphatemia, may maintain calcium balance and prevent secondary hyperparathyroidism. A rise in urinary cyclic AMP excretion after furosemide-induced calciuria supports this hypothesis.


TRIM25 and DEAD-Box RNA Helicase DDX3X Cooperate to Regulate RIG-I-Mediated Antiviral Immunity.
The cytoplasmic retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) initiate interferon (IFN) production and antiviral gene expression in response to RNA virus infection. Consequently, RLR signalling is tightly regulated by both host and viral factors. Tripartite motif protein 25 (TRIM25) is an E3 ligase that ubiquitinates multiple substrates within the RLR signalling cascade, playing both ubiquitination-dependent and -independent roles in RIG-I-mediated IFN induction. However, additional regulatory roles are emerging. Here, we show a novel interaction between TRIM25 and another protein in the RLR pathway that is essential for type I IFN induction, DEAD-box helicase 3X (DDX3X). In vitro assays and knockdown studies reveal that TRIM25 ubiquitinates DDX3X at lysine 55 (K55) and that TRIM25 and DDX3X cooperatively enhance IFNB1 induction following RIG-I activation, but the latter is independent of TRIM25's catalytic activity. Furthermore, we found that the influenza A virus non-structural protein 1 (NS1) disrupts the TRIM25:DDX3X interaction, abrogating both TRIM25-mediated ubiquitination of DDX3X and cooperative activation of the IFNB1 promoter. Thus, our results reveal a new interplay between two RLR-host proteins that cooperatively enhance IFN-β production. We also uncover a new and further mechanism by which influenza A virus NS1 suppresses host antiviral defence.


Morphological and Molecular Characterization of Phoma complanata,a New Causal Agent of Archangelica officinalis Hoffm. in Poland.
The paper concerns the fungus Phoma complanata, isolated for the first time in Poland, from the roots and umbels of angelica (Archangelica officinalis) in 2009. The morphology of fungal isolates was tested on standard culture media. Moreover, the sequence analysis of ITS regions was conducted. Morphological similarity of P. complanata Polish isolates to the reference isolate obtained from CBS culture collection was determined and together with the molecular analysis confirmed the affiliation of the fungus to the species.


Attitudes of Sport Fans Toward the Electronic Sign-Stealing Scandal in Major League Baseball: Differing Associations With Perfectionism and Excellencism.
The winners of the 2017 World Series were found guilty of illegally using electronic devices to steal the signs of their opponents. Many but not all sport fans negatively reacted to this cheating incident. We relied on the model of excellencism and perfectionism to determine if perfection strivers are less unfavorable toward electronic sign stealing (cheating) compared with excellence strivers. Sport fans (N = 321) completed a measure of excellencism and perfectionism. We used three different approaches to measure attitudes toward electronic sign stealing in baseball. Results of a multivariate multiple regression showed that sport fans who are perfection strivers held more favorable attitudes toward electronic sign stealing compared with excellence strivers. Perfection strivers also reported higher moral disengagement and winning-at-all-cost mentality. These findings are insightful because they indicate that perfectionistic standards significantly relate to sport cheating-related attitudes once we separate excellencism from perfectionism.


Interacting laser beams in a resonant medium.
For potential applications in scanning and measurement, we consider two interacting laser beams in an active nonlinear medium. The nonlinear medium generates two new beams at the same frequency and in directions different from the incident beams. The Kerr effect is used as a means of phase matching in the isotropic medium.


Characterization of the chemical composition of a block copolymer by liquid chromatography/mass spectrometry using atmospheric pressure chemical ionization and electrospray ionization.
Liquid chromatography/mass spectrometry (LC/MS) with electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) in the positive and negative ion modes was used for the characterization of a block copolymer consisting of methoxy poly(ethylene oxide) (mPEO), an epsilon-caprolactone (CL) segment and linoleic acid (LA), used as surfactant in water-based latex paints. Chromatographic separation was obtained based on the number of CL units in the polymer species and the presence of an mPEO and/or LA tail. Different ionization methods were found to be complementary and only their combination allowed the qualitative profiling of the chemical composition. The LC/MS method has proven valuable for following the reaction in time, as well as for comparison of different polymeric surfactants.


The Poor Fit of Model Fit for Selecting Number of Factors in Exploratory Factor Analysis for Scale Evaluation.
Model fit indices are being increasingly recommended and used to select the number of factors in an exploratory factor analysis. Growing evidence suggests that the recommended cutoff values for common model fit indices are not appropriate for use in an exploratory factor analysis context. A particularly prominent problem in scale evaluation is the ubiquity of correlated residuals and imperfect model specification. Our research focuses on a scale evaluation context and the performance of four standard model fit indices: root mean square error of approximate (RMSEA), standardized root mean square residual (SRMR), comparative fit index (CFI), and Tucker-Lewis index (TLI), and two equivalence test-based model fit indices: RMSEAt and CFIt. We use Monte Carlo simulation to generate and analyze data based on a substantive example using the positive and negative affective schedule (N = 1,000). We systematically vary the number and magnitude of correlated residuals as well as nonspecific misspecification, to evaluate the impact on model fit indices in fitting a two-factor exploratory factor analysis. Our results show that all fit indices, except SRMR, are overly sensitive to correlated residuals and nonspecific error, resulting in solutions that are overfactored. SRMR performed well, consistently selecting the correct number of factors; however, previous research suggests it does not perform well with categorical data. In general, we do not recommend using model fit indices to select number of factors in a scale evaluation framework.


A leptin dose-response study in obese (ob/ob) and lean (+/?) mice.
This experiment determined the amount of leptin required to correct different abnormalities in leptin-deficient ob/ob mice. Baseline food intakes and body weights of lean (+/?) and obese (ob/ob) C57B1/6J <ob> mice were recorded for 7 days. An Alzet miniosmotic pump was placed in the peritoneal cavity of each mouse and delivered 0, 1, 2, 5, 10, or 42 microg/day human leptin for 7 days. In ob/ob mice, 2 microg leptin/day reduced food intake and body weight, and increased hypothalamic and brain stem serotonin concentrations. All fat pads were reduced 35-40% by 10 microg leptin/day, and liver weight, lipid, and glycogen decreased. Serum insulin and glucose were reduced in all leptin-treated ob/ob mice, and levels were normalized by 10 microg/day leptin. Low rectal temperatures of ob/ob mice were corrected by 10 and 42 microg/day leptin. These doses also increased brown adipose tissue uncoupling protein expression. The only responses in lean mice were a transient reduction in food intake and weight loss with 10 or 42 microg/day leptin. This study shows enhanced leptin sensitivity in ob/ob mice and suggests that increased temperature and sympathetic activity are indirect responses to high concentrations of protein.


Plasma extracellular superoxide dismutase concentration, allelic variations in the SOD3 gene and risk of myocardial infarction and all-cause mortality in people with type 1 and type 2 diabetes.
Oxidative stress is involved in development of diabetes complications. Extracellular superoxide dismutase (EC-SOD, SOD3) is a major extracellular antioxidant enzyme and is highly expressed in arterial walls. Advanced oxidation protein products (AOPP) and 8-iso-prostaglandin (isoprostane) are markers of oxidative stress. We investigated association of SOD3 gene variants, plasma concentrations of EC-SOD, AOPP and isoprostane with myocardial infarction and mortality in diabetic patients. We studied three cohorts designed to evaluate the vascular complications of diabetes: the GENEDIAB study (469 participants with type 1 diabetes at baseline; follow-up data for 259 participants), the GENESIS study (603 participants with type 1 diabetes at baseline; follow-up data for 525 participants) and the DIABHYCAR study (3137 participants with type 2 diabetes at baseline and follow-up). Duration of follow-up was 9, 5, and 5 years, respectively. Main outcome measures were incidence of myocardial infarction, and cardiovascular and total mortality during follow-up. Six single nucleotide polymorphisms in the SOD3 locus were genotyped in the three cohorts. Plasma concentrations of EC-SOD, AOPP, and isoprostane were measured in baseline samples of GENEDIAB participants. In GENEDIAB/GENESIS pooled cohorts, the minor T-allele of rs2284659 variant was inversely associated with the prevalence at baseline (Odds Ratio 0.48, 95% CI 0.29-0.78, p = 0.004) and the incidence during follow-up of myocardial infarction (Hazard Ratio 0.58, 95% CI 0.40-0.83, p = 0.003) and with cardiovascular (HR 0.33, 95% CI 0.08-0.74, p = 0.004) and all-cause mortality (HR 0.44, 95% CI 0.21-0.73, p = 0.0006). The protective allele was associated with higher plasma EC-SOD and lower plasma AOPP concentrations in GENEDIAB. It was also inversely associated with incidence of myocardial infarction (HR 0.75, 95% CI 0.59-0.94, p = 0.01) and all-cause mortality (HR 0.87, 95% CI 0.79-0.97, p = 0.008) in DIABHYCAR. The T-allele of rs2284659 in the promoter of SOD3 was associated with a more favorable plasma redox status and with better cardiovascular outcomes in diabetic patients. Our results suggest that EC-SOD plays an important role in the mechanisms of vascular protection against diabetes-related oxidative stress.


Toxocariasis and childhood asthma: A case-control study.
The objective of this study is to investigate the association between anti-Toxocara IgG seropositivity and asthma in children. This was a case-control study conducted in a university hospital in south Brazil between May 2012 and June 2013. Were recruited 208 children up to 12 years old of whom 156 had asthma (cases) and 52 did not have asthma (controls), with a case-control ratio of 3:1 matched by age. Children's parents or guardians were interviewed using a structured questionnaire with closed questions. Serology was performed using enzyme-linked immunosorbent assay (ELISA) with excretory-secretory antigen of Toxocara canis (TES). The seroprevalence of IgG anti-T. canis antibodies was 12.8% in the cases and 7.7% in the controls. There was no significant association between seropositivity to T. canis and risk of asthma (adjusted odds ratio [OR]: 1.89, 95% CI: 0.52 to 6.89, p = 0.33). Household income < 2 minimum salaries, paternal school years < 9, allergic rhinitis in children, a positive family history of asthma and rhinitis and contact with cats were significantly associated with asthma, with adjusted ORs (95% CIs) of 3.05 (1.21 to 7.73), 2.83 (1.11 to 7.18), 10.5 (4.32 to 25.6), 2.65 (1.14 to 6.17), 2.49 (1.07 to 5.78) and 2.73 (1.03 to 7.27), respectively. This study did not find a statistically significant association between seropositivity to Toxocara sp. and risk of asthma in children. Low family income, low paternal education level, concomitant allergic rhinitis, family history of asthma and allergic rhinitis and contact with cats were independent factors associated with childhood asthma.


Physical workload during use of speech recognition and traditional computer input devices.
Musculoskeletal symptoms among computer users are frequently found. The aim was to investigate the musculoskeletal workload during computer work using speech recognition and traditional computer input devices (keyboard/mouse). Ten experienced computer users (nine female, one male) participated. They performed three different computer tasks: (1). text entry and (2). text editing of a standard text and (3). a self-selected work task. These tasks were performed twice using speech recognition and traditional computer input devices (keyboard/mouse). Additionally, a task consisting of reading aloud of the standard text was performed. Surface EMG from the forearm (m. extensor carpi ulnaris, m. extensor carpi radialis), the shoulder (m. trapezius) and the neck extensor muscles was recorded, in addition to the voice-related muscles (m. scalenii, m. cricothyroideus). Using speech recognition during text entry and text editing reduced the static muscle activity of the forearm, neck and to some extent the shoulder muscles. Furthermore, tendencies to longer periods of muscle activity pause (relative time with EMG gaps) in the forearm and shoulder muscles were found. This was seen at the expense of a tendency to an increased static activity and a decreased relative time with EMG gaps in m. cricothyroideus. Finally, during use of speech recognition the hand was tied to the keyboard/mouse for a shorter period of time, while the eyes were viewing the screen for a longer period of time compared to the condition with traditional computer input devices. It is recommended to use speech recognition as a supplementary tool to traditional computer input devices.


Adverse drug reactions in patients with COVID-19 in Brazil: analysis of spontaneous notifications of the Brazilian pharmacovigilance system.
In March 2020, the World Health Organization announced the new COVID-19 pandemic, which represented a challenge for health services and professionals. An effective treatment against this disease has not yet been developed; as such, several drugs are used without evidence of efficacy, which in some cases may lead to unwanted events. This is a cross-sectional study with the objective of evaluating adverse drug reactions (ADRs) in patients with COVID-19, identified between March 1 and August 15, 2020, in Brazil, as well as assessing the factors associated with the emergence of severe reactions. To compare the proportions of samples related to the notifier, patient, drugs and adverse events, we used Fisher's chi-square and exact nonparametric tests; and to compare the means of the data with normal distribution, we used the Student's t-test and Mann-Whitney's test. A multivariate logistic regression analysis was also performed, estimating the crude and adjusted odds ratio (OR) by the Stata software, version 10.0. A total of 631 ADRs were identified in 402 patients. The main drugs were hydroxychloroquine (59.5%), azithromycin (9.8%) and chloroquine (5.2%). The reactions manifested primarily in the cardiac system (38.8%), gastrointestinal system (14.4%), skin tissue (12.2%) and hepatic system (8.9%). Chloroquine (OR = 5.4; 95%CI: 1.9-15.6) and hydroxychloroquine (OR = 2.1; 95CI%: 1.2-3.6) were the only drugs associated with severe ADR. Our findings provide support for better practices in pharmacovigilance, contributing to effective and secure regulatory decision-making by the Brazilian Health Regulatory Agency, patients and society as a whole.


A Typology of Interactional Patterns Between Youth and Their Stepfathers: Associations with Family Relationship Quality and Youth Well-Being.
Stepfamilies are an increasingly common family form, many of which are headed by a resident mother and stepfather. Stepfather-child relationships exert notable influence on stepfamily stability and individual well-being. Although various stepfather roles have been observed, more research is warranted by which stepfather-child interactions are explored holistically and across a variety of life domains (e.g., recreational, personal, academic, and disciplinary). Thus, the primary purpose of the current study is to explore varying interactional patterns between youth and their stepfathers. A latent class analysis is conducted using a representative sample of 1,183 youth (53% female; mean age = 15.64 years, SD = 1.70 years; 62% non-Hispanic White) residing in mother-stepfather families from Wave I of the National Longitudinal Study of Adolescent to Adult Health. Latent-class enumeration processes support a four-class solution, with latent classes representing inactive, academically oriented, casually connected, and versatile and involved patterns of youth-stepparent interaction. Notable differences and similarities are evident across patterns with respect to family relationship quality, youth well-being, and socio-demographic characteristics. Differences are most stark between the inactive and versatile and involved patterns. Ultimately, the results showcase notable variation in youth-stepparent interactional patterns, and one size does not necessarily fit all stepfamilies. Family practitioners should be mindful of variation in youth-stepparent interactional patterns and assist stepfamilies in seeking out stepparent-child dynamics that are most compatible with the needs and dynamics of the larger family system.


Human embryonic stem cell-derived oligodendrocyte progenitor cells express the serotonin receptor and are susceptible to JC virus infection.
We studied the susceptibility of human embryonic stem cell-derived oligodendrocyte progenitor cells to infection with JC virus, the causative agent of progressive multifocal leukoencephalopathy (PML). A human embryonic stem cell line, H7, was used to derive an enriched population of cells expressing the oligodendrocyte progenitor cell-specific marker NG2. These cells expressed the 5HT2a receptor (5HT2aR) for JC virus and were highly susceptible to infection. Infection was reduced by treatment with anti-5HT2aR antibodies and by the 5HT2aR antagonists ritanserin and ketanserin. This is the first demonstration that human embryonic stem cell-derived oligodendrocyte progenitor cells are susceptible to JC virus infection and indicates that cells poised to replenish mature oligodendrocytes in PML lesions may also be a target of viral infection.


The antilesion actions of anticholinergic agents on ethanol-induced injury in rat stomachs: the importance of gastric vascular integrity and tonicity.
1. The antilesion actions of two antimuscarinic drugs on ethanol-induced gastric injury and mucosal integrity were examined in male rats. Histological examinations were made and gastric emptying rates determined after in vivo administration of the drugs to conscious rats. In anaesthetized rats, with an ex vivo gastric chamber, effects on gastric transmucosal potential difference, Evan's blue leakage and Na+ output were examined. 2. In conscious animals, atropine (1 mgkg-1, i.p.) and pirenzepine (1 mgkg-1, i.p.) both significantly reduced macroscopic lesion formation, but not microscopic damage and functional alterations, caused by orally administered absolute ethanol. Moreover, these drugs did not show any effect on the basal gastric adherent mucus level, nor the depleting action of ethanol on both adherent mucus and the mucosal mucus layer. Nevertheless, both atropine and pirenzepine significantly reduced gastric emptying rate. 3. In anaesthetized animals, pirenzepine but not atropine increased the basal transmucosal potential difference (PD); however, it could not prevent the ethanol-induced drop in PD. Furthermore, the inhibitory action of ethanol on sodium ion output from the gastric mucosa was not attenuated by these drugs. Pirenzepine, however, significantly lessened the increase in vascular permeability caused by 100% ethanol. This action was not shared by atropine. 4. These findings indicate that both atropine and pirenzepine exert their antilesion actions through the relaxation of the stomach. Pirenzepine also preserves the integrity of the gastric mucosal vasculature, which is distinct from the action of atropine. The protective action of these drugs occurs only at the macroscopic level.


Diuretic combinations in refractory oedema states: pharmacokinetic-pharmacodynamic relationships.
Diuretic resistance is encountered in a number of disease states, such as chronic renal failure, nephrotic syndrome, congestive heart failure (CHF) and cirrhosis. Diuretic stratagems which produce sequential nephron segment blockade, and thus a synergistic diuretic response, are frequently necessary and are regularly employed in these conditions. Pharmacokinetic determinants of diuretic response, including dose administered, absolute bioavailability, and tubular transport capacity and transport rate, are reviewed here. Pharmacodynamic factors are perhaps more important to overall response, and often result in modification of the dose-response relationship; these are also reviewed here. Stratagems used to maximise the diuretic response to loop diuretics include correcting abnormal haemodynamic parameters, utilising larger doses or constant intravenous infusions, and using albumin as a vehicle to deliver the loop diuretic to the site of tubular secretion. If these measures fail, then diuretic combinations are useful. Perhaps the most effective is the combination of metolazone (a thiazide-type diuretic) and a loop diuretic. The rationale for and use of various diuretic combinations, with particular emphasis on the metolazone-loop diuretic combination, is reviewed here and applied to the major disease states associated with diuretic resistance.


Uveal melanoma.
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. UMs are usually initiated by a mutation in GNAQ or GNA11, unlike cutaneous melanomas, which usually harbour a BRAF or NRAS mutation. The annual incidence in Europe and the USA is ~6 per million population per year. Risk factors include fair skin, light-coloured eyes, congenital ocular melanocytosis, ocular melanocytoma and the BAP1-tumour predisposition syndrome. Ocular treatment aims at preserving the eye and useful vision and, if possible, preventing metastases. Enucleation has largely been superseded by various forms of radiotherapy, phototherapy and local tumour resection, often administered in combination. Ocular outcomes are best with small tumours not extending close to the optic disc and/or fovea. Almost 50% of patients develop metastatic disease, which usually involves the liver, and is usually fatal within 1 year. Although UM metastases are less responsive than cutaneous melanoma to chemotherapy or immune checkpoint inhibitors, encouraging results have been reported with partial hepatectomy for solitary metastases, with percutaneous hepatic perfusion with melphalan or with tebentafusp. Better insight into tumour immunology and metabolism may lead to new treatments.


Centering Single Cells in Microgels via Delayed Crosslinking Supports Long-Term 3D Culture by Preventing Cell Escape.
Single-cell-laden microgels support physiological 3D culture conditions while enabling straightforward handling and high-resolution readouts of individual cells. However, their widespread adoption for long-term cultures is limited by cell escape. In this work, it is demonstrated that cell escape is predisposed to off-center encapsulated cells. High-speed microscopy reveals that cells are positioned at the microgel precursor droplets' oil/water interface within milliseconds after droplet formation. In conventional microencapsulation strategies, the droplets are typically gelled immediately after emulsification, which traps cells in this off-center position. By delaying crosslinking, driving cells toward the centers of microgels is succeeded. The centering of cells in enzymatically crosslinked microgels prevents their escape during at least 28 d. It thereby uniquely enables the long-term culture of individual cells within <5-µm-thick 3D uniform hydrogel coatings. Single cell analysis of mesenchymal stem cells in enzymatically crosslinked microgels reveals unprecedented high cell viability (>90%), maintained metabolic activity (>70%), and multilineage differentiation capacity (>60%) over a period of 28 d. The facile nature of this microfluidic cell-centering method enables its straightforward integration into many microencapsulation strategies and significantly enhances control, reproducibility, and reliability of 3D single cell cultures.


Chlamydial development is blocked in host cells transfected with Chlamydophila caviae incA.
Chlamydiae produce a set of proteins, termed Inc proteins, that are localized to the inclusion membrane and exposed to the host cell cytosol. Little information exists regarding the interaction of Inc proteins with the eukaryotic cell. To examine these interactions, Vaccinia virus vectors and mammalian plasmid-based systems were used to express inc genes in mammalian cells. Cells transfected with plasmids expressing Chlamydophila caviae incA were not productively infected by C. caviae. Expression of C. caviae incA also reduced inclusion formation by Chlamydia trachomatis, but not to the degree seen for C. caviae. Chlamydia trachomatis incA did not block development of either C. trachomatis or C. caviae. Deletion mutagenesis was used to demonstrate that plasmids encoding either the amino or carboxy-terminal regions of the protein, as well as the changing of a single amino acid within IncA (serine 17) could not block C. caviae infection. Immunoblot analysis of truncated IncA in a Vaccinia virus system provided evidence that serine 17 of C. caviae IncA is a target for phosphorylation. These experiments provide insight into the interaction of Inc proteins with the host cell and introduce a model system where these interactions can be explored further.


Spotted Gar and the Evolution of Innate Immune Receptors.
The resolution of the gar genome affords an opportunity to examine the diversification and functional specialization of immune effector molecules at a distant and potentially informative point in phylogenetic development. Although innate immunity is effected by a particularly large number of different families of molecules, the focus here is to provide detailed characterization of several families of innate receptors that are encoded in large multigene families, for which orthologous forms can be identified in other species of bony fish but not in other vertebrate groups as well as those for which orthologs are present in other vertebrate species. The results indicate that although teleost fish and the gar, as a holostean reference species, share gene families thought previously to be restricted to the teleost fish, the manner in which the members of the multigene families of innate immune receptors have undergone diversification is different in these two major phylogenetic radiations. It appears that both the total genome duplication and different patterns of genetic selection have influenced the derivation and stabilization of innate immune genes in a substantial manner during the course of vertebrate evolution.


Foot Problems in Patients in Acute Care: A Point-Prevalence Survey.
Determine the prevalence of foot problems in an inpatient population and to describe demographic data, comorbid conditions, and type of footwear worn. Observational point-prevalence cross-sectional design. The study setting was a 722-bed licensed hospital in Western Australia. A convenience sampling was used to include adults hospitalized in the study setting during the period of data collection. A subset of foot questions, guided by a literature review, and input from foot, wound, diabetes, and psychometric researchers and clinicians, was incorporated into the hospital point-prevalence survey conducted annually for nursing safety and quality. Trained nurses collected data during the 1-day survey. Data were analyzed using descriptive statistics and 2-tailed tests; associations between study variables were analyzed. Two hundred twenty-one patients participated in the survey; a majority (n = 193, 87%) self-reported at least 1 foot problem. More than half (n = 124) reported 3 foot problems and nearly one-third (n = 67) had 5 or more foot problems. Thick nails, damaged nails, and calluses and corns were the most frequently occurring foot problems. Older participants were more likely to have certain foot problems such as calluses and thick nails. Eleven (5%) participants were admitted to the hospital for a foot-related condition. The majority of foot problems in our study were found to be minor and not the primary admitting diagnosis. However, even minor foot problems can pose a risk of worsening, especially in high-risk populations such as those with diabetes. Thus, detection is critical in overall patient assessment, and nurses play a critical role in assessment and management of minor foot problems through the delivery of skin and nail care and through collaboration with other professionals who provide specialized foot care.


Detection of autoantibodies against 3,5,3'-triiodothyronine in a hyperthyroid patient (a case report).
A 35-year-old female patient was evaluated for thyroid function and was found to be hyperthyroid clinically and by laboratory tests. During the course of treatment with neomercazole, she developed a bizarre picture with consistently low T3 levels irrespective of her clinical thyroid status and other laboratory tests like serum T4 and TSH levels. The serum of the patient when analysed for the presence of autoantibodies was positive for those against T3. The presence of T3 autoantibodies was confirmed by other laboratory techniques like assessment of blank values in radioimmunoassay, binding of T3-125I to isolated gamma globulin and starch gel electrophoresis. Autoantibodies were found to be present only against T3 and not against. T4 The affinity constant of T3 antibodies was 4 x 10(9) lit. mol-1 as determined by Scatchard plot analysis while total binding capacity was 23 x 10(-11) mol/L.


Kidney intragraft donor-specific antibodies as determinant of antibody-mediated lesions and poor graft outcome.
Allograft pathology, antibody-tissue interaction as demonstrated by C4d deposition and serological evidence of donor-specific antibodies (DSA) are the cardinal diagnostic features of antibody-mediated lesions (AML) in kidney transplantation. However, discrepancy between histological and serological findings is common, and more reliable diagnostic tools are called for. Here, we asked whether the in situ detection of DSA could serve as marker for AML. To that end, we applied the anti-HLA single antigen flow bead assay to eluates from 51 needle core graft biopsies performed for cause. Intragraft antibody profiles were correlated to serum DSA (sDSA), histological data and transplant outcome. The prevalence and the mean number of intragraft DSA (gDSA) were lower than that of sDSA (15/51 gDSA+ vs. 37/51 sDSA+ patients; 1.64 gDSA vs. 2.24 sDSA per patient). DSA were detected in all anti-HLA antibody-positive biopsies (15/15). The presence of gDSA was significantly associated with (1) microcirculation lesions taken individually (g, cg) and analyzed in functional clusters (ptc + g + cg > 0, cg + mm > 0), (2) C4d positivity and (3) a worse short-term transplant outcome (p = 0.05). These associations were not found for patients presenting only sDSA. Taken together, these results indicate that gDSA is a severity marker of antibody-mediated pathogenic process.


An Approach to Support Collaborative Ontology Construction.
The increasing number of terms used in textbooks for information management (IM) in hospitals makes it difficult for medical informatics students to grasp IM concepts and their interrelations. Formal ontologies which comprehend and represent the essential content of textbooks can facilitate the learning process in IM education. The manual construction of such ontologies is time-consuming and thus very expensive [3]. Moreover, most domain experts lack skills in using a formal language like OWL [2] and usually have no experience with standard editing tools like Protégé <fnr rid="fn001" /><fn id="fn001">http://protege.stanford.edu </fn> [4,5]. This paper presents an ontology modeling approach based on Excel2OWL, a self-developed tool which efficiently supports domain experts in collaboratively constructing ontologies from textbooks. This approach was applied to classic IM textbooks, resulting in an ontology called SNIK. Our method facilitates the collaboration between domain experts and ontologists in the development process. Furthermore, the proposed approach enables ontologists to detect modeling errors and also to evaluate and improve the quality of the resulting ontology rapidly. This approach allows us to visualize the modeled textbooks and to analyze their semantics automatically. Hence, it can be used for e-learning purposes, particularly in the field of IM in hospitals.


Applying neuroimaging to detect neuroanatomical dysconnectivity in psychosis.
This editorial discusses the application of a novel brain imaging analysis technique in the assessment of neuroanatomical dysconnectivity in psychotic illnesses. There has long been a clinical interest in psychosis as a disconnection syndrome. In recent years graph theory metrics have been applied to functional and structural imaging datasets to derive measures of brain connectivity, which represent the efficiency of brain networks. These metrics can be derived from structural neuroimaging datasets acquired using diffusion imaging whereby cortical structures are parcellated into nodes and white matter tracts represent edges connecting these nodes. Furthermore neuroanatomical measures of connectivity may be decoupled from measures of physiological connectivity as assessed using functional imaging, underpinning the need for multi-modal imaging approaches to probe brain networks. Studies to date have reported a number of structural brain connectivity abnormalities associated with schizophrenia that carry potential as illness biomarkers. Structural connectivity abnormalities have also been reported in well patients with bipolar disorder and in unaffected relatives of patients with schizophrenia. Such connectivity metrics may represent clinically relevant biomarkers in studies employing a longitudinal design of illness course in psychosis.


Osteochondritis dissecans (OCD), an endoplasmic reticulum storage disease?: a morphological and molecular study of OCD fragments.
Osteochondritis dissecans (OCD) fragments, cartilage and blood from four patients were used for morphological and molecular analysis. Controls included articular cartilage and blood samples from healthy individuals. Light microscopy and transmission electron microscopy (TEM) showed abnormalities in chondrocytes and extracellular matrix of cartilage from OCD patients. Abnormal type II collagen heterofibrils in "bundles" and chondrocytes with abnormal accumulation of matrix proteins in distended rough endoplasmic reticulum were typical findings. Further, Von Kossa staining and TEM showed empty lacunae close to mineralized "islands" in the cartilage and hypertrophic chondrocytes containing accumulated matrix proteins. Immunostaining revealed: (1) that types I, II, VI and X collagens and aggrecans were deposited intracellulary and (2) co-localization within the islands of types I, II, X collagens and aggrecan indicating that hypertrophic chondrocytes express a phenotype of bone cells during endochondral ossification. Types I, VI and X collagens were also present across the entire dissecates suggesting that chondrocytes were dedifferentiated. DNA sequencings were non-conclusive, only single nucleotide polymorphism was found within the COL2A1 gene for one patient. We suggest that OCD lesions are caused by an alteration in chondrocyte matrix synthesis causing an endoplasmic reticulum storage disease phenotype, which disturbs or abrupts endochondral ossification.


The effect of watching shoulder ROM changes on functional outcome and quality of life following arthroscopic rotator cuff repair.
PurposeThis study aimed to evaluate the effectiveness of watching video records of their shoulder motion changes on functional outcomes and quality of life after arthroscopic rotator cuff repair (ARCR). Methods The patients were divided into two groups. In Group 1, video records of pre- and postoperative shoulder motions were recorded and showed. In Group 2, no video was showed to the patients. In Group 1, the first postoperative evaluation was done before video watching, and the second evaluation was done just after watching video records. In Group 2, the first and second postoperative measurements were performed with 10-20 days interval. The Constant Murley score (CS), the American Shoulder and Elbow Surgeons score (ASES), the Short-Form 36 (SF-36) score, and active shoulder range of motion (ROM) values were used as an outcome tool. Results A total of 196 patients (Group 1; 76 patients and Group 2; 120 patients) with a mean age of 62.06 ± 7.17 years were included. There was a significant improvement in postoperative scores of SF-36 subscales (except emotional well-being and energy/fatigue), ASES, CM scores, and joint ROM values when compared to preoperative values for both groups (p < .001). The first postoperative outcomes were similar between groups (p > .05). In the second postoperative evaluation, emotional role functioning, energy/fatigue, emotional well-being, health change subscales of SF-36, and ASES scores were significantly higher in Group 1 compared with Group 2 (p < .05). Conclusion When patients watch the pre- and postoperative video records of their shoulder ROM after ARCR, patients' satisfaction and well-being perception increase in the short-term despite unchanged shoulder ROM.


Actual aspects of image-guided surgery.
Use of surgical navigation systems is becoming an increasingly important part of both planning and performing intracranial and spinal surgery. Numerous clinical reports have described neuronavigation as a useful adjunct to surgery that allows neurosurgery to be less invasive and more effective. Although the method of image-guided surgery was introduced more than a decade ago, new technologies have changed and refined the procedure substantially. This chapter summarizes the recent developments of advanced image-guided surgery. For most operations, microscope navigation has replaced pointer navigation. Using the microscope as the localizing device, the workflow is not interrupted and microsurgical procedure can be continued as usual. New chip technology allows integration of magnetic resonance images, angiography findings, endoscopic view, or other pictures in the eyepiece of the microscope. A new method of patient registration is laser scanning and surface matching. When using high-quality images, this new method can be used without additionally acquired images, may reduce costs, simplify the pre-registration procedure, and increase application accuracy compared to skin-fiducial registration. Moreover, integration of other imaging modalities is becoming an increasingly used feature and provides useful information during surgery.


Effect of PD 098059, a specific inhibitor of mitogen-activated protein kinase kinase, on urokinase expression and in vitro invasion.
The elevated expression of the urokinase-type plasminogen activator gene, which is necessary for the invasive phenotype of several types of cancers, is controlled by growth factors such as epidermal growth factor, transforming growth factor a, and fibroblast growth factor which bind to and activate protein tyrosine kinase transmembrane receptors. Since these activated receptors communicate with the nucleus via a signaling pathway in which c-Raf-1, mitogen-activated protein kinase kinase 1 (MEK1), and the extracellular signal-regulated kinases are sequentially activated, we determined the effect of a specific MEK1 inhibitor (PD 098059) on urokinase expression in two squamous cell carcinoma cell lines (UM-SCC-1 and MDA-TU-138) characterized as avid secretors of the plasminogen activator. PD 098059 treatment of either cell line reduced the amount of secreted urokinase in a dose-dependent manner. In contrast, a compound (daidzein) chemically unrelated to PD 098059 had little effect on urokinase secretion. The effect of PD 098059 on urokinase secretion in UM-SCC-1 cells was reversible and correlated with decreased extracellular signal-regulated kinase 1 activity. PD 098059 caused a dose-dependent reduction in the in vitro invasiveness of UM-SCC-1 cells whereas it had little effect on proliferation rates. Transient transfection assays with a chloramphenicol acetyl transferase reporter driven by the urokinase promoter indicated that diminished secretion of the protease was largely a consequence of reduced promoter activity. These findings suggest that interfering with MEK1 may provide a novel means of controlling the invasiveness of tumors in which this signaling cascade is activated by autocrine and/or paracrine growth factors.


Safety and efficacy of using the LigaSure vessel sealing system for securing the pedicles in vaginal hysterectomy: randomised controlled trial.
To assess the safety and efficacy of using the LigaSure vessel sealing system for securing the pedicles during vaginal hysterectomy in comparison with the conventional method of securing the pedicles by suture ligation. Randomised controlled trial. Gynaecology Department, Benenden Hospital, Kent. One hundred and sixteen women undergoing vaginal hysterectomy were prospectively randomised to either LigaSure (Group I) or suture ligation (Group II) for securing the pedicles. Data of patients were collected prospectively. Statistical analysis was performed using the Mann-Whitney U test, chi(2) and Fisher's exact test as appropriate. Operating time, operative blood loss and peri-operative complications. The operating time was significantly shorter in the LigaSure group compared with the control group (P < 0.04). There was no statistical significant difference between the two groups in operative blood loss (P= 0.433), but peri-operative haemorrhagic complications were less frequent in the LigaSure group (0%vs 6.8%, P= 0.057). Four patients in the control group required either conversion to laparotomy because of bleeding, return to theatre for immediate post-operative haemorrhage or readmission for vault haematoma, whereas none in the LigaSure group had bleeding from unsecured pedicles. The LigaSure vessel sealing system is a safe alternative for securing pedicles in vaginal hysterectomy when compared with conventional suture ligation. Larger studies are required to determine its place in gynaecological surgery.


[Control of vomiting induced by antineoplastic chemotherapy in childhood].
Twenty four children aged 2 to 13 years who were to receive cancer chemotherapy were enrolled in a prospective study (before-after-trial) in order to evaluate the efficacy of systematic antiemetic prophylaxis. The regimen of three drugs (metilpednisolone 4 mg/Kg/dose/iv 2 doses; metodopamide 0.5 mg/Kg/dose/iv 4 doses; diphenydramine 1 mg/Kg/dose/iv 4 doses) was used. We found a significative reduction (P less than 0.001) in the incidence of vomiting and nauseousness duration when the antiemetic prophylaxis was used. There were very few and slight adverse effects secondary to antiemetic drugs: Sedation happened in 25% of chemotherapic cycles and hypotension without clinical repercussion in 15%. No patient had distonia. We conclude that systematical antiemetic protection should be used in children receiving chemotherapy. The association of metilpednisolone, metopramide and diphenhydramine is a safe and effective combination.


Substrate and product binding inside a stimuli-responsive coordination cage acting as a singlet oxygen photosensitizer.
An acridone-based, interpenetrated double cage [3BF4Pd4L8] acts as a photosensitizer for generating singlet oxygen which adds to 1,3-cyclohexadiene in a [2+4] hetero-Diels-Alder reaction to form 2,3-dioxabicyclo[2.2.2]oct-5-ene. Photocatalytic activity was exclusively observed for the assembled cage, whereas the free organic ligand L decomposes upon irradiation. While cage [3BF4Pd4L8] does not accept any organic guests, NMR, MS and single crystal X-ray results reveal that both substrate and product are readily encapsulated in the central pocket of its chloride-activated form [2Cl@Pd4L8]. The system combines multiple functions (photosensitization, allosteric activation and guest uptake) within a structurally complex, mechanically-bound self-assembly built up from a simple and readily accessible ligand.


Coactivators for a proline-rich activator purified from the multisubunit human TFIID complex.
The mechanisms of transcriptional activation directed by sequence-specific regulators is central to understanding gene regulation. Here, we report the isolation of coactivators responsible for mediating transcriptional activation by Gal4-Pro, a hybrid regulator containing the proline-rich activation domain of human CTF/NFI. Chromatographic studies indicate that endogenous human TFIID consists of a multisubunit complex containing the TATA-binding protein (TBP), coactivators, and other associated factors. A fraction containing the coactivator activity was separated from the endogenous TBP after disrupting the tightly associated complex with urea. The urea-purified TBP was active for basal level transcription but no longer could support activation by Gal4-Pro. However, when the two separated components were added together, activated levels of transcription were restored in the presence of Gal4-Pro. Immunoaffinity purification of the TFIID complex identifies several polypeptides specifically associated with the endogenous TBP, some or all of which function as coactivators when reconstituted with Gal4-Pro. The isolated coactivators also mediate activation by a chimeric glutamine-rich activator derived from Sp1 but not the Gal4-VP16 activator, suggesting distinct factor requirements for different types of transcriptional regulators.


HEMATOLOGY AND PLASMA CHEMISTRY OF THE PLOUGHSHARE TORTOISE (ASTROCHELYS YNIPHORA) IN A CAPTIVE BREEDING PROGRAM.
Blood samples from 172 captive and 40 wild, healthy, juvenile and adult, ploughshare tortoises ( Astrochelys yniphora ) were analyzed to determine hematological and biochemical reference intervals. Hematological analytes included packed cell volume (PCV), white blood cell count (WBC), and WBC differential estimates. Biochemical analysis included total protein measured by photometry (TP) and by refractometry (TPr), albumin (ALB), creatine kinase (CK), aspartate aminotransferase (AST), glutamate dehydrogenase (GLDH), bile acids (BA), calcium (Ca), phosphorus (P), urea (UREA), and uric acid (UA). The jugular vein was identified as the preferred venipuncture site as subcarapacial vein venipuncture resulted in regular hemodilution. In due consideration of small sample sizes in some of the groups studied, adult tortoises had significantly higher plasma GLDH activity and TPr, TP, ALB, BA, and UREA concentrations and significantly lower AST activity and P concentration than juveniles. Captivity had a significant influence in some reference intervals, with captive adults presenting significantly higher WBC, and estimated counts of all white cell types as well as UREA and TPr than wild counterparts. Captive juveniles also showed significantly higher estimated monocyte and lower estimated eosinophil and basophil counts. Although these differences most likely reflect local environmental or dietary differences, without representing pathology or a deviation from the normal, they question the applicability of reference values from captive animals to wild animals and vice versa. Significant sex differences were only observed for PCV and UA. The reported reference intervals may serve as benchmarks for clinical assessment and conservation of this critically endangered species.


Direct and indirect effects of climate on richness drive the latitudinal diversity gradient in forest trees.
Climate is widely recognised as an important determinant of the latitudinal diversity gradient. However, most existing studies make no distinction between direct and indirect effects of climate, which substantially hinders our understanding of how climate constrains biodiversity globally. Using data from 35 large forest plots, we test hypothesised relationships amongst climate, topography, forest structural attributes (stem abundance, tree size variation and stand basal area) and tree species richness to better understand drivers of latitudinal tree diversity patterns. Climate influences tree richness both directly, with more species in warm, moist, aseasonal climates and indirectly, with more species at higher stem abundance. These results imply direct limitation of species diversity by climatic stress and more rapid (co-)evolution and narrower niche partitioning in warm climates. They also support the idea that increased numbers of individuals associated with high primary productivity are partitioned to support a greater number of species.


Health Related Quality of Life in Iranian Elderly Citizens: A Systematic Review and Meta-Analysis.
The ever-growing elderly population of Iran and their physical and mental consequences put emphasis on the necessity of determining the quality of life (QoL) in this social group. This systematic review and meta-analysis aimed to estimate the mean score of QoL in Iranian elderly citizens. Twenty-one articles that were indexed in Iranian (MagIran and Iran Medex) and international (Scientific Information Database, Google Scholars, Science Direct, PubMed, ProQuest, Scopus) databases were selected. The articles have used the Short Form Health Survey (SF-36) to measure QoL in Iranian elderly. The collected data were analyzed using a random effects model, while heterogeneity of the studies was measured by I2 index. The data analysis was performed by STATA. The sample size of the 21 articles was 5318 and the mean score of QoL in the healthy and sick elderly citizens was 53.8 (CI 95%: 49.4-58.2) and 50.6 (CI 95%: 38.4-62.9) respectively. In addition, there was no significant relationship between the score of QoL and the year of publication of the articles. (P=0.748). Given that QoL of the studied elderly was almost at an average level, there is a need to codify and implement comprehensive programs through effective training programs toward improving QoL of the elderly.


The economic impact of decreased mortality and increased growth associated with preventing, replacing or improving current methods for delousing farmed Atlantic salmon in Norway.
Impacts of salmon lice is a major concern for a sustainable production of farmed Atlantic salmon in Norway. Most treatment methods for removal of salmon lice have associated increased mortality and decreased growth in a period after delousing, which affects the profitability of the farmer, and causes poor welfare and sustainability. In addition, the variance in mortality and growth, especially after non-medicinal treatment methods, is high, which makes it hard for a farmer to decide which control measure to apply to keep lice levels below the legal limit. In this study, we have applied a stochastic partial budget approach to assess the economic impact of reducing mortality and increasing growth of farmed Atlantic salmon by preventing, replacing and improving current delousing methods in Norway. We have simulated a production cycle of two different smolt-groups to find the outcome (harvested biomass, average end weight of the salmon, number of dead fish and feed consumption) of production cycles without or with two, three or four delousing treatments in the on-growing phase at sea. The results suggest that accounting for the biological losses associated with lice treatments is important when making choices of delousing strategies. The biological costs of increased mortality and decreased growth associated with especially non-medicinal treatments are expected to be high, but varies substantially. Therefore, the economic benefit of preventing or improving can also be high. The calculations imply that salmon producers could invest a considerable amount in measures for prevention or improvement of thermal treatments before break-even. For example could a farmer use on average 535,313 €/cage/ 1-yearling production in measure to prevent four thermal treatments before it is no longer economical beneficial. Depending on the performance of the four thermal treatments a farmer could use from 319,196-737,934 €/cage/ 1-yearling production on measures of improvement. Replacing one thermal treatment with another immediate treatment method has a minor economic benefit. The results further shows that sales value and feed consumption constitutes the largest share of the change in profit between different treatment regimes. The results from this study also show that not taking into account the risk of mortality and reduced growth associated with the different treatment methods of delousing, could lead to underestimating the benefit of improving, preventing and replacing treatments.


Contrasting the processes of texture segmentation and discrimination with static and phase-reversing stimuli.
Regions of visual texture can be automatically segregated from one another when they abut but also discriminated from one another if they are separated in space or time. A difference in mean orientation between two textures serves to facilitate their segmentation, whereas a difference in orientation variance does not. The present study further supports this notion, by replicating the findings of Wolfson and Landy (1998) in showing that judgments (odd-one-out) made for textures that differ in mean orientation were more accurate (and more rapid) when the textures were abutting than when separated, whereas judgments of variance were made no more accurately for abutting relative to separated textures. Interestingly, however, responses were overall faster for textures differing in variance when they were separated compared to when they were abutting. This is perhaps due to the clear separation boundary, which serves to delineate the regions on which to perform some regional estimation of orientation variance. A second experiment highlights the phase-insensitivity of texture segmentation, in that locating a texture edge (defined by a difference in mean orientation) in high frequency orientation-reversing stimuli can be performed at much higher frequencies than the discrimination of the same regions but with the texture contour masked. Textures that differed in variance did not exhibit this effect. A final experiment demonstrates that the phase-insensitive perception of texture borders improves with eccentric viewing relative to the fovea, whereas perception of the texture regions does not. Together, these experiments show dissociations between edge- and region-based texture analysis mechanisms and suggest a fast, sign-invariant contour extraction system mediating texture segmentation, which may be closely linked to the magnocellular subdivision of visual processing.


Risk factors for incident neck and shoulder pain in hospital nurses.
To assess the incidence and risk factors for neck and shoulder pain in nurses. A longitudinal study of neck and shoulder pain was carried out in female nurses at two hospitals in England. Personal and occupational risk factors were assessed at baseline. The self reported incidence of symptoms in the neck and shoulder region was ascertained at three-monthly intervals over two years. A Cox regression model was used to estimate hazard ratios (HRs) for incident neck/shoulder pain during follow up in nurses who had been pain free for at least one month at baseline. The baseline response rate was 56%. Of 903 women who were pain free at baseline, 587 (65%) completed at least one follow up while still in the same job. During an average of 13 months, 34% of these (202 women) reported at least one episode of neck/shoulder pain. The strongest predictor of pain in the neck/shoulder was previous history of the symptom (HRs up to 3.3). For physical exposures at work, the highest risks (HRs up to 1.7) were associated with specific patient handling tasks that involved reaching, pushing, and pulling. Nurses who reported low mood or stress at baseline were more likely to develop neck/shoulder pain later (HR 1.5). Workplace psychosocial factors (including job demands, satisfaction, and control) were not associated with incident neck/shoulder symptoms. Neck/shoulder pain is common among hospital nurses, and patient handling tasks that involve reaching and pulling are the most important target for risk reduction strategies.


Positive correlation of insulin-like growth factor-II with proliferating cell index in patients with colorectal neoplasia.
Insulin-like growth factor-II (IGF-II) stimulates cell proliferation and is considered a potential risk factor for colorectal cancer. Tumor levels of IGF-II seem to positively correlate with colorectal cancer cell proliferation. This investigation examined the association of circulating IGF-II to the proliferating cell index (PCI) of tumor and matched normal mucosa in patients with colorectal neoplasia. Circulating IGF-II level (ng/mL) was determined in the peripheral blood plasma by ELISA. The proliferating cells in tumor or matched normal mucosa were immunohistochemically stained using the primary antibody against Ki-67. Computer image analysis was used and PCI was expressed as the percentage of Ki-67-positive cells/total counted cells. Sixty-four patients were evaluated; 45 had colorectal neoplasia (27 males/18 females; mean age, 66.8 +/- 11.8 years) and 19 had hyperplastic polyps (6 males and 13 females; mean age, 58.4 +/- 14.4 years). Among patients with colorectal neoplasia, blood IGF-II levels were positively correlated with PCI in the matched normal mucosa (r = 0.46, P < 0.05) but not in the tumor. In patients with hyperplastic polyps, blood IGF-II levels were not correlated with the PCI in the polyps. Blood IGF-II levels were higher in colorectal cancer patients with Dukes' C/D stage (P < 0.01) or with positive lymph nodes (P < 0.01). Circulating IGF-II positively correlated with PCI in normal colonic mucosa of patients with colorectal neoplasia, suggesting that IGF-II may have a role in initiating the carcinogenic pathway by stimulating cell proliferation. Blood IGF-II was increased in advanced colorectal cancer, indicating that it might enhance colorectal cancer progression and be a useful marker of poor prognosis.


Muscle contractile and metabolic dysfunction is a common feature of sarcopenia of aging and chronic diseases: from sarcopenic obesity to cachexia.
Skeletal muscle is the most abundant body tissue accounting for many physiological functions. However, muscle mass and functions are not routinely assessed. Sarcopenia is defined as skeletal muscle loss and dysfunction in aging and chronic diseases. Inactivity, inflammation, age-related factors, anorexia and unbalanced nutrition affect changes in skeletal muscle. Mechanisms are difficult to distinguish in individual subjects due to the multifactorial character of the condition. Sarcopenia includes both muscle loss and dysfunction which induce contractile impairment and metabolic and endocrine abnormalities, affecting whole-body metabolism and immune/inflammatory response. There are different metabolic trajectories for muscle loss versus fat changes in aging and chronic diseases. Appetite regulation and physical activity affect energy balance and changes in body fat mass. Appetite regulation by inflammatory mediators is poorly understood. In some patients, inflammation induces anorexia and fat loss in combination with sarcopenia. In others, appetite is maintained, despite activation of systemic inflammation, leading to sarcopenia with normal or increased BMI. Inactivity contributes to sarcopenia and increased fat tissue in aging and diseases. At the end of the metabolic trajectories, cachexia and sarcopenic obesity are paradigms of the two patient categories. Pre-cachexia and cachexia are observed in patients with cancer, chronic heart failure or liver cirrhosis. Sarcopenic obesity and sarcopenia with normal/increased BMI are observed in rheumatoid arthritis, breast cancer patients with adjuvant chemotherapy and in most of patients with COPD or chronic kidney disease. In these conditions, sarcopenia is a powerful prognostic factor for morbidity and mortality, independent of BMI.


Gut Microbiota-brain Axis.
To systematically review the updated information about the gut microbiota-brain axis. All articles about gut microbiota-brain axis published up to July 18, 2016, were identified through a literature search on PubMed, ScienceDirect, and Web of Science, with the keywords of "gut microbiota", "gut-brain axis", and "neuroscience". All relevant articles on gut microbiota and gut-brain axis were included and carefully reviewed, with no limitation of study design. It is well-recognized that gut microbiota affects the brain's physiological, behavioral, and cognitive functions although its precise mechanism has not yet been fully understood. Gut microbiota-brain axis may include gut microbiota and their metabolic products, enteric nervous system, sympathetic and parasympathetic branches within the autonomic nervous system, neural-immune system, neuroendocrine system, and central nervous system. Moreover, there may be five communication routes between gut microbiota and brain, including the gut-brain's neural network, neuroendocrine-hypothalamic-pituitary-adrenal axis, gut immune system, some neurotransmitters and neural regulators synthesized by gut bacteria, and barrier paths including intestinal mucosal barrier and blood-brain barrier. The microbiome is used to define the composition and functional characteristics of gut microbiota, and metagenomics is an appropriate technique to characterize gut microbiota. Gut microbiota-brain axis refers to a bidirectional information network between the gut microbiota and the brain, which may provide a new way to protect the brain in the near future.


An Introduction to the Outcomes of Children with Hearing Loss Study.
The landscape of service provision for young children with hearing loss has shifted in recent years as a result of newborn hearing screening and the early provision of interventions, including hearing technologies. It is expected that early service provision will minimize or prevent linguistic delays that typically accompany untreated permanent childhood hearing loss. The post-newborn hearing screening era has seen a resurgence of interest in empirically examining the outcomes of children with hearing loss to determine if service innovations have resulted in expected improvements in children's functioning. The Outcomes of Children with Hearing Loss (OCHL) project was among these recent research efforts, and this introductory article provides background in the form of literature review and theoretical discussion to support the goals of the study. The Outcomes of Children with Hearing Loss project was designed to examine the language and auditory outcomes of infants and preschool-age children with permanent, bilateral, mild-to-severe hearing loss, and to identify factors that moderate the relationship between hearing loss and longitudinal outcomes. The authors propose that children who are hard of hearing experience limitations in access to linguistic input, which lead to a decrease in uptake of language exposure and an overall reduction in linguistic experience. The authors explore this hypothesis in relation to three primary factors that are proposed to influence children's access to linguistic input: aided audibility, duration and consistency of hearing aid use, and characteristics of caregiver input.


Inhibitory effects of chronic ethanol consumption on cellular immune responses to hepatitis C virus core protein are reversed by genetic immunizations augmented with cytokine-expressing plasmids.
Chronic hepatitis C viral (HCV) infection is a major clinical problem in alcoholics with liver disease and may result from ethanol effects on the host immune response. To experimentally assess such effects, the DNA-based immunization approach was used to produce humoral and cellular immune responses against the HCV core protein in mice. Mice were fed an ethanol or isocaloric pair-fed control liquid diet followed by immunizations with HCV core DNA-expressing constructs. Chronic ethanol feeding was found to inhibit Th cell and CTL activities and substantially reduced cytokine secretion as well. In addition, a switch from Th1 to Th0 subtype was observed in proliferating CD4+ T cells derived from chronic ethanol-fed mice. These immunosuppressive effects were directly due to ethanol since crossover experiments to an isocaloric control diet restored the defects in cellular immunity. Furthermore, we determined if coadministration of an IL-2 or GM-CSF DNA expression plasmid with a plasmid expressing the HCV core protein (pHCV2-2) would reverse the inhibitory effects of chronic ethanol feeding on cellular immune responses. Coimmunization of chronic ethanol-fed mice with either IL-2 or GM-CSF expression plasmids restored cellular immunity and induced CD4+ inflammatory T cell and CD8+ CTL responses comparable with control mice immunized with pHCV2-2 alone. These studies provide evidence of how chronic ethanol feeding may effect cellular immune responses to a viral structural protein in the context of genetic immunization.


Suppression of allograft rejection with FK506. I. Prolonged cardiac and liver survival in rats following short-course therapy.
Heterotopic heart and orthotopic liver grafts from ACI donors were transplanted to Lewis rat recipients that were treated with a 3 (or 4) day course of FK506 IM that was started on postoperative day 0, 2, 3, 4, 5, or 6. Hearts, which rejected after a median of 6 days in untreated controls, always had prolonged survival (median 91 days) when treatment was started on postoperative day 4. The results were inferior when treatment was started earlier or later than this, but even when the first dose of FK506 was on postoperative day 5, one day before rejection was imminent in controls, the median survival was 50 days. The poorest results with a median graft survival of only 36 days were obtained when injections were on days 0-3. Results were similar with liver grafts that rejected after a median time of 10 days in nontreated controls but that usually survived permanently after a 3 (or 4) day FK506 course starting on day 0, 2, 3, or 4. Therapy started on day 6 was too late.


LEAN SIX SIGMA TECHNIQUES TO IMPROVE OPHTHALMOLOGY CLINIC EFFICIENCY.
Ophthalmologists serve an increasing volume of a growing elderly population undergoing increasingly complex outpatient medical care, including extensive diagnostic testing and treatment. The resulting prolonged patient visit times ("patient flow times") limit quality, patient and employee satisfaction, and represent waste. Lean Six Sigma process improvement was used in a vitreoretinal practice to decrease patient flow time, demonstrating that this approach can yield significant improvement in health care. Process flow maps were created to determine the most common care pathways within clinic. Three months' visits from the electronic medical record system, which tracks patient task times at each process step in the office were collected. Care tasks and care pathways consuming the greatest time and variation were identified and modified. Follow-up analysis from 6 weeks' visits was conducted to assess improvement. Nearly all patients took one of five paths through the office. Patient flow was redesigned to reduce waiting room time by having staff members immediately start patients into one of those five paths; staffing was adjusted to address high demand tasks, and scheduling was optimized around derived predictors of patient flow times. Follow-up analysis revealed a statistically significant decline in mean patient flow time by 18% and inpatient flow time SD by 4.6%. Patient and employee satisfaction scores improved. Manufacturing industry techniques, such as Lean and Six Sigma, can be used to improve patient care, minimize waste, and enhance patient and staff satisfaction in outpatient clinics.


Associations that Cardiorespiratory Fitness and Body Mass Index Loss Have with Deficit Accumulation Frailty.
Lower cardiorespiratory fitness and obesity may accelerate aging processes. The degree to which changes in fitness and body mass index (BMI) may alter the rate of aging may be important for planning treatment. We assessed cross-sectional and longitudinal associations that cardiorespiratory fitness and BMI had with a deficit accumulation frailty index. Fitness, based on standardized graded exercise tests, and weight to calculate body mass index at baseline and year 4 were collected from 3,944 participants, ages 45-76, in the Action for Health in Diabetes (Look AHEAD) randomized controlled clinical trial. A validated 38-item deficit accumulation frailty index (FI) was used as a marker of aging. Associations between baseline and changes in fitness and BMI with changes in FI were assessed using linear models. Both baseline and 4-year changes in fitness and BMI were independently associated with 4-year changes in frailty (all p < 0.001). Mean [95% confidence interval] changes in FI ranged from -0.001 [-0.005,0.002] for participants in the group with the greatest fitness increase and BMI loss to 0.017 [0.013,0.020] for participants in the group with the greatest fitness loss and BMI gain. Associations of 4-year changes in fitness and BMI with FI changes were similar across subgroups based on age, gender, baseline BMI, diabetes duration, and cardiovascular disease history. Increased fitness across 4 years was associated with less FI accumulation independent of baseline fitness. Adults with type 2 diabetes and overweight or obesity may slow aging processes captured by a FI by increasing their cardiorespiratory fitness and losing weight.


A novel OCT technique to measure in vivo the corneal adhesiveness for sodium carboxymethylcellulose in humans and its validity in the diagnosis of dry eye.
The purpose of this work was to gather preliminary data on tear film stability, and the adhesive properties of the corneal surface in dry eye patients and control group subjects, using a new, minimally invasive optical coherence tomography (OCT) imaging method. We screened 85 human subjects for dry eye and classified them in two groups, as dry eye or normal patients. Sodium carboxymethylcellulose (NaCMC) adhesiveness over the central cornea was measured using Fourier domain anterior segment OCT. The corneal adhesiveness for NaCMC was compared between the two groups, correlated with classical tests, and analyzed for diagnostic validity and repeatability. The corneal adhesiveness for NaCMC median and mode values was fair (between 1 and 3 minutes) for dry eye subjects (n = 36) and borderline (between 3 and 5 minutes) for control group subjects (n = 49), and was significantly different between the two groups (P < 0.001). Significant correlations were observed between the corneal adhesiveness measures and dry eye patients' symptoms (P < 0.001), Schirmer I test (P < 0.001), ocular surface staining (P < 0.001), and, particularly, fluorescein break-up time (P < 0.001). The area under the receiver operating characteristic curve was 0.94 (P < 0.001), suggesting reliable sensitivity and specificity of OCT imaging. A statistically significant intraclass correlation (ICC) value of 0.99 was found for measurements of corneal adhesiveness on two subsequent days at the same time (P < 0.001). This minimally invasive, novel technique of OCT imaging of the corneal surface following NaCMC drop instillation provides a measure of corneal adhesiveness. This technique may improve the clinician's ability in the understanding and diagnosis of the dry eye syndrome.


Natural products as antiparasitic drugs.
Natural products are not only the basis for traditional or ethnic medicine. Only recently, they have provided highly successful new drugs such as Artemisinin. Furthermore, screening natural products found in all sorts of environments such as the deep sea, rain forests and hot springs, and produced by all sorts of organisms ranging from bacteria, fungi and plants to protozoa, sponges and invertebrates, is a highly competitive field where all of the major pharmaceutical companies are encountered. Already, many new natural product groups have revealed antiparasitic properties of surprising efficacy and selectivity, as will be shown in this review for plant-derived alkaloids, terpenes and phenolics. Many novel lead structures, however, have severe chemico-physical drawbacks such as poor solubility. Here, innovative drug formulations and carrier systems might help, as discussed by the authors in another article of this series.


Insurance Barriers, Gendering, and Access: Interviews with Central North Carolinian Women About Their Health Care Experiences.
Women face unique logistical and financial barriers to health care access. They also have higher health care expenditures and higher rates of morbidity. Women's experiences while utilizing health care are historically less well researched and warrant exploration. We conducted 14 semistructured interviews about women's health care experiences with 11 women health consumers and 3 women health care practitioners in central North Carolina. When discussing their experiences, participants noted scheduling challenges, barriers related to insurance and cost, and dismissive or negative in-person encounters. Participants frequently discussed lack of resources for care postpartum. Practitioners noted lack of knowledge of disease burden, overmedicalization of women's care, lack of care postpartum, and trends around changes in primary care.Women health consumers in this study faced challenges related to access and in-person experience of care delivery, which were echoed by the clinician interviewees. Barriers to optimal women's health care exist even for those with insurance coverage and point to systemwide constraints as well as deficits in organizational culture. Future clinical and research efforts should include 1) increasing awareness of and facilitating access to affordable postpartum care, 2) easing burdens around scheduling appointments and improved care coordination, and 3) more research exploring women's experiences during in-person health care encounters. Concerns and barriers that women described may be due to systems-level requirements and constraints.


Fluoxetine administration to pregnant rats increases anxiety-related behavior in the offspring.
Fluoxetine (Prozac®) is the most frequently prescribed drug to battle depression in pregnant women, but its safety in the unborn child has not yet been established. Fluoxetine, a selective serotonin reuptake inhibitor, crosses the placenta, leading to increased extracellular serotonin levels and potentially neurodevelopmental changes in the fetus. The purpose of this study was to elucidate the long-term consequences of prenatal fluoxetine in rats. Pregnant rats were injected daily with 12 mg/kg fluoxetine or vehicle from gestational day 11 until birth, and the behavior of the offspring was monitored. Plasma fluoxetine transfer from mother to pup was 83%, and high levels of fluoxetine (13.0 μg/g) were detected in the pup brain 5 h after the last injection. Fluoxetine-treated dams gave birth to litters 15% smaller than usual and to pups of reduced weight (until postnatal day 7). Furthermore, prenatal fluoxetine exposure significantly increased anxiety in the novelty-suppressed feeding test, the footshock-induced conditioned place aversion test, and the elevated plus maze test (following footshock pre-exposure) during adulthood, and also significantly decreased components of social play behavior at 4 weeks of age, and a strong tendency for increased self-grooming and making less contact in adults. Behavioral despair, anhedonia, and sexual behavior were not different between treatment groups. Finally, the hypothermic response to the 5-HT(1A) agonist flesinoxan was observed at a lower dose in prenatally fluoxetine-exposed rats than in controls. Prenatal fluoxetine exposure in rats leads to detrimental behavioral outcomes in later life, which may partly be due to altered 5-HT(1A) receptor signaling.