Gut microbiota dysbiosis might be responsible to different toxicity caused by Di-(2-ethylhexyl) phthalate exposure in murine rodents.
Di-(2-ethylhexyl) phthalate (DEHP) is widely used as a plasticizer, which can enter the body through a variety of ways and exerted multiple harmful effects, including liver toxicity, reproductive toxicity and even glucose metabolism disorder. Many studies have suggested that changes of gut microbiota are closely related to the occurrence of various diseases, but the effects of DEHP exposure on gut microbiota are still unclear. It was found in this study that the damage to different tissues by DEHP on two strains each from two different species of male rodents before puberty was dose and time of exposure dependent, and also depending on the strain and species of rodent. Sprague-Dawley (SD) rats showed highest sensitivity to DEHP exposure, with most severe organ damage, highest Th1 inflammatory response and most significant body weight gain. Correspondingly, the gut microbiota of SD rats showed most significant changes after DEHP exposure. Only SD rats, but not Wistar rats, BALB/c and C57BL/6J mice showed an increase in Firmicutes/Bacteroidetes ratio and Proteobacteria abundance in the fecal samples, which are known to associate with obesity and diabetes. This is consistent with the increasing body weight gain which was only found in SD rats. In addition, the decrease in the level of butyrate, increase in the abundance of potential pathogens and microbial genes linked to colorectal cancer, Parkinson's disease, and type 2 diabetes in the SD rats were associated with issue and functional damages and Th1 inflammatory response caused by DEHP exposure. We postulate that the differential effects of DEHP on gut microbiota may be an important cause of the differences in the toxicity on different strains and species of rodents to DEHP.


Medications for opioid use disorder in the Department of Veterans Affairs (VA) health care system: Historical perspective, lessons learned, and next steps.
The US Department of Veterans Affairs (VA), the largest health care system in the US, has been confronted with the health care consequences of opioid disorder (OUD). Increasing access to quality OUD treatment, including pharmacotherapy, is a priority for the VA. We examine the history of medications (e.g., methadone, buprenorphine, injectable naltrexone) used in the treatment of OUD within VA, document early and ongoing efforts to increase access and build capacity, primarily through the use of buprenorphine, and summarize research examining barriers and facilitators to prescribing and medication receipt. We find that there has been a slow but steady increase in the use of medications for OUD and, despite system-wide mandates and directives, uneven uptake across VA facilities and within patient sub-populations, including some of those most vulnerable. We conclude with recommendations intended to support the greater use of medication for OUD in the future, both within VA as well as other large health care systems.


Expression of matrix metalloproteinase-9 in oral potentially malignant disorders: A systematic review.
Matrix metalloproteinase-9 (MMP-9) is an inducible enzyme. Oral potentially malignant disorders (OPMDs) are considered as the early tissue changes that happen due to various habits such as smoking tobacco, chewing tobacco or stress. This alteration in the tissues alters the expression of MMP-9. The rationale of the review is to know the expression of MMP-9 in OPMDs. Hand searching and electronic databases such as PubMed and ScienceDirect were done for mesh terms such as OPMDs and MMP-9. Eight articles were obtained, after applying inclusion and exclusion criteria. These articles were assessed with QUADAS and data were extracted and evaluated. The included eight studies were done in 182 oral squamous cell carcinoma cases, 430 OPMDs (146 oral lichen planus, 264 leukoplakia and 20 oral submucous fibrosis) and 352 healthy controls evaluated for MMP-9. MMP-9 expression was found to be elevated in tissue, serum and saliva samples of OPMDs than in healthy controls. There is only one study in each serum and saliva samples to evaluate MMP-9. Saliva being noninvasive and serum being minimally invasive, more studies need to be done in both serum and saliva to establish MMP-9 as an early diagnostic marker in OPMDs to know its potential in malignant transformation.


A comparison of real-time, two dimensional echocardiography and cineangiography in detecting left ventricular asynergy.
Left ventricular wall motion was assessed in 105 consecutive patients both invasively, using biplane cineangiography, and noninvasively, by a real-time, phased-array, two-dimensional echocardiography system. Ventricular wall motion in five anatomic areas of the ventricle (anterolateral, posterolateral, apical, septal, and inferior) was analyzed by both methods in a double-blind manner. Two-dimensional echocardiographic images were deemed adequate for analysis in 82% of the regions (430 of 525). Fifty-five discrepancies were noted in the comparison of the remaining 430 regions. The reasons for discrepancies in interpretation between the two methods were established for 54 during retrospective review: 33 were due to echocardiography (inadequate target visualization, observer error, or tangential echo views). Fifteen were related to angiography (overlay of silhouettes or observer error), and six were due to other reasons including definition problems or spatial orientation difficulties. Both real-time, two-dimensional echocardiography and cineangiography have advantages and disadvantages. The techniques used together could provide more complete information concerning ventricular wall movement than is now currently available.


Superacids.
Superacids, although first referred to as early as 1927, were only extensively studied in the last decade. Acidities up to 10(12) times that of sulfuric acid have now been obtained. The extremely low nucleophilicity of the counterions in superacidic systems is especially useful for the preparation of stable, electron-deficient cations, particularly carbocations. Many of these cations, which were formerly detectable only in the gas phase, can now be studied in solution. Novel organic syntheses that are not possible in ordinary acidic media can also be achieved in superacids, including syntheses of economically important hydrocarbons. The unique ability of superacids to bring about hydrocarbon transformations, even to activate methane to undergo electrophilic oligocondensation, can open up new fields in chemistry.


Emergency contraceptive knowledge, attitudes and practices among female students at the University of Botswana: A descriptive survey.
Unintended pregnancies are associated with unsafe abortions and maternal deaths, particularly in countries such as Botswana, where abortion is illegal. Many of these unwanted pregnancies could be avoided by using emergency contraception, which is widely available in Botswana. To assess the level of knowledge, attitudes and practices of female students with regard to emergency contraception at the University of Botswana. Students from University of Botswana, Gaborone, Botswana. A descriptive survey among 371 students selected from all eight faculties at the university. Data were collected using a self-administered questionnaire and analysed using the Statistical Package for Social Sciences. The mean age was 20.6 years (SD 1.62), 58% were sexually active, 22% had used emergency contraception and 52% of pregnancies were unintended. Of the total respondents, 95% replied that they had heard of emergency contraception; however, only 53% were considered to have good knowledge, and 55% had negative attitudes towards its use. Students from urban areas had better knowledge than their rural counterparts (p = 0.020). Better knowledge of emergency contraception was associated with more positive attitudes towards actual use (p < 0.001). Older students (p < 0.001) and those in higher years of study (p = 0.001) were more likely to have used emergency contraception. Although awareness of emergency contraception was high, level of knowledge and intention to use were low. There is a need for a targeted health education programme to provide accurate information about emergency contraception.


Lack of paraoxonase 1 alters phospholipid composition, but not morphology and function of the mouse retina.
Biochemical and genetic analyses established a contribution of lipid metabolism to AMD pathology. Paraoxonase 1 (PON1) is an antioxidative protein involved in high density lipoprotein (HDL) function and was found to be associated with AMD. Here, we used Pon1(-/-) mice to study the influence of PON1 on retinal physiology and to reveal the potential impact of PON1 on AMD etiology. Laser capture microdissection served to isolate single retinal layers. Retinal function was assessed by ERG. Retinal and RPE morphology were monitored by fundus imaging, fluorescein angiography, light and transmission electron microscopy, and immunofluorescence microscopy. Levels of mRNA and composition of phospholipid species were determined by real-time PCR and LC-MS, respectively. Adult (8 weeks old) Pon1(-/-) mice displayed normal retinal function and morphology, but their retinas contained reduced amounts of lysophosphatidylcholines (LPCs) compared to controls. Aged (12 months old) Pon1(-/-) animals did not show any morphologic or molecular signs of photoreceptor or RPE degeneration, or of accelerated aging. Photoreceptors of Pon1(-/-) and control mice were similarly susceptible to light damage. Results indicated that PON1 is not essential for normal development, function, ageing, and the defense against light damage of the mouse retina. Reduced levels of LPCs in eyes of Pon1(-/-) mice may reflect a decreased activity of phospholipase A2 or altered antioxidative activity in aged eyes.


Impact of geography on the control of type 2 diabetes mellitus: a review of geocoded clinical data from general practice.
To review the clinical data for people with diabetes mellitus with reference to their location and clinical care in a general practice in Australia. Patient data were extracted from a general practice in Western Australia. Iterative data-cleansing steps were taken. Data were grouped into Statistical Area level 1 (SA1), designated as the smallest geographical area associated with the Census of Population and Housing. The data were analysed to identify if SA1s with people aged 70 years and older, and with relatively high glycosylated haemoglobin (HbA1c) were significantly clustered, and whether this was associated with their medical consultation rate and treatment. The analysis included Cluster and Outlier Analysis using Moran's I test. The overall median age of the population was 70 years with more males than females, 53% and 47%, respectively. Older people (>70 years) with relatively high HbA1c comprised 9.3% of all people with diabetes in the sample, and were clustered around two 'hotspot' locations. These 111 patients do not attend the practice more or less often than people with diabetes living elsewhere in the practice (p=0.098). There was some evidence that they were more likely to be recorded as having consulted with regard to other chronic diseases. The average number of prescribed medicines over a 13-month time period, per person in the hotspots, was 4.6 compared with 5.1 in other locations (p=0.26). Their prescribed therapy was deemed to be consistent with the management of people with diabetes in other locations with reference to the relevant diabetes guidelines. Older patients with relatively high HbA1c are clustered in two locations within the practice area. Their hyperglycaemia and ongoing cardiovascular risk indicates causes other than therapeutic inertia. The causes may be related to the social determinants of health, which are influenced by geography.


Fear-learning deficits in subjects with fibromyalgia syndrome?
Fibromyalgia syndrome (FMS) is frequently associated with psychiatric conditions, particularly anxiety. Deficits in contingency learning during fear conditioning have been hypothesized to increase anxiety and, consequently, pain sensation in susceptible individuals. The goal of this study was to examine the relationship between contingency learning and pain experience in subjects with FMS and rheumatoid arthritis (RA). Fourteen female FMS subjects, 14 age-matched female RA subjects and 14 age-matched female healthy controls (HCs) were included in a fear-conditioning experiment. The conditioned stimulus (CS) consisted of visual signs, the unconditioned stimulus (US) of thermal stimuli. CS- predicted low-temperature exposure (US), while CS+ was followed by low or high temperature. In the FMS group, only 50% of the subjects were aware of the US-CS contingency, whereas 86% of the RA subjects and all of the HCs were aware of the contingency. CS+ induced more anxiety than CS- in RA subjects and HCs. As expected, low-temperature exposure was experienced as less painful after CS- than after CS+ in these subjects. FMS subjects did not show such adaptive conditioning. The effects of the type of CS on heart rate changes were significant in the HCs and the aware FMS subjects, but not in the unaware FMS subjects. Contingency learning deficits represent a potentially promising and specific, but largely unstudied, psychopathological factor in FMS. Deficits in contingency learning may increase anxiety and, consequently, pain sensation. These findings have the potential to contribute to the development of novel therapeutic approaches for FMS.


An introduction to tree-structured modeling with application to quality of life data.
Investigators addressing nursing research are faced increasingly with the need to analyze data that involve variables of mixed types and are characterized by complex nonlinearity and interactions. Tree-based methods, also called recursive partitioning, are gaining popularity in various fields. In addition to efficiency and flexibility in handling multifaceted data, tree-based methods offer ease of interpretation. The aims of this study were to introduce tree-based methods, discuss their advantages and pitfalls in application, and describe their potential use in nursing research. In this article, (a) an introduction to tree-structured methods is presented, (b) the technique is illustrated via quality of life (QOL) data collected in the Breast Cancer Education Intervention study, and (c) implications for their potential use in nursing research are discussed. As illustrated by the QOL analysis example, tree methods generate interesting and easily understood findings that cannot be uncovered via traditional linear regression analysis. The expanding breadth and complexity of nursing research may entail the use of new tools to improve efficiency and gain new insights. In certain situations, tree-based methods offer an attractive approach that help address such needs.


Localization of glucocorticoid receptors at postsynaptic membranes in the lateral amygdala.
Glucocorticoids, released in high concentrations from the adrenal cortex during stressful experiences, bind to glucocorticoid receptors in nuclear and peri-nuclear sites in neuronal somata. Their classically known mode of action is to induce gene promoter receptors to alter gene transcription. Nuclear glucocorticoid receptors are particularly dense in brain regions crucial for memory, including memory of stressful experiences, such as the hippocampus and amygdala. While it has been proposed that glucocorticoids may also act via membrane bound receptors, the existence of the latter remains controversial. Using electron microscopy, we found glucocorticoid receptors localized to non-genomic sites in rat lateral amygdala, glia processes, presynaptic terminals, neuronal dendrites, and dendritic spines including spine organelles and postsynaptic membrane densities. The lateral nucleus of the amygdala is a region specifically implicated in the formation of memories for stressful experiences. These newly observed glucocorticoid receptor immunoreactive sites were in addition to glucocorticoid receptor immunoreactive signals observed using electron and confocal microscopy in lateral amygdala principal neuron and GABA neuron soma and nuclei, cellular domains traditionally associated with glucocorticoid immunoreactivity. In lateral amygdala, glucocorticoid receptors are thus also localized to non-nuclear-membrane translocation sites, particularly dendritic spines, where they show an affinity for postsynaptic membrane densities, and may have a specialized role in modulating synaptic transmission plasticity related to fear and emotional memory.


Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm.
Approximately 10% of cases of Alzheimer's disease are familial and associated with autosomal dominant inheritance of mutations in genes encoding the amyloid precursor protein, presenilin 1 (PS1) and presenilin 2 (PS2). Mutations in PS1 are linked to about 25% of cases of early-onset familial Alzheimer's disease. PS1, which is endoproteolytically processed in vivo, is a multipass transmembrane protein and is a functional homologue of SEL-12, a Caenorhabditis elegans protein that facilitates signalling mediated by the Notch/LIN-12 family of receptors. To examine potential roles for PS1 in facilitating Notch-mediated signalling during mammalian embryogenesis, we generated mice with targeted disruptions of PS1 alleles (PS1-/- mice). PS1-/- embryos exhibited abnormal patterning of the axial skeleton and spinal ganglia, phenotypes traced to defects in somite segmentation and differentiation. Moreover, expression of mRNA encoding Notch1 and Dll1 (delta-like gene 1), a vertebrate Notch ligand, is markedly reduced in the presomitic mesoderm of PS1-/- embryos compared to controls. Hence, PS1 is required for the spatiotemporal expression of Notch1 and Dll1, which are essential for somite segmentation and maintenance of somite borders.


Using liminality to understand mothers' experiences of long-term breastfeeding: 'Betwixt and between', and 'matter out of place'.
Breastmilk is widely considered as the optimum nutrition source for babies and an important factor in both improving public health and reducing health inequalities. Current international/national policy supports long-term breastfeeding. UK breastfeeding initiation rates are high but rapidly decline, and the numbers breastfeeding in the second year and beyond are unknown. This study used the concept of liminality to explore the experiences of a group of women breastfeeding long-term in the United Kingdom, building on Mahon-Daly and Andrews. Over 80 breastfeeding women were included within the study, which used micro-ethnographic methods (participant observation in breastfeeding support groups, face-to-face interviews and online asynchronous interviews via email). Findings about women's experiences are congruent with the existing literature, although it is mostly dated and from outside the United Kingdom. Liminality was found to be useful in providing insight into women's experiences of long-term breastfeeding in relation to both time and place. Understanding women's experience of breastfeeding beyond current usual norms can be used to inform work with breastfeeding mothers and to encourage more women to breastfeed for longer.


Evaluation of brief screens for gambling disorder in the substance use treatment setting.
The goal of this study was to determine the diagnostic accuracy of brief screens for Gambling Disorder within a sample of people receiving outpatient treatment for substance use disorders. Individuals (n = 300) recruited from intensive outpatient substance use treatment (23.67%) or methadone maintenance programs (76.34%) participated in the study. Four brief screens for Gambling Disorder were administered and compared to DSM-5 criteria. Receiver operator curves were created and an Area Under the Curve (AUC) analysis (an overall summary of the utility of the scale to correctly identify Gambling Disorder) was assessed for each. On average participants were aged 46.4 years (SD = 10.2), African American/Black (70.7%), with an income less than $20,000/year (89.5%). Half the participants were female. Approximately 40% of participants (40.5%; n = 121) met DSM-5 criteria for Gambling Disorder. Accuracy of the brief screens as measured by hit rate were .88 for the BBGS, .77 for the Lie/Bet, .75 for NODS-PERC, and .73 for the NODS-CLiP. AUC analysis revealed that the NODS-PERC (AUC: .93 (95% CI: .91-.96)) and NODS-CLiP (AUC: .90 (95% CI: .86-.93)) had excellent accuracy. The NODS-PERC and NODS-CLiP had excellent accuracy at all cut-off points. However, the BBGS appeared to have the best accuracy at its specified cut-off point. Commonly used brief screens for Gambling Disorder appear to be associated with good diagnostic accuracy when used in substance use treatment settings. The choice of which brief screen to use may best be decided by the needs of the clinical setting.


Nurse-led patient-centered self-management support improves HbA1c in patients with type 2 diabetes-A randomized study.
The aim of this study was to evaluate the effect of a patient-centered self-management support, in type 2 diabetes (T2D) with regard to metabolic changes. 182 patients were randomized into group intervention (GI), individual intervention (II) or internal controls (IC). An external control (EC) group was recruited from another county council. The intervention consisted of six sessions that featured themes, which regarded different views of their illness experiences. Data were collected in 2010 and 2011. HbA1c was significantly decreased at 12-month follow-up with 5mmol/mol in the GI and 4mmol/mol in the II. In the IC group, the HbA1c was close to baseline. The EC group had increased HbA1c, though not significantly. When the HbA1c difference at baseline was adjusted, there was a significant difference between intervention groups and the EC-group. Patient-centered self-management support, led by nurses, can lower HbA1c among patients with type 2 diabetes. It is possible to train diabetes specialist nurses in clinical patient-centered care, and simultaneously influence patients' metabolic balance positively.


Glutathione species and metabolomic prints in subjects with liver disease as biological markers for the detection of hepatocellular carcinoma.
The incidence of liver disease is increasing in USA. Animal models had shown glutathione species in plasma reflects liver glutathione state and it could be a surrogate for the detection of hepatocellular carcinoma (HCC). The present study aimed to translate methods to the human and to explore the role of glutathione/metabolic prints in the progression of liver dysfunction and in the detection of HCC. Treated plasma from healthy subjects (n = 20), patients with liver disease (ESLD, n = 99) and patients after transplantation (LTx, n = 7) were analyzed by GC- or LC/MS. Glutathione labeling profile was measured by isotopomer analyzes of 2H2O enriched plasma. Principal Component Analyzes (PCA) were used to determined metabolic prints. There was a significant difference in glutathione/metabolic profiles from patients with ESLD vs healthy subjects and patients after LTx. Similar significant differences were noted on patients with ESLD when stratified by the MELD score. PCA analyses showed myristic acid, citric acid, succinic acid, l-methionine, d-threitol, fumaric acid, pipecolic acid, isoleucine, hydroxy-butyrate and glycolic, steraric and hexanoic acids were discriminative metabolites for ESLD-HCC+ vs ESLD-HCC- subject status. Glutathione species and metabolic prints defined liver disease severity and may serve as surrogate for the detection of HCC in patients with established cirrhosis.


Circulating angiogenic monocyte progenitor cells are reduced in JAK2V617F high allele burden myeloproliferative disorders.
The clinical course of patients with Philadelphia chromosome negative myeloproliferative disorder is frequently complicated by thrombotic events. Post-natal vasculogenesis has been proposed to play a critical role in angiogenesis by acting through a hierarchy of endothelial progenitor cells. Some endothelial progenitor cells have been shown to share a number of features associated with monocytes while other more primitive progenitor cells produce endothelial cells in vitro exclusively. The cells which share features of monocytes and endothelial cells have been termed angiogenic monocytes. Reduced levels of angiogenic monocyte progenitor cells have been reported to be predictive of atherosclerotic disease progression. Angiogenic monocyte progenitor cells were assayed in vitro from the peripheral blood mononuclear cells of myeloproliferative disorder patients. Angiogenic monocyte colonies were plucked and analyzed for endothelial cells and hematopoietic cell markers, JAK2V617F and their ability to incorporate into vascular endothelium following their transplantation into non-obese diabetic, severe combine immunodeficient mice. Myeloproliferative disorder angiogenic monocyte colonies that were detected were uniformly JAK2V617F positive and produced cells that expressed phenotypic markers characteristic of both monocytes and endothelial cells. Reduced numbers of angiogenic monocyte colonies were present in the blood of myeloproliferative disorder patients with a high JAK2V617F burden (>50%), (p<0.01). Transplanted angiogenic monocytes were able to contribute to the vascular endothelium of non-obese diabetic, severe combine immunodeficient mice. These studies suggest that reduced numbers of circulating angiogenic monocyte progenitors contribute to the propensity to develop thrombotic complications in myeloproliferative disorder patients.


A longitudinal study of drug and alcohol use by psychosis-prone and impulsive-nonconforming individuals.
The rates of substance use and abuse are higher among psychotic patients and antisocial individuals than in the general population. In a 10-year longitudinal study, psychosis-prone individuals identified by the Perceptual Aberration (L. J. Chapman, J. P. Chapman, M. L. Raulin, 1976) and Magical Ideation (Per-Mag) scales (M. Eckblad & L. J. Chapman, 1983), and individuals with antisocial traits, identified by the Impulsive Nonconformity (Noncon) scale (L. J. Chapman et al., 1984), exceeded a control group on rates of substance use disorders. As hypothesized, the Per-Mag group demonstrated preferential patterns of substance use similar to those reported for schizophrenic patients. Participants who scored deviantly on both the Per-Mag and Noncon scales were at especially heightened risk for substance use disorders. Psychosis proneness at the initial screening predicted substance abuse at the follow-up evaluation, but substance abuse at the initial interview did not predict later clinical psychosis or psychoticlike experiences.


Feature selection with redundancy-constrained class separability.
Scatter-matrix-based class separability is a simple and efficient feature selection criterion in the literature. However, the conventional trace-based formulation does not take feature redundancy into account and is prone to selecting a set of discriminative but mutually redundant features. In this brief, we first theoretically prove that in the context of this trace-based criterion the existence of sufficiently correlated features can always prevent selecting the optimal feature set. Then, on top of this criterion, we propose the redundancy-constrained feature selection (RCFS). To ensure the algorithm's efficiency and scalability, we study the characteristic of the constraints with which the resulted constrained 0-1 optimization can be efficiently and globally solved. By using the totally unimodular (TUM) concept in integer programming, a necessary condition for such constraints is derived. This condition reveals an interesting special case in which qualified redundancy constraints can be conveniently generated via a clustering of features. We study this special case and develop an efficient feature selection approach based on Dinkelbach's algorithm. Experiments on benchmark data sets demonstrate the superior performance of our approach to those without redundancy constraints.


Etiopathogenesis of inflammatory bowel diseases.
Theories explaining the etiopathogenesis of inflammatory bowel disease (IBD) have been proposed ever since Crohn's disease (CD) and ulcerative colitis (UC) were recognized as the two major forms of the disease. Although the exact cause(s) and mechanisms of tissue damage in CD and UC have yet to be completely understood, enough progress has occurred to accept the following hypothesis as valid: IBD is an inappropriate immune response that occurs in genetically susceptible individuals as the result of a complex interaction among environmental factors, microbial factors, and the intestinal immune system. Among an almost endless list of environmental factors, smoking has been identified as a risk factor for CD and a protective factor for UC. Among microbial factors, no convincing evidence indicates that classical infectious agents cause IBD, while mounting evidence points to an abnormal immune response against the normal enteric flora as being of central importance. Gut inflammation is mediated by cells of the innate as well as adaptive immune systems, with the additional contribution of non-immune cells, such as epithelial, mesenchymal and endothelial cells, and platelets.


Premature psychotherapy termination in an outpatient treatment program for personality disorders: a survival analysis.
Psychological treatment for patients with personality disorders (PD) is plagued with a high proportion of early dropouts, and attempts to identify risk factors for attrition have generated very few conclusive results. The purpose of the present study is to identify significant predictors of early treatment termination in a long-term psychotherapy program for PD. Data was retrospectively retrieved from 174 files of patients who began long-term psychotherapy in an outpatient treatment program in Quebec City, Canada. Socio-demographic, initial disturbance, and diagnostic variables were considered for prediction, along with a measure specifically designed to identify PD patients at risk of dropping out early from psychotherapy, the Treatment Attrition-Retention Scale for Personality Disorders (TARS-PD). Survival analysis using Cox proportional hazard regression was performed to identify significant predictors. Results using univariate Cox proportional hazards regressions revealed that unemployment, Global Assessment of Functioning scores, and recent hetero-aggressive behavior were significant predictors of early dropout in the first six months of therapy. Adjusting for these three confounders, four of the factor scores from the TARS-PD (Narcissism, Secondary gains, Low distress, and Cluster A features) were significantly associated with dropout in univariate Cox proportional hazards regressions. Secondary gains and Narcissism remained significant predictors after entering all five TARS-PD factors in a multivariate Cox proportional hazards regression adjusting for confounders. Taking into consideration specific treatment prognosis variables, such as those measured by the TARS-PD, might be more useful for dropout prediction in PD patients in comparison with more general demographic and diagnostic variables.


Rathke cleft cysts: a review of clinical and surgical management.
The aim of this paper is to provide a comprehensive review of clinical, imaging, and histopathological features, as well as operative and nonoperative management strategies in patients with Rathke cleft cysts (RCCs). A literature review was performed to identify previous articles that reported surgical and nonsurgical management of RCCs. Rathke cleft cysts are often incidental lesions found in the sellar and suprasellar regions and do not require surgical intervention in the majority of cases. In symptomatic RCCs, the typical clinical presentation includes headache, visual loss, and/or endocrine dysfunction. Visual field testing and endocrine laboratory studies may reveal more subtle deficiencies associated with RCCs. When indicated, the transsphenoidal approach typically offers the least invasive and safest method for treating these lesions. Various surgical strategies including cyst wall resection, intralesional alcohol injection, and sellar floor reconstruction are discussed. Although headache and visual symptoms frequently improve after surgical drainage of RCCs, hypopituitarism and diabetes insipidus are less likely to do so. A subset of more aggressive, atypical RCCs associated with pronounced clinical symptoms and higher recurrence rates is discussed, as well as the possible relationship of these lesions to craniopharyngiomas. Rathke cleft cysts are typically benign, asymptomatic lesions that can be monitored. In selected patients, transsphenoidal surgery provides excellent rates of improvement in clinical symptoms and long-term cyst resolution. Complete cyst wall resection, intraoperative alcohol cauterization, and sellar floor reconstruction in the absence of a CSF leak are not routinely recommended.


Comparison of measurements of cardiac output by bioimpedance and thermodilution in severely ill surgical patients.
In order to evaluate a new thoracic electrical bioimpedance (TEB) system for measurement of stroke volume based on the Sramek-Bernstein equation, 391 paired values of cardiac output were measured simultaneously with the standard thermodilution method. These values were obtained from 16 patients selected for having the most severe illness during a 6-month period; the intent was to evaluate the bioimpedance method in the worst possible situations. The correlation coefficient (r) was 0.83, slope was 0.87, intercept was 1.53, and the mean difference between the two methods was 16.2 +/- 11.8 (SD)% in the total series. In 285 paired samples where satisfactory conditions were met, r was 0.90, slope was 0.98, intercept was 0.34, and the mean difference was 11.8 +/- 8.9%. The data indicate satisfactory correlations between these two methods. When the TEB waveform is satisfactory, the agreement between TEB and thermodilution is as good as the agreement between serial thermodilution methods. Difficulties may arise with dysrhythmias, tachycardia (heart rate greater than 150 beat/min), metal in the chest or chest wall, sepsis, hypertension, and extremely oily skin. Mechanical ventilation did not appear to be a problem.


Implementation of a publication strategy in the context of reporting biases. A case study based on new documents from Neurontin litigation.
Previous studies have documented strategies to promote off-label use of drugs using journal publications and other means. Few studies have presented internal company communications that discussed financial reasons for manipulating the scholarly record related to off-label indications. The objective of this study was to build on previous studies to illustrate implementation of a publication strategy by the drug manufacturer for four off-label uses of gabapentin (Neurontin, Pfizer, Inc.): migraine prophylaxis, treatment of bipolar disorders, neuropathic pain, and nociceptive pain. We included in this study internal company documents, email correspondence, memoranda, study protocols and reports that were made publicly available in 2008 as part of litigation brought by consumers and health insurers against Pfizer for fraudulent sales practices in its marketing of gabapentin (see http://pacer.mad.uscourts.gov/dc/cgi-bin/recentops.pl?filename=saris/pdf/ucl%20opinion.pdf for the Court's findings).We reviewed documents pertaining to 20 clinical trials, 12 of which were published. We categorized our observations related to reporting biases and linked them with topics covered in internal documents, that is, deciding what should and should not be published and how to spin the study findings (re-framing study results to explain away unfavorable findings or to emphasize favorable findings); and where and when findings should be published and by whom. We present extracts from internal company marketing assessments recommending that Pfizer and Parke-Davis (Pfizer acquired Parke-Davis in 2000) adopt a publication strategy to conduct trials and disseminate trial findings for unapproved uses rather than an indication strategy to obtain regulatory approval. We show internal company email correspondence and documents revealing how publication content was influenced and spin was applied; how the company selected where trial findings would be presented or published; how publication of study results was delayed; and the role of ghost authorship. Taken together, the extracts we present from internal company documents illustrate implementation of a strategy at odds with unbiased study conduct and dissemination. Our findings suggest that Pfizer and Parke-Davis's publication strategy had the potential to distort the scientific literature, and thus misinform healthcare decision-makers.


Characterization of Tear Immunoglobulins in a Small-Cohort of Keratoconus Patients.
Keratoconus (KC) is classically considered a non-inflammatory condition caused by central corneal thinning that leads to astigmatism and reduced visual acuity. Previous studies have identified increased systemic levels of pro-inflammatory factors, including interleukin-6, tumor necrosis factor-α, and matrix metalloproteinase-9, suggesting that KC may have an inflammatory component in at least a subset of patients. In this study, we evaluated the levels of different immunoglobulins (light and heavy chains) based on Ig α, Ig λ, Ig κ, Ig µ, and Ig heavy chain subunits in non-KC tears (n = 7 control individuals) and KC tears (n = 7 KC patients) using tandem-liquid chromatography mass spectrometry. The most abundant Ig heavy chains detected in both control individuals and KC patients were Ig α-1 and Ig α-2 likely correlating to the higher IgA levels reported in human tears. We identified significant differences in immunoglobulin κ-chain V-II levels in KC patients compared to control individuals with no significant difference in Ig κ/Ig λ ratios or heavy chain levels. Our study supports previous findings suggesting that KC possesses a systemic component that may contribute to the KC pathology. Further studies are required to define causality and establish a role for systemic immune system-dependent factors and pro-inflammatory processes in KC development or progression.


Grandmothering drives the evolution of longevity in a probabilistic model.
We present a mathematical model based on the Grandmother Hypothesis to simulate how human post-menopausal longevity could have evolved as ancestral grandmothers began to assist the reproductive success of younger females by provisioning grandchildren. Grandmothers׳ help would allow mothers to give birth to subsequent offspring sooner without risking the survival of existing offspring. Our model is an agent-based model (ABM), in which the population evolves according to probabilistic rules governing interactions among individuals. The model is formulated according to the Gillespie algorithm of determining the times to next events. Grandmother effects drive the population from an equilibrium representing a great-ape-like average adult lifespan in the lower twenties to a new equilibrium with a human-like average adult lifespan in the lower forties. The stochasticity of the ABM allows the possible coexistence of two locally-stable equilibria, corresponding to great-ape-like and human-like lifespans. Populations with grandmothering that escape the ancestral condition then shift to human-like lifespan, but the transition takes longer than previous models (Kim et al., 2012). Our simulations are consistent with the possibility that distinctive longevity is a feature of genus Homo that long antedated the appearance of our species.


CHLAMYDOMONAS AS A MODEL ORGANISM.
The unicellular green alga Chlamydomonas offers a simple life cycle, easy isolation of mutants, and a growing array of tools and techniques for molecular genetic studies. Among the principal areas of current investigation using this model system are flagellar structure and function, genetics of basal bodies (centrioles), chloroplast biogenesis, photosynthesis, light perception, cell-cell recognition, and cell cycle control. A genome project has begun with compilation of expressed sequence tag data and gene expression studies and will lead to a complete genome sequence. Resources available to the research community include wild-type and mutant strains, plasmid constructs for transformation studies, and a comprehensive on-line database.


Asthma and obesity in three-year-old urban children: role of sex and home environment.
To examine whether the relationship between obesity and asthma in young girls and boys can be explained by social and physical characteristics of the home environment. We examined the relationship between asthma and obesity in children in the Fragile Families and Child Wellbeing Study (n=1815). Asthma was determined through maternal report of asthma diagnosis by a doctor (active in past 12 months). Weight and height of child was measured during an in-home visit. Data on home social (maternal depression, intimate partner violence) and physical environmental factors (housing quality, tobacco exposure) were collected via questionnaire. Ten percent of children had active asthma, 19% of children were overweight, and 17% of children were obese. In fully adjusted models, obese children had twice the odds of having asthma (OR, 2.3; 95% CI, 1.5-3.3) compared with children of normal body weight. In stratified analyses, overweight boys, but not overweight girls, had increased of odds of asthma. Obese boys and girls had increased odds of asthma compared with boys and girls of normal body weight. The relationship between asthma and obesity is present in boys and girls as young as 3 years of age; a relationship between being overweight and asthma is only present among boys. This relationship is not attributable to shared social and environmental factors of the children's home.


Application of flow karyotyping in prenatal detection of chromosome aberrations.
This paper describes the application of bivariate flow karyotyping to (1) classification of chromosomes isolated from cultures of cells taken by amniocentesis and (2) detection of numerical and structural aberrations. Chromosomes were isolated from primary cultures 2-5 wk after amniocentesis, stained with Hoechst 33258 and chromomycin A3, and analyzed using dual beam flow cytometry. Information about chromosome DNA content and DNA base composition was derived from the locations of the peaks in the flow karyotypes, each peak being produced by one or more chromosome types with similar DNA content and DNA base composition. Information about the relative frequency of each chromosome type was determined on the basis of the relative volume of the peak for that chromosome type. Cytogenetic information determined on the basis of flow karyotypes was compared with that obtained by visual analysis following G-banding. Variability among the peak means and volumes in flow karyotypes was determined from analyses of 50 normal amniocyte cultures. Numerical aberrations involving chromosomes 21, 18, and Y were detected correctly in all of 28 analyses, including eight in a blind study. Structural aberrations involving chromosomes 1, 2, 3, 6, 9-12, 13, 14, 15, 21, and 22 were detected in all of seven cultures in a blind study. Flow karyotypes proved to be insensitive to small, normally occurring chromosome polymorphisms detected by banding analysis. In addition, a few samples were erroneously scored as having numerical aberrations.


Regulation and mindful resident care in nursing homes.
Regulatory oversight is intended to improve the health outcomes of nursing home residents, yet evidence suggests that regulations can inhibit mindful staff behaviors that are associated with effective care. We explored the influence of regulations on mindful staff behavior as it relates to resident health outcomes, and offer a theoretical explanation of why regulations sometimes enhance mindfulness and other times inhibit it. We analyzed data from an in-depth, multiple-case study including field notes, interviews, and documents collected in eight nursing homes. We completed a conceptual/thematic description using the concept of mindfulness to reframe the observations. Shared facility mission strongly impacted staff perceptions of the purpose and utility of regulations. In facilities with a resident-centered culture, regulations increased mindful behavior, whereas in facilities with a cost-focused culture, regulations reduced mindful care practices. When managers emphasized the punitive aspects of regulation we observed a decrease in mindful practices in all facilities.


Theoretical Study of the Photochemical Isomerization of Colchicine.
The photochemical reaction of colchicine to β- and γ-lumicolchicine, through a mechanism involving a disrotatory cyclization, is studied by theoretical methods. The energetics of the reaction, including one or two methanol solvent molecules, are studied at the DFT-B3LYP and multireference perturbation levels of theory using the 6-31G(d) basis set. The results show that, in agreement with experimental results, the first excited state of colchicine at ∼3.6 eV can lead to both β- and γ-lumicolchicine, whose energy is about 15 kcal mol(-)(1) above the colchicine energy. Owing to the high steric tension of the condensed four- and five-atom rings arising from cyclization, the two trans-lumicolchicines are higher in energy (>60 kcal mol(-)(1)), and their formation appears much less probable. A partial inclusion of the solvent effects through the addition of two solvent molecules does not alter the general conclusions based on the free energy in the gas phase. The photochemical reaction path is studied by choosing the distance between the two carbon atoms which form the new σ bond as the leading coordinate of the minimum-energy path of both the ground and the first singlet excited states. The energies are computed by Multi Configurational self-consistent-field calculations on a model molecule, retaining those atoms that presumably play an active role in the reaction. A reasonable mechanism starting from colchicine in the first singlet excited state and leading to γ-lumicolchicine is proposed. On the contrary, a high-energy transition state is found for trans-lumicolchicines, whose formation, although not strictly forbidden for energetic reasons, appears to be rather improbable.


Morphology control of the perovskite films for efficient solar cells.
In the past two years, the power conversion efficiency (PCE) of organic-inorganic hybrid perovskite solar cells has significantly increased up to 20.1%. These state-of-the-art new devices surpass other third-generation solar cells to become the most promising rival to the silicon-based solar cells. Since the morphology of the perovskite film is one of the most crucial factors to affect the performance of the device, many approaches have been developed for its improvement. This review provides a systematical summary of the methods for morphology control. Introductions and discussions on the mechanisms and relevant hotspots are also given. Understanding the growth process of perovskite crystallites has great benefits for further efficiency improvement and enlightens us to exploit new technologies for large-scale, low-cost and high-performance perovskite solar cells.


Development of the Chinese family support scale in a sample of Chinese patients with hypertension.
Despite strong recommendations to involve family social support in hypertension control, few questionnaires have been designed to measure family support in Chinese patients. The Chinese Family Support Scale is a self-rated questionnaire that assesses family support over a 6-month period. A total of 282 patients with hypertension participated in this study and 136 of them completed the questionnaire twice within an interval of two to three weeks. Exploratory factor analysis was conducted to assess the structural validity of the scale. Concurrent validity was determined by measuring the correlation between the Chinese Family Support Scale, and Hospital Anxiety and Depression Scale using the Sperman's Correlation Coefficient. Cronbach's alpha and intraclass correlation coefficients were employed to evaluate the internal and test-retest reliability of the scale. Exploratory factor analysis revealed a three-factor solution accounting for 62% of the total variance. The three underlying sub-scale dimensions were kinship, nuclear family, and social resources. Significant correlation (r=-0.266; p<0.01) was found between the depression subscales of the Hospital Anxiety and Depression Scale and the extent of support perceived by the patients as measured by the Chinese Family Support Scale. The Chinese Family Support Scale had an acceptable internal consistency (Cronbach's alpha = 0.84) and test-retest reliability (intraclass correlation coefficient = 0.82). The study provides preliminary evidence that the 12-item Chinese Family Support Scale is acceptable, valid and reliable for measuring the perceived family support in hypertension patients. It is a promising tool which can be easily incorporated into epidemiological surveys.


Predictors of the post-thrombotic syndrome with non-invasive venous examinations in patients 6 weeks after a first episode of deep vein thrombosis.
Post-thrombotic syndrome (PTS) is a chronic complication of deep vein thrombosis (DVT) affecting a large number of patients. Because of its potential debilitating effects, identification of patients at high risk for the development of this syndrome is relevant, and only a few predictors are known. To assess the incidence and potential predictors of PTS. We prospectively followed 111 consecutive patients for 2 years after a first episode of objectively documented DVT of the leg. With non-invasive venous examinations, residual thrombosis, valvular reflux, calf muscle pump function and venous outflow resistance were assessed at 6 weeks, 3 months, 6 months, 1 year, and 2 years. The Clinical, Etiologic, Anatomic, and Pathophysiologi classification was used to record the occurrence and severity of PTS. Regression analysis with area under the receiver operating characteristic (ROC) curve was performed to identify potential predictors. The cumulative incidence of PTS was 46% after 3 months, and the incidence and severity did not increase further. Men appeared to be at increased risk as compared with women (risk ratio [RR] 1.4, 95% confidence interval [CI] 0.9-2.2), as were patients over 50 years as compared with younger patients (RR 1.4%, 95% CI 0.9-2.1). Patients with thrombosis localized in the proximal veins at diagnosis had an increased risk of PTS as compared with patients with distal thrombosis (RR 2.3%, 95% CI 1.0-5.6). PTS developed in 32 of 52 patients (62%) with residual thrombosis in the proximal veins 6 weeks after diagnosis, as compared with 17 of 45 patients (38%) without residual proximal thrombosis, leading to a 1.6-fold increased risk (95% CI 1.0-2.5). The presence of valvular reflux in the superficial veins was also a predictor at 6 weeks, with a 1.6-fold increased risk as compared with patients without superficial reflux (95% CI 1.1-2.3). A multivariate analysis of these predictors yielded an area under the ROC curve of 0.72 (95% CI 0.62-0.82). PTS develops in half of all patients within 3 months, with no further increase being seen up to 2 years of follow-up. Male sex, age over 50 years, proximal localization of the thrombus at entry, residual proximal thrombosis and superficial valvular reflux at 6 weeks seem to be the most important predictors of PTS in patients with a first episode of DVT. Duplex scanning 6 weeks after diagnosis appears to be clinically useful for the identification of patients at risk of PTS.


Urinary biomarkers in bladder cancer: A review of the current landscape and future directions.
This narrative review aims to describe established and emerging urinary biomarkers in the diagnosis and surveillance of non-muscle invasive bladder cancer. It provides a comprehensive account of classical, FDA-approved protein biomarkers and discusses their limitations. Further, we discuss the role that epigenetic, genetic, and exosomal markers can play to enhance sensitivity and specificity of the available tests. The initial diagnosis and surveillance of bladder cancer involves a combination of cystoscopy, upper urinary tract imaging, and urine cytology. Despite high specificity, cytology is limited by low sensitivity. There are currently 6 urinary assays approved by the FDA to enhance diagnosis and surveillance of bladder cancer. While these have improved diagnosis and surveillance when combined with cytology, these tests are still not sufficiently sensitive and false positives often occur in benign conditions which result in inflammation of the urinary tract. Advancements in laboratory techniques have produced significant advancements in epigenetic and genetic markers, as well as extracellular vesicles, with DNA- and RNA-based markers dominating the research in this area in recent years. We identified relevant published data, using the PubMed/ Medline search engines as well as Google Scholar. We performed an online search using the terms "bladder cancer", "non-muscle invasive bladder cancer" in combination with "urine biomarkers" and limited articles in English published up to February 2020. This review consolidated on all available narrative and systematic reviews published in the 5 years in this field, while also reviewing the original data of each clinical trial or observational study which led to the development of the biomarkers. The development of laboratory techniques and understanding urine-based biomarkers in BC has fuelled the use of noninvasive liquid-based biomarkers to complement urine cytology. Nonetheless, none are sufficiently effective when used in isolation, and cytology remains the gold standard in many practices. Future efforts will be focused on using these markers in combination as a predictive signature, and moving on to validating them for use in everyday clinical practice.


Magnetic resonance imaging of hepatic neoplasms in the rat.
Magnetic resonance imaging (MRI) at microscopic resolution was done on a live rat that had chemically induced hepatic neoplasms. Beginning at the anterior aspect of the liver, 16 contiguous transaxial slices (each 1.25 mm thick) were produced using three-dimensional Fourier transform sequences. The rat had been treated with diethylnitrosamine (200 mg/kg) at 70 days of age, and, subsequently, received periodic implants of 17a-ethynylestradiol for 60 weeks. Carr-Purcell-Meiboom-Gill (CPMG) sequences (repetition time = 2,000 and echo time = 20, 40, 60, 80 ms) were done to give quantitative measures of spin-spin relaxation times (T2). Pixel-by-pixel curve fitting from these multiple images yielded calculated T2 images. Histologic evaluation of three abnormal areas in the liver revealed solid and cystic hepatocellular adenomas. Although lesions were evident in early-echo images of the CPMG sequence, they were more apparent in the late-echo images. This was consistent with longer T2 relaxation times for the lesions. The voxels of dimensions (230 x 230 x 1,250 microns) permitted resolution of volume elements less than 0.07 mm3. This in turn permitted clear delineation of focal lesions less than 3 mm in diameter. The potential for MRI at microscopic resolution in toxicologic research is clearly demonstrated.


Analysis of polymorphisms of the interleukin-18 gene in type 1 diabetes and Hardy-Weinberg equilibrium testing.
Recently, the interleukin-18 cytokine gene (IL18) was reported to be associated with type 1 diabetes. In the present report, we calculated that the reported genotypes of the two 5' region/promoter single nucleotide polymorphisms (SNPs), -607 (C-->A) (rs1946518) and -137 (G-->C) (rs187238), were not in Hardy-Weinberg equilibrium (HWE). We therefore investigated the association of the -607 and -137 SNPs in a U.K. type 1 diabetic Caucasian case-control collection (1,560 case and 1,715 control subjects tested at -607 and 4,323 case and 4,610 control subjects tested at -137) as well as a type 1 diabetic Caucasian collection comprised of families of European ancestry (1,347 families tested at -137 and 1,356 families tested at -607). No evidence for association with type 1 diabetes was found, including for the -607 A/A and C/A genotypes. To evaluate whether common variation elsewhere in the gene was associated with disease susceptibility, we analyzed eight IL18 tag SNPs in a type 1 diabetic case-control collection (1,561 case and 1,721 control subjects). No evidence for association was obtained (P = 0.11). We conclude that common allelic variation in IL18 is unlikely to contribute substantially to type 1 diabetes susceptibility in the populations tested and recommend routine application of tests for HWE in population-based studies for genetic association.


Cancer Prevention: Obstacles, Challenges and the Road Ahead.
Approaches to reduce the global burden of cancer include two major strategies: screening and early detection and active preventive intervention. The latter is the topic of this Commentary and spans a broad range of activities. The genetic heterogeneity and complexity of advanced cancers strongly support the rationale for early interruption of the carcinogenic process and an enhanced focus on prevention as a priority strategy to reduce the burden of cancer; however, the focus of cancer prevention management should be on individuals at high risk and on primary localized disease in which screening and detection should also play a vital role. The timing and dose of (chemo-)preventive intervention also affects response. The intervention may be ineffective if the target population is very high risk or already presenting with preneoplastic lesions with cellular changes that cannot be reversed. The field needs to move beyond general concepts of carcinogenesis to targeted organ site prevention approaches in patients at high risk, as is currently being done for breast and colorectal cancers. Establishing the benefit of new cancer preventive interventions will take years and possibly decades, depending on the outcome being evaluated. We also propose that comparative effectiveness research designs and the value of information obtained from large-scale prevention studies are necessary in order for preventive interventions to become a routine part of cancer management.


Genome-wide array-based comparative genomic hybridization analysis of pancreatic adenocarcinoma: identification of genetic indicators that predict patient outcome.
We analyzed the subchromosomal numerical aberrations of 44 surgically resected pancreatic adenocarcinomas by array-based comparative genomic hybridization. The aberration profile ranged widely between cases, suggesting the presence of multiple or complementary mechanisms of evolution in pancreatic cancer, and was associated with lymph node metastasis and venous or serosal invasion. A large number of small loci, previously uncharacterized in pancreatic cancer, showed non-random loss or gain. Frequent losses at 1p36, 4p16, 7q36, 9q34, 11p15, 11q13, 14q32-33, 16p13, 17p11-13, 17q11-25, 18q21-tel, 19p13, 21q22 and 22q11-12, and gains at 1q25, 2p16, 2q21-37, 3q25, 5p14, 5q11-13, 7q21, 7p22, 8p22, 8q21-23, 10q21, 12p13, 13q22, 15q13-22 and 18q11 were identified. Sixteen loci were amplified recurrently. We identified novel chromosomal alterations that were significantly associated with a range of malignant phenotypes. Gain of LUNX, HCK, E2F1 and DNMT3b at 20q11, loss of p73 at 1p36 and gain of PPM1D at 17q23 independently predicted patient outcome. Expression profiling of amplified genes identified Smurf1 and TRRAP at 7q22.1, BCAS1 at 20q13.2-3, and VCL at 10q22.1 as potential novel oncogenes. Our results contribute to a complete description of genomic structural aberrations and the identification of potential therapeutic targets and genetic indicators that predict patient outcome in pancreatic adenocarcinoma.


Comparing the oral health status of diabetic and non-diabetic children from Puerto Rico: a case-control pilot study.
Children with type 1 diabetes have infrequently been the subjects of studies examining oral health status (caries and gingival diseases); in addition, no study of this type has ever been on Puerto Rican children. The purpose of this study was to evaluate the oral health status of Puerto Rican children (ranging in age from 6 to 12 years) either with or without type 1 diabetes and compare the two groups with regard to that status. This was a matched case-control study. A convenience sample of 25 children with type 1 diabetes (cases) and 25 non-diabetic children (controls), all ranging in age from 6 to 12 years and matched by age and gender, was evaluated by a calibrated dentist for caries, bleeding on probing, and plaque and calculus indexes. A sample of saliva was taken from each subject and analyzed to determine Streptococcus mutans and Lactobacillus counts. Descriptive statistics, chi-square test, and t-test were used to describe and assess the data. We used the caries index to evaluate the teeth of the children participating in our study; we found significant differences in the number of lesions in the permanent teeth of diabetic children compared to the number found in the permanent teeth of non-diabetic children (1.43 and 0.56, respectively; p = 0.05). The mean number of sites of bleeding on probing for diabetic children was 23.9; for non-diabetic children it was 4.2. Diabetic children had more plaque than did the control children (plaque index = 2.5 vs. 0.8; p = 0.007) and more bleeding on probing (p = 0.001). High levels of glycosylated hemoglobin in diabetic children were statistically significantly associated with a greater number of sites with bleeding on probing. Diabetic children are at higher risk for caries and gum disease than are non-diabetic children.


Revealing the results of whole-genome sequencing and whole-exome sequencing in research and clinical investigations: some ethical issues.
The introduction of new sequencing technologies whole-genome sequencing (WGS) and whole-exome sequencing (WES) that are much less finely targeted than previous genetic tests has resulted in ethical debate about what should be done with clinically significant findings that may arise during the sequencing process. In this piece we argue that, in addition to whether the finding has been intentionally sought or arises incidentally, the ethical issues concerning what should be done with WES and WGS findings are also influenced by whether sequencing occurs in a clinical or research setting. We argue that decisions about the disclosure of WGS and WES findings generated in the clinical context are much less ethically contentious than decision making about the feedback of research results. We conclude by calling for greater transparency about the purpose of sample collection, more explicit protocols for transitioning between research and clinical contexts and patients and research participants to be warned of the potential for incidental findings to be generated, their potential significance and the actions that might be taken as a result.


Climate and landscape influence on indicators of lake carbon cycling through spatial patterns in dissolved organic carbon.
Freshwater ecosystems are strongly influenced by both climate and the surrounding landscape, yet the specific pathways connecting climatic and landscape drivers to the functioning of lake ecosystems are poorly understood. Here, we hypothesize that the links that exist between spatial patterns in climate and landscape properties and the spatial variation in lake carbon (C) cycling at regional scales are at least partly mediated by the movement of terrestrial dissolved organic carbon (DOC) in the aquatic component of the landscape. We assembled a set of indicators of lake C cycling (bacterial respiration and production, chlorophyll a, production to respiration ratio, and partial pressure of CO2 ), DOC concentration and composition, and landscape and climate characteristics for 239 temperate and boreal lakes spanning large environmental and geographic gradients across seven regions. There were various degrees of spatial structure in climate and landscape features that were coherent with the regionally structured patterns observed in lake DOC and indicators of C cycling. These different regions aligned well, albeit nonlinearly along a mean annual temperature gradient; whereas there was a considerable statistical effect of climate and landscape properties on lake C cycling, the direct effect was small and the overall effect was almost entirely overlapping with that of DOC concentration and composition. Our results suggest that key climatic and landscape signals are conveyed to lakes in part via the movement of terrestrial DOC to lakes and that DOC acts both as a driver of lake C cycling and as a proxy for other external signals.


Economic value of Acinetobacter baumannii screening in the intensive care unit.
Although Acinetobacter baumannii (A. baumannii) is an increasingly common nosocomial pathogen that can cause serious infections in the intensive care unit (ICU), most ICUs do not actively screen admissions for this pathogen. We developed an economic computer simulation model to determine the potential cost-consequences to the hospital of implementing routine A. baumannii screening of ICU admissions and isolating those patients who tested positive, comparing two screening methods, sponge and swab, with each other and no screening. Sensitivity analyses varied the colonization prevalence, percentage of colonized individuals who had active A. baumannii infections, A. baumannii reproductive rate (R), and contact isolation efficacy. Both screening methods were cost-effective for almost all scenarios tested, yielding cost-savings ranging from -$1 to -$1563. Sponge screening was not cost-saving when colonization prevalence was ≤1%, probability of infection ≤30%, R ≤ 0.25, and contact isolation efficacy ≤25%. Swab screening was not cost-saving under these same conditions when the probability of infection was ≤40%. Sponge screening tended to be more cost-saving than swab screening (additional savings ranged from $1 to $421). Routine A. baumannii screening of ICU patients may save costs for hospitals.


A new mass spectrometry-based method for the quantification of histones in plasma from septic shock patients.
The aim of this study was to develop a novel method to detect circulating histones H3 and H2B in plasma based on multiple reaction monitoring targeted mass spectrometry and a multiple reaction monitoring approach (MRM-MS) for its clinical application in critical bacteriaemic septic shock patients. Plasma samples from 17 septic shock patients with confirmed bacteraemia and 10 healthy controls were analysed by an MRM-MS method, which specifically detects presence of histones H3 and H2B. By an internal standard, it was possible to quantify the concentration of circulating histones in plasma, which were significantly higher in patients, and thus confirmed their potential as biomarkers for diagnosing septic shock. After comparing surviving patients and non-survivors, a correlation was found between higher levels of circulating histones and unfavourable outcome. Indeed, histone H3 proved a more efficient and sensitive biomarker for septic shock prognosis. In conclusion, these findings suggest the accuracy of the MRM-MS technique and stable isotope labelled peptides to detect and quantify circulating plasma histones H2B and H3. This method may be used for early septic shock diagnoses and for the prognosis of fatal outcomes.


Aged citrus peel (chenpi) extract causes dynamic alteration of colonic microbiota in high-fat diet induced obese mice.
Aged citrus peels (chenpi) have been used as a dietary supplement for gastrointestinal health maintenance in China. Recently, it was reported to exhibit anti-obesity activity. However, the relationship between the modulation effect of chenpi on gut microbiota and obesity prevention is not clearly understood. In this study, mice were fed with a high-fat diet (HFD), HFD supplemented with 0.25%- and 0.5%-chenpi extract, and normal diet, respectively, for 11 weeks. Chenpi extract significantly increased fecal short chain fatty acids by 43% for acetic acid and 86% for propionic acid. In addition, chenpi could decrease the prevalence of Proteobacteria and the ratio of Firmicutes to Bacteroidetes by about 88% and 70%, respectively. Moreover, this study was the first work to demonstrate the dynamics of two beneficial bacteria-Akkermansia spp. and Allobaculum spp. in a dose- and time-dependent manner for chenpi treatment via monitoring the dynamic change of the gut microbiota. Metagenomic analysis of the gut microbiota showed that several pathways, such as a two-component system, a tight junction, Staphylococcus aureus infection and others, were enhanced dynamically. The improved biological process of metabolism especially in benzoate derivatives might refer to the increased metabolic transformation of polymethoxyflavones from chenpi in the colon. Our study indicated that the modulation effect of chenpi on the gut microbiota may be an important pathway for its anti-obesity mechanisms.


Polymorphisms of GLUT2 and GLUT4 genes. Use in evaluation of genetic susceptibility to NIDDM in blacks.
The liver/islet (GLUT2) and muscle/adipose tissue (GLUT4) glucose-transporter gene products, membrane proteins that facilitate glucose uptake into cells, are important molecules for normal carbohydrate metabolism. Recent isolation of the genes encoding these proteins provides a means to assess the role of possible defects that might contribute to impaired glucose-stimulated insulin secretion or impaired insulin-mediated glucose uptake, both prominent phenotypic features of non-insulin-dependent diabetes (NIDDM). A GLUT2 cDNA clone was isolated from a human liver cDNA library to search for polymorphisms at this locus in American Blacks. Three highly polymorphic sites were identified, one of which (EcoRI-Hae III) appears to be due to an insertion and/or deletion of 200 base pairs of DNA. Significant linkage disequilibrium between these sites over approximately 30 kilobases of genomic DNA suggested that these polymorphisms could be in linkage disequilibrium with mutations at this locus if they exist. A GLUT4 cDNA clone was also utilized to search for polymorphisms at this locus, but only one previously described polymorphism was observed. GLUT2 and GLUT4 cDNA probes were used to evaluate DNA polymorphisms in genomic DNA from American Blacks with NIDDM. The allelic, genotypic, and haplotypic frequencies of the DNA polymorphisms at these loci did not differ from the frequencies in nondiabetic subjects. Because no associations with NIDDM were found, it appears unlikely that mutations at these loci contribute in a major way to the genetic susceptibility to NIDDM observed in American Blacks.


A systematic review of patient reported outcomes in phase II or III clinical trials of myelodysplastic syndromes and acute myeloid leukemia.
The purpose of this systematic literature review was to identify clinical trials of MDS and AML that included patient-reported outcome (PRO) instruments, and to summarize the symptom and other health related quality of life (HRQOL) concepts most frequently assessed and the PRO instruments that were used. Sixteen manuscripts describing 14 distinct trials met all criteria (i.e., phase 2 or 3 clinical trial for MDS or AML which included PRO assessment) and were published between 1996-2017. In trials evaluating anemia, PRO scores showed significant improvement in relevant domains (e.g. fatigue, function) among patients identified as responders. In trials evaluating the impact of anti-cancer therapies, improvements the baseline to end of treatment were observed in physical functioning and HRQOL, however the rates of missing data in many of the trials was high or unreported. PRO instruments have the ability to capture changes over time in patients' function and well-being, and PRO instruments and guidance documents are available to support the assessment of HRQOL in AML/MDS clinical trials.


Technical parameters affecting image characteristics in in vivo MR microscopy of the mouse.
The aim of the study was to assess the effects of changing acquisition parameters used for high-resolution in vivo magnetic resonance (MR) microscopy on image quality and scan time. The head or abdomen of 11 normal and 1 glioblastoma-bearing anesthetized BALB/c mice were imaged using a high-resolution 7.0-Tesla magnet. Scan parameters such as matrix size (MTX), slice thickness (ST), number of excitations (NEX), pulse sequence type including repetition time (TR) and echo time (TE), respiratory gating, and intraperitoneal contrast medium administration were altered to assess their actual effect on signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) as compared to calculated effects. As expected, SNR increased with increasing ST or NEX and with decreasing MTX. However, although the empirical increase in SNR was similar to that expected for increased ST, it was less than that anticipated for increasing NEX or decreasing MTX. Increasing NEX and applying respiratory gating both increased SNR and reduced the image degradation associated with respiratory motion in images of the abdomen. Intraperitoneal contrast medium administration produced a marked increase in CNR in the subject with the implanted glioblastoma, suggesting that this route is satisfactory for the enhancement of lesions disrupting the blood-brain barrier. The consequence of improving image quality in terms of spatial and contrast resolution is increased scan time. However, the actual increase in SNR when altering acquisition parameters may not be as much as predicted by theory.


Replicon clusters may form structurally stable complexes of chromatin and chromosomes.
Nuclear DNA replication was monitored 'in situ' in pea nuclei with the bromodeoxyuridine antibody technique. The labelling appeared to be restricted to a number of finely distinct spots. The labelling was followed through three subsequent cell cycles in meristematic and differentiating pea root cells. The results show that the spots as seen just after the labelling persist distinctly over the mitotic chromosomes as well as in the nuclei of the following cell cycles up to 44 hours after the pulse. Moreover, they are also present in the nuclei of differentiating cells. The spots over the mitotic chromosomes in specific cases give rise to a dynamic banding. Nuclei of the second and third cycle show absence of labelling in specific zones, owing to the segregation of the labelled strands of chromosomal DNA. The maintenance of the spotted appearance of the replication clusters through all stages of the three subsequent cell cycles may be an indication in favour of the hypothesis that such clusters represent structurally stable replicon complexes held together by the nuclear matrix and the chromosome scaffold.


Changes in corticospinal excitability and the direction of evoked movements during motor preparation: a TMS study.
Preparation of the direction of a forthcoming movement has a particularly strong influence on both reaction times and neuronal activity in the primate motor cortex. Here, we aimed to find direct neurophysiologic evidence for the preparation of movement direction in humans. We used single-pulse transcranial magnetic stimulation (TMS) to evoke isolated thumb-movements, of which the direction can be modulated experimentally, for example by training or by motor tasks. Sixteen healthy subjects performed brisk concentric voluntary thumb movements during a reaction time task in which the required movement direction was precued. We assessed whether preparation for the thumb movement lead to changes in the direction of TMS-evoked movements and to changes in amplitudes of motor-evoked potentials (MEPs) from the hand muscles. When the required movement direction was precued early in the preparatory interval, reaction times were 50 ms faster than when precued at the end of the preparatory interval. Over time, the direction of the TMS-evoked thumb movements became increasingly variable, but it did not turn towards the precued direction. MEPs from the thumb muscle (agonist) were differentially modulated by the direction of the precue, but only in the late phase of the preparatory interval and thereafter. MEPs from the index finger muscle did not depend on the precued direction and progressively decreased during the preparatory interval. Our data show that the human corticospinal movement representation undergoes progressive changes during motor preparation. These changes are accompanied by inhibitory changes in corticospinal excitability, which are muscle specific and depend on the prepared movement direction. This inhibition might indicate a corticospinal braking mechanism that counteracts any preparatory motor activation.


Kidney-Failure Risk Projection for the Living Kidney-Donor Candidate.
Evaluation of candidates to serve as living kidney donors relies on screening for individual risk factors for end-stage renal disease (ESRD). To support an empirical approach to donor selection, we developed a tool that simultaneously incorporates multiple health characteristics to estimate a person's probable long-term risk of ESRD if that person does not donate a kidney. We used risk associations from a meta-analysis of seven general population cohorts, calibrated to the population-level incidence of ESRD and mortality in the United States, to project the estimated long-term incidence of ESRD among persons who do not donate a kidney, according to 10 demographic and health characteristics. We then compared 15-year projections with the observed risk among 52,998 living kidney donors in the United States. A total of 4,933,314 participants from seven cohorts were followed for a median of 4 to 16 years. For a 40-year-old person with health characteristics that were similar to those of age-matched kidney donors, the 15-year projections of the risk of ESRD in the absence of donation varied according to race and sex; the risk was 0.24% among black men, 0.15% among black women, 0.06% among white men, and 0.04% among white women. Risk projections were higher in the presence of a lower estimated glomerular filtration rate, higher albuminuria, hypertension, current or former smoking, diabetes, and obesity. In the model-based lifetime projections, the risk of ESRD was highest among persons in the youngest age group, particularly among young blacks. The 15-year observed risks after donation among kidney donors in the United States were 3.5 to 5.3 times as high as the projected risks in the absence of donation. Multiple demographic and health characteristics may be used together to estimate the projected long-term risk of ESRD among living kidney-donor candidates and to inform acceptance criteria for kidney donors. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).


The importance of study design for detecting differentially abundant features in high-throughput experiments.
High-throughput assays, such as RNA-seq, to detect differential abundance are widely used. Variable performance across statistical tests, normalizations, and conditions leads to resource wastage and reduced sensitivity. EDDA represents a first, general design tool for RNA-seq, Nanostring, and metagenomic analysis, that rationally selects tests, predicts performance, and plans experiments to minimize resource wastage. Case studies highlight EDDA's ability to model single-cell RNA-seq, suggesting ways to reduce sequencing costs up to five-fold and improving metagenomic biomarker detection through improved test selection. EDDA's novel mode-based normalization for detecting differential abundance improves robustness by 10% to 20% and precision by up to 140%.


Salmonella typhimurium has two homologous but different umuDC operons: cloning of a new umuDC-like operon (samAB) present in a 60-megadalton cryptic plasmid of S. typhimurium.
Expression of the umuDC operon is required for UV and most chemical mutagenesis in Escherichia coli. The DNA which can restore UV mutability to a umuD44 strain and to a umuC122::Tn5 strain of E. coli has been cloned from Salmonella typhimurium TA1538. DNA sequence analysis indicated that the cloned DNA potentially encoded proteins with calculated molecular weights of 15,523 and 47,726 and was an analog of the E. coli umuDC operon. We have termed this cloned DNA the samAB (for Salmonella mutagenesis) operon and tentatively referred to the umuDC operon of S. typhimurium LT2 (C. M. Smith, W. H. Koch, S. B. Franklin, P. L. Foster, T. A. Cebula, and E. Eisenstadt, J. Bacteriol. 172:4964-4978, 1990; S. M. Thomas, H. M. Crowne, S. C. Pidsley, and S. G. Sedgwick, J. Bacteriol. 172:4979-4987, 1990) as the umuDCST operon. The samAB operon is 40% diverged from the umuDCST operon at the nucleotide level. Among five umuDC-like operons so far sequenced, i.e., the samAB, umuDCST, mucAB, impAB, and E. coli umuDC operons, the samAB operon shows the highest similarity to the impAB operon of TP110 plasmid while the umuDCST operon shows the highest similarity to the E. coli umuDC operon. Southern hybridization experiments indicated that (i) S. typhimurium LT2 and TA1538 had both the samAB and the umuDCST operons and (ii) the samAB operon was located in a 60-MDa cryptic plasmid. The umuDCST operon is present in the chromosome. The presence of the two homologous but different umuDC operons may be involved in the poor mutability of S. typhimurium by UV and chemical mutagens.


The role of the physician in laboratory medicine: a European perspective.
Advances in medical laboratory technology have driven major changes in the practice of laboratory medicine over the past two decades by the development of automated, cross-disciplinary single platform analysers. This has led to the blurring of boundaries between traditional disciplines and the emergence of core automated or blood science laboratories. This paper was commissioned by the Union of European Medical Specialists to examine the changing role of laboratory-based physicians in the light of these advances by focusing on the added value of expert interpretation of test results and resultant improvements in clinical outcomes. The paper also considers the broad range of responsibilities of laboratory-based physicians and the difficulties in precisely measuring how this translates into improved clinical outcomes. Given its provenance, the paper concentrates predominantly on the role of laboratory-based physicians while acknowledging the essential and vital role of scientists in running diagnostic laboratory services.


Long-term changes in visual acuity and refractive error in amblyopes.
To report long-term changes in visual acuity and refractive error for strabismic, anisometropic, and isoametropic amblyopes. Records of patients with strabismic amblyopia, anisometropic amblyopia, and isoametropic amblyopia who were treated from 1983 to 1993 were reviewed. Excluded were patients having ocular or neurological diseases, developmental delay, and follow-up <4 years after treatment cessation. Data included best-correctable visual acuity and spherical equivalent refractive error of the amblyopic and the nonamblyopic eye at pretreatment, posttreatment, and long-term follow-up. Records for 61 patients met the inclusion criteria. For strabismic amblyopia (n = 22), mean visual acuity in amblyopic and nonamblyopic eyes improved 0.36 and 0.05 logarithm of the minimum angle of resolution (logMAR) units after a mean treatment time of 1 year. At long-term follow-up (mean = 9.3 years after treatment), visual acuity in the amblyopic eye regressed 0.09 logMAR and visual acuity in the nonamblyopic eye improved 0.10 logMAR units. For anisometropic amblyopia (n = 26), mean visual acuity in amblyopic and nonamblyopic eyes improved 0.30 and 0.02 logMAR units, respectively, after a mean treatment period of 1.1 year. At the long-term follow-up visit (mean = 7.1 years after treatment), visual acuity in the amblyopic eye regressed 0.09 logMAR unit and in the nonamblyopic eye improved 0.03 logMAR unit. Repeated-measures analysis of variance showed no significant effect of type of amblyopia on visual acuity of the amblyopic eye and a significant effect of visit due to treatment but not regression. The changes in visual acuity in the nonamblyopic eye from the pretreatment to the follow-up visit were significant and interacted with type, the changes being larger in strabismic amblyopia. For strabismic amblyopia, the mean refractive error in amblyopic and nonamblyopic eyes changed from +2.15 D and +1.85 D, respectively, initially to +0.45 D and +0.58 D, respectively, at the follow-up visit. For anisometropic amblyopia, the mean refractive error in amblyopic and nonamblyopic eyes changed from +1.04 D and +0.12 D, respectively, initially to +0.23 D and -0.94 D, respectively, at the follow-up visit. The effect of visit on amblyopic and nonamblyopic refractive errors was significant. For isoametropic amblyopia (n = 13), visual acuity in both right and left eyes initially was 0.39 logMAR unit and improved to 0.14 logMAR unit in each eye after a mean follow-up of 8.9 years. Refractive error in the right and the left eyes changed from -1.22 D and -1.14 D, respectively, to -2.68 D and -2.56 D, respectively, at follow-up. These differences were all significant. After treatment and with long-term follow up, visual acuity regresses but not significantly in the amblyopic eye in strabismic amblyopia and anisometropic amblyopia. At the same time, visual acuity in the nonamblyopic eye improves slightly. Visual acuity also improves significantly over time in isoametropic amblyopia. The refractive error of both amblyopic and nonamblyopic eyes tends to show a myopic shift regardless of the type of amblyopia.


First Report of Leaf Spot of Sesame Caused by Xanthomonas sp. In the United States.
In July 2010 in Texas, extensive leaf spots (10 to 30% leaf area affected) occurred on a commercial planting of sesame (Sesamum indicum L.) in Hidalgo County and to a lesser extent (1 to 5% leaf area) on leaves of several varieties in experimental trials in Colorado and Victoria Counties. The leaf spots were light to dark brown, somewhat circular, and 1 to 3 mm in diameter. A symptomatic leaf from each of three to five plants per county was sampled for isolations. Leaves were sprayed with 70% ethanol and immediately blotted dry with a paper towel. The margins of spots (2 mm2) were excised with a scalpel and placed in a drop of sterile water for 5 min. Drops were streaked on nutrient agar (NA) and incubated at 30°C. The 12 isolations consistently yielded gram-negative, rod-shaped bacteria with yellow, translucent colonies that were visible after 2 days of incubation. The DNA of 11 isolates was extracted with the Norgen (Thorold, ON) Bacterial genomic DNA isolation kit (Cat. #17900) and the ITS region was amplified by 16S uni 1330 and 23S uni 322 anti primers (1). PCR products were treated with the ZymoResearch (Irvine, CA) DNA clean & concentrator kit (Cat. #D4003) and sequenced. With the NCBI database, a BLAST search of the 1,100 bp amplicons showed 93 to 99% identity with pathovars of either Xanthomonas oryzae or X. axonopodis (GenBank Accession Nos. CP003057.1 and CP002914.1, respectively). Amplicon sequences of the sesame isolates were deposited in GenBank as Accession Nos. JQ975037 through JQ975047. The reported species on sesame is X. campestris pv. sesami (2). To fulfill Koch's postulates, potted sesame plants (var. Sesaco 25), 15 to 20 cm tall, were sprayed until runoff with a suspension of bacteria (106 to 107 CFU/ml) from a 2-day-old NA culture. All 12 isolates were evaluated, with five to seven plants per isolate. Plants were maintained in a mist chamber in a greenhouse at 27 to 30°C and 100% relative humidity. The pathogenicity trial was repeated once. Leaf spots were first seen 7 days after inoculation and were prevalent 14 days after inoculation. All 12 isolates were pathogenic. There were no symptoms on leaves sprayed with sterile water. Bacteria that produced colonies consistent with Xanthomonas were reisolated on NA from symptomatic leaves but not from controls. The identities of three isolates were reconfirmed with PCR analysis and sequencing. In 2007, more than 2,000 ha of sesame were grown in the continental United States, with 80% of that in Texas. Currently, acreage of shatter-free varieties of sesame is increasing in arid areas of Texas, Oklahoma, and Kansas. In such areas, the yield impact of this disease is likely to be minimal, except in years with above-average rainfall. To our knowledge, this is the first report of this disease in the United States. References: (1) E. R. Gonçalves and Y. B. Rosato. Int. J. Syst. Evol. Microbiol. 52:355, 2002. (2) J. M. Young et al., New Zealand J. Agric. Res. 21:153, 1978.


Comparison of the effectiveness of non-nucleoside reverse transcriptase inhibitor-containing and protease inhibitor-containing regimens using observational databases.
To compare the effectiveness of first protease inhibitor (PI)-containing and non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens. Data were analysed from three large HIV patient databases: Apache HIV Insight (APACHE), Target Management Services (TMS) and Clinical Partners (CP). The effectiveness of therapy was the time taken for HIV-1 RNA to fall below detectable levels on first highly active antiretroviral therapy regimen (PI- or NNRTI-containing) and the subsequent time to failure (two consecutive detectable measurements). Comparisons were made using proportional hazards models, adjusting for differences in age, sex, previous reverse transcriptase inhibitor use, calendar year and baseline viral load and CD4 T-cell count. The type of regimen was not associated with time to undetectable viral load in any of the three databases, all of which had high power to detect a difference. PI-containing regimens were significantly less likely to fail after reaching undetectable viral loads for APACHE and CP patients (relative hazard, 1.7; 95% confidence interval, 1.3--2.1 and relative hazard, 1.6; 95% confidence interval, 1.0--2.5 respectively). These results remained significant after allowing for an unmeasured confounder with moderate effect on risk. No significant association between time to failure and regimen was found for TMS patients, possibly due to low power (67% to detect a relative hazard of 1.5). No difference was found between regimens in the time taken for an increase of > 100 x 10(9)cells/l in CD4 T-cell count. In the APACHE database, those on NNRTI-containing regimens were more likely to have a failing CD4 T-cell response. PI-containing regimens have a lower risk of treatment failure than NNRTI-containing regimens.


Polarization holography for vortex retarders recording.
We present an original static recording method for vortex retarders (VRs) made from liquid crystal polymers (LCPs) using the superimposition of several polarized beams. VRs are birefringent plates characterized by a rotation of their fast axis about their center. The new method is based on polarization holography and photo-orientable LCP. Combining several polarized beams induces the polarization patterns required for the recording process of VRs without mechanical action. A mathematical description of the method, the outcomes of the numerical simulations, and the first experimental results are presented.


Comparison of an electromagnetic and an electrohydraulic lithotripter: Efficacy, pain and complications.
We analyzed efficacy and complications of extracorporeal shock wave lithotripsy (SWL) and analgesia requirement during the treatment in two groups of patients treated with different lithotripters. The patients treated were 189, 102 between September 2016 and April 2017 with HMT Lithotron® LITS 172, electrohydraulic, and 87 between May and September 2017 with Storz Medical Modulith® SLK, electromagnetic. The main differences between the lithotripters are: type of energy source, patient position, frequency and number of shock waves. All the patients underwent sonography before and four to eight weeks after the treatment. The targeting was sonographic for renal stones and X-ray for ureteral stones. All the patients received Ketorolac before the treatment with a supplement of Pethidine if needed. People lost to follow-up and with incomplete data were excluded. We enrolled 173 patients, 94 treated with the electrohydraulic lithotripter and 79 with the electromagnetic one. 43 patients (54%) in the electromagnetic group and 31 (33%) in the electrohydraulic group were stone free or presented clinically insignificant residual fragments (CIRFs), defined as asymptomatic, noninfectious, ≤ 3 mm. The association between CIRFs and the kind of lithotripter was statistically significant (p = 0.004). An increased need for analgesia was found in 14.9% of patients in the electromagnetic group and in 81% of patients in the electrohydraulic group (p < 0.001). The access to emergency room (intractable pain, kidney failure, fever, Steintrasse) after the treatment was similar in the two groups (p = 0.37). The best results in stones fragmentation and less analgesia requirement were demonstrated in the electromagnetic lithotripter group. No differences were demonstrated considering the need for emergency room after the treatment.


Interplay Between V-ATPase G1 and Small EV-miRNAs Modulates ERK1/2 Activation in GBM Stem Cells and Nonneoplastic Milieu.
The ATP6V1G1 subunit (V1G1) of the vacuolar proton ATPase (V-ATPase) pump is crucial for glioma stem cells (GSC) maintenance and in vivo tumorigenicity. Moreover, V-ATPase reprograms the tumor microenvironment through acidification and release of extracellular vesicles (EV). Therefore, we investigated the role of V1G1 in GSC small EVs and their effects on primary brain cultures. To this end, small EVs were isolated from patients-derived GSCs grown as neurospheres (NS) with high (V1G1HIGH-NS) or low (V1G1LOW-NS) V1G1 expression and analyzed for V-ATPase subunits presence, miRNA contents, and cellular responses in recipient cultures. Our results show that NS-derived small EVs stimulate proliferation and motility of recipient cells, with small EV derived from V1G1HIGH-NS showing the most pronounced activity. This involved activation of ERK1/2 signaling, in a response reversed by V-ATPase inhibition in NS-producing small EV. The miRNA profile of V1G1HIGH-NS-derived small EVs differed significantly from that of V1G1LOW-NS, which included miRNAs predicted to target MAPK/ERK signaling. Mechanistically, forced expression of a MAPK-targeting pool of miRNAs in recipient cells suppressed MAPK/ERK pathway activation and blunted the prooncogenic effects of V1G1HIGH small EV. These findings propose that the GSC influences the brain milieu through a V1G1-coordinated EVs release of MAPK/ERK-targeting miRNAs. Interfering with V-ATPase activity could prevent ERK-dependent oncogenic reprogramming of the microenvironment, potentially hampering local GBM infiltration. IMPLICATIONS: Our data identify a novel molecular mechanism of gliomagenesis specific of the GBM stem cell niche, which coordinates a V-ATPase-dependent reprogramming of the brain microenvironment through the release of specialized EVs.


Guided and Unguided Internet-Based Treatment for Problematic Alcohol Use - A Randomized Controlled Pilot Trial.
The Internet has increasingly been studied as mode of delivery for interventions targeting problematic alcohol use. Most interventions have been fully automated, but some research suggests that adding counselor guidance may improve alcohol consumption outcomes. An eight-module Internet-based self-help program based on cognitive behavioral therapy (CBT) was tested among Internet help-seekers. Eighty participants with problematic alcohol use according to the Alcohol Use Disorders Identification Test (AUDIT; scores of ≥ 6 for women and ≥ 8 for men) were recruited online from an open access website and randomized into three different groups. All groups were offered the same self-help program, but participants in two of the three groups received Internet-based counselor guidance in addition to the self-help program. One of the guidance groups was given a choice between guidance via asynchronous text messages or synchronous text-based chat, while the other guidance group received counselor guidance via asynchronous text messages only. In the choice group, 65% (13 of 20 participants) chose guidance via asynchronous text messages. At the 10-week post-treatment follow-up, an intention-to-treat (ITT) analysis showed that participants in the two guidance groups (choice and messages) reported significantly lower past week alcohol consumption compared to the group without guidance; 10.8 (SD = 12.1) versus 22.6 (SD = 18.4); p = 0.001; Cohen's d = 0.77. Participants in both guidance groups reported significantly lower scores on the AUDIT at follow-up compared to the group without guidance, with a mean score of 14.4 (SD = 5.2) versus 18.2 (SD = 5.9); p = 0.003; Cohen's d = 0.68. A higher proportion of participants in the guidance groups said that they would recommend the program compared to the group without guidance (81% for choice; 93% for messages versus 47% for self-help). Self-help programs for problematic alcohol use can be more effective in reducing alcohol consumption over a 10-week period when counselor guidance is added. Clinicaltrials.gov NCT02384304.