Occurrence of Actinomyces in infections of endodontic origin.
Species of Actinomyces have been associated with endodontic treatment that failed to heal. In this study polymerase chain reaction was used with a pair of universal primers for Actinomyces and species-specific primers to evaluate the contents of infected root canals and aspirates from abscesses or cellulitis for the presence of Actinomyces israelii, A. naeslundii, and A. viscosus. DNA was extracted from 131 clinical samples. DNA from 2 of the original 131 samples was not available for polymerase chain reaction with the universal primer for Actinomyces and A. naeslundii. DNA reacting with the universal primer for Actinomyces was detected in 72 of 129 (55.8%) clinical samples. Of those 41 of 51 (80.4%) were from infected root canals, 22 of 48 (45.8%) were from abscesses, and 9 of 30 (30%) were associated with cellulitis. A. viscosus was detected in 42 of 131 (32.1%) clinical samples. Of those 31 of 52 (59.6%) were from infected root canals, 6 of 43 (14%) were from abscesses, and 5 of 36 (13.9%) were associated with cellulitis. A. israelii was detected in 31 of 131 (23.7%) clinical samples. Of those 14 of 52 (26.9%) were from infected root canals, 11 of 43 (25.6%) were from abscesses, and 6 of 36 (16.7%) were associated with cellulitis. A. naeslundii was detected in 11 of 131 (8.5%) clinical samples. Of those 7 of 51 (13.7%) were from infected root canals, 2 of 48 (4.2%) were from abscesses, and 2 of 30 (6.7%) were associated with cellulitis.


A potential mucus precursor in Tetrahymena wild type and mutant cells.
By using an antibody to a specific mucus polypeptide (34 kDa) to study whole cell extracts of both a secretory mutant (SB281) and wild type (wt) Tetrahymena, we demonstrate that a 57-kDa polypeptide is a probable precursor to the 34-kDa secretory polypeptide. We postulate that the precursor accumulates in the mutant cells because it cannot be cleaved. This mutant contains no recognizable mature secretory granules (mucocysts). By immunoelectron microscopy, the 34-kDa polypeptide was localized in wt cells specifically to the mature mucocysts and to their released products. Localization in mutant cells occurred in two different types of cytoplasmic vesicles: small electron dense vesicles (0.3-0.5 microns in diameter) and large electron lucent vacuoles (1.2-3.5 microns in diameter). Immunoblot analyses of homogenates of mutant and wt cells with the anti-34-kDa serum revealed a dominant band in the mutant at Mr 57 kDa whereas the wt showed a dominant band only at Mr 34 kDa. Furthermore, the 57-kDa polypeptide is immunoprecipitated with anti-34-kDa serum from the mutant cell. Further evidence for a precursor relation of the 57-kDa polypeptide in mutant cells to the 34-kDa mucus polypeptide of wt cells was obtained by the use of drugs (monensin, chloroquine, NH4Cl) that block secretory product processing in wt cells. Extracts of drug-treated wt cells showed the presence of a 57-kDa cross reacting band even after 18 h of incubation in growth medium whereas untreated control cells contained the 34-kDa mature protein almost exclusively. These results indicate that processing of the precursor to the 34-kDa polypeptide occurs in an acidic compartment(s) possibly in either the trans Golgi network, or condensing vacuoles or both.


Modelling the viability of heat recovery from combined sewers.
Modelling of wastewater temperatures along a sewer pipe using energy balance equations and assuming steady-state conditions was achieved. Modelling error was calculated, by comparing the predicted temperature drop to measured ones in three combined sewers, and was found to have an overall root mean squared error of 0.37 K. Downstream measured wastewater temperature was plotted against modelled values; their line gradients were found to be within the range of 0.9995-1.0012. The ultimate aim of the modelling is to assess the viability of recovering heat from sewer pipes. This is done by evaluating an appropriate location for a heat exchanger within a sewer network that can recover heat without impacting negatively on the downstream wastewater treatment plant (WWTP). Long sewers may prove to be more viable for heat recovery, as heat lost can be reclaimed before wastewater reaching the WWTP.


Organised crime and the efforts to combat it: a concern for public health.
This paper considers the public health impacts of the income-generating activities of organised crime. These range from the traditional vice activities of running prostitution and supplying narcotics, to the newer growth areas of human trafficking in its various forms, from international supply of young people and children as sex workers through deceit, coercion or purchase from family, through to smuggling of migrants, forced labour and the theft of human tissues for transplant, and the sale of fake medications, foodstuffs and beverages, cigarettes and other counterfeit manufactures. It looks at the effect of globalisation on integrating supply chains from poorly-regulated and impoverished source regions through to their distant markets, often via disparate groups of organised criminals who have linked across their traditional territories for mutual benefit and enhanced profit, with both traditional and newly-created linkages between production, distribution and retail functions of cooperating criminal networks from different cultures. It discusses the interactions between criminals and the structures of the state which enable illegal and socially undesirable activities to proceed on a massive scale through corruption and subversion of regulatory mechanisms. It argues that conventional approaches to tackling organised crime often have deleterious consequences for public health, and calls for an evidence-based approach with a focus on outcomes rather than ideology.


The cost of insulin-dependent diabetes mellitus (IDDM) in England and Wales.
This study estimates the direct health and social care costs of insulin-dependent diabetes mellitus (IDDM) in England and Wales in 1992 to be 96 million pounds, or 1021 pounds per person in a population with IDDM estimated at 94,000 individuals. These costs include insulin maintenance, hospitalization, GP and out-patient consultations, renal replacement therapy, and payments to informal carers. Expenditure is concentrated on younger age groups, with one-third of the total expended on those aged 0-24. Around one-half of the total costs can be directly attributed to IDDM, with the remainder associated with a range of complications of the disease. The single largest area of service expenditure is renal replacement therapy. The cost estimates are most sensitive to incidence rates of IDDM, numbers on dialysis and average duration of dialysis. A further 113 million pounds may be lost each year due to premature deaths resulting in lost productive contributions to the economy. The direct and indirect costs of IDDM are therefore significant. The cost of illness framework presented here should facilitate the economic evaluation of new and existing treatment regimens, which may improve value for money by reducing costs and/or increasing the quality or quantity of life for people with IDDM.


Neuroprotective strategies in Alzheimer's disease.
In addition to strategies designed to decrease amyloid beta (A beta) levels, it is likely that successful Alzheimer's disease (AD) therapeutic regimens will require the concomitant application of neuroprotective agents. Elucidation of pathophysiological processes occurring in AD and identification of the molecular targets mediating these processes point to potential high-yield neuroprotective strategies. Candidate neuroprotective agents include those that interact specifically with neuronal targets to inhibit deleterious intraneuronal mechanisms triggered by A beta and other toxic stimuli. Strategies include creating small molecules that block A beta interactions with cell surface and intracellular targets, down-regulate stress kinase signaling cascades, block activation of caspases and expression of pro-apoptotic proteins, and inhibit enzymes mediating excessive tau protein phosphorylation. Additional potential neuroprotective compounds include those that counteract loss of cholinergic function, promote the trophic state and plasticity of neurons, inhibit accumulation of reactive oxygen species, and block excitotoxicity. Certain categories of compounds, such as neurotrophins or neurotrophin small molecule mimetics, have the potential to alter neuronal signaling patterns such that several of these target actions might be achieved by a single agent.


Intestinal trefoil factor (TFF-3) and extracellular signal-regulated kinase (ERK) in cholangiocarcinoma.
The mucin-associated trefoil factor (TFF) peptides are integral to cytoprotection. TFF-3 is aberrantly expressed in colorectal and hepatocellular cancer and associated with an invasive phenotype. TFF-3 is also expressed in normal biliary epithelium. However, its role in biliary cancers is unknown. The biological effects of TFFs may result from EGFR, PI3 kinase, COX-2 and STAT-mediated signaling. We investigated the expression of TFF-3, Erk, Akt, EGFR and COX-2 in biliary cancer. Twenty-four consecutive cases of cholangiocarcinoma treated from 1996-2002 were studied. Immunohistochemistry was performed using monoclonal antibodies to TFF-3, EGFR, pEGFR, Erk, pErk, Akt, pAkt and COX-2 using validated techniques. Kendall's tau (exact method) and Pearson correlation test were employed to investigate the associations between biomarkers. Median age was 67 years. Surveillance, Epidemiology and End Results (SEER) stage was local in 1, regional in 15 and distant in 8. TFF-3 expression was detected in 19 cases. There were no significant associations between TFF-3 expression and sex, stage, grade, survival or SEER score. Erk expression in the tumor showed a borderline, negative correlation with TFF-3 (Pearson's p= -0.3988, p = 0.0588). TFF-3 is commonly expressed in biliary cancers and may have a negative reciprocal relationship with Erk expression.


In situ studies of the phylogeny and physiology of filamentous bacteria with attached growth.
Among the filamentous bacteria occasionally causing bulking problems in activated sludge treatment plants, three morphotypes with attached microbial growth are common, Eikelboom Type 0041, Type 1851 and Type 1701. A better knowledge of the phylogeny and physiology of these filamentous bacteria is necessary in order to develop control strategies for bulking. In this study we have used a combination of fluorescence in situ hybridization (FISH) and microautoradiography (MAR) to investigate the identity and in situ physiology of the Type 0041-morphotype and its attached bacteria in two wastewater treatment plants. Identification and enumeration of Type 0041 using group-specific 16S rRNA-targeted FISH probes revealed that approximately 15% of the filaments hybridized with a gene probe specific for the TM7 group, a recently recognized major lineage in the bacterial domain. All other filaments morphologically identified as Type 0041 only hybridized to the general bacterial EUB338-probe, indicating that they probably do not belong to commonly isolated bacterial phyla such as the Proteobacteria, Firmicutes, Actinobacteria and Bacteroidetes, for which group-specific probes were used. The phylogenetic heterogeneity of Type 0041 again highlights the inadequacy of a morphology-based classification system. Like the filaments, most of the attached microbial cells were not identified beyond their affiliation to the Bacteria using the group-specific FISH probes. However, several different bacterial phyla were represented in the identified fraction suggesting that the attached microorganisms are phylogenetically diverse. The study of the in situ physiology of Type 0041 using MAR-FISH revealed that both the filaments and the attached bacteria on Type 0041 were versatile in the use of organic substrates and electron acceptors. It was observed that all Type 0041 could consume glucose, but none of the filaments were able to consume acetate under any conditions tested, in contrast to some of the attached bacteria. No significant physiological differences were found between TM7-positive and TM7-negative Type 0041 filaments, and only minor differences were observed between the two treatment plants tested. These are the first data on the physiology of the almost entirely uncharacterized TM7 phylum and show that TM7 filamentous bacteria can uptake carbon substrates under aerobic and anaerobic conditions.


Active Commuting to School in Mexican Adolescents: Evidence From the Mexican National Nutrition and Health Survey.
Travel to school offers a convenient way to increase physical activity (PA) levels in youth. We examined the prevalence and correlates of active commuting to school (ACS) in a nationally representative sample of Mexican adolescents. A secondary objective was to explore the association between ACS and BMI status. Using data of adolescents (10-14 years old) from the 2012 Mexican National Health and Nutrition Survey (n = 2952) we ran multivariate regression models to explore the correlates of ACS and to test the association between ACS and BMI z-score or overweight/obesity. Models were adjusted for potential confounders and design effect. 70.8% of adolescents engaged in ACS (walking: 68.8%, bicycling: 2.0%). ACS was negatively associated with travel time, age, mother's education level, household motor vehicle ownership, family socioeconomic status, and living in urban areas or the North region of the country (P < .05). Time in ACS was negatively associated with overweight/obesity: Each additional minute of ACS was associated with a 1% decrease in the odds for being overweight or obese (P < .05). Potential correlates of ACS that may result in benefits for Mexican adolescents are identified. More studies on this relationship are needed to develop interventions aimed at increasing PA through ACS in Mexico.


High-resolution MR imaging of pituitary microadenomas at 1.5 T: experience with Cushing disease.
The MR images of 27 patients with clinically and biochemically suspected Cushing disease were evaluated retrospectively in a blinded fashion. The MR interpretation was compared with detailed operative diagrams and operative and pathologic reports. The examinations were performed on a 1.5-T MR system with thin-section sagittal and coronal T1-weighted (short TR/TE) images. Each pituitary half was considered separately (54 "halves"). Twenty-one pituitary halves were considered to have glandular abnormalities on MR. Compared with surgical findings, 17 MR findings were true positives and four were false positives (one pars intermedia cyst, three normal tissue). Of the 33 pituitary halves considered normal on MR, 26 were true negatives and seven were false negatives. MR had an overall sensitivity of 71% and a specificity of 87% for these adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas. A focal glandular hypointensity identified on coronal images was the most sensitive predictor of adenoma location. Sagittal images were not useful in either detection or localization. Upward convexity of the gland and deviation of the stalk were less useful indicators. Abnormalities of the sellar floor were the least reliable. In comparison with the capabilities of CT detection of microadenomas described in the current literature, it appears that high-field thin-section MR of the sella is the most sensitive imaging method for preoperative localization of ACTH-secreting adenomas in patients with Cushing disease.


Innate immunity and alcoholic liver disease.
Innate immunity provides the primary response to danger signals from pathogens or injured host cells and tissues. The cells of the innate immune system include monocytes, macrophages, dendritic cells, neutrophils, NK cells and NKT cells that orchestrate innate immune and initiate adaptive immune responses via cell interactions, cytokines, chemokines and other mediators. The most robust and common response of the innate immune system to danger signals is inflammation. In the multifactorial pathophysiology of alcoholic liver disease (ALD), activation of innate immune cells and the inflammatory cascade play a central role. Recent studies have demonstrated that Toll-like receptors (TLRs), the sensors of microbial and endogenous danger signals, are expressed and activated in innate immune cells as well as in parenchymal cells in the liver, and thereby contribute to ALD. The importance of gut-derived endotoxin and its recognition by TLR4 expressed on innate immune cells and liver parenchymal cells and the specificity of TLR4-induced downstream signaling via the interferon regulator factor 3 (IRF3) has recently been investigated. We have shown that mice deficient in IRF3 or TLR4 expression are protected from alcohol-induced liver steatosis, inflammation and hepatocyte injury. In addition to pathogen-derived danger molecules, the inflammatory cascade can also be activated by endogenous danger signals released from damaged cells. The inflammasome, a multiprotein complex, senses endogenous danger molecules to result in caspase-1-mediated cleavage of IL-1β. Our recent results suggest that inflammasome and caspase-1 activation occur in ALD and that IL-1 significantly contributes to both steatosis and inflammation in the liver in ALD.


Alignment and Proficiency of Virgin Olive Oil Sensory Panels: The OLEUM Approach.
A set of 334 commercial virgin olive oil (VOO) samples were evaluated by six sensory panels during the H2020 OLEUM project. Sensory data were elaborated with two main objectives: (i) to classify and characterize samples in order to use them for possible correlations with physical-chemical data and (ii) to monitor and improve the performance of panels. After revision of the IOC guidelines in 2018, this work represents the first published attempt to verify some of the recommended quality control tools to increase harmonization among panels. Specifically, a new "decision tree" scheme was developed, and some IOC quality control procedures were applied. The adoption of these tools allowed for reliable classification of 289 of 334 VOOs; for the remaining 45, misalignments between panels of first (on the category, 21 cases) or second type (on the main perceived defect, 24 cases) occurred. In these cases, a "formative reassessment" was necessary. At the end, 329 of 334 VOOs (98.5%) were classified, thus confirming the effectiveness of this approach to achieve a better proficiency. The panels showed good performance, but the need to adopt new reference materials that are stable and reproducible to improve the panel's skills and agreement also emerged.


Novel Intravenous Immunoglobulin Therapy for the Prevention and Treatment of Candida auris and Candida albicans Disseminated Candidiasis.
Disseminated candidiasis is a life-threatening disease and remains the most common bloodstream infection in hospitalized patients in the United States. Despite the availability of modern antifungal therapy, the crude mortality rate in the last decade has remained unacceptably high. Novel approaches are urgently needed to supplement or replace current antifungal therapies. In our study, we show that human intravenous immunoglobulin (IVIG) can provide protection against Candida auris and Candida albicans disseminated infections in A/J and C57BL/6 mouse models. The protective efficacy of IVIG is evidenced by the prolonged survival of mice with invasive candidiasis that were treated with human IVIG alone or in combination with amphotericin B. Our previous studies have led to the identification of a panel of Candida cell surface peptide and glycan epitopes, which are targeted by protective mouse monoclonal antibodies (mAbs) against invasive candidiasis. Of interest, the peptide- and glycan-specific IgGs could be detected in all 18 human IVIG samples. In particular, the specific IVIG lots with the highest protective peptide- and glycan-related IgGs provided the best protection. The combination of IVIG and amphotericin B had enhanced efficacy in protection compared to monotherapy against both multidrug-resistant (MDR) C. auris and C. albicans, with evidence of significantly prolonged survival and lower fungal burdens in targeted organs. This study provides evidence that the protective effects of IVIG were associated with the protective antibodies found in normal human donor sera against pathogenic Candida, and IVIG can be a novel therapy or adjunctive therapy with modern antifungal drugs against disseminated candidiasis. IMPORTANCE Since current antifungal treatments are ineffective in the immunocompromised population and no vaccine is available for humans, hope remains that antibody preparations selected for specific fungal antigens may make it possible to reduce the incidence and mortality of invasive candidiasis. Intravenous immunoglobulin (IVIG) has long been approved as a standard treatment for patients with immunodeficiency disorders who are also susceptible to fungal infection. IVIG has been widely used as prophylaxis or supplemental treatment for sepsis and septic shock; however, this form of adjunctive therapy lacks convincing data to establish its efficacy. In this study, 18 samples from commercial IVIG preparations were screened and evaluated by enzyme-linked immunosorbent assays (ELISAs); Candida peptide- and glycan-specific IgGs were detected with various titers among all IVIG lots. Importantly, significantly reduced organ fungal burdens and mortality were demonstrated in IVIG-treated mouse models of invasive candidiasis. IVIG lots with higher titers of Candida-specific IgGs provided better protection. These findings are important in (i) selecting Candida-specific IVIG therapy that may overcome several shortcomings of conventional IVIG therapy by targeting specific antigens responsible for disease pathogenesis, (ii) enhancing protective efficacy, and (iii) validating data from our previous studies and those of others showing that antibodies combined with conventional antifungal drugs provided enhanced resistance to disease. To our knowledge, this study is the first to demonstrate that human IVIG samples contain protective IgGs targeting Candida cell surface antigens and can be a novel therapy or adjunctive therapy with modern antifungal drugs against disseminated candidiasis.


Richardson-Lucy algorithm with total variation regularization for 3D confocal microscope deconvolution.
Confocal laser scanning microscopy is a powerful and popular technique for 3D imaging of biological specimens. Although confocal microscopy images are much sharper than standard epifluorescence ones, they are still degraded by residual out-of-focus light and by Poisson noise due to photon-limited detection. Several deconvolution methods have been proposed to reduce these degradations, including the Richardson-Lucy iterative algorithm, which computes maximum likelihood estimation adapted to Poisson statistics. As this algorithm tends to amplify noise, regularization constraints based on some prior knowledge on the data have to be applied to stabilize the solution. Here, we propose to combine the Richardson-Lucy algorithm with a regularization constraint based on Total Variation, which suppresses unstable oscillations while preserving object edges. We show on simulated and real images that this constraint improves the deconvolution results as compared with the unregularized Richardson-Lucy algorithm, both visually and quantitatively.


Type 2 diabetes and cardiac autonomic neuropathy screening using dynamic pupillometry.
To determine if changes in pupillary response are useful as a screening tool for diabetes and to assess whether pupillometry is associated with cardiac autonomic neuropathy. We conducted a cross-sectional study with participants drawn from two settings: a hospital and a community site. At the community site, individuals with newly diagnosed diabetes as well as a random sample of control individuals without diabetes, confirmed by oral glucose tolerance test, were selected. Participants underwent an LED light stimulus test and eight pupillometry variables were measured. Outcomes were diabetes, defined by oral glucose tolerance test, and cardiac autonomic dysfunction, determined by a positive readout on two of four diagnostic tests: heart rate response to the Valsalva manoeuvre; orthostatic hypotension; 30:15 ratio; and expiration-to-inspiration ratio. The area under the curve, best threshold, sensitivity and specificity of each pupillometry variable was calculated. Data from 384 people, 213 with diabetes, were analysed. The mean (±sd) age of the people with diabetes was 58.6 (±8.2) years and in the control subjects it was 56.1 (±8.6) years. When comparing individuals with and without diabetes, the amplitude of the pupil reaction had the highest area under the curve [0.69 (sensitivity: 78%; specificity: 55%)]. Cardiac autonomic neuropathy was present in 51 of the 138 people evaluated (37.0%; 95% CI 28.8-45.1). To diagnose cardiac autonomic neuropathy, two pupillometry variables had the highest area under the curve: baseline pupil radius [area under the curve: 0.71 (sensitivity: 51%; specificity: 84%)], and amplitude of the pupil reaction [area under the curve: 0.70 (sensitivity: 82%; specificity: 55%)]. Pupillometry is an inexpensive technique to screen for diabetes and cardiac autonomic neuropathy, but it does not have sufficient accuracy for clinical use as a screening tool.


Lifetime risks of cardiovascular disease.
The lifetime risks of cardiovascular disease have not been reported across the age spectrum in black adults and white adults. We conducted a meta-analysis at the individual level using data from 18 cohort studies involving a total of 257,384 black men and women and white men and women whose risk factors for cardiovascular disease were measured at the ages of 45, 55, 65, and 75 years. Blood pressure, cholesterol level, smoking status, and diabetes status were used to stratify participants according to risk factors into five mutually exclusive categories. The remaining lifetime risks of cardiovascular events were estimated for participants in each category at each age, with death free of cardiovascular disease treated as a competing event. We observed marked differences in the lifetime risks of cardiovascular disease across risk-factor strata. Among participants who were 55 years of age, those with an optimal risk-factor profile (total cholesterol level, <180 mg per deciliter [4.7 mmol per liter]; blood pressure, <120 mm Hg systolic and 80 mm Hg diastolic; nonsmoking status; and nondiabetic status) had substantially lower risks of death from cardiovascular disease through the age of 80 years than participants with two or more major risk factors (4.7% vs. 29.6% among men, 6.4% vs. 20.5% among women). Those with an optimal risk-factor profile also had lower lifetime risks of fatal coronary heart disease or nonfatal myocardial infarction (3.6% vs. 37.5% among men, <1% vs. 18.3% among women) and fatal or nonfatal stroke (2.3% vs. 8.3% among men, 5.3% vs. 10.7% among women). Similar trends within risk-factor strata were observed among blacks and whites and across diverse birth cohorts. Differences in risk-factor burden translate into marked differences in the lifetime risk of cardiovascular disease, and these differences are consistent across race and birth cohorts. (Funded by the National Heart, Lung, and Blood Institute.).


Monocyte metabolic reprogramming promotes pro-inflammatory activity and Staphylococcus aureus biofilm clearance.
Biofilm-associated prosthetic joint infections (PJIs) cause significant morbidity due to their recalcitrance to immune-mediated clearance and antibiotics, with Staphylococcus aureus (S. aureus) among the most prevalent pathogens. We previously demonstrated that S. aureus biofilm-associated monocytes are polarized to an anti-inflammatory phenotype and the adoptive transfer of pro-inflammatory macrophages attenuated biofilm burden, highlighting the critical role of monocyte/macrophage inflammatory status in dictating biofilm persistence. The inflammatory properties of leukocytes are linked to their metabolic state, and here we demonstrate that biofilm-associated monocytes exhibit a metabolic bias favoring oxidative phosphorylation (OxPhos) and less aerobic glycolysis to facilitate their anti-inflammatory activity and biofilm persistence. To shift monocyte metabolism in vivo and reprogram cells to a pro-inflammatory state, a nanoparticle approach was utilized to deliver the OxPhos inhibitor oligomycin to monocytes. Using a mouse model of S. aureus PJI, oligomycin nanoparticles were preferentially internalized by monocytes, which significantly reduced S. aureus biofilm burden by altering metabolism and promoting the pro-inflammatory properties of infiltrating monocytes as revealed by metabolomics and RT-qPCR, respectively. Injection of oligomycin alone had no effect on monocyte metabolism or biofilm burden, establishing that intracellular delivery of oligomycin is required to reprogram monocyte metabolic activity and that oligomycin lacks antibacterial activity against S. aureus biofilms. Remarkably, monocyte metabolic reprogramming with oligomycin nanoparticles was effective at clearing established biofilms in combination with systemic antibiotics. These findings suggest that metabolic reprogramming of biofilm-associated monocytes may represent a novel therapeutic approach for PJI.


Outcomes of drug and alcohol treatment programs among American Indians in California.
We examined differences in substance abuse treatment outcomes between American Indians and their non-American Indian counterparts in California, during 2000 to 2002. A total of 368 American Indians and a matched sample of 368 non-American Indians from 39 substance abuse treatment programs in 13 California counties were assessed at multiple time points. Records on arrests, driving while under the influence of alcohol or drugs, and mental health care were obtained 1 year before and 1 year after treatment entry. Differences in pretreatment characteristics, services received, treatment satisfaction, treatment completion and retention, and outcomes were examined. Pretreatment problems were similarly severe among American Indians and non-American Indians. About half in both groups either completed treatment or stayed in treatment more than 90 days; American Indians in residential care had significantly shorter treatment retention. American Indians received fewer individual sessions and out-of-program services, especially for alcohol abuse, but were nevertheless generally satisfied with their treatment. Both groups improved after treatment, with American Indians demonstrating greater reductions in arrests than non-American Indians. American Indians benefit from substance abuse treatment programs, although the type and intensity of services offered could be improved.


Mind and body therapy for fibromyalgia.
Mind-body interventions are based on the holistic principle that mind, body and behaviour are all interconnected. Mind-body interventions incorporate strategies that are thought to improve psychological and physical well-being, aim to allow patients to take an active role in their treatment, and promote people's ability to cope. Mind-body interventions are widely used by people with fibromyalgia to help manage their symptoms and improve well-being. Examples of mind-body therapies include psychological therapies, biofeedback, mindfulness, movement therapies and relaxation strategies. To review the benefits and harms of mind-body therapies in comparison to standard care and attention placebo control groups for adults with fibromyalgia, post-intervention and at three and six month follow-up. Electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), EMBASE (Ovid), PsycINFO (Ovid), AMED (EBSCO) and CINAHL (Ovid) were conducted up to 30 October 2013. Searches of reference lists were conducted and authors in the field were contacted to identify additional relevant articles. All relevant randomised controlled trials (RCTs) of mind-body interventions for adults with fibromyalgia were included. Two authors independently selected studies, extracted the data and assessed trials for low, unclear or high risk of bias. Any discrepancy was resolved through discussion and consensus. Continuous outcomes were analysed using mean difference (MD) where the same outcome measure and scoring method was used and standardised mean difference (SMD) where different outcome measures were used. For binary data standard estimation of the risk ratio (RR) and its 95% confidence interval (CI) was used. Seventy-four papers describing 61 trials were identified, with 4234 predominantly female participants. The nature of fibromyalgia varied from mild to severe across the study populations. Twenty-six studies were classified as having a low risk of bias for all domains assessed. The findings of mind-body therapies compared with usual care were prioritised.There is low quality evidence that in comparison to usual care controls psychological therapies have favourable effects on physical functioning (SMD -0.4, 95% CI -0.6 to -0.3, -7.5% absolute change, 2 point shift on a 0 to 100 scale), pain (SMD -0.3, 95% CI -0.5 to -0.2, -3.5% absolute change, 2 point shift on a 0 to 100 scale) and mood (SMD -0.5, 95% CI -0.6 to -0.3, -4.8% absolute change, 3 point shift on a 20 to 80 scale). There is very low quality evidence of more withdrawals in the psychological therapy group in comparison to usual care controls (RR 1.38, 95% CI 1.12 to 1.69, 6% absolute risk difference). There is lack of evidence of a difference between the number of adverse events in the psychological therapy and control groups (RR 0.38, 95% CI 0.06 to 2.50, 4% absolute risk difference).There was very low quality evidence that biofeedback in comparison to usual care controls had an effect on physical functioning (SMD -0.1, 95% CI -0.4 to 0.3, -1.2% absolute change, 1 point shift on a 0 to 100 scale), pain (SMD -2.6, 95% CI -91.3 to 86.1, -2.6% absolute change) and mood (SMD 0.1, 95% CI -0.3 to 0.5, 1.9% absolute change, less than 1 point shift on a 0 to 90 scale) post-intervention. In view of the quality of evidence we cannot be certain that biofeedback has a little or no effect on these outcomes. There was very low quality evidence that biofeedback led to more withdrawals from the study (RR 4.08, 95% CI 1.43 to 11.62, 20% absolute risk difference). No adverse events were reported.There was no advantage observed for mindfulness in comparison to usual care for physical functioning (SMD -0.3, 95% CI -0.6 to 0.1, -4.8% absolute change, 4 point shift on a scale 0 to 100), pain (SMD -0.1, CI -0.4 to 0.3, -1.3% absolute change, less than 1 point shift on a 0 to 10 scale), mood (SMD -0.2, 95% CI -0.5 to 0.0, -3.7% absolute change, 2 point shift on a 20 to 80 scale) or withdrawals (RR 1.07, 95% CI 0.67 to 1.72, 2% absolute risk difference) between the two groups post-intervention. However, the quality of the evidence was very low for pain and moderate for mood and number of withdrawals. No studies reported any adverse events.Very low quality evidence revealed that movement therapies in comparison to usual care controls improved pain (MD -2.3, CI -4.2 to -0.4, -23% absolute change) and mood (MD -9.8, 95% CI -18.5 to -1.2, -16.4% absolute change) post-intervention. There was no advantage for physical functioning (SMD -0.2, 95% CI -0.5 to 0.2, -3.4% absolute change, 2 point shift on a 0 to 100 scale), participant withdrawals (RR 1.95, 95% CI 1.13 to 3.38, 11% absolute difference) or adverse events (RR 4.62, 95% CI 0.23 to 93.92, 4% absolute risk difference) between the two groups, however rare adverse events may include worsening of pain.Low quality evidence revealed that relaxation based therapies in comparison to usual care controls showed an advantage for physical functioning (MD -8.3, 95% CI -10.1 to -6.5, -10.4% absolute change) and pain (SMD -1.0, 95% CI -1.6 to -0.5, -3.5% absolute change, 2 point shift on a 0 to 78 scale) but not for mood (SMD -4.4, CI -14.5 to 5.6, -7.4% absolute change) post-intervention. There was no difference between the groups for number of withdrawals (RR 4.40, 95% CI 0.59 to 33.07, 31% absolute risk difference) and no adverse events were reported. Psychological interventions therapies may be effective in improving physical functioning, pain and low mood for adults with fibromyalgia in comparison to usual care controls but the quality of the evidence is low. Further research on the outcomes of therapies is needed to determine if positive effects identified post-intervention are sustained. The effectiveness of biofeedback, mindfulness, movement therapies and relaxation based therapies remains unclear as the quality of the evidence was very low or low. The small number of trials and inconsistency in the use of outcome measures across the trials restricted the analysis.


Longitudinal molecular trajectories of diffuse glioma in adults.
The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.


Patients who discontinue day hospitalisation - an analysis.
Treatment discontinuation has been noted as a problem with psychiatric patients. This would equally be the case when long term measures for the rehabilitation of the mentally ill are concerned. In this study of patients who discontinued psychiatric day hospitalisation, it was found that over 90 % had dropped out in the first month of treatment. Schizophrenics, Manic Depressives, Epileptics and others contributed to the largest extent to this group whereas Mental Retardates discontinued less often. The discontinued patients either had better prognostic factors and maintained well subsequently (usually Manic Depressives) or relapsed soon after (usually Schizophrenics). The implications of the findings are discussed whilst comparing the discontinuers with those continuing day hospitalisation.


[Prevalence of thrombocytopenia in HIV infected children].
Thrombocytopenia is a common hematologic finding in patients infected with the human immunodeficiency virus. Multiple mechanisms may contribute to the development of chronic thrombocytopenia as immune-mediated platelet destruction, enhanced platelet splenic sequestration and impaired platelet production. Acute thrombocytopenia is frequently associated with coexisting disorders. In this study, the prevalence of thrombocytopenia was evaluated in a cohort of HIV infected children analyzing the clinical features and the association with the immunological and virological status of the disease in a 14 year-follow-up period. Thrombocytopenia prevalence was of 8.5% (29 out 339 children evaluated). Chronic and acute thrombocytopenia was observed in 22 and 7 children respectively. The percentages of CD4+ T cells were variable and not related with the presence of thrombocytopenia. Thrombocytopenic patients showed viral load levels significantly increased; being the thrombocytopenia the initial clinical manifestation of HIV infection in 10 out 29 children. Mild chronic thrombocytopenia bleeding found in 23% of children evaluated was not correlated with the immunologic status of the disease. In contrast, the severity of acute thrombocytopenia depended on the evolution of associated clinical conditions. Constant viral activity and failure in the use of antiretroviral agents might induce the development of thrombocytopenia in HIV-infected children.


Pindolol decreases prolactin and growth hormone responses to intravenous L-tryptophan.
The effects of pindolol on the prolactin (PRL) and growth hormone (GH) responses to intravenous tryptophan (LTP) were studied in eight healthy male volunteers. Pindolol pretreatment (40 mg over 48 h) markedly attenuated the GH response to LTP and modestly, but significantly, reduced the LTP-induced increase in plasma PRL. The disposition of LTP following infusion was not altered by pindolol. While the data are consistent with 5-HT1A receptor mediation of PRL and GH responses to LTP, the intrinsic sympathomimetic actions of pindolol might also be involved in the attenuation of the endocrine responses to LTP.


Ventriculoperitoneal shunt surgery and shunt infections in children with non-tumour hydrocephalus at the Kenyatta National Hospital, Nairobi.
To study infections complicating ventriculoperitoneal (VP) shunt surgery in children with non-tumour hydrocephalus at the Kenyatta National Hospital, Nairobi. A retrospective survey. Kenyatta National Hospital, Nairobi between January 1982 and December 1991. Three hundred and forty five patients who underwent V-P shunt placement for non-tumour hydrocephalus. Three hundred and forty five patients underwent V-P shunt placement for non-tumour hydrocephalus. There were 107 infection episodes involving 85 patients. The ages of these patients ranged from three months to 12 years. Most of the patients had congenital hydrocephalus. The infection rate was high (24.6%) although comparable to infection rates reported for clean surgery in the hospital. Fever, septic wounds and features of shunt malfunction were the main presenting features. Bacteriological studies confirmed Staphylococcus aureus and coagulase negative staphylococci as the two most commonly isolated micro-organisms. This study emphasises need to reduce infection rate in ventriculoperitoneal shunt surgery at the Kenyatta National Hospital. Definitive surgical treatment for hydrocephalus was in most cases delayed and this problem was also observed during revision of infected shunts. Late presentation was often due to ignorance and the fact that many patients went for traditional forms of treatment first before going to hospital.


Systematic Review of Prevalence, Risk Factors, and Risk for Metachronous Advanced Neoplasia in Patients With Young-Onset Colorectal Adenoma.
The incidence and mortality of early-onset colorectal cancer (CRC) are increasing. Adenoma detection, removal, and subsequent endoscopic surveillance might modify risk of CRC diagnosed before age 50 years (early-onset CRC). We conducted a systematic review of young-onset adenoma (YOA) prevalence, associated risk factors, and rate of metachronous advanced neoplasia after YOA diagnosis. We performed a systematic search of multiple electronic databases through February 12, 2019 and identified studies of individuals 18 to 49 years old that reported prevalence of adenoma, risk factors for adenoma, and/or risk for metachronous advanced neoplasia. Summary estimates were derived using random effects meta-analysis, when feasible. The pooled overall prevalence of YOA was 9.0% (95% CI, 7.1%-11.4%), based on 24 studies comprising 23,142 individuals. On subgroup analysis, the pooled prevalence of YOA from autopsy studies was 3.9% (95% CI, 1.9%-7.6%), whereas the prevalence from colonoscopy studies was 10.7% (95% CI, 8.5%-13.5). Only advancing age was identified as a consistent risk factor for YOA, based on 4 studies comprising 78,880 individuals. Pooled rate of metachronous advanced neoplasia after baseline YOA diagnosis was 6.0% (95% CI, 4.1%-8.6%), based on 3 studies comprising 1493 individuals undergoing follow-up colonoscopy, with only 1 CRC case reported. Overall, few studies reported metachronous advanced neoplasia and no studies evaluated whether routine surveillance colonoscopy decreases risk of CRC. In a systematic review, we estimated the prevalence of YOA to be 9% and to increase with age. Risk for metachronous advanced neoplasia after YOA diagnosis is estimated to be 6%. More research is needed to understand the prevalence, risk factors, and risk of CRC associated with YOA.


Tie1 deletion inhibits tumor growth and improves angiopoietin antagonist therapy.
The endothelial Tie1 receptor is ligand-less, but interacts with the Tie2 receptor for angiopoietins (Angpt). Angpt2 is expressed in tumor blood vessels, and its blockade inhibits tumor angiogenesis. Here we found that Tie1 deletion from the endothelium of adult mice inhibits tumor angiogenesis and growth by decreasing endothelial cell survival in tumor vessels, without affecting normal vasculature. Treatment with VEGF or VEGFR-2 blocking antibodies similarly reduced tumor angiogenesis and growth; however, no additive inhibition was obtained by targeting both Tie1 and VEGF/VEGFR-2. In contrast, treatment of Tie1-deficient mice with a soluble form of the extracellular domain of Tie2, which blocks Angpt activity, resulted in additive inhibition of tumor growth. Notably, Tie1 deletion decreased sprouting angiogenesis and increased Notch pathway activity in the postnatal retinal vasculature, while pharmacological Notch suppression in the absence of Tie1 promoted retinal hypervasularization. Moreover, substantial additive inhibition of the retinal vascular front migration was observed when Angpt2 blocking antibodies were administered to Tie1-deficient pups. Thus, Tie1 regulates tumor angiogenesis, postnatal sprouting angiogenesis, and endothelial cell survival, which are controlled by VEGF, Angpt, and Notch signals. Our results suggest that targeting Tie1 in combination with Angpt/Tie2 has the potential to improve antiangiogenic therapy.


Salvage of instrumental lumbar fusions complicated by surgical wound infection.
This study retrospectively reviewed instrumented lumbar fusions complicated by surgical wound infection and managed by a protocol including antibiotic impregnated beads. To evaluate the potential for an acceptable clinical outcome in cases of instrumented lumbar fusion complicated by wound infection. Initial studies of pedicle screw instrumentation suggested an increased infection rate versus noninstrumented fusion. The presence of a metallic implant also complicates wound management. Eight hundred fifty-eight instrumented fusions were reviewed with 22 (2.6%) deep wound infections identified. Analysis included preoperative risk factors, surgical procedure, postoperative course, and clinical outcome. Nineteen patients (mean age, 55 years) were reviewed at a minimum of 1 year after surgery. Sixteen (83%) reported significant preoperative health problems. Forty-seven percent of the patients had three- and four-level fusions. Mean operative time was 342 minutes. Mean estimated blood loss was 1620 mL. Infection was diagnosed at an average of 16 days after surgery with wound drainage as the most common presenting feature. Patients underwent between two and 10 (mean, 4.7) irrigation procedures. Seven patients had other significant noninfectious complications. At follow-up evaluation, no patient had recurrence of infection. By comparison to preoperative symptoms, 15 patients were improved, three were unchanged, and one deteriorated. Fusion was apparently solid in 14 patients, probable in four patients, and nonunion occurred in one patient. Although wound infection is a significant complication, this study suggests that aggressive surgical management can result in preservation of an adequate fusion rate and maintenance of an acceptable postoperative outcome.


Essential functions of primate frontopolar cortex in cognition.
Brodmann's area 10 is one of the largest cytoarchitecturally defined regions in the human cerebral cortex, occupying the most anterior part of the prefrontal cortex [frontopolar cortex (FPC)], and is believed to sit atop a prefrontal hierarchy. The crucial contributions that the FPC makes to cognition are unknown. Rodents do not possess such [corrected] a FPC, but primates do, and we report here the behavioral effects of circumscribed FPC lesions in nonhuman primates. FPC lesions selectively impaired rapid one-trial learning about unfamiliar objects and unfamiliar objects-in-scenes, and also impaired rapid learning about novel abstract rules. Object recognition memory, shifting between established abstract behavioral rules, and the simultaneous application of two distinct rules were unaffected by the FPC lesion. The distinctive pattern of impaired and spared performance across these seven behavioral tasks reveals that the FPC mediates exploration and rapid learning about the relative value of novel behavioral options, and shows that the crucial contributions made by the FPC to cognition differ markedly from the contributions of other primate prefrontal regions.


The value of induction chemotherapy for survival in patients with non-small cell lung cancer treated with radiotherapy.
The aim of the present study was to retrospectively investigate the impact of induction chemotherapy on treatment outcome in patients treated with curatively intended radiotherapy for non-small cell lung cancer (NSCLC). Patients with a diagnosed NSCLC that have been subjected to curatively intended irradiation (≥50 Gy) and treated in an oncology department in Sweden during the years 1990-2000 were included in the study. Operated patients and patients having received concomitant chemotherapy were excluded. The included patients were localised by a manual search of all the oncology departments' medical records and radiation charts. Patients treated with induction chemotherapy (n=79) had a significantly better overall survival compared with patients treated with radiotherapy alone (p=0.0097) in a univariate Cox regression analysis. A platinum/taxane combination produced the greatest survival benefit; hazard ratio=0.49 (95% confidence interval=0.31 to 0.75). We found that patients treated with induction chemotherapy in addition to radiotherapy for NSCLC have a better overall survival than patients treated with radiotherapy alone and that the best results are achieved using a platinum/taxane combination.


Developing quality assurance practices and measures for implementing and sustaining the Transition to Independence Process (TIP) model.
For interventions, like the Transition to Independence Process (TIP) Model, to be implemented effectively, efficient and accessible quality assurance tools are needed. The purpose of this article is to describe the process of developing an online staff self-report quality assurance tool for a key process in the TIP Model: the TIP Solution Review (TSR) and to provide data on the acceptability and perceived impact of both the measure and the TSR process. We used an iterative approach to pilot test and seek feedback from multidisciplinary teams trained in TIP. Initially, a team of 7 completed the online TSR Quality Assurance Scale, followed by a focus group. The tool was refined and administered to three additional TIP Model trained teams (n = 23 practitioners) in 3 different states. Team supervisors (n = 3) were then interviewed about their perceptions of the TSR process and the new tool. Thematic analyses were conducted on open-ended survey questions and interview and focus group responses. Findings suggest the new tool and TSR processes are acceptable and feasible. Staff feedback provided for further TSR process refinement. Conclusions and Implications for Clinical Practice: The process of developing, refining and evaluating a tool to capture the TSR (an important TIP quality improvement process) led to increased TSR process specification. Findings have implications for systematically guiding how intervention developers structure supervision and preparation of intervention planning and delivery. Future research will more rigorously test the tool to establish its empirical properties and effectiveness in assessing adherence to TSR procedures. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


The OMERACT Ultrasound Group: status of current activities and research directions.
Ultrasound (US) is a relatively new imaging modality in rheumatology that offers great potential as a diagnostic and management tool. In 2004, an OMERACT Ultrasound Special Interest Group was formed to address the metric qualities of US as a potential outcome measure. A preliminary systematic review highlighted the deficiencies in the literature, particularly with regard to the reliability of interpreting and acquiring images; as a consequence, a number of exercises were proposed to address these issues. This report describes a series of iterative studies that have resulted in improved intra- and inter-reader reliability for detecting and scoring synovitis from both static and real-time images of the hand joints of patients with rheumatoid arthritis. The reliability of acquiring images was also enhanced using standardized positions. Future studies will assess the value of US in clinical trials.


Gonadal steroids modulate the growth-associated protein GAP-43 (neuromodulin) mRNA in postnatal rat brain.
Gonadal steroid hormone action during early postnatal life determines the growth and connectivity of certain neuronal populations in the hypothalamus. The results of recent studies indicate that steroid hormones modulate the growth-associated protein GAP-43 mRNA in the adult rodent hypothalamus. Since GAP-43 is concentrated in axonal growth cones and has been implicated in axonal elongation and synaptogenesis, the present study investigated the effect of various gonadal hormonal conditions on GAP-43 mRNA levels in postnatal rat brain. On postnatal day 1, male rats were castrated or sham-operated and injected with sesame oil. Additional intact female rats were also injected with oil, while a group of female pups were injected with testosterone propionate. On postnatal day 6, brains were frozen and 16-microns cryostat sections processed and hybridized with a 35S-labeled antisense riboprobe complimentary to GAP-43 mRNA. Slide-mounted sections were stringently washed, apposed to X-ray film and then dipped in liquid emulsion. Evaluation of slide and film autoradiograms revealed an extensive presence of GAP-43 mRNA in the medial preoptic nucleus, bed nucleus of the stria terminalis and cerebral cortex, while the intensity of hybridization signal in other brain regions including the striatum was low. Quantitative assessment of GAP-43 mRNA in the medial preoptic area revealed that the level of GAP-43 mRNA was highest in the sham-operated male, attenuated after male castration, low in the intact female and markedly augmented in the testosterone-treated female. The pattern of change in the bed nucleus of the stria terminalis and laminae II and III of the frontal cortex was similar to that observed in the preoptic area. The changes in hybridization signal were positively correlated with changes in serum testosterone levels as determined by RIA. The results of these studies indicate that GAP-43 mRNA levels in the medial preoptic area, bed nucleus of the stria terminalis and cerebral cortex are sexually dimorphic and modulated by changes in gonadal steroid hormone levels. The results further suggest that the differential regulation of GAP-43 mRNA by sex steroids in the male and female postnatal brain may influence the phenotype of forebrain neuronal circuitry and thereby determine the phenotype of adult neuronal function.


A Critical Review of Negative Affect and the Application of CBT for PTSD.
Forms of cognitive and behavioral therapies (CBTs), including prolonged exposure and cognitive processing therapy, have been empirically validated as efficacious treatments for posttraumatic stress disorder (PTSD). However, the assumption that PTSD develops from dysregulated fear circuitry possesses limitations that detract from the potential efficacy of CBT approaches. An analysis of these limitations may provide insight into improvements to the CBT approach to PTSD, beginning with an examination of negative affect as an essential component to the conceptualization of PTSD and a barrier to the implementation of CBT for PTSD. As such, the literature regarding the impact of negative affect on aspects of cognition (i.e., attention, processing, memory, and emotion regulation) necessary for the successful application of CBT was systematically reviewed. Several literature databases were explored (e.g., PsychINFO and PubMed), resulting in 25 articles that met criteria for inclusion. Results of the review indicated that high negative affect generally disrupts cognitive processes, resulting in a narrowed focus on stimuli of a negative valence, increased rumination of negative autobiographical memories, inflexible preservation of initial information, difficulty considering counterfactuals, reliance on emotional reasoning, and misinterpretation of neutral or ambiguous events as negative, among others. With the aim to improve treatment efficacy of CBT for PTSD, suggestions to incorporate negative affect into research and clinical contexts are discussed.


The impact of age on the diagnosis and therapy of myelodysplastic syndromes: results from a retrospective multicenter analysis in Germany.
Myelodysplastic syndromes (MDS) is a disease of predominantly elderly patients with a median age of >70 yrs. However, data on the management of these patients outside of clinical trials are scarce. To assess patterns of MDS management in routine patient care with regard to the impact of age, we conducted a multicenter, representative survey of MDS health services in Germany. Data of 269 patients treated at 57 institutions were collected from preplanned chart reviews and were analyzed retrospectively. At diagnosis, median age was 70 yrs, 50% of patients had a Karnofsky index (KI) of 90%, and 12% had a comorbidity index ≥ 3 according to Sorror et al. (J Clin Oncol, 25, 2007, 4246). Cytogenetic analysis and International Prognostic Scoring System (IPSS) risk assessment were performed significantly less frequently in patients >75 yrs than in patients ≤ 75 yrs (P < 0.001 and P = 0.019). In bivariate analysis, potential predictors for performing IPSS risk assessment were age ≤ 75 yrs (y/n, P = 0.019), diagnosis at a university hospital (y/n, P = 0.001), WHO subtypes RCUD (y/n, P = 0.028), RARS (y/n, P = 0.002), or RAEB II (y/n, P = 0.037). Patients ≤ 75 yrs were more likely to receive active therapies (i.e., chemotherapy, immunomodulatory therapy, or epigenetic therapy) than patients >75 yrs (51% vs. 37%, P = 0.007). In bivariate analysis age ≤ 75 yrs (y/n, P = 0.007) was a significant predictor for active treatment with no correlation with the other predictors [IPSS risk score int-2 or high (y/n, P = 0.005), WHO subtypes RCUD (y/n, P < 0.001), RCMD (y/n, P = 0.003), RAEB II (y/n, P < 0.001), or CMML I (y/n, P = 0.020)]. This survey confirms the impact of age on the thoroughness of MDS diagnosis and the decision for active treatment. As cytogenetic analysis and risk assessment are essential for the choice of appropriate therapy, elderly patients in particular may not be receiving adequate treatment.


Transcriptional regulation of the ABCC6 gene and the background of impaired function of missense disease-causing mutations.
The human ATP-binding cassette family C member 6 (ABCC6) gene encodes an ABC transporter protein expressed primarily in the liver and to a lesser extent in the kidneys and the intestines. We review here the mechanisms of this restricted tissue-specific expression and the role of hepatocyte nuclear factor 4α which is responsible for the expression pattern. Detailed analyses uncovered further regulators of the expression of the gene pointing to an intronic primate-specific regulator region, an activator of the expression of the gene by binding CCAAT/enhancer-binding protein beta, which interacts with other proteins acting in the proximal promoter. This regulatory network is affected by various environmental stimuli including oxidative stress and the extracellular signal-regulated protein kinases 1 and 2 pathway. We also review here the structural and functional consequences of disease-causing missense mutations of ABCC6. A significant clustering of the missense disease-causing mutations was found at the domain-domain interfaces. This clustering means that the domain contacts are much less permissive to amino acid replacements than the rest of the protein. We summarize the experimental methods resulting in the identification of mutants with preserved transport activity but failure in intracellular targeting. These mutants are candidates for functional rescue by chemical chaperons. The results of such research can provide the basis of future allele-specific therapy of ABCC6-mediated disorders like pseudoxanthoma elasticum or the generalized arterial calcification in infancy.


A review of Neuropharmacology Effects of Nigella sativa and Its Main Component, Thymoquinone.
Neuropharmacology is the scientific study of drug effect on nervous system. In the last few years, different natural plants and their active constituents have been used in neurological therapy. The availability, lower price, and less toxic effects of herbal medicines compared with synthetic agents make them as simple and excellent choice in the treatment of nervous diseases. Nigella sativa, which belongs to the botanical family of Ranunculaceae, is a widely used medicinal plant all over the world. In traditional and modern medicines several beneficial properties have been attributed to N. sativa and its main component, thymoquinone (TQ). In this review, various studies in scientific databases regarding the neuropharmacological aspects of N. sativa and TQ have been introduced. Results of these studies showed that N. sativa and TQ have several properties including anticonvulsant, antidepressant, anxiolytic, anti-ischemic, analgesic, antipsychotic, and memory enhancer. Furthermore, its protective effects against neurodegenerative diseases such as Alzheimer, Parkinson and multiple sclerosis have been discussed. Although there are many studies indicating the beneficial actions of this plant in nervous system, the number of research projects relating to the human reports is rare. Copyright © 2016 John Wiley & Sons, Ltd.


Prenatal low-dose bisphenol A enhances behavioral responses induced by a predator odor.
Bisphenol A (BPA) is an environmental endocrine disrupter (EED). Previous studies by our group showed that pre- and postnatal administration of low-level BPA induced depression-like behavior in rats. In this study, we evaluated the effects of prenatal BPA on behavioral responses to a predator odor by using a novel cross-form apparatus consisting of 4 plastic chambers. On the first day, nothing was placed into the chambers (Session 1). On the second day, a predator odor (fox odor) was located in separate chambers at 2 opposite corners of the apparatus (Session 2). Pregnant Wistar rats were exposed to low-dose BPA (less than the reference dose) during the 7 days just before birth, and the offspring of the treated rats were evaluated as adults. The locomotor activity and avoidance response of each rat on both test days were compared. The control and BPA groups showed reduced locomotor activity in the presence of the predator odor, but the odor-avoidance response was significant only in the BPA rats. The BPA-exposed rats were obviously sensitive to the predator odor. These results suggest that prenatal BPA exposure has an amplifying effect on avoidance responses to predator odor stress.


Radiation therapy as a component of high-dose salvage strategies in Hodgkin's disease.
The expected event-free survival for patients undergoing high-dose salvage therapy for Hodgkin's disease is 40%-60%. Three-quarters of these patients will relapse in prior sites of disease. Radiation therapy is a very effective local-regional modality in Hodgkin's disease. It is possible that the judicious use of radiation can improve the event-free survival of high-dose salvage programs. Retrospective analysis supports this concept, but the rationale should be incorporated and tested in prospective clinical trials.


Subclinical Atherosclerosis, Statin Eligibility, and Outcomes in African American Individuals: The Jackson Heart Study.
Modern prevention guidelines substantially increase the number of individuals who are eligible for treatment with statins. Efforts to refine statin eligibility via coronary calcification have been studied in white populations but not, to our knowledge, in large African American populations. To compare the relative accuracy of US Preventive Services Task Force (USPSTF) and American College of Cardiology/American Heart Association (ACC/AHA) recommendations in identifying African American individuals with subclinical and clinical atherosclerotic cardiovascular disease (ASCVD). In this prospective, community-based study, 2812 African American individuals aged 40 to 75 years without prevalent ASCVD underwent assessment of ASCVD risk. Of these, 1743 participants completed computed tomography. Nonzero coronary artery calcium (CAC) score, abdominal aortic calcium score, and incident ASCVD (ie, myocardial infarction, ischemic stroke, or fatal coronary heart disease). Of the 2812 included participants, the mean (SD) age at baseline was 55.4 (9.4) years, and 1837 (65.3%) were female. The USPSTF guidelines captured 404 of 732 African American individuals (55.2%) with a CAC score greater than 0; the ACC/AHA guidelines identified 507 individuals (69.3%) (risk difference, 14.1%; 95% CI, 11.2-17.0; P < .001). Statin recommendation under both guidelines was associated with a CAC score greater than 0 (odds ratio, 5.1; 95% CI, 4.1-6.3; P < .001). While individuals indicated for statins under both guidelines experienced 9.6 cardiovascular events per 1000 patient-years, those indicated under only ACC/AHA guidelines were at low to intermediate risk (4.1 events per 1000 patient-years). Among individuals who were statin eligible by ACC/AHA guidelines, the 10-year ASCVD incidence per 1000 person-years was 8.1 (95% CI, 5.9-11.1) in the presence of CAC and 3.1 (95% CI, 1.6-5.9) without CAC (P = .02). While statin-eligible individuals by USPSTF guidelines did not have a significantly higher 10-year ASCVD event rate in the presence of CAC, African American individuals not eligible for statins by USPSTF guidelines had a higher ASCVD event rate in the presence of CAC (2.8 per 1000 person-years; 95% CI, 1.5-5.4) relative to without CAC (0.8 per 1000 person-years; 95%, CI 0.3-1.7) (P = .03). The USPSTF guidelines focus treatment recommendations on 38% of high-risk African American individuals at the expense of not recommending treatment in nearly 25% of African American individuals eligible for statins by ACC/AHA guidelines with vascular calcification and at low to intermediate ASCVD risk.


A Framework for Including Family Health Spillovers in Economic Evaluation.
Health care interventions may affect the health of patients' family networks. It has been suggested that these "health spillovers" should be included in economic evaluation, but there is not a systematic method for doing this. In this article, we develop a framework for including health spillovers in economic evaluation. We focus on extra-welfarist economic evaluations where the objective is to maximize health benefits from a health care budget (the "health care perspective"). Our framework involves adapting the conventional cost-effectiveness decision rule to include 2 multiplier effects to internalize the spillover effects. These multiplier effects express the ratio of total health effects (for patients and their family networks) to patient health effects. One multiplier effect is specified for health benefit generated from providing a new intervention, one for health benefit displaced by funding this intervention. We show that using multiplier effects to internalize health spillovers could change the optimal funding decisions and generate additional health benefits to society.


Audio computer-assisted self-interviewing in reproductive health research: reliability assessment among women in Harare, Zimbabwe.
Research on the measurement of HIV risk demonstrates that interview mode can affect reporting; however, few studies have applied these findings to assessments of hormonal contraceptive use. This paper examines how audio computer-assisted self-interviewing (ACASI) influenced reports of hormonal contraceptive use and pregnancy among Zimbabwean women. Using a prospective, randomized, cross-over design, we compared self-reports obtained with ACASI and face-to-face (FTF) interview among 655 women enrolled in a prospective study on hormonal contraceptive use and HIV acquisition. In addition, self-report data were compared to those collected during clinical exams. Compared to FTF interviews, reports of hormonal contraceptive use were lower in ACASI [odds ratio (OR)=0.6; 95% confidence interval (95% CI)=0.5-0.6], and reports of pregnancy were higher (OR=1.5; 95% CI=1.1-1.9). Both modes of self-report differed from records on contraceptive method disbursement. Although ACASI yielded higher reports of several reproductive health behaviors, discrepancies between self-reports and clinical data on method disbursement highlight persistent measurement challenges.


The short form 36 health status questionnaire: clues from the Oxford region's normative data about its usefulness in measuring health gain in population surveys.
To determine the potential of the short form 36 health status questionnaire (SF-36) for indicating changes in the health status of a general population by examining the recently published normative data. The sensitivity of the SF-36 was tested through hypothesising two dramatic changes in health status whereby (i) the scores of people in social class V are improved to the level of social class I, and (ii) the scores of men and women aged 55 to 64 are altered to the level of current 45 to 54 year olds. The size of the effect measured by the SF-36 was considered. Small to moderate effects were evident when SF-36 mean scores for social class V were increased to the level of social class I, and primarily negligible effects were apparent on all domains but physical function for the postulated "10 years of age" improvement. The SF-36 may be a useful measure for detecting changes in health status in homogenous treatment groups, but the variation in responses in a general population make it an inadequate tool for assessing the diffuse impact of health interventions directed at the whole community.


Sonographic diagnosis of colitis in children.
To assist the radiologist in differentiating the colitis in children, this review proposes a systematic US approach to the disease, presents the US aspect of the normal colon and describes three distinctive US patterns reflecting the intramural extension of the histopathological changes. Each pattern corresponds to one or several diseases producing alterations in the same layer(s). Stratified thickening suggests an inflammatory mucosal process resulting from infection (as in advanced appendicitis or in infectious colitis) or to inflammation (as in IBD). Nonstratified thickening with loss of the haustral folds reflects a marked submucosal infiltrate. Color Doppler is required to distinguish between an inflammatory disease (as advanced CD or neutropenic colitis) and an ischemic colitis (HUS in children). Nonstratified thickening with preservation of the length of the haustral folds is the sign of an intraluminal deposit due to PMC. Correlating the sonographic pattern and the anatomic distribution of the disease with the clinical and laboratory findings often permits to propose a specific diagnosis.


Home-based caregiver training: Benefits differ by care receivers' dementia diagnosis.
Patients with dementia differ in their behavioral and psychological symptoms according to their diagnosis with Alzheimer's disease (AD) or vascular dementia (VaD), requiring different symptom-management strategies. This study analyzed data from a sub-sample of a randomized clinical trial to determine the effects of a home-based training program on family caregivers of patients with dementia in northern Taiwan. Our sub-sample comprised patient-caregiver dyads (46 VaD and 68 AD patients) followed for 18 months. Caregivers of AD patients in the intervention group had better competence, preparedness, health-related quality of life, and fewer depressive symptoms than those in the control group. Caregivers of VaD patients in the intervention group had better competence and health-related quality of life than those in the control group. The training program benefited family caregivers of AD patients more than caregivers of VaD patients. Specific training programs need to be developed for family caregivers of VaD patients.


Staphylococcal alpha toxin promotes blood coagulation via attack on human platelets.
Staphylococcus aureus plays a major role as a bacterial pathogen in human medicine, causing diseases that range from superficial skin and wound to systemic nosocomial infections . The majority of S. aureus strains produces a toxin, a proteinaceous exotoxin whose hemolytic, dermonecrotic, and lethal properties have long been known (1-6). The toxin is secreted as a single- chained, nonglycosylated polypeptide with a M(r) of 3.4 x 10(4) (7, 8). The protein spontaneously binds to lipid monolayers and bilayers (9-14), producing functional transmembrane pores that have been sized to 1.5-2.0-nm diameters (15-18). The majority of pores formed at high toxin concentrations (20 mug/ml) is visible in the electron microscope as circularized rings with central pores of approximately 2 nm in diameter. The rings have been isolated, and molecular weight determinations indicate that they represent hexamers of the native toxin (7). We have proposed that transmembrane leakiness is due to embedment of these ring structures in the bilayer, with molecular flux occurring through the central channels (15, 19). Pore formation is dissectable into two steps (20, 21). Toxin monomers first bind to the bilayer without invoking bilayer leakiness . Membrane-bound monomers then laterally diffuse and associate to form non-covalently bonded oligomers that generate the pores. When toxin pores form in membranes of nucleated cells, they may elicit detrimental secondary effects by serving as nonphysiologic calcium channels, influx of this cation triggering diverse reactions, including release of potent lipid mediators originating from the arachidonate cascade (22-24). That alpha toxin represents an important factor of staphylococcal pathogenicity has been clearly established in several models of animal infections through the use of genetically engineered bacterial strains deleted of an active alpha toxin gene (25-27). Whether the toxin is pathogenetically relevant in human disease, however, is a matter of continuing debate. Doubts surrounding this issue originate from two main findings. First, whereas 60 percent hemolysis of washed rabbit erythrocytes is effected by approximately 75 ng/ml alpha toxin, approximately 100-fold concentrations are required to effect similar lysis of human cells (4-6, 13). The general consensus is that human cells display a natural resistance towards toxin attack. The reason for the wide inter-species variations in susceptibility towards alpha toxin is unknown but does not seem to be due to the presence or absence of high-affinity binding sites on the respective target cells (20, 21). Second, low-density lipoprotein (28) and neutralizing antibodies present in plasma of all healthy human individuals inactivate a substantial fraction of alpha toxin in vitro. These inactivating mechanisms presumably further raise the concentration threshold required for effective toxin attack, and it is most unlikely that such high toxin levels will ever be encountered during infections in the human organism. The aforegoing arguments rest on the validity of two general assumptions. First, the noted natural resistance of human erythrocytes to alpha toxin must be exhibited by other human cells. Second, toxin neutralization by plasma components, usually tested and quantified after their preincubation with toxin in vitro, must be similarly effective under natural conditions, and protection afforded by these components must not be restricted to specific cell species.


Maybe If We Turn It Off and Then Turn It Back On Again? Exploring Health Care Reform as a Means to Curb Cyber Attacks.
The health care industry has moved at a rapid pace away from paper records to an electronic platform across almost all sectors - much of it at the encouragement and insistence of the federal government. Such rapid expansion has increased exponentially the risk to individuals in the privacy of their data and, increasingly, to their physical well-being when medical records are inaccessible through ransomware attacks. Recognizing the unique and critical nature of medical records, the United States Congress established the Health Care Industry Cybersecurity Task Force under the Cybersecurity Information Sharing Act of 2015 for the purpose of reviewing cybersecurity risks within the health care industry and identifying who will lead and coordinate efforts to address such risks among the various agencies. The Task Force has since issued a report setting forth six high-level imperatives that the health care industry needs to achieve in order to combat cybersecurity, and, notably, many of the vulnerabilities plaguing the industry identified in the Report as requiring correction are not necessarily related to specific flaws in the current cybersecurity framework, but rather susceptibilities presented by the infrastructure and associated regulatory regime that has evolved over the last few decades over the health care industry generally. That is, the current health care infrastructure by its nature exacerbates cybersecurity risk. Between a lack of information sharing of industry threats, risks, and mitigations, disparate leadership and governance goals for cybersecurity, the confluence and contradiction of existing federal and state laws, fragmentation in the fee-for-service delivery system, lack of care coordination, and disparate resources across and among sectors, the industry suffers from heightened cyber risk. Solutions that are reactive to problems within the current infrastructure will likely have little long term impact toward reducing cybersecurity vulnerabilities because they do not address the underlying system challenges. All of these confluences causes one to wonder whether if in fact the current health care delivery infrastructure is a contributing factor to the incidents of cybersecurity attacks and the exorbitant costs associated with resolving data breaches, should Congress look not just to curb breach incidents, but to address root cause systematic challenges in the health industry infrastructure that create increased exposure of cybersecurity threats? This article argues that cybersecurity risks will continue to be heightened and more costly to the health care industry as compared to other industries unless and until some general system redesign is achieved that allows for (1) greater sharing of resources among industry participants to ensure the same protections are implemented at all levels of the industry, which can be strengthened through greater interoperability of systems across the health care industry; and (2) increased focus and attention on the importance of cybersecurity issues as a priority among system reforms.


A scientific update on biosimilar infliximab (CT-P13) in rheumatic diseases.
The development of biologic drugs has undoubtedly enhanced the spectrum of treatments available for immune-mediated inflammatory rheumatic diseases such as rheumatoid arthritis. However, despite their clear clinical benifits, use of biologics is often hindered by their high costs. The manufacture and subsequent approval of more cost-effective 'biosimilar' versions of these drugs may address this issue and improve patient access. CT-P13 (Remsima(®), Inflectra(®)), a biosimilar of infliximab (Remicade(®)), has shown comparable efficacy, safety and pharmacokinetics to its originator drug in clinical studies. The articles in this supplement present a scientific update on the development and use of biosimilars in rheumatic disorders, with specific focus on CT-P13. The information discussed highlights the predicted positive clinical and economic impact of biosimilars on the management of rheumatic diseases.


APOBEC1 and APOBEC3 cytidine deaminases as restriction factors for hepadnaviral genomes in non-humans in vivo.
Reverse transcription of the hepadnavirus RNA pre-genome means that nascent cDNA may be vulnerable to genetic editing by host cell APOBEC cytidine deaminases that have specificity single-stranded DNA as substrate. Hepatitis B virus (HBV) is particularly vulnerable to editing by APOBEC3G (hA3G) in late-stage disease where up to 35% of genomes can be edited. Yet, the organization of the A3 locus varies considerably among mammals with a single gene for the mouse and seven genes for Old and New World monkeys, which suggests that the outcome may be very variable for other natural hepadnavirus infections. In addition, there is the powerful mouse transgenic model of HBV replication (mHBV) that has proved to be immensely useful in understanding HBV immunopathogenesis. Here, we show that mHBV is edited in vivo by mAPOBEC1 (mA1) and not mAPOBEC3 (mA3), which follows from the fact that unlike humans, the mA1 gene is highly expressed in the liver. For woodchuck hepatitis virus, an mA3 ortholog is probably operative. For HBV-infected tree shrew primary liver cultures, the editing profile more resembles that observed in humans in keeping with fact that this species belongs to the order closest to Primates. There seems to be more genetic editing in liver or cell-associated genomes than serum or culture supernatants, suggesting that too much editing of virion cDNA might impede completion of DNA synthesis.


Non-canonical CRL4A/4B(CDT2) interacts with RAD18 to modulate post replication repair and cell survival.
The Cullin-4(CDT2) E3 ubiquitin ligase plays an essential role in DNA replication origin licensing directing degradation of several licensing factors at the G1/S transition in order to prevent DNA re-replication. Recently a RAD18-independent role of Cullin-4(CDT2) in PCNA monoubiquitylation has been proposed. In an effort to better understand the function of Cullin-4(CDT2) E3 ubiquitin ligase in mammalian Post-Replication Repair during an unperturbed S-phase, we show that down-regulation of Cullin-4(CDT2) leads to two distinguishable independent phenotypes in human cells that unveil at least two independent roles of Cullin-4(CDT2) in S-phase. Apart from the re-replication preventing activity, we identified a non-canonical Cullin-4(CDT2) complex, containing both CUL4A and CUL4B, associated to the COP9 signalosome, that controls a RAD18-dependent damage avoidance pathway essential during an unperturbed S-phase. Indeed, we show that the non-canonical Cullin-4A/4B(CDT2) complex binds to RAD18 and it is required to modulate RAD18 protein levels onto chromatin and the consequent dynamics of PCNA monoubiquitylation during a normal S-phase. This function prevents replication stress, ATR hyper-signaling and, ultimately, apoptosis. A very similar PRR regulatory mechanism has been recently described for Spartan. Our findings uncover a finely regulated process in mammalian cells involving Post-Replication Repair factors, COP9 signalosome and a non-canonical Cullin4-based E3 ligase which is essential to tolerate spontaneous damage and for cell survival during physiological DNA replication.


Molecular analysis of retroviral transduction in chronic myelogenous leukemia.
We have developed a polymerase chain reaction (PCR) assay for detection of integrated retroviral transgenomes containing the neo G418 resistance gene in colonies (40 cells or more) grown in G418 selection after exposure to the neo-positive retrovirus LNL6. This assay also provides for simultaneous characterization of these colonies as belonging to a chronic myelogenous leukemic (bcr-abl positive) or nonleukemic population (bcr-abl negative). Using these techniques, we assessed transduction of the LNL6 retrovirus into the normal and leukemic cells of a blast-crisis chronic myelogenous leukemia (CML) patient. This work was designed to support the use of the LNL6 retroviral marker to help identify the origin of relapse after autologous marrow infusion. The data from these experiments show that the majority of CML blast crisis cells that, following exposure to the LNL6 virus, produce colonies under rigorous G418 selection are indeed transduced by the virus, as shown by the presence of the neo retroviral gene. Most of these colonies are also shown to be leukemic by PCR detection of the bcr-abl RNA. This demonstrates the feasibility of the study of CML marrow for retroviral marking. These procedures will be of use in establishing if relapse arises from leukemic blasts which contaminate purged autologous bone marrow infused following intensive therapy for leukemia.


SmartEye: Developing a Novel Eye Tracking System for Quantitative Assessment of Oculomotor Abnormalities.
Eye movements are a continuous and ubiquitous part of sensory perception. To properly generate highly accurate and co-ordinate ocular movements, a vast network of brain areas are engaged, from low-level visual processing to motor control of gaze orientation. This renders oculomotor system vulnerable to various neurological disorders with unique clinical patterns. Therefore, oculomotor examination can serve as an early and sensitive indicator for various neurological conditions. A simple-to-use, clinically valid system for objectively assessing the oculomotor function can thus bring a paradigm shift in diagnosis and treatment of brain disorders. In principal accordance, this paper presents a gaze assessment tool, called SmartEye, which is based on eye fixation, smooth pursuit, and blinking in response to both static and dynamic visual stimuli. The gaze related indices were evaluated in real-time by SmartEye and these were mapped to the reported pathological state in chronic ( > 3 months) patients with stroke. Our preliminary feasibility study with eight pairs of chronic ( > 3 months) stroke survivors and healthy individuals revealed that gaze related indices in response to both static and dynamic visual stimuli may serve as potential quantitative biomarkers for stroke assessment.


Per cent of patients with chronic migraine who responded per onabotulinumtoxinA treatment cycle: PREEMPT.
The approved use of onabotulinumtoxinA for prophylaxis of headaches in patients with chronic migraine (CM) involves treatment every 12 weeks. It is currently unknown whether patients who fail to respond to the first onabotulinumtoxinA treatment cycle will respond to subsequent treatment cycles. To help inform decisions about treating non-responders, we examined the probability of treatment cycle 1 non-responders responding in cycle 2, and cycle 1 and 2 non-responders responding in cycle 3. Pooled PREEMPT data (two studies: a 24-week, 2-cycle, double-blind, randomised (1:1), placebo-controlled, parallel-group phase, followed by a 32-week, 3-cycle, open-label phase) evaluated onabotulinumtoxinA (155-195 U) for prophylaxis of headaches in persons with CM (≥15 days/month with headache ≥4 h/day). End points of interest included the proportion of study patients who first achieved a ≥50% reduction in headache days, moderate/severe headache days, total cumulative hours of headache on headache days, or a ≥5-point improvement in Headache Impact Test (HIT)-6. For treatment cycle 1, all eligible participants were included. For subsequent cycles, responders in a previous cycle were no longer considered first responders. Among onabotulinumtoxinA-treated patients (n=688) 49.3% had a ≥50% reduction in headache-day frequency during treatment cycle 1, with 11.3% and 10.3% of patients first responding during cycles 2 and 3, respectively. 54.2%, 11.6% and 7.4% of patients first responded with a ≥50% reduction in cumulative hours of headache, and 56.3%, 14.5% and 7.7% of patients first responded with a ≥5-point improvement in total HIT-6 during treatment cycles 1, 2 and 3, respectively. A meaningful proportion of patients with CM treated with onabotulinumtoxinA who did not respond to the first treatment cycle responded in the second and third cycles of treatment. NCT00156910, NCT00168428.


Projection scenarios of body mass index (2013-2030) for Public Health Planning in Quebec.
Projection analyses can provide estimates of the future health burden of increasing BMI and represent a relevant and useful tool for public health planning. Our study presents long-term (2013-2030) projections of the prevalence and numbers of individuals by BMI category for adult men and women in Quebec. Three applications of projections to estimate outcomes more directly pertinent to public health planning, as well as an in-depth discussion of limits, are provided with the aim of encouraging greater use of projection analyses by public health officers. The weighted compositional regression method is applied to prevalence time series derived from sixteen cross-sectional survey cycles, for scenarios of linear change and deceleration. Estimation of the component of projected change potentially amenable to intervention, future health targets and the projected impact on type 2 diabetes, were done. Obesity prevalence in Quebec is projected to rise steadily from 2013 to 2030 in both men (from 18.0-19.4% to 22.2-30.4%) and women (from 15.5-16.3% to 18.2-22.4%). Corresponding projected numbers of obese individuals are (579,000-625,000 to 790,000-1,084,000) in men and (514,000-543,000 to 661,000-816,000) in women. These projected increases are found to be primarily an 'epidemiologic' rather than 'demographic' phenomenon and thus potentially amenable to public health intervention. Assessment of obesity targets for 2020 illustrates the necessity of using projected rather than current prevalence; for example a targeted 2% drop in obesity prevalence relative to 2013 translates into a 3.6-5.4% drop relative to 2020 projected levels. Type 2 diabetes is projected to increase from 6.9% to 9.2-10.1% in men and from 5.7% to 7.1-7.5% in women, from 2011-2012 to 2030. A substantial proportion of this change (25-44% for men, and 27-43% for women) is attributable to the changing BMI distribution. Obesity in Quebec is projected to increase and should therefore continue to be a public health priority. Application of projections to estimate the proportion of change potentially amenable to intervention, feasible health targets, and future chronic disease prevalence are demonstrated. Projection analyses have limitations, but represent a pertinent tool for public health planning.


Cognitive function and duration of rooflessness in entrants to a hostel for homeless men.
Four previous studies of homeless adults have yielded conflicting results regarding the presence of cognitive impairment. A consecutive series of 80 roofless entrants to a hostel for homeless men were sampled and 62 (76%) completed a range of assessments, including measures of mental state, cognitive functions and substance use. Estimated premorbid IQ (mean = 96), current IQ (mean = 84) and cognitive speed were significantly lower than the norm. There was a significant IQ drop in all diagnostic groups. IQ drop, but not current IQ, correlated with duration of rooflessness. Those with schizophrenia or alcohol problems were roofless for longest. Alcohol misuse did not correlate with IQ drop, excepting alcohol withdrawal symptoms in those with schizophrenia. The hypothesis that low IQ is a risk factor for rooflessness is supported. However, length of rooflessness was more closely related to IQ drop than to current IQ, suggesting that some third factor may be affecting both rooflessness and intellectual functioning. Roofless men with schizophrenia or alcohol problems may be especially at risk of long-term rooflessness.


miR-958 inhibits Toll signaling and Drosomycin expression via direct targeting of Toll and Dif in Drosophila melanogaster.
Drosophila melanogaster is widely used as a model system to study innate immunity and signaling pathways related to innate immunity, including the Toll signaling pathway. Although this pathway is well studied, the precise mechanisms of posttranscriptional regulation of key components of the Toll signaling pathway by microRNAs (miRNAs) remain obscure. In this study, we used an in silico strategy in combination with the Gal80ts-Gal4 driver system to identify microRNA-958 (miR-958) as a candidate Toll pathway regulating miRNA in Drosophila We report that overexpression of miR-958 significantly reduces the expression of Drosomycin, a key antimicrobial peptide involved in Toll signaling and the innate immune response. We further demonstrate in vitro and in vivo that miR-958 targets the Toll and Dif genes, key components of the Toll signaling pathway, to negatively regulate Drosomycin expression. In addition, a miR-958 sponge rescued the expression of Toll and Dif, resulting in increased expression of Drosomycin. These results, not only revealed a novel function and modulation pattern of miR-958, but also provided a new insight into the underlying molecular mechanisms of Toll signaling in regulation of innate immunity.


Passive sampling methods for contaminated sediments: practical guidance for selection, calibration, and implementation.
This article provides practical guidance on the use of passive sampling methods (PSMs) that target the freely dissolved concentration (Cfree ) for improved exposure assessment of hydrophobic organic chemicals in sediments. Primary considerations for selecting a PSM for a specific application include clear delineation of measurement goals for Cfree , whether laboratory-based "ex situ" and/or field-based "in situ" application is desired, and ultimately which PSM is best-suited to fulfill the measurement objectives. Guidelines for proper calibration and validation of PSMs, including use of provisional values for polymer-water partition coefficients, determination of equilibrium status, and confirmation of nondepletive measurement conditions are defined. A hypothetical example is described to illustrate how the measurement of Cfree afforded by PSMs reduces uncertainty in assessing narcotic toxicity for sediments contaminated with polycyclic aromatic hydrocarbons. The article concludes with a discussion of future research that will improve the quality and robustness of Cfree measurements using PSMs, providing a sound scientific basis to support risk assessment and contaminated sediment management decisions.


Large-scale comparative analysis of microbial pan-genomes using PanOCT.
The JCVI pan-genome pipeline is a collection of programs to run PanOCT and tools that support and extend the capabilities of PanOCT. PanOCT (pan-genome ortholog clustering tool) is a tool for pan-genome analysis of closely related prokaryotic species or strains. The JCVI Pan-Genome Pipeline wrapper invokes command-line utilities that prepare input genomes, invoke third-party tools such as NCBI Blast+, run PanOCT, generate a consensus pan-genome, annotate features of the pan-genome, detect sets of genes of interest such as antimicrobial resistance (AMR) genes and generate figures, tables and html pages to visualize the results. The pipeline can run in a hierarchical mode, lowering the RAM and compute resources used. Source code, demo data, and detailed documentation are freely available at https://github.com/JCVenterInstitute/PanGenomePipeline.


Racial disparity in renal cell carcinoma patient survival according to demographic and clinical characteristics.
Patients with renal cell carcinoma (RCC) who are black tend to have poorer prognosis than similar patients who are white. This study examined whether the racial disparity in RCC patient survival varies by demographic and clinical characteristics. Nearly 40,000 patients (4359 black and 34,991 white) diagnosed with invasive RCC from 1992 to 2007 were identified from 12 registries in the National Cancer Institute Surveillance, Epidemiology, and End Results program, covering approximately 14% of the US population. Relative survival rates through 2008 were computed using the actuarial method. Proportionally more blacks than whites were diagnosed with RCC under age 50 and with localized cancer. Overall, the 5-year relative survival rates were 72.6% (95% confidence interval 72.0%-73.2%) for white and 68.0% (66.2%-69.8%) for black patients. Survival was higher among women than men and among younger than older patients. Survival decreased with advancing tumor stage and, within each stage, decreased with increasing tumor size. Patients with clear cell RCC, a more common form among whites, had poorer prognosis than patients with papillary or chromophobe subtypes, which are more common among blacks. Survival for patients who received no surgical treatment (10.5% of white patients and 14.5% of black patients) was substantially lower than for patients treated with nephrectomy, with similar survival among whites and blacks. In all other demographic and clinical subgroups of patients, whites consistently had a survival advantage over blacks. Patients with RCC who are white consistently have a survival advantage over those RCC patients who are black, regardless of age, sex, tumor stage or size, histological subtype, or surgical treatment.