Bender Visual-Motor Gestalt Test in adolescents: relationship between visual-motor development and the Tanner Stages.
Visual-motor skill is fundamental to human development and is an important component of psychological evaluations. The goal of the present study was to determine whether there is a correlation between visual-motor development, as measured by the Bender Visual-Motor Gestalt Test (Bender test), and sexual maturity in adolescents, based on the Tanner Stages in Adolescents. 134 adolescents from 10 to 15 years of age participated in the study. The Bender test and the Raven's Progressive Matrices Test were employed. The measures were administered individually and information on sexual maturity and the presence of developmental disorders was collected from medical charts. The results of the Bender test were not affected by gender, age, schooling, or changes stemming from puberty, but were significantly affected by having repeated a school year and by developmental disorders. An association was found with Raven's scores. The Bender test proved sensitive to developmental disorders in adolescence. No association was found between visual-motor development and sexual maturity in adolescents.


A national survey of practice patterns in the noninvasive diagnosis of deep venous thrombosis.
Recent studies have recommended unilateral venous duplex scanning for the diagnosis of deep venous thrombosis (DVT) in patients who are unilaterally symptomatic. Vascular laboratory accreditation standards, however, imply that bilateral leg scanning should be performed. We examined whether actual practice patterns have evolved toward limited unilateral scanning in such patients. A questionnaire was mailed to all 808 vascular laboratories in the United States that were accredited by the Intersocietal Commission for the Accreditation of Vascular Laboratories (ICAVL). To encourage candid responses, the questionnaires were numerically coded and confidentiality was assured. A total of 608 questionnaires (75%) were completed and returned. Most of the respondents (442; 73%) were either community-hospital or office-based laboratories, and the remaining 163 (27%) were university or affiliated-hospital laboratories. Most of the laboratories (460; 76%) had been in existence for 9 years or more, and 65% had been ICAVL-accredited in venous studies for 3 years or more. Board-certified vascular surgeons were the medical directors in 54% of the laboratories. Duplex ultrasound scanning was the diagnostic method used by 98% of the laboratories. In patients with unilateral symptoms, 75% of the laboratories did not routinely scan both legs for DVT. A large majority (75%) believe that bilateral scanning is not clinically indicated. Only 57 laboratories (14%) recalled having patients return with a DVT in the previously unscanned leg, with 93% of these laboratories reporting between one and five such patients. This observation correlated with larger volumes of venous studies performed by those laboratories (P <.05). Similarly, only 52 laboratories (12%) recalled having patients return with subsequent pulmonary emboli. Of these laboratories, only five reported proximal DVT in the previously unscanned legs of such patients. Of all these laboratories, therefore, only 1% (5 of 443) have potentially missed the diagnosis of a DVT that caused a preventable pulmonary embolus with such a policy. Among those laboratories that always perform bilateral examinations, 41% do so because of habit. Most (61%) of the laboratories that perform bilateral scanning would do unilateral scanning if it were specifically approved by ICAVL. Three quarters of the ICAVL-accredited vascular laboratories perform limited single-extremity scanning for the diagnosis of DVT in patients with unilateral symptoms. This broad clinical experience suggests that this practice is widespread in selected patients. Clinical protocols should be established to provide guidelines for local laboratory implementation.


Teaching the medical interview: an intervention study.
To study the effects of teaching specific interviewing techniques on verbal behaviors and on health outcomes, internal medicine residents working in a screening clinic were assigned to either an experimental or a control group. The entire clinic visit was audiotaped, transcribed, and coded according to the Verbal Response Mode (VRM) system. Residents in the experimental group were taught interviewing behaviors (patient exposition and physician explanation) that had been found in previous studies to be associated with patient outcomes. Through telephone interviews, patient satisfaction, compliance, and symptom status were determined for all patients. Two hundred and sixty-eight interviews (156 in the experimental group and 112 in the control group) were included in the study. Training did increase patient exposition and physician explanation, but did not affect health outcomes. Residents' attitudes and behaviors during the training are described.


MCPIP1 ribonuclease exhibits broad-spectrum antiviral effects through viral RNA binding and degradation.
Monocyte chemoattractant protein 1-induced protein 1 (MCPIP1), belonging to the MCPIP family with highly conserved CCCH-type zinc finger and Nedd4-BP1, YacP Nuclease domains, has been implicated in negative regulation of the cellular inflammatory responses. In this report, we demonstrate for the first time that this RNA-binding nuclease also targets viral RNA and possesses potent antiviral activities. Overexpression of the human MCPIP1, but not MCPIP2, MCPIP3 or MCPIP4, inhibited Japanese encephalitis virus (JEV) and dengue virus (DEN) replication. The functional analysis of MCPIP1 revealed that the activities of RNase, RNA binding and oligomerization, but not deubiqutinase, are required for its antiviral potential. Furthermore, infection of other positive-sense RNA viruses, such as sindbis virus and encephalomyocarditis virus, and negative-sense RNA virus, such as influenza virus, as well as DNA virus, such as adenovirus, can also be blocked by MCPIP1. Moreover, the endogenous MCPIP1 gene expression was induced by JEV and DEN infection, and knockdown of MCPIP1 expression enhanced the replication of JEV and DEN in human cells. Thus, MCPIP1 can act as a host innate defense via RNase activity for targeting and degrading viral RNA.


Complications Related to the Endoscopic Endonasal Transsphenoidal Approach for Nonfunctioning Pituitary Macroadenomas in 300 Consecutive Patients.
To analyze complications of endoscopic transsphenoidal surgery (ETS) for nonfunctioning pituitary macroadenomas (NFPAs). A retrospective study of 300 NFPAs was performed. Complications and factors that could influence these complications were analyzed. Visual and pituitary functions worsened in 2.4% and 13.7% of cases, respectively. Postoperative diabetes insipidus was permanent in 6.2% of cases. Postoperative meningitis occurred in 3.3% of patients. Meningitis was strongly associated with intraoperative cerebrospinal fluid (CSF) leaks (P = 0.01), postoperative CSF leaks (P = 0.0001), and operation times longer than 1 hour (P = 0.023). Detection of Staphylococcus aureus and preoperative treatment with mupirocin in the nostrils did not impact the occurrence of meningitis. Two patients with meningitis died (unique causes of death). Postoperative CSF leaks occurred in 2.7% of cases and were associated with intraoperative CSF leaks (P = 0.007) and permanent diabetes insipidus (P = 0.028). The rate of CSF leak decreased from 4% to 0.8% (P = 0.048) after we moved from a soft to hard reconstruction of the sella. The rate of postoperative epistaxis decreased from 6.7% to 1.25% after we stopped using monopolar coagulation (P = 0.013). ETS permits a wide view, allowing good conditions for a satisfactory resection in the majority of NFPAs. Some pitfalls of endoscopy can lead to complications that improve with modification of the operative technique (i.e., CSF leak and postoperative epistaxis). This study confirms an acceptable rate of complications associated with ETS.


Prevalence and causes of vision loss in Southeast Asia and Oceania: 1990-2010.
To assess prevalence and causes of vision impairment in Southeast Asia and Oceania in 1990 and 2010. Based on a systematic review of medical literature, prevalence of moderate and severe vision impairment (MSVI; presenting visual acuity <6/18 but ≥3/60 in the better eye) and blindness (presenting visual acuity <3/60) was estimated for 1990 and 2010. In Oceania, the age-standardised prevalence of blindness and MSVI did not decrease significantly (1.3% to 0.8% and 6.6% to 5.1%) respectively, but in Southeast Asia, blindness decreased significantly from 1.4% to 0.8%, a 43% decrease. There were significantly more women blind (2.18 million) compared with men (1.28 million) in the Southeast Asian population in 2010, but no significant gender differences in MSVI in either subregion. Cataract was the most frequent cause of blindness in Southeast Asia and Oceania in 1990 and 2010. Uncorrected refractive error, followed by cataract, macular degeneration, glaucoma and diabetic retinopathy were the most common causes for MSVI in 1990 and 2010. With the increasing size of the older population, there have been relatively small increases in the number of blind (2%), and with MSVI (14%) in Southeast Asia, whereas increases have been greater in Oceania of 14% for blindness and of 31% for MSVI. The prevalence of blindness has reduced significantly from 1990 to 2010, with moderate but non-significant lowering of MSVI. Cataract and uncorrected refractive error are the main causes of vision impairment and blindness; cataract continues as the main cause of blindness, but at lower proportions.


[The association between self-rated health and health care utilization in retired].
This article attests the association between self-rated health and health care utilization in a retired population by a narrative review. A systematic review was carried out from 1967 to 2007 to identify studies on self-rated health, in the databases MEDLINE, LILACS e SCIELO. The OVID software was used to Medline research. Contacts with experts were used. The key words retirement, self-rated health, health care utilization and narrative review were used in Portuguese, Spanish and English versions. Al the abstracts were analyzed, but only trials that associated self-rated health in retirement and health care utilization were fully analyzed. Thirty one out of 443 abstracts were selected to be fully analyzed. Current data indicates that health deterioration, poor self-rated health and increased health care utilization are associated with early retirement, due to disability, but not with individuals who worked until retirement by age. Retirement is probably associated with increased public expenses and increased health care utilization in retired with a poor self-rated health.


Comprehensive site-specific whole genome profiling of stromal and epithelial colonic gene signatures in human sigmoid colon and rectal tissue.
The strength of associations between various exposures (e.g., diet, tobacco, chemopreventive agents) and colorectal cancer risk may partially depend on the complex interaction between epithelium and stroma across anatomic subsites. Currently, baseline data describing genome-wide coding and long noncoding gene expression profiles in the healthy colon specific to tissue type and location are lacking. Therefore, colonic mucosal biopsies from 10 healthy participants who were enrolled in a clinical study to evaluate effects of lignan supplementation on gut resiliency were used to characterize the site-specific global gene expression signatures associated with stromal vs. epithelial cells in the sigmoid colon and rectum. Using RNA-seq, we demonstrate that tissue type and location patterns of gene expression and upstream regulatory pathways are distinct. For example, consistent with a key role of stroma in the crypt niche, mRNAs associated with immunoregulatory and inflammatory processes (i.e., CXCL14, ANTXR1), smooth muscle contraction (CALD1), proliferation and apoptosis (GLP2R, IGFBP3), and modulation of extracellular matrix (MMP2, COL3A1, MFAP4) were all highly expressed in the stroma. In comparison, HOX genes (HOXA3, HOXD9, HOXD10, HOXD11, and HOXD-AS2, a HOXD cluster antisense RNA 2), and WNT5B expression were also significantly higher in sigmoid colon compared with the rectum. These findings provide strong impetus for considering colorectal tissue subtypes and location in future observational studies and clinical trials designed to evaluate the effects of exposures on colonic health.


The relationship between body-mass index and overall survival in non-small cell lung cancer by sex, smoking status, and race: A pooled analysis of 20,937 International lung Cancer consortium (ILCCO) patients.
The relationship between Body-Mass-Index (BMI) and lung cancer prognosis is heterogeneous. We evaluated the impact of sex, smoking and race on the relationship between BMI and overall survival (OS) in non-small-cell-lung-cancer (NSCLC). Data from 16 individual ILCCO studies were pooled to assess interactions between BMI and the following factors on OS: self-reported race, smoking status and sex, using Cox models (adjusted hazard ratios; aHR) with interaction terms and adjusted penalized smoothing spline plots in stratified analyses. Among 20,937 NSCLC patients with BMI values, females = 47 %; never-smokers = 14 %; White-patients = 76 %. BMI showed differential survival according to race whereby compared to normal-BMI patients, being underweight was associated with poor survival among white patients (OS, aHR = 1.66) but not among black patients (aHR = 1.06; pinteraction = 0.02). Comparing overweight/obese to normal weight patients, Black NSCLC patients who were overweight/obese also had relatively better OS (pinteraction = 0.06) when compared to White-patients. BMI was least associated with survival in Asian-patients and never-smokers. The outcomes of female ever-smokers at the extremes of BMI were associated with worse outcomes in both the underweight (pinteraction<0.001) and obese categories (pinteraction = 0.004) relative to the normal-BMI category, when compared to male ever-smokers. Underweight and obese female ever-smokers were associated with worse outcomes in White-patients. These BMI associations were not observed in Asian-patients and never-smokers. Black-patients had more favorable outcomes in the extremes of BMI when compared to White-patients. Body composition in Black-patients, and NSCLC subtypes more commonly seen in Asian-patients and never-smokers, may account for differences in these BMI-OS relationships.


Evaluation of atorvastatin efficacy and toxicity on spermatozoa, accessory glands and gonadal hormones of healthy men: a pilot prospective clinical trial.
Recommendations for cardiovascular disease prevention advocate lowering both cholesterol and low-density lipoprotein cholesterol systemic levels, notably by statin intake. However, statins are the subject of questions concerning their impact on male fertility. This study aimed to evaluate, by a prospective pilot assay, the efficacy and the toxicity of a decrease of cholesterol blood levels, induced by atorvastatin on semen quality and sexual hormone levels of healthy, normocholesterolaemic and normozoospermic men. Atorvastatin (10 mg daily) was administrated orally during 5 months to 17 men with normal plasma lipid and standard semen parameters. Spermatozoa parameters, accessory gland markers, semen lipid levels and blood levels of gonadal hormones were assayed before statin intake, during the treatment, and 3 months after its withdrawal. Atorvastatin treatment significantly decreased circulating low-density lipoprotein cholesterol (LDL-C) and total cholesterol concentrations by 42% and 24% (p<0.0001) respectively, and reached the efficacy objective of the protocol. During atorvastatin therapy and/or 3 months after its withdrawal numerous semen parameters were significantly modified, such as total number of spermatozoa (-31%, p<0.05), vitality (-9.5%, p<0.05), total motility (+7.5%, p<0.05), morphology (head, neck and midpiece abnormalities, p<0.05), and the kinetics of acrosome reaction (p<0.05). Seminal concentrations of acid phosphatases (p<0.01), α-glucosidase (p<0.05) and L-carnitine (p<0.05) were also decreased during the therapy, indicating an alteration of prostatic and epididymal functions. Moreover, we measured at least one altered semen parameter in 35% of the subjects during atorvastatin treatment, and in 65% of the subjects after withdrawal, which led us to consider that atorvastatin is unsafe in the context of our study. Our results show for the first time that atorvastatin significantly affects the sperm parameters and the seminal fluid composition of healthy men.


A community-level evaluation of the impact of prey behavioural and ecological characteristics on predator diet composition.
Although predation avoidance is the most commonly invoked explanation for vertebrate social evolution, there is little evidence that individuals in larger groups experience lower predation rates than those in small groups. We compare the morphological and behavioural traits of mammal prey species in the Taï forest, Ivory Coast, with the diet preferences of three of their non-human predators: leopards, chimpanzees and African crowned eagles. Individual predators show marked differences in their predation rates on prey species of different body sizes, but clear patterns with prey behaviour were apparent only when differences in prey habitat use were incorporated into the analyses. Leopard predation rates are highest for terrestrial species living in smaller groups, whereas eagle predation rates are negatively correlated with group size only among arboreal prey. When prey predation rates are summed over all three predators, terrestrial species incur higher predation rates than arboreal species and, within both categories, predation rates decline with increasing prey group size and decreasing density of groups in the habitat. These results reveal that it is necessary to consider anti-predator strategies in the context of a dynamic behavioural interaction between predators and prey.


Experimental evidence indicating that mastreviruses probably did not co-diverge with their hosts.
Despite the demonstration that geminiviruses, like many other single stranded DNA viruses, are evolving at rates similar to those of RNA viruses, a recent study has suggested that grass-infecting species in the genus Mastrevirus may have co-diverged with their hosts over millions of years. This "co-divergence hypothesis" requires that long-term mastrevirus substitution rates be at least 100,000-fold lower than their basal mutation rates and 10,000-fold lower than their observable short-term substitution rates. The credibility of this hypothesis, therefore, hinges on the testable claim that negative selection during mastrevirus evolution is so potent that it effectively purges 99.999% of all mutations that occur. We have conducted long-term evolution experiments lasting between 6 and 32 years, where we have determined substitution rates of between 2 and 3 x 10(-4) substitutions/site/year for the mastreviruses Maize streak virus (MSV) and Sugarcane streak Réunion virus (SSRV). We further show that mutation biases are similar for different geminivirus genera, suggesting that mutational processes that drive high basal mutation rates are conserved across the family. Rather than displaying signs of extremely severe negative selection as implied by the co-divergence hypothesis, our evolution experiments indicate that MSV and SSRV are predominantly evolving under neutral genetic drift. The absence of strong negative selection signals within our evolution experiments and the uniformly high geminivirus substitution rates that we and others have reported suggest that mastreviruses cannot have co-diverged with their hosts.


Anti-müllerian hormone compared with other ovarian markers after childhood cancer treatment.
Gonadal dysfunction is one of the major late complications after cancer diagnosis and treatment. The best markers of ovarian reserve in clinical practice are antral follicle count (AFC) and ovarian volume. We aimed to study the prevalence of premature ovarian insufficiency (POI) and evaluate anti-Müllerian hormone (AMH) and other serum markers for ovarian function in adult women who were childhood cancer survivors (CCS) in comparison with a control group. Altogether, 167 female CCS were compared to 164 matched controls. Prevalence of POI was documented and serum levels of AMH, inhibin B, follicle stimulating hormone (FSH), and estradiol (E2) were compared with AFC and ovarian volume. POI was reported in 22 (13%) of the CCS and in none of the controls. Serum levels of AMH, inhibin B, and FSH, but not E2, correlated significantly with AFC and ovarian volume; AMH showed the highest correlation. There was no difference between CCS and controls regarding the different serum markers as measured by linear regression analysis. ROC curve AUC for primary POI showed the highest values for AMH (0.930) and AFC (0.944). For AFC <10, ROC curve AUC showed highest value for AMH for CCS (0.866) and controls (0.878). In a subgroup of female CCS <40 years (n = 120), the results were similar. We found POI in 13% among CCS, slightly more than in other studies. Serum levels of AMH, inhibin B, and FSH correlated significantly with AFC and ovarian volume, and no difference was noted between CCS and controls. AMH was the most reliable serum marker for ovarian function in terms of POI and low AFC.


Inter-kingdom Signaling by the Legionella Quorum Sensing Molecule LAI-1 Modulates Cell Migration through an IQGAP1-Cdc42-ARHGEF9-Dependent Pathway.
Small molecule signaling promotes the communication between bacteria as well as between bacteria and eukaryotes. The opportunistic pathogenic bacterium Legionella pneumophila employs LAI-1 (3-hydroxypentadecane-4-one) for bacterial cell-cell communication. LAI-1 is produced and detected by the Lqs (Legionella quorum sensing) system, which regulates a variety of processes including natural competence for DNA uptake and pathogen-host cell interactions. In this study, we analyze the role of LAI-1 in inter-kingdom signaling. L. pneumophila lacking the autoinducer synthase LqsA no longer impeded the migration of infected cells, and the defect was complemented by plasmid-borne lqsA. Synthetic LAI-1 dose-dependently inhibited cell migration, without affecting bacterial uptake or cytotoxicity. The forward migration index but not the velocity of LAI-1-treated cells was reduced, and the cell cytoskeleton appeared destabilized. LAI-1-dependent inhibition of cell migration involved the scaffold protein IQGAP1, the small GTPase Cdc42 as well as the Cdc42-specific guanine nucleotide exchange factor ARHGEF9, but not other modulators of Cdc42, or RhoA, Rac1 or Ran GTPase. Upon treatment with LAI-1, Cdc42 was inactivated and IQGAP1 redistributed to the cell cortex regardless of whether Cdc42 was present or not. Furthermore, LAI-1 reversed the inhibition of cell migration by L. pneumophila, suggesting that the compound and the bacteria antagonistically target host signaling pathway(s). Collectively, the results indicate that the L. pneumophila quorum sensing compound LAI-1 modulates migration of eukaryotic cells through a signaling pathway involving IQGAP1, Cdc42 and ARHGEF9.


A standard system to study vertebrate embryos.
Staged embryonic series are important as reference for different kinds of biological studies. I summarise problems that occur when using 'staging tables' of 'model organisms'. Investigations of developmental processes in a broad scope of taxa are becoming commonplace. Beginning in the 1990s, methods were developed to quantify and analyse developmental events in a phylogenetic framework. The algorithms associated with these methods are still under development, mainly due to difficulties of using non-independent characters. Nevertheless, the principle of comparing clearly defined newly occurring morphological features in development (events) in quantifying analyses was a key innovation for comparative embryonic research. Up to date no standard was set for how to define such events in a comparative approach. As a case study I compared the external development of 23 land vertebrate species with a focus on turtles, mainly based on reference staging tables. I excluded all the characters that are only identical for a particular species or general features that were only analysed in a few species. Based on these comparisons I defined 104 developmental characters that are common either for all vertebrates (61 characters), gnathostomes (26), tetrapods (3), amniotes (7), or only for sauropsids (7). Characters concern the neural tube, somite, ear, eye, limb, maxillary and mandibular process, pharyngeal arch, eyelid or carapace development. I present an illustrated guide listing all the defined events. This guide can be used for describing developmental series of any vertebrate species or for documenting specimen variability of a particular species. The guide incorporates drawings and photographs as well as consideration of species identifying developmental features such as colouration. The simple character-code of the guide is extendable to further characters pertaining to external and internal morphological, physiological, genetic or molecular development, and also for other vertebrate groups not examined here, such as Chondrichthyes or Actinopterygii. An online database to type in developmental events for different stages and species could be a basis for further studies in comparative embryology. By documenting developmental events with the standard code, sequence heterochrony studies (i.e. Parsimov) and studies on variability can use this broad comparative data set.


Extending Zelterman's approach for robust estimation of population size to zero-truncated clustered Data.
Estimation of population size with missing zero-class is an important problem that is encountered in epidemiological assessment studies. Fitting a Poisson model to the observed data by the method of maximum likelihood and estimation of the population size based on this fit is an approach that has been widely used for this purpose. In practice, however, the Poisson assumption is seldom satisfied. Zelterman (1988) has proposed a robust estimator for unclustered data that works well in a wide class of distributions applicable for count data. In the work presented here, we extend this estimator to clustered data. The estimator requires fitting a zero-truncated homogeneous Poisson model by maximum likelihood and thereby using a Horvitz-Thompson estimator of population size. This was found to work well, when the data follow the hypothesized homogeneous Poisson model. However, when the true distribution deviates from the hypothesized model, the population size was found to be underestimated. In the search of a more robust estimator, we focused on three models that use all clusters with exactly one case, those clusters with exactly two cases and those with exactly three cases to estimate the probability of the zero-class and thereby use data collected on all the clusters in the Horvitz-Thompson estimator of population size. Loss in efficiency associated with gain in robustness was examined based on a simulation study. As a trade-off between gain in robustness and loss in efficiency, the model that uses data collected on clusters with at most three cases to estimate the probability of the zero-class was found to be preferred in general. In applications, we recommend obtaining estimates from all three models and making a choice considering the estimates from the three models, robustness and the loss in efficiency.


Simple, flexible calibration of phase calculation-based three-dimensional imaging system.
One important step of phase-based three-dimensional imaging system is calibration, which defines the relationship between phase and depth data. Existing calibration methods are complicated and hard to carry out because of using a translation stage or gauge block in a laboratory environment. This Letter introduces a new simple, flexible calibration method by using a checkerboard and a white plate having discrete markers with known separation. The checkerboard determines the internal parameters of a CCD camera. The plate gives phase and depth data of each pixel to establish their relationship. Experimental results and performance evaluation show that the proposed calibration method can reliably build up the accurate relationship between phase map and depth data in a simple, flexible way.


Governance and implementation of sports safety practices by municipal offices in Swedish communities.
The objective of this study was to explore whether all-purpose health or safety promotion programmes and sports safety policies affect sports safety practices in local communities. Case study research methods were used to compare sports safety activities among offices in 73 Swedish municipalities; 28 with ongoing health or safety promotion programmes and 45 controls. The offices in municipalities with the WHO Healthy Cities (HC) or Safe Communities programmes were more likely to perform frequent inspections of sports facilities, and offices in the WHO HC programme were more likely to involve sports clubs in inspections. More than every second, property management office and environmental protection office conducted sports safety inspections compared with less than one in four planning offices and social welfare offices. It is concluded that all-purpose health and safety promotion programmes can reach out to have an effect on sports safety practices in local communities. These safety practices also reflect administrative work routines and managerial traditions.


Infectious disease outbreaks related to drinking water in Canada, 1974-2001.
Recent public attention on drinking water supplies in the aftermath of waterborne infection outbreaks in Walkerton and North Battleford raises questions about safety. We analyzed information on waterborne outbreaks occurring between 1974 and 2001 in order to identify apparent trends, review the current status of monitoring and reporting, and gain a better understanding of the impact of drinking water quality on public health and disease burden. Data from outbreak investigations, published and unpublished, were categorized by the type of drinking water provider and were assessed to be definitely, probably or possibly waterborne in nature. The final data set consisted of 288 outbreaks of disease linked to a drinking water source. There were 99 outbreaks in public water systems, 138 outbreaks in semi-public systems and 51 outbreaks in private systems. The main known causative agents of waterborne disease outbreaks were (in descending frequency of occurrence) Giardia, Campylobacter, Cryptosporidium, Norwalk-like viruses, Salmonella and hepatitis A virus. We found that severe weather, close proximity to animal populations, treatment system malfunctions, poor maintenance and treatment practices were associated with the reported disease outbreaks resulting from drinking water supplies. However, issues related to the accuracy, co-ordination, compatibility and detail of data exist. A systematic and coordinated national surveillance system for comparison purposes, trend identification and policy development is needed so that future waterborne disease outbreaks can be avoided.


Solid Phase Extraction and Preconcentration of Trace Gallium, Indium, and Thallium Using New Modified Amino Silica.
Amino silica gel functionalized with 2-hydroxy-5 -(2-hydroxybenzylideneamino)benzoic acid was synthesized, characterized and used as adsorbent for the removal of Ga3+, In3+ and Tl3+ from aqueous solution prior to their determination by flame atomic absorption spectrometry. Experimental parameters that affect the separation process were investigated in both batch and column modes. The maximum adsorption capacities of the sorbent are 61.7 mg g-1, 81.3 mg g-1 and 133.0 mg g-1 for Ga3+, In3+ and Tl3+, respectively. The preconcentration factor is 200 and the limits of detection of Ga3+, In3+ and Tl3+ are 4.10 μg L-1, 1.55 μg L-1 and 1.21 μg L-1, respectively. Interference by Al3+ can be masked by the addition of F-; and that of Fe3+ by its reduction to Fe2+ using 10% ascorbic acid. The method was successfully applied for the determination of these ions in water, sediments and liquid crystal display samples.


A novel approach of groupwise fMRI-guided tractography allowing to characterize the clinical evolution of Alzheimer's disease.
Guiding diffusion tract-based anatomy by functional magnetic resonance imaging (fMRI), we aim to investigate the relationship between structural connectivity and functional activity in the human brain. To this purpose, we introduced a novel groupwise fMRI-guided tractographic approach, that was applied on a population ranging between prodromic and moderate stages of Alzheimer's disease (AD). The study comprised of 15 subjects affected by amnestic mild cognitive impairment (aMCI), 14 diagnosed with AD and 14 elderly healthy adults who were used as controls. By creating representative (ensemble) functionally guided tracts within each group of participants, our methodology highlighted the white matter fiber connections involved in verbal fluency functions for a specific population, and hypothesized on brain compensation mechanisms that potentially counteract or reduce cognitive impairment symptoms in prodromic AD. Our hope is that this fMRI-guided tractographic approach could have potential impact in various clinical studies, while investigating white/gray matter connectivity, in both health and disease.


Differential sirtuin expression patterns in amyotrophic lateral sclerosis (ALS) postmortem tissue: neuroprotective or neurotoxic properties of sirtuins in ALS?
Sirtuins (SIRT1-7; class III histone deactylases) modulate fundamental mechanisms in age-related neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We assessed the expression levels of sirtuins in human postmortem ALS and control brain and spinal cord. By quantitative real-time PCR, a significant reduction of SIRT1 and SIRT2 was detected in homogenates of the primary motor cortex (white and gray matter), while there were no differences in spinal cord homogenates. When specifically analyzing mRNA and protein expression in the gray matter (cortical layers I-VI of the precentral gyrus, ventral/dorsal horn of the spinal cord) by in situ hybridization histochemistry and immunohistochemistry, we found increased levels of SIRT1, SIRT2 and SIRT5 in ALS which were significant for SIRT1 and SIRT5 mRNA in the spinal cord. Our results indicate a general reduction of SIRT1 and SIRT2 in ALS primary motor cortex, while in situ hybridization histochemistry and immunohistochemistry showed neuron-specific upregulation of SIRT1, SIRT2 and SIRT5, particularly in the spinal cord. Opposed effects have been described for SIRT1 and SIRT2: while SIRT1 activation is mainly associated with neuroprotection, SIRT2 upregulation is toxic to neuronal cells. Novel therapeutic approaches in ALS could therefore target SIRT1 activation or SIRT2 inhibition.


Neuromodulation of decision-making in the addictive brain.
Noninvasive brain stimulation of the dorsolateral prefrontal cortex with repetitive transcranial magnetic stimulation and transcranial direct current stimulation can modify decision-making behaviors in healthy subjects. The same type of noninvasive brain stimulation can suppress drug craving in substance user patients, who often display impaired decision-making behaviors. We discuss the implications of these studies for the cognitive neurosciences and their translational applications to the treatment of addictions. We propose a neurocognitive model that can account for our findings and suggests a promising therapeutic role of brain stimulation in the treatment of substance abuse and addictive behavior disorders.


Exposure to metal welding fume particles and risk for cardiovascular disease in Denmark: a prospective cohort study.
To study welding fume particles in relation to cardiovascular diseases. In 1986, 10,059 male metal workers in 75 welding companies were sent a questionnaire about their welding experience and lifestyle (83.3% response rate). Of these, 5866 were available for analysis and had ever welded at baseline. Information on exposure to welding fumes after 1986 was obtained by individual linkage to the National Pension Fund. Lifelong exposure to welding fume particles was estimated from a job-exposure matrix based on more than 1000 welding-specific measures of fume particles. Hospital contacts for cardiovascular disease were obtained from the Danish National Patient Registry by individual linkage. The nine disease outcomes considered were acute myocardial infarct (AMI), angina pectoris, other acute ischaemic heart diseases, chronic ischaemic heart disease (CHD), cardiac arrythmias, cardiac arrest, heart failure, cerebral infarct, arterial embolism and thrombosis. The cohort was followed up from baseline until the end of 2006. When the incidence of each of the nine cardiovascular outcomes among welders was compared with 5-year age- and calendar year-specific male national rates, the number of observed cases significantly exceeded that expected for AMI (standardised incidence ratio, 95% CI) (1.12, 1.01 to 1.24), angina pectoris (1.11, 1.01 to 1.22), CHD (1.17, 1.05 to 1.31) and cerebral infarct (1.24, 1.06 to 1.44). Internal comparisons of the cohort with adjustment for tobacco smoking, alcohol and hypertension medicines showed a significantly increasing hazard rate ratio for CHD and non-significant increases for AMI, angina pectoris and cerebral infarct with increasing exposure to particles. This study supports the hypothesis that exposure to welding processed particles increases the risk for cardiovascular disease.


Helicobacter pylori infection activates Src homology-2 domain-containing phosphatase 2 to suppress IFN-γ signaling.
Helicobacter pylori infection not only induces gastric inflammation but also increases the risk of gastric tumorigenesis. IFN-γ has antimicrobial effects; however, H. pylori infection elevates IFN-γ-mediated gastric inflammation and may suppress IFN-γ signaling as a strategy to avoid immune destruction through an as-yet-unknown mechanism. This study was aimed at investigating the mechanism of H. pylori-induced IFN-γ resistance. Postinfection of viable H. pylori decreased IFN-γ-activated signal transducers and activators of transcription 1 and IFN regulatory factor 1 not only in human gastric epithelial MKN45 and AZ-521 but also in human monocytic U937 cells. H. pylori caused an increase in the C-terminal tyrosine phosphorylation of Src homology-2 domain-containing phosphatase (SHP) 2. Pharmacologically and genetically inhibiting SHP2 reversed H. pylori-induced IFN-γ resistance. In contrast to a clinically isolated H. pylori strain HP238, the cytotoxin-associated gene A (CagA) isogenic mutant strain HP238(CagAm) failed to induce IFN-γ resistance, indicating that CagA regulates this effect. Notably, HP238 and HP238(CagAm) differently caused SHP2 phosphorylation; however, imaging and biochemical analyses demonstrated CagA-mediated membrane-associated binding with phosphorylated SHP2. CagA-independent generation of reactive oxygen species (ROS) contributed to H. pylori-induced SHP2 phosphorylation; however, ROS/SHP2 mediated IFN-γ resistance in a CagA-regulated manner. This finding not only provides an alternative mechanism for how CagA and ROS coregulate SHP2 activation but may also explain their roles in H. pylori-induced IFN-γ resistance.


Three phases of CD8 T cell response in the lung following H1N1 influenza infection and sphingosine 1 phosphate agonist therapy.
Influenza-induced lung edema and inflammation are exacerbated by a positive feedback loop of cytokine and chemokine production termed a 'cytokine storm', a hallmark of increased influenza-related morbidity and mortality. Upon infection, an immune response is rapidly initiated in the lungs and draining lymph node, leading to expansion of virus-specific effector cells. Using two-photon microscopy, we imaged the dynamics of dendritic cells (DC) and virus-specific eGFP(+)CD8(+) T cells in the lungs and draining mediastinal lymph nodes during the first two weeks following influenza infection. Three distinct phases of T cell and CD11c(+) DC behavior were revealed: 1) Priming, facilitated by the arrival of lung DCs in the lymph node and characterized by antigen recognition and expansion of antigen-specific CD8(+) T cells; asymmetric T cell division in contact with DCs was frequently observed. 2) Clearance, during which DCs re-populate the lung and T cells leave the draining lymph node and re-enter the lung tissue where enlarged, motile T cells come into contact with DCs and form long-lived interactions. 3) Maintenance, characterized by T-cell scanning of the lung tissue and dissociation from local antigen presenting cells; the T cells spend less time in association with DCs and migrate rapidly on collagen. A single dose of a sphingosine-1-phosphate receptor agonist, AAL-R, sufficient to suppress influenza-induced cytokine-storm, altered T cell and DC behavior during influenza clearance, delaying T cell division, cellular infiltration in the lung, and suppressing T-DC interactions in the lung. Our results provide a detailed description of T cell and DC choreography and dynamics in the lymph node and the lung during influenza infection. In addition, we suggest that phase lags in T cell and DC dynamics induced by targeting S1P receptors in vivo may attenuate the intensity of the immune response and can be manipulated for therapeutic benefit.


Genetic dissection of primary and secondary responses to a widespread natural pathogen of the gut, Eimeria vermiformis.
Because most pathogens initially challenge the body at epithelial surfaces, it is important to dissect the mechanisms that underlie T-cell responses to infected epithelial cells in vivo. The coccidian parasites of the genus Eimeria are protozoan gut pathogens that elicit a potent, protective immune response in a wide range of host species. CD4+ alpha beta T cells and gamma interferon (IFN-gamma) are centrally implicated in the primary immunoprotective response. To define any additional requirements for the primary response and to develop a comparison between the primary and the secondary response, we have studied Eimeria infections of a broad range of genetically altered mice. We find that a full-strength primary response depends on beta(2)-microglobulin (class I major histocompatibility complex [MHC] and class II MHC and on IFN-gamma and interleukin-6 (IL-6) but not on TAP1, perforin, IL-4, Fas ligand, or inducible nitric oxide synthetase. Indeed, MHC class II-deficient and IFN-gamma-deficient mice are as susceptible to primary infection as mice deficient in all alpha beta T cells. Strikingly, the requirements for a highly effective alpha beta-T-cell-driven memory response are less stringent, requiring neither IFN-gamma nor IL-6 nor class I MHC. The class II MHC dependence was also reduced, with adoptively transferable immunity developing in MHC class II(-/-) mice. Besides the improved depiction of an immune response to a natural gut pathogen, the finding that effective memory can be elicited in the absence of primary effector responses appears to create latitude in the design of vaccine strategies.


Resilience in Daily Occupations of Indonesian Mothers of Children With Autism Spectrum Disorder.
This qualitative study investigated how resilience functions in the context of daily occupations for mothers of children with autism spectrum disorder (ASD). Fourteen mothers of children with ASD participated in two focus groups that were used to elicit stories of the mothers' resilience in daily occupations. A constant comparative method was used for data analysis. A model of resilience in daily occupations of mothers of children with ASD was developed consisting of four categories: (1) creating and re-creating accepting conditions, (2) finding solutions, (3) striving for balance among daily occupations, and (4) thinking about the child's future. Sources of resilience were found to reside in both the mothers themselves and their social environments. Occupational therapy practitioners can use these findings in developing supportive approaches aimed at mothers, family members, and other people in the lives of children with ASD.


Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior.
Fifty years ago, increased whole-blood serotonin levels, or hyperserotonemia, first linked disrupted 5-HT homeostasis to Autism Spectrum Disorders (ASDs). The 5-HT transporter (SERT) gene (SLC6A4) has been associated with whole blood 5-HT levels and ASD susceptibility. Previously, we identified multiple gain-of-function SERT coding variants in children with ASD. Here we establish that transgenic mice expressing the most common of these variants, SERT Ala56, exhibit elevated, p38 MAPK-dependent transporter phosphorylation, enhanced 5-HT clearance rates and hyperserotonemia. These effects are accompanied by altered basal firing of raphe 5-HT neurons, as well as 5HT(1A) and 5HT(2A) receptor hypersensitivity. Strikingly, SERT Ala56 mice display alterations in social function, communication, and repetitive behavior. Our efforts provide strong support for the hypothesis that altered 5-HT homeostasis can impact risk for ASD traits and provide a model with construct and face validity that can support further analysis of ASD mechanisms and potentially novel treatments.


Optimization of exposure parameters in full field digital mammography.
Optimization of exposure parameters (target, filter, and kVp) in digital mammography necessitates maximization of the image signal-to-noise ratio (SNR), while simultaneously minimizing patient dose. The goal of this study is to compare, for each of the major commercially available full field digital mammography (FFDM) systems, the impact of the selection of technique factors on image SNR and radiation dose for a range of breast thickness and tissue types. This phantom study is an update of a previous investigation and includes measurements on recent versions of two of the FFDM systems discussed in that article, as well as on three FFDM systems not available at that time. The five commercial FFDM systems tested, the Senographe 2000D from GE Healthcare, the Mammomat Novation DR from Siemens, the Selenia from Hologic, the Fischer Senoscan, and Fuji's 5000MA used with a Lorad M-IV mammography unit, are located at five different university test sites. Performance was assessed using all available x-ray target and filter combinations and nine different phantom types (three compressed thicknesses and three tissue composition types). Each phantom type was also imaged using the automatic exposure control (AEC) of each system to identify the exposure parameters used under automated image acquisition. The figure of merit (FOM) used to compare technique factors is the ratio of the square of the image SNR to the mean glandular dose. The results show that, for a given target/filter combination, in general FOM is a slowly changing function of kVp, with stronger dependence on the choice of target/filter combination. In all cases the FOM was a decreasing function of kVp at the top of the available range of kVp settings, indicating that higher tube voltages would produce no further performance improvement. For a given phantom type, the exposure parameter set resulting in the highest FOM value was system specific, depending on both the set of available target/filter combinations, and on the receptor type. In most cases, the AECs of the FFDM systems successfully identified exposure parameters resulting in FOM values near the maximum ones, however, there were several examples where AEC performance could be improved.


A method for using epidemiologic data to estimate the potential impact of an intervention on the health status of a target population.
A general method is proposed for estimating the potential impact of a prevention program involving risk factor modification on the incidence of specific diseases in a target population. An evaluative framework for comparing alternative intervention strategies is also presented. On the basis of results from epidemiologic studies, the user must specify certain parameters regarding the distribution of the risk factor that is to be modified in the population, the magnitude of the association between the risk factor and disease, and the total risk of disease in the population. A quantitative measure, called the potential impact fraction, is derived to estimate the proportion of expected new cases that may be prevented under intervention programs of varying success. Estimates of this measure are then used to assess the potential efficacy, effectiveness, adequacy, and efficiency of planned intervention strategies. The method is illustrated with published data relating relative weight and coronary heart disease among middle-aged U.S. men, comparing different strategies of weight reduction. Key assumptions of the method and interpretation of results are discussed.


Health-related lifestyle and perceived health among people with severe mental illness: Gender differences and degree of sense of coherence.
People with severe mental illness (SMI) experience an increased risk of physical ill health and premature death, which appears to be partly related to unhealthy lifestyle habits. The aim of this study was to describe the distribution of health-related lifestyle habits and perceived health among people with severe mental illness. A further aim was to explore if there were any gender differences or differences based on degree of sense of coherence. The study adopted a cross-sectional design based on data from 65 people with SMI. The results show that degree of Sense of Coherence (SOC) does have relevance for perceived health and for dimensions of Quality of Life (QOL). Furthermore, among the participants with strong SOC, there were less daily smokers and they seemed to have less sedentary leisure time than those with low SOC. Men reported more anxiety/depression than women and women ate fruit more often than men, otherwise there were no gender differences. In comparison with the general population, people with SMI show a higher Body Mass Index are more sedentary, more often daily smokers, have lower SOC and perceive a lower QOL. This emphasizes the importance of health-promotion support that focuses on lifestyle changes, and support for strengthening SOC and QOL for people with SMI.


Met1-linked ubiquitination in immune signalling.
N-terminal methionine-linked ubiquitin (Met1-Ub), or linear ubiquitin, has emerged as a central post-translational modification in innate immune signalling. The molecular machinery that assembles, senses and, more recently, disassembles Met1-Ub has been identified, and technical advances have enabled the identification of physiological substrates for Met1-Ub in response to activation of innate immune receptors. These discoveries have significantly advanced our understanding of how nondegradative ubiquitin modifications control proinflammatory responses mediated by nuclear factor-κB and mitogen-activated protein kinases. In this review, we discuss the current data on Met1-Ub function and regulation, and point to some of the questions that still remain unanswered.


Xanthobacter tagetidis sp. nov., an organism associated with Tagetes species and able to grow on substituted thiophenes.
Members of the marigold genus of flowering plants (the genus Tagetes), which synthesize and accumulate thiophene compounds in their roots, were investigated as potential sources of bacteria able to degrade substituted thiophenes. Batch and continuous enrichment cultures inoculated with compost from root balls of Tagetes patula and Tagetes erecta reproducibly produced the same predominant type of bacterium when they were supplied with thiophene-2-carboxylate (T2C) or thiophene-2-acetate (T2A) as a carbon and energy substrate. This organism was a yellow-pigmented, neutrophilic, mesophilic, gram-negative, pleomorphic, rodshaped bacterium, which we classify as a new species of the genus Xanthobacter, Xanthobacter tagetidis; strain TagT2C (= DSM 11105) is the type strain. Strain TagT2CT (T = type strain) grew on simple thiophenes, such as T2C, thiophene-3-carboxylate, and T2A, on analogs of these compounds (pyrrole-2-carboxylate and furan-2-carboxylate), and on the condensed thiophene dibenzothiophene. X. tagetidis was facultatively autotrophic, fixing carbon dioxide by means of ribulose bisphosphate carboxylase, and was able to grow on hydrogen, thiosulfate, or sulfide as an energy substrate. It also grew on a wide range of other heterotrophic, chemolithotrophic, and methylotrophic substrates. Its growth on T2C was optimal at 28 to 31 degrees C and pH 7.6 to 7.8, and the maximum growth rate in batch culture was 0.22 h-1. The DNA base composition of X.tagetidis is 68 mol% G + C. A 16S ribosomal DNA sequence analysis of strain TagT2CT showed that this organism represents a distinct lineage within the Aquabacter-Azorhizobium-Xanthobacter cluster of the alpha-2 subclass of the Pro-teobacteria. Discrimination of X. tagetidis from the other genera in this group and from other Xanthobacter species is discussed.


Environmental risk assessment for the serotonin re-uptake inhibitor fluoxetine: Case study using the European risk assessment framework.
The serotonin re-uptake inhibitor fluoxetine was selected for an environmental risk assessment, using the most recent European guideline (EMEA 2006) within the European Union (EU)-funded Environmental Risk Assessment of Pharmaceuticals (ERAPharm) project due to its environmental persistence, acute toxicity to nontarget organisms, and unique pharmacokinetics associated with a readily ionizable compound. As a widely prescribed psychotropic drug, fluoxetine is frequently detected in surface waters adjacent to urban areas because municipal wastewater effluents are the primary route of entry to aquatic environments. In Phase I of the assessment, the initial predicted environmental concentration of fluoxetine in surface water (initial PEC(SW)) reached or exceeded the action limit of 10 ng/L, when using both a default market penetration factor and prescription data for Sweden, Germany, and the United Kingdom. Consequently, a Phase II risk assessment was conducted in which green algae were identified as the most sensitive species with a NOEC of <0.6 microg/L. From this value, a predicted no effect concentration for surface waters (PNEC(SW)) of 0.012 microg/L was derived. The PEC/PNEC ratio was above the trigger value of 1 in worst-case exposure scenarios indicating a potential risk to the aquatic compartment. Similarly, risks of fluoxetine for sediment-dwelling organisms could not be excluded. No risk assessment was conducted for the terrestrial compartment due to a lack of data on effects of fluoxetine on soil organisms. The need for a separate risk assessment for the main metabolite of fluoxetine, norfluoxetine, was not conducted because of a lack of fate and effect studies. Based on published data, fluoxetine and norfluoxetine appeared to have a low to moderate bioaccumulation potential, which should be confirmed in formal studies according to OECD guidelines. Exposure assessments for fluoxetine according to the current framework rely heavily on K(OC) and K(OW) values. This approach is problematic, because fluoxetine is predominantly a cationic substance at environmental pH values. Consequently, the fate of fluoxetine (and other ionic substances) cannot be predicted using partition coefficients established for nonionic compounds. Further, published estimates for partition coefficients of fluoxetine vary, resulting in considerable uncertainties in both the exposure and environmental risk assessments of fluoxetine.


Could interspecies differences in the protein binding of flavone acetic acid contribute to the failure to predict lack of efficacy in patients?
We investigated the differences in plasma protein binding of flavone acetic acid (FAA) in mice and men in an attempt to explain the inter-species differences in response. In vitro data indicate both qualitative and quantitative differences in FAA protein binding: approximately 80% is bound in humans, with two different types of binding site identified; in mice, 70% is bound and only one binding site could be described. Protein binding is dose-dependent in both species. Plasma samples from 20 patients receiving FAA showed that most achieved levels that would be active in mice. We conclude that these differences in protein binding are insufficient to explain totally the observed differences in response.


Retrospective study of carcinoma of the esophagus in Kenya.
A clinical, radiological, histological, and geographical study of carcinoma of the esophagus in Kenya is reported. It was found that this cancer is diagnosed more often in males than in females, with a ration of 8:1 (Kenya Cancer Registry). The most common age in males and females is 50 to 59 years. The regions of the esophagus most commonly involved are the middle and lower thirds, in almost equal proportions. An unexplained tendency for the tumor to be poorly differentiated towards the lower third is noted. In addition a review on the possible etiological factors is presented.


Treatment Effectiveness in Heart Failure with Comorbidity: Lung Disease and Kidney Disease.
To assess the clinical effectiveness of beta-blocker therapy in individuals with heart failure (HF) and chronic lung disease and of angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) in individuals with HF and chronic kidney disease. Retrospective cohort study. Community. Individuals with HF with reduced ejection fraction (HFrEF) or HF with preserved ejection fraction (HFpEF). We undertook separate new-user cohort studies to assess the effectiveness of beta-blocker therapy in treating HF and chronic lung disease and ACE-Is and ARBs in treating HF and chronic kidney disease (CKD). Individuals with a chronic lung disease diagnosis were included in the group with HF and chronic lung disease (International Classification of Diseases, Ninth Revision, codes 490-496, 518). Individuals with an estimated glomerular filtration rate less than 60 mL/min per 1.73 m2 were included in the group with HF and CKD. The clinical outcomes of interest were death from any cause, hospitalization for HF, and hospitalization for any reason. We fitted pooled logistic marginal structural models using inverse probability weighting, stratified according to HF type. For individuals with HFrEF with chronic lung disease, beta-blocker therapy was protective against death (relative risk (RR) = 0.58, 95% confidence interval (CI) = 0.44-0.77) and hospitalization for HF (RR = 0.78, 95% CI = 0.60-1.00). For those with HFpEF, no statistically significant associations between beta-blocker therapy use and any of the outcomes were observed. We found ACE-I and ARB use to be protective against all three outcomes of interest in individuals with HFrEF (death from any cause: RR = 0.60, 95% 0.40-0.91; hospitalization for HF: RR = 0.43, 95% CI = 0.28-0.67; hospitalization for any reason: RR = 0.63, 95% CI = 0.45-0.89, respectively) and those with HFpEF (death from any cause: RR = 0.52, 95% CI = 0.33-0.81; hospitalization for HF: RR = 0.35, 95% CI = 0.18-0.68; hospitalization for any reason: RR = 0.67, 95% CI = 0.47-0.95). Large observational studies may allow for identification of important subgroups of individuals with HF that might benefit from existing treatment approaches. Our findings may also better inform the design of more-definitive future observational studies and randomized trials.


Retinovascular findings in newborns with critical congenital heart disease: A case series.
Critical congenital heart disease (CCHD) may cause changes in retinal vasculature. However, there is lack of data in this issue in newborns. We evaluated retinovascular changes in a series of 43 newborn with CCHD. They were divided into 2 groups according to the type of CCHD; group 1 (n= 18): left obstructive CCHD and group 2 (n= 25): right obstructive CCHD. Retinovascular pathologies were detected in 21 patients (48.8%); it was more frequent in group 1 (p= 0.04). The most common pathology was retinal vascular tortuosity in 6 patients (33.3%) of group 1, and 4 (16.0%) in group 2. None of 21 patients with retinovascular changes required any therapy at follow-up. In multivariate analysis, only having a left obstructive CCHD was associated with the development of any retinovascular pathology (P= 0.03, OR: 2.8, CI95%: 1.1-7.4). Retinovascular changes are frequent in newborn patients with CCHD.


GRADE guidelines: 21 part 1. Study design, risk of bias, and indirectness in rating the certainty across a body of evidence for test accuracy.
This article provides updated GRADE guidance about how authors of systematic reviews and health technology assessments and guideline developers can assess the results and the certainty of evidence (also known as quality of the evidence or confidence in the estimates) of a body of evidence addressing test accuracy (TA). We present an overview of the GRADE approach and guidance for rating certainty in TA in clinical and public health and review the presentation of results of a body of evidence regarding tests. Part 1 of the two parts in this 21st guidance article about how to apply GRADE focuses on understanding study design issues in test accuracy, provide an overview of the domains, and describe risk of bias and indirectness specifically. Supplemented by practical examples, we describe how raters of the evidence using GRADE can evaluate study designs focusing on tests and how they apply the GRADE domains risk of bias and indirectness to a body of evidence of TA studies. Rating the certainty of a body of evidence using GRADE in Cochrane and other reviews and World Health Organization and other guidelines dealing with in TA studies helped refining our approach. The resulting guidance will help applying GRADE successfully for questions and recommendations focusing on tests.


Acquisition of the curves of the human crystalline lens from slit lamp images: an application of the Hough transform.
To accurately model lens-based functions such as accommodation and image formation on the retina, it is essential to know anterior chamber depth, anterior segment length, lens thickness, and, most importantly, lens curvature both on the surfaces and internally. With the exception of lens curvatures, all these data can be obtained with a high degree of precision by one or more techniques (i.e., A-scan ultrasonography and pachymetry). Lens curvatures can be collected by Scheimpflug slit lamp photography, but the curvature data must be extracted from these images, a problem complicated by both linear and nonlinear image distortion. Previous approaches have involved significant magnification of the image combined with major subjective input and judgment. We present here a computer-based application of the Hough technique for measurement of curvature of lens surfaces observed in Scheimpflug slit lamp photography and related evaluation of (and solutions for) the associated image distortion. Minimal user input is required for successful application of this method, but the time required to obtain a fit for each surface is >1 min. Results obtained by this technique on test images compare favorably with those obtained by independent methods.


Default Drug Doses in Anesthesia Information Management Systems.
In the United States, anesthesia information management systems (AIMS) are well established, especially within academic practices. Many hospitals are replacing their stand-alone AIMS during migration to an enterprise-wide electronic health record. This presents an opportunity to review choices made during the original implementation, based on actual usage. One area amenable to this informatics approach is the configuration in the AIMS of quick buttons for typical drug doses. The use of such short cuts, as opposed to manual typing of doses, simplifies and may improve the accuracy of drug documentation within the AIMS. We analyzed administration data from 3 different institutions, 2 of which had empirically configured default doses, and one in which defaults had not been set up. Our first hypothesis was that most (ie, >50%) of drugs would need at least one change to the existing defaults. Our second hypothesis was that for most (>50%) drugs, the 4 most common doses at the site lacking defaults would be included among the most common doses at the 2 sites with defaults. If true, this would suggest that having default doses did not affect the typical administration behavior of providers. The frequency distribution of doses for all drugs was determined, and the 4 most common doses representing at least 5% of total administrations for each drug were identified. The appropriateness of the current defaults was determined by the number of changes (0-4) required to match actual usage at the 2 hospitals with defaults. At the institution without defaults, the most frequent doses for the 20 most commonly administered drugs were compared with the default doses at the other institutions. At the 2 institutions with defaults, 84.7% and 77.5% of drugs required at least 1 change in the default drug doses (P < 10 for both compared with 50%), confirming our first hypothesis. At the institution lacking the default drug doses, 100% of the 20 most commonly administered doses (representing ≥5% of use for that drug) were included in the most commonly administered doses at the other 2 institutions (P < 10), confirming our second hypothesis. We recommend that default drug doses should be analyzed when switching to a new AIMS because most drugs needed at least one change. Such analysis is also recommended periodically so that defaults continue to reflect current practice. The use of default dose buttons does not appear to modify the selection of drug doses in clinical practice.


Does temporary chest wall closure with or without chest packing improve survival for trauma patients in shock after emergent thoracotomy?
Many surgeons avoid the damage-control techniques of intrathoracic packing and temporary chest wall closure after thoracotomy for trauma because of concerns about packing's effects on intrathoracic pressure and infectious risks. We hypothesized that temporary chest closure with or without intrathoracic packing (TCC-P) as a method of thoracic damage control would yield higher than expected survival rates for trauma thoracotomy patients with metabolic exhaustion, whereas traditional definitive chest closure (DEF) would exhibit predicted survival rates. This was a retrospective cohort study by two urban Level I trauma centers on patients who (1) underwent emergent thoracotomy for trauma, (2) received ≥10 units (U) packed red blood cells and/or sustained a cardiac arrest before starting chest closure, and (3) survived to intensive care unit arrival. Demographic/physiologic data, chest closure method, and thoracic complications were gathered. Trauma injury severity scores (TRISS) were used to calculate survival probability for TCC-P and DEF. Nonparametric statistics were used for all comparisons. All values are expressed as medians and interquartile ranges (IQR). Sixty-one patients met inclusion criteria. Both TCC-P (n = 17) and DEF (n = 44) were severely injured (ISS=35 [IQR, 25-42] vs. 29 [IQR 19-45] and packed red blood cells = 16.5 U [IQR, 12.3-25.5 U] vs. 15 U [IQR, 11-23 U], respectively; p=ns). Patient demographics were similar except for the findings that the TCC-P cohort had higher rates of cardiac arrest before starting chest closure (TCC-P 82% vs. DEF 48%, p=0.04), significantly more severe abdominal injuries, and less severe head injuries than the DEF group. No significant differences were observed in survival of the overall samples (TCC-P=47% vs. DEF=57%), nor for observed:expected (O:E) survival ratio in 13 patients with TCC-P and 30 with DEF meeting criteria for TRISS calculation (TCC-P O:E, 46%:39%; DEF O:E, 53%:57%). No significant differences were found for TCC-P and DEF thoracic infectious (24% vs. 25%) or hemorrhagic (18% vs. 14%) complications. Surprisingly, peak inspiratory pressures on intensive care unit arrival were markedly better after TCC-P (20 cm H2O [IQR, 18-31 cm H2O]) than after DEF (32.5 cm H2O [IQR, 28-37.5 cm H2O], p=0.003). Concerns about TCC-P are not borne out as thoracic infection rates are unaffected and peak pressures are actually lower, possibly due to greater pleural volume from an open chest wall and skin-only closure. However, no significant survival benefit was seen with TCC-P.


Mechanistic insights into arrhythmogenic right ventricular cardiomyopathy caused by desmocollin-2 mutations.
Recent immunohistochemical studies observed the loss of plakoglobin (PG) from the intercalated disc (ID) as a hallmark of arrhythmogenic right ventricular cardiomyopathy (ARVC), suggesting a final common pathway for this disease. However, the underlying molecular processes are poorly understood. We have identified novel mutations in the desmosomal cadherin desmocollin 2 (DSC2 R203C, L229X, T275M, and G371fsX378). The two missense mutations (DSC2 R203C and T275M) have been functionally characterized, together with a previously reported frameshift variant (DSC2 A897fsX900), to examine their pathogenic potential towards PG's functions at the ID. The three mutant proteins were transiently expressed in various cellular systems and assayed for expression, processing, localization, and binding to other desmosomal components in comparison to wild-type DSC2a protein. The two missense mutations showed defects in proteolytic cleavage, a process which is required for the functional activation of mature cadherins. In both cases, this is thought to cause a reduction of functional DSC2 at the desmosomes in cardiac cells. In contrast, the frameshift variant was incorporated into cardiac desmosomes; however, it showed reduced binding to PG. Despite different modes of action, for all three variants, the reduced ability to provide a ligand for PG at the desmosomes was observed. This is in agreement with the reduced intensity of PG at these structures observed in ARVC patients.


Reactive oligo(dimethylsiloxane) mesogens and their nanostructured thin films.
Oligo(dimethylsiloxane)-based reactive mesogens were prepared and shown to form room-temperature smectic phases which were 'frozen-in' by photopolymerization. Homeotropically aligned, nanostructured thin films were obtained by spincoating, and micropatterning was demonstrated. These hybrid reactive mesogens are suitable for the preparation of aligned nanostructured polymer thin films with potential applications ranging from stimuli responsive coatings to nanoporous membranes.


Antinociceptive synergism of gabapentin and nortriptyline in mice with partial sciatic nerve ligation.
Neuropathic pain results from nerve injury, and gabapentin, an antiepileptic drug, has been approved for the treatment of several types of neuropathic pain. On the other hand, nortriptyline, an antidepressant drug, has been suggested as an alternative treatment. In partial sciatic nerve ligation (PSNL) mice, the interaction of gabapentin with nortriptyline was evaluated by the hot plate assay using isobolographic analysis. Gabapentin (3-100 mg/kg, i.p.) or nortriptyline (1-30 mg/kg, i.p.) induced dose-dependent antinociception, with an ED50 of 11.60 ± 0.54 mg/kg for gabapentin and of 5.16 ± 0.21 mg/kg for nortriptyline. The potency of gabapentin and nortriptyline in PSNL mice at 7 and 14 days after ligation was significantly increased (p < 0.05). Coadministration of gabapentin with nortriptyline, at a 1:1 ratio of their ED50, had a synergistic effect, with an interaction index of 0.311 and 0.348 for these mice at 7 and 14 days, respectively. The data showed a synergy in antinociception at a gabapentin-to-nortriptyline ratio of 1:1 in PSNL mice. This finding suggests that this combination could provide a therapeutic alternative that can be used for neuropathic pain management.


Targeting Prodromal Alzheimer Disease With Avagacestat: A Randomized Clinical Trial.
Early identification of Alzheimer disease (AD) is important for clinical management and affords the opportunity to assess potential disease-modifying agents in clinical trials. To our knowledge, this is the first report of a randomized trial to prospectively enrich a study population with prodromal AD (PDAD) defined by cerebrospinal fluid (CSF) biomarker criteria and mild cognitive impairment (MCI) symptoms. To assess the safety of the γ-secretase inhibitor avagacestat in PDAD and to determine whether CSF biomarkers can identify this patient population prior to clinical diagnosis of dementia. A randomized, placebo-controlled phase 2 clinical trial with a parallel, untreated, nonrandomized observational cohort of CSF biomarker-negative participants was conducted May 26, 2009, to July 9, 2013, in a multicenter global population. Of 1358 outpatients screened, 263 met MCI and CSF biomarker criteria for randomization into the treatment phase. One hundred two observational cohort participants who met MCI criteria but were CSF biomarker-negative were observed during the same study period to evaluate biomarker assay sensitivity. Oral avagacestat or placebo daily. Safety and tolerability of avagacestat. Of the 263 participants in the treatment phase, 132 were randomized to avagacestat and 131 to placebo; an additional 102 participants were observed in an untreated observational cohort. Avagacestat was relatively well tolerated with low discontinuation rates (19.6%) at a dose of 50 mg/d, whereas the dose of 125 mg/d had higher discontinuation rates (43%), primarily attributable to gastrointestinal tract adverse events. Increases in nonmelanoma skin cancer and nonprogressive, reversible renal tubule effects were observed with avagacestat. Serious adverse event rates were higher with avagacestat (49 participants [37.1%]) vs placebo (31 [23.7%]), attributable to the higher incidence of nonmelanoma skin cancer. At 2 years, progression to dementia was more frequent in the PDAD cohort (30.7%) vs the observational cohort (6.5%). Brain atrophy rate in PDAD participants was approximately double that of the observational cohort. Concordance between abnormal amyloid burden on positron emission tomography and pathologic CSF was approximately 87% (κ = 0.68; 95% CI, 0.48-0.87). No significant treatment differences were observed in the avagacestat vs placebo arm in key clinical outcome measures. Avagacestat did not demonstrate efficacy and was associated with adverse dose-limiting effects. This PDAD population receiving avagacestat or placebo had higher rates of clinical progression to dementia and greater brain atrophy compared with CSF biomarker-negative participants. The CSF biomarkers and amyloid positron emission tomography imaging were correlated, suggesting that either modality could be used to confirm the presence of cerebral amyloidopathy and identify PDAD. clinicaltrials.gov Identifier: NCT00890890.


Activation of Soluble Polysaccharides with 1-Cyano-4-Dimethylaminopyridine Tetrafluoroborate (CDAP) for Use in Protein-Polysaccharide Conjugate Vaccines and Immunological Reagents. III Optimization of CDAP Activation.
CDAP (1-cyano-4-dimethylaminopyridine tetrafluoroborate) is employed in the synthesis of conjugate vaccines as a cyanylating reagent. In the published method, which used pH 9 activation at 20 °C (Vaccine, 14:190, 1996), the rapid reaction made the process difficult to control. Here, we describe optimizing CDAP activation using dextran as a model polysaccharide. CDAP stability and reactivity were determined as a function of time, pH and temperature. While the rate of dextran activation was slower at lower pH and temperature, it was balanced by the increased stability of CDAP, which left more reagent available for reaction. Whereas maximal activation took less than 2.5 min at pH 9 and 20 °C, it took 10-15 min at 0 °C. At pH 7 and 0 °C, the optimal time increased to >3 h to achieve a high level of activation. Many buffers interfered with CDAP activation, but DMAP could be used to preadjust the pH of polysaccharide solutions so that the pH only needed to be maintained. We found that the stability of the activated dextran was relatively independent of pH over the range of pH 1-9, with the level of activation decreased by 40-60% over 2 h. The use of low temperature and a less basic pH, with an optimum reaction time, requires less CDAP, improving activation levels while making the process more reliable and easier to scale up.


Cardiovascular Risk Assessment and Impact of Medications on Cardiovascular Disease in Inflammatory Bowel Disease.
There is increased risk of cardiovascular disease in patients with chronic inflammatory disorders such as rheumatoid arthritis, psoriatic arthritis, and systemic lupus erythematosus. Studies have shown association between cardiovascular disease (eg, myocardial infarction, heart failure, stroke) and inflammatory bowel disease. Medications such as infliximab and adalimumab (monoclonal antibodies to tumor necrosis factor α) may help decrease the inflammatory burden and cardiovascular risk; however, there have been reports of hypertriglyceridemia and worsening of moderate to severe heart failure with these medications. Janus kinase inhibitors, such as tofacitinib, have been associated with hyperlipidemia and thromboembolism. We aim to discuss clinical and imaging modalities to assess cardiovascular risk in inflammatory bowel disease patients and review the role of various medications with respect to cardiovascular disease in this population.


A review of quantitative risk-benefit methodologies for assessing drug safety and efficacy-report of the ISPOR risk-benefit management working group.
Although regulatory authorities evaluate the risks and benefits of any new drug therapy during the new drug-approval process, quantitative risk-benefit assessment (RBA) is not typically performed, nor is it presented in a consistent and integrated framework when it is used. Our purpose is to identify and describe published quantitative RBA methods for pharmaceuticals. Using MEDLINE and other Internet-based search engines, a systematic literature review was performed to identify quantitative methodologies for RBA. These distinct RBA approaches were summarized to highlight the implications of their differences for the pharmaceutical industry and regulatory agencies. Theoretical models, parameters, and key features were reviewed and compared for the 12 quantitative RBA methods identified in the literature, including the Quantitative Framework for Risk and Benefit Assessment, benefit-less-risk analysis, the quality-adjusted time without symptoms and toxicity, number needed to treat (NNT), and number needed to harm and their relative-value-adjusted versions, minimum clinical efficacy, incremental net health benefit, the risk-benefit plane (RBP), the probabilistic simulation method, multicriteria decision analysis (MCDA), the risk-benefit contour (RBC), and the stated preference method (SPM). Whereas some approaches (e.g., NNT) rely on subjective weighting schemes or nonstatistical assessments, other methods (e.g., RBP, MCDA, RBC, and SPM) assess joint distributions of benefit and risk. Several quantitative RBA methods are available that could be used to help lessen concern over subjective drug assessments and to help guide authorities toward more objective and transparent decision-making. When evaluating a new drug therapy, we recommend the use of multiple RBA approaches across different therapeutic indications and treatment populations in order to bound the risk-benefit profile.


Micropatterned single lens for wide-angle light-emitting diodes.
This work presents a simple and effective method for a wide-angle light-emitting diode module by using a single lens corrugated with micropattern arrays. Impinged onto the micropattern arrays of a curved surface, light undergoes an enhancement of the illumination angle due to omnidirectional diffraction. A hemispherical dome lens with micropattern arrays is microfabricated by a reconfigurable microtemplating and a replica molding method. Depending on the micropattern size, the experimental and simulation results show the micropatterned single lens has the wide illumination angle as well as the high extraction efficiency of an incoming LED light source, compared with a conventional dome lens.


High internal phase emulsions stabilized solely by whey protein isolate-low methoxyl pectin complexes: effect of pH and polymer concentration.
In recent years, there has been significant progress in edible emulsion technology especially with respect to creating and stabilizing surfactant-free emulsion systems for food applications. In this paper, we demonstrate the fabrication of high internal phase emulsions (HIPE) (φoil = 0.82) stabilized using colloidal complexes of non-gelling biopolymers (at concentrations as low as 0.3 wt%). The colloidal complexes were pre-formed by combining whey protein isolate (WPI) and low-methoxyl pectin (LMP) at three different pH values (i.e. pH 3.5, 4.5, 5.5) and used further for fabricating stable HIPEs. In addition to the effect of pH, the influence of total biopolymer concentration on the formation and properties of HIPEs was also evaluated. Depending on the total concentration of biopolymers used, the WPI-LMP complexes (formed at pH 4.5) showed a Z-average diameter in the range of 250-350 nm. It was found that the formation of HIPEs was strongly influenced by the pH of the colloidal complexes. At a pH close to the isoelectric point of WPI (≈pH 4.8) and WPI-LMP complexes (≈pH 3.4), severe aggregation of colloidal particles occurred, resulting in poor formation and stability of HIPEs. On comparing the stabilization behaviour of the complexes with the uncomplexed protein, it was noticed that the former provided comparatively better stabilization to the HIPEs against coalescence at pH 4.5 and 5.5. Based on the rheological data (low amplitude oscillatory shear rheology and flow measurements), all HIPE samples showed viscoelastic and shear-thinning behaviour. We believe that such viscoelastic gel-like systems could find potential commercial applications in the development of label-friendly novel food products with interesting textures.


Effects of intracerebroventricular infusion of somatostatin-14 on peripheral glucoregulation in dogs.
Somatostatin (SST) is an inhibitory hormone that regulates numerous biological processes and circulates in two bioactive isoforms: SST-14 and SST-28. SST-14 is the predominant form in the hypothalamus and regulates the secretion of growth hormone (GH) (directly) and of thyroid-stimulating hormone (indirectly). In the periphery, SST is a potent inhibitor of glucagon and insulin secretion. In the present study, we aimed to investigate the effect of i.c.v. administration of SST-14 on glucose metabolism. Twenty healthy adult dogs randomly received either a bolus i.c.v. infusion of 5, 25 or 50 μg of SST-14 or an equivalent amount of artificial cerebrospinal fluid through an epicranial apparatus during fasting. The same experiment was repeated during concomitant intraduodenal infusion of glucose solution through a Mann-Bollman fistula. Serum levels of glucose, insulin and glucose-dependent insulinotrophic peptide (GIP), plasma SST and serum GH levels were assayed. Circulating levels of SST and GH did not change significantly during i.c.v. infusions. Bolus infusion of 50 μg of SST-14 produced an increase in serum glucose levels at 10 min (94 ± 2.5 mg/dl at baseline versus 101 ± 3 mg/dl, P = 0.04) and significantly suppressed insulin levels, reaching maximal suppression at 60 min after infusion (9 ± 1.3 μIU/ml at baseline versus 4.6 ± 0.5 μIU/ml P = 0.04) in fasting animals. Similar results were obtained during intraduodenal infusion of glucose through a Mann-Bollman fistula. GIP levels did not change significantly during i.c.v. administration of SST-14. Intracerebroventricular infusion of SST-14 increases glucose and suppresses insulin levels in the periphery independently of circulating SST levels.


Complexes from Trypanosoma brucei that exhibit deletion editing and other editing-associated properties.
Transcripts from many mitochondrial genes in kinetoplastids undergo RNA editing, a posttranscriptional process which inserts and deletes uridines. By assaying for deletion editing in vitro, we found that the editing activity from Trypanosoma brucei mitochondrial lysates (S.D. Seiwert and K.D. Stuart), Science 266:114-117,1994) sediments with a peak of approximately 20S. RNA helicase, terminal uridylyl transferase, RNA ligase, and adenylation activities, which may have a role in editing, cosediment in a broad distribution, with most of each activity at 35 to 40S. Most ATPase 6 (A6) guide RNA and unedited A6 mRNA sediments at 20 to 30S, with some sedimenting further into the gradient, while most edited A6 mRNA sediments at >35S. Several mitochondrial proteins which cross-link specifically with guide RNA upon UV treatment also sediment in glycerol gradients. Notably, a 65-kDa protein sediments primarily at approximately 20S, a 90-kDa protein sediments at 35 to 40S, and a 25-kDa protein is present at <10S. Most ribonucleoprotein complexes that form with gRNA in vitro sediment at 10 to 20S, except for one, which sediments at 30 to 45S. These results suggest that RNA editing takes place within a multicomponent complex. The potential functions of and relationships between the 20S and 35 to 40S complexes are discussed.


Tanning accelerators: prevalence, predictors of use, and adverse effects.
Tanning accelerators are topical products used by indoor tanners to augment and hasten the tanning process. These products contain tyrosine, psoralens, and/or other chemicals. We sought to better define the population using accelerators, identify predictors of their use, and describe any related adverse effects. This cross-sectional study surveyed 200 indoor tanners about their tanning practices and accelerator use. Primary analysis compared accelerator users with nonusers with respect to questionnaire variables. Descriptive statistics and χ(2) contingency tables were applied to identify statistically significant variables. Of respondents, 53% used accelerators; 97% were female and 3% were male with a median age of 22 years (range: 19-67). Users were more likely to spray tan, tan frequently, and be addicted to tanning. Acne and rashes were more common in accelerator users. Adverse reactions to accelerators prevented their further use 31% of the time. A limited adult population was evaluated; exact accelerator ingredients were not examined. Tanning accelerator users are high-risk indoor tanners who tan more frequently and who are more likely addicted to tanning. Acne and rashes are more common with these products and act as only mild deterrents to continued use. Additional research should investigate accelerators' longer-term health effects.


An evaluation of the impact of antibiotic stewardship on reducing the use of high-risk antibiotics and its effect on the incidence of Clostridium difficile infection in hospital settings.
To evaluate the impact of a high-risk antibiotic stewardship programme on reducing antibiotic use and on hospital Clostridium difficile infection (CDI) incidence rates. A secondary objective was to present the possible utility of time-series analysis as an antibiotic risk classification tool. This was an interventional, retrospective, ecological investigation in a medium-sized hospital over 6.5 years (January 2004 to June 2010). The intervention was the restriction of high-risk antibiotics (second-generation cephalosporins, third-generation cephalosporins, fluoroquinolones and clindamycin). Amoxicillin/clavulanic acid and macrolides were classified as medium-risk antibiotics based on time-series analysis findings and their use was monitored. The intervention was evaluated by segmented regression analysis of interrupted time series. The intervention was associated with a significant change in level of use of high-risk antibiotics (coefficient -17.3, P < 0.0001) and with a borderline significant trend change in their use being reduced by 0.156 defined daily doses/100 bed-days per month (P = 0.0597). The reduction in the use of high-risk antibiotics was associated with a significant change in the incidence trend of CDI (P = 0.0081), i.e. the CDI incidence rate decreased by 0.0047/100 bed-days per month. Analysis showed that variations in the incidence of CDI were affected by the age-adjusted comorbidity index with a lag of 1 month (coefficient 0.137051, P = 0.0182). Significant decreases in slope (coefficient -0.414, P = 0.0309) post-intervention were also observed for the monitored medium-risk antibiotics. The restriction of the high-risk antibiotics contributed to both a reduction in their use and a reduction in the incidence of CDI in the study site hospital. Time-series analysis can be utilized as a risk classification tool with utility in antibiotic stewardship design and quality improvement programmes.


The Primary Care Practice Improvement Tool (PC-PIT) process for organisational improvement in primary care: application by Australian Primary Health Networks.
The Primary Care Practice Improvement Tool (PC-PIT) is an organisational performance improvement tool recently implemented by two Primary Health Networks (PHNs). This study explored barriers and facilitators to implementing the PC-PIT process at scale, from the initial introduction of the tool to completion of Plan-Do-Study-Act cycles with general practices. Using a qualitative design, in-depth, semi-structured interviews were conducted with 10 PHN staff to seek feedback on the delivery of the PC-PIT to general practices. Interview results were analysed using a grounded theory approach. The identification of barriers such as difficulty engaging practices and lack of report sharing with the PHNs will help streamline future implementation. The PC-PIT was highly compatible with existing quality improvement programs and offers enhanced opportunity to support capacity building and implementation of the Health Care Home model.


Halloysite nanotube blended nanocomposite ultrafiltration membranes for reactive dye removal.
In this paper, ultrafiltration (UF) flat sheet membranes were manufactured by introducing two diverse halloysite nanotubes (HNT) size (5 μm and 63 μm) and five different (0, 0.63, 1.88, 3.13, 6.30 wt %) ratios by wet phase inversion. Some characterization methods which are contact angle, zeta potential, viscosity, scanning electron microscopy (SEM) and Young's modulus measurements were used for ultrafiltration membranes. Synthetic dye waters which were Setazol Red and Reactive Orange were used for filtration performance tests. These dye solutions were filtered in three different pH conditions and three different temperature conditions for pH and temperature resistance to understand how flux and removal efficiency change. The best water permeability results were obtained as 190.5 LMH and 192 LMH, for halloysite nanotubes (HNT) sizes of 5 μm and 63 μm respectively. The best water and dye performance of UF membrane contains 1.88% w/w ratio of HNT, which showed increased water flux and dye flux of membranes according to different HNT concentrations including ultrafiltration membranes.


Routine intraoperative angiography during aneurysm surgery.
The routine use of intraoperative angiography as an aid in the surgical treatment of aneurysms is uncommon. The advantages of the ability to visualize residual aneurysm or unintended occlusion of parent vessels intraoperatively must be weighed against the complications associated with repeated angiography and prolonged vascular access. The authors reviewed the results of their routine use of intraoperative angiography to determine its safety and efficacy. Prospectively gathered data from all aneurysm cases treated surgically between January 1996 and June 2000 were reviewed. A total of 303 operations were performed in 284 patients with aneurysms; 24 patients also underwent postoperative angiography. Findings on intraoperative angiographic studies prompted reexploration and clip readjustment in 37 (11%) of the 337 aneurysms clipped. Angiography revealed parent vessel occlusion in 10 cases (3%), residual aneurysm in 22 cases (6.5%), and both residual lesion and parent vessel occlusion in five cases (1.5%). When compared with subsequent postoperative imaging, false-negative results were found on two intraoperative angiograms (8.3%) and a false-positive result was found on one (4.2%). Postoperative angiograms obtained in both false-negative cases revealed residual anterior communicating artery aneurysms. Both of these aneurysms also subsequently rebled, requiring reoperation. In the group that underwent intraoperative angiography, in 303 operations eight patients (2.6%) suffered complications, of which only one was neurological. In the surgical treatment of intracranial aneurysms, the use of routine intraoperative angiography is safe and helpful in a significant number of cases, although it does not replace careful intraoperative inspection of the surgical field.


Rheumatoid arthritis associated autoantibodies in patients with synovitis of recent onset.
STATEMENT OF FINDINGS: An inception cohort of 238 patients having peripheral joint synovitis of less than 12 months duration was evaluated clinically and followed prospectively for 1 year to determine the clinical significance of a number of rheumatoid arthritis (RA) associated autoantibodies. Serum samples collected at the time of the initial evaluation were tested for rheumatoid factor (RF) and antibodies to Sa (anti-Sa), RA-33, (pro)filaggrin [antifilaggrin antibody (AFA)], cyclic citrullinated peptide (anti-CCP), calpastatin, and keratin [antikeratin antibody (AKA)]. RF had a sensitivity of 66% and a specificity of 87% for RA. Anti-Sa, AFA, and anti-CCP all had a specificity of more than 90%, but a sensitivity of less than 50% for this diagnosis. Overall, there was a high degree of correlation between AFA, AKA, anti-Sa or anti-CCP, this being highest between anti-Sa and anti-CCP (odds ratio, 13.3; P < 0.001). Of the 101 patients who were positive for at least one of these four autoantibodies, 57% were positive for only one. Finally, anti-SA identified a subset of predominantly male RA patients with severe, erosive disease. Anti-SA, AFA and anti-CCP are all specific for early RA but, overall, have little additional diagnostic value over RF alone. Although these antibodies may preferentially recognize citrullinated antigens, the modest degree of concordance between them in individual patient sera suggests that it is unlikely a single antigen is involved in generating these responses.


A Large-Scale Community-Based Outbreak of Paratyphoid Fever Caused by Hospital-Derived Transmission in Southern China.
Since the 1990s, paratyphoid fever caused by Salmonella Paratyphi A has emerged in Southeast Asia and China. In 2010, a large-scale outbreak involving 601 cases of paratyphoid fever occurred in the whole of Yuanjiang county in China. Epidemiological and laboratory investigations were conducted to determine the etiology, source and transmission factors of the outbreak. A case-control study was performed to identify the risk factors for this paratyphoid outbreak. Cases were identified as patients with blood culture-confirmed S. Paratyphi A infection. Controls were healthy persons without fever within the past month and matched to cases by age, gender and geography. Pulsed-field gel electrophoresis and whole-genome sequencing of the S. Paratyphi A strains isolated from patients and environmental sources were performed to facilitate transmission analysis and source tracking. We found that farmers and young adults were the populations mainly affected in this outbreak, and the consumption of raw vegetables was the main risk factor associated with paratyphoid fever. Molecular subtyping and genome sequencing of S. Paratyphi A isolates recovered from improperly disinfected hospital wastewater showed indistinguishable patterns matching most of the isolates from the cases. An investigation showed that hospital wastewater mixed with surface water was used for crop irrigation, promoting a cycle of contamination. After prohibition of the planting of vegetables in contaminated fields and the thorough disinfection of hospital wastewater, the outbreak subsided. Further analysis of the isolates indicated that the origin of the outbreak was most likely from patients outside Yuanjiang county. This outbreak is an example of the combined effect of social behaviors, prevailing ecological conditions and improper disinfection of hospital wastewater on facilitating a sustained epidemic of paratyphoid fever. This study underscores the critical need for strict treatment measures of hospital wastewater and the maintenance of independent agricultural irrigation systems in rural areas.