Mitomycin-C/5-fluorouracil/leucovorin and hyperfractionated radiation therapy for rectal carcinoma: a phase II study with long-term follow-up.
Preoperative chemotherapy followed by surgery and adjuvant chemotherapy is a standard treatment for most patients with rectal cancer. We aimed to determine efficacy and tolerability of preoperative mitomycin, fluorouracil (5-FU), and leucovorin (LV) concurrent with hyperfractionated radiation therapy (RT) followed by surgery and adjuvant chemotherapy. Patients with clinical stage II/III disease were treated with mitomycin 10 mg/m(2) on day 1, continuous venous infusion 5-FU 600 mg/m(2) per day for 96 hours, and oral LV 25 mg every 6 hours on days 1-5. All patients received concurrent RT in fractions of 150 cGy twice daily beginning on day 1. Unfixed tumors received 3000 cGy, whereas fixed tumors received a dose of 4500 cGy. Patients then underwent resection and postoperative adjuvant chemotherapy with oral LV and continuous venous infusion 5-FU 600 mg/m(2) per day on days 1-5 on a 28-day cycle for 6 cycles. Primary endpoints were to determine the rate of pathologic response and downstaging, long-term locoregional control, progression-free survival, and overall survival. Between the years 1993 and 2000, 83 patients were enrolled. Eighteen patients (31%) were downstaged. Six patients (7%) had pathologic complete response. Median follow-up was 62 months with a 5-year overall survival of 71%. Local control rate was 96%. Treatment was well tolerated with stomatitis, diarrhea, and radiation proctitis being the most common toxicities. This regimen is effective in the treatment of rectal carcinoma. The favorable toxicity profile of mitomycin and hyperfractionated RT allows these strategies to be utilized with the newer chemotherapies for this disease.


When Rensch meets Bergmann: does sexual size dimorphism change systematically with latitude?
Bergmann's and Rensch's rules describe common large-scale patterns of body size variation, but their underlying causes remain elusive. Bergmann's rule states that organisms are larger at higher latitudes (or in colder climates). Rensch's rule states that male body size varies (or evolutionarily diverges) more than female body size among species, resulting in slopes greater than one when male size is regressed on female size. We use published studies of sex-specific latitudinal body size clines in vertebrates and invertebrates to investigate patterns equivalent to Rensch's rule among populations within species and to evaluate their possible relation to Bergmann's rule. Consistent with previous studies, we found a continuum of Bergmann (larger at higher latitudes: 58 species) and converse Bergmann body size clines (larger at lower latitudes: 40 species). Ignoring latitude, male size was more variable than female size in only 55 of 98 species, suggesting that intraspecific variation in sexual size dimorphism does not generally conform to Rensch's rule. In contrast, in a significant majority of species (66 of 98) male latitudinal body size clines were steeper than those of females. This pattern is consistent with a latitudinal version of Rensch's rule, and suggests that some factor that varies systematically with latitude is responsible for producing Rensch's rule among populations within species. Identifying the underlying mechanisms will require studies quantifying latitudinal variation in sex-specific natural and sexual selection on body size.


Accumulation of specific amino acid substitutions in HLA-B35-restricted human immunodeficiency virus type 1 cytotoxic T lymphocyte epitopes.
HLA is one of the genetic factors that influence the clinical course of HIV-1 infection, and patients with HLA-B35 are prone to rapid disease progression. Nine viral epitopes that are recognized by cytotoxic T lymphocytes (CTLs) in an HLA-B35-restricted manner were determined. To examine how HIV-1 sequences are selected by CTLs in vivo, we sequenced the nine CTL epitopes of the virus in patient plasma. Here we show that certain amino acid substitutions at three epitopes were observed with significantly higher frequency in HLA-B35-positive patients than in HLA-B35-negative patients. By performing experiments with CTL clones established from the HLA-B35-positive patients, it was determined that one of the three substitutions was probably an escape mutation. However, concerning the other two epitopes, representative CTL clones killed target cells pulsed with mutant peptides as efficiently as those pulsed with wild-type peptides, suggesting that CTLs that can be established in vitro are not functioning properly in vivo. Amino acid sequence drift in all HLA-B35-restricted epitopes was rare during the observation period (1 year). Our results may have relevance in understanding the rapid clinical progression in HLA-B35-positive patients.


Pedigree with frontotemporal lobar degeneration--motor neuron disease and Tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9.
Frontotemporal lobar degeneration (FTLD) represents a clinically, pathologically and genetically heterogenous neurodegenerative disorder, often complicated by neurological signs such as motor neuron-related limb weakness, spasticity and paralysis, parkinsonism and gait disturbances. Linkage to chromosome 9p had been reported for pedigrees with the neurodegenerative disorder, frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND). The objective in this study is to identify the genetic locus in a multi-generational Australian family with FTLD-MND. Clinical review and standard neuropathological analysis of brain sections from affected pedigree members. Genome-wide scan using microsatellite markers and single nucleotide polymorphism fine mapping. Examination of candidate genes by direct DNA sequencing. Neuropathological examination revealed cytoplasmic deposition of the TDP-43 protein in three affected individuals. Moreover, we identify a family member with clinical Alzheimer's disease, and FTLD-Ubiquitin neuropathology. Genetic linkage and haplotype analyses, defined a critical region between markers D9S169 and D9S1845 on chromosome 9p21. Screening of all candidate genes within this region did not reveal any novel genetic alterations that co-segregate with disease haplotype, suggesting that one individual carrying a meiotic recombination may represent a phenocopy. Re-analysis of linkage data using the new affection status revealed a maximal two-point LOD score of 3.24 and a multipoint LOD score of 3.41 at marker D9S1817. This provides the highest reported LOD scores from a single FTLD-MND pedigree. Our reported increase in the minimal disease region should inform other researchers that the chromosome 9 locus may be more telomeric than predicted by published recombination boundaries. Moreover, the existence of a family member with clinical Alzheimer's disease, and who shares the disease haplotype, highlights the possibility that late-onset AD patients in the other linked pedigrees may be mis-classified as sporadic dementia cases.


Cognitive influences on the affective representation of touch and the sight of touch in the human brain.
We show that the affective experience of touch and the sight of touch can be modulated by cognition, and investigate in an fMRI study where top-down cognitive modulations of bottom-up somatosensory and visual processing of touch and its affective value occur in the human brain. The cognitive modulation was produced by word labels, 'Rich moisturizing cream' or 'Basic cream', while cream was being applied to the forearm, or was seen being applied to a forearm. The subjective pleasantness and richness were modulated by the word labels, as were the fMRI activations to touch in parietal cortex area 7, the insula and ventral striatum. The cognitive labels influenced the activations to the sight of touch and also the correlations with pleasantness in the pregenual cingulate/orbitofrontal cortex and ventral striatum. Further evidence of how the orbitofrontal cortex is involved in affective aspects of touch was that touch to the forearm [which has C fiber Touch (CT) afferents sensitive to light touch] compared with touch to the glabrous skin of the hand (which does not) revealed activation in the mid-orbitofrontal cortex. This is of interest as previous studies have suggested that the CT system is important in affiliative caress-like touch between individuals.


Thermal effects on fracture and the brittle-to-ductile transition.
The fracture behavior of brittle and ductile materials can be strongly influenced by thermal fluctuations, especially in micro- and nanodevices as well as in rubberlike and biological materials. However, temperature effects, in particular on the brittle-to-ductile transition, still require a deeper theoretical investigation. As a step in this direction we propose a theory, based on equilibrium statistical mechanics, able to describe the temperature-dependent brittle fracture and brittle-to-ductile transition in prototypical discrete systems consisting in a lattice with breakable elements. Concerning the brittle behavior, we obtain closed form expressions for the temperature-dependent fracture stress and strain, representing a generalized Griffith criterion, ultimately describing the fracture as a genuine phase transition. With regard to the brittle-to-ductile transition, we obtain a complex critical scenario characterized by a threshold temperature between the two fracture regimes (brittle and ductile), an upper and a lower yield strength, and a critical temperature corresponding to the complete breakdown. To show the effectiveness of the proposed models in describing thermal fracture behaviors at small scales, we successfully compare our theoretical results with molecular dynamics simulations of Si and GaN nanowires.


Using data mining to predict emergency department length of stay greater than 4 hours: Derivation and single-site validation of a decision tree algorithm.
Health services have an imperative to reduce prolonged patient length of stay (LOS) in ED. Our objective is to develop and validate an accurate prediction model for patient LOS in ED greater than 4 hours using a data mining technique. Data were collected from a regional Australian public hospital for all ED presentations between 1 January 2016 and 31 December 2017. A decision tree algorithm was built to predict patients with an ED LOS >4 hours. A total of 33 attributes were analysed. The performance of the final model was internally validated. Clinically relevant patterns from the model were analysed. The accuracy of the model was 85%. We identified that patients at our site who were at high risk of ED LOS >4 hours were those who were waiting in ED for a medical consultation, or those who were waiting for a urology, surgical, orthopaedic or paediatric consultation if the request for consultation occurred more than 2 hours after the patient was first seen by an ED doctor. This model performed very well in predicting ED LOS >4 hours for each individual patient and demonstrated a number of clinically relevant patterns. Identifying patterns that influence ED LOS is important for health managers in order to develop and implement interventions targeted at those clinical scenarios. Future work should look at the utility of displaying individual patient risk of ED LOS >4 hours using this model in real-time at the point-of-care.


Erythrocyte inosine triphosphatase activity is decreased in HIV-seropositive individuals.
Inosine triphosphatase (ITPase) is encoded by the polymorphic gene ITPA and maintains low intracellular levels of the inosine nucleotides ITP and dITP. The most frequently reported polymorphisms are ITPA c.94C>A (rs 1127354) and ITPA c. 124+21 A>C (rs7270101). Some nucleoside-analogues used in the treatment of HIV-seropositive (HIV+) patients are potential substrates for ITPase. Therefore, the frequency of ITPA SNPs and ITPase activity were studied in a population of HIV+-patients. The study population consisted of 222 patients, predominantly Caucasian males, >95% using HAART. Erythrocyte ITPase activity was determined by measuring the formation of IMP from ITP. ITPA genotype was determined by sequencing genomic DNA. Distribution of ITPase activity, genotype-phenotype correlation and allele frequencies were compared to 198 control subjects. The effect of nucleoside analogues on ITPase activity was studied using lymphoblastic T-cell cultures and human recombinant ITPase. Enzyme kinetic experiments were performed on erythrocyte ITPase from HIV+ patients and controls. No difference was observed in the allele frequencies between the HIV+-cohort (± HAART) and the control population. HIV+ carriers of the wild type and ITPA c.94C>A had significantly lower ITPase activities than control subjects with the same genotype (p<0.005). This was not observed in ITPA c. 124+21 A>C carriers. Nucleoside analogues did not affect ITPase activity in cell culture and human recombinant ITPase. ITPA population genetics were identical in HIV+ and control populations. However, the majority of HIV+-patients had decreased erythrocyte ITPase activity compared to controls, probably due to decreased amounts of ITPase protein. It seems unlikely that ITPase activity is decreased due to nucleoside analogues (HAART). Long-term effects of HIV-infection altering ITPase protein expression or stability may explain the phenomenon observed.


Neuropathology and cognitive performance in self-reported cognitively healthy centenarians.
With aging, the incidence of neuropathological hallmarks of neurodegenerative diseases increases in the brains of cognitively healthy individuals. It is currently unclear to what extent these hallmarks associate with symptoms of disease at extreme ages. Forty centenarians from the 100-plus Study cohort donated their brain. Centenarians self-reported to be cognitively healthy at baseline, which was confirmed by a proxy. Objective ante-mortem measurements of cognitive performance were associated with the prevalence, distribution and quantity of age- and AD-related neuropathological hallmarks. Despite self-reported cognitive health, objective neuropsychological testing suggested varying levels of ante-mortem cognitive functioning. Post-mortem, we found that neuropathological hallmarks related to age and neurodegenerative diseases, such as Aβ and Tau pathology, as well as atherosclerosis, were abundantly present in most or all centenarians, whereas Lewy body and pTDP-43 pathology were scarce. We observed that increased pathology loads correlated across pathology subtypes, and an overall trend of higher pathology loads to associate with a lower cognitive test performance. This trend was carried especially by the presence of neurofibrillary tangles (NFTs) and granulovacuolar degeneration (GVD) and to a lesser extent by Aβ-associated pathologies. Cerebral Amyloid Angiopathy (CAA) specifically associated with lower executive functioning in the centenarians. In conclusion, we find that while the centenarians in this cohort escaped or delayed cognitive impairment until extreme ages, their brains reveal varying levels of disease-associated neuropathological hallmarks, some of which associate with cognitive performance.


Socioeconomic inequalities in suicide in Europe: the widening gap.
Suicide has been decreasing over the past decade. However, we do not know whether socioeconomic inequality in suicide has been decreasing as well.AimsWe assessed recent trends in socioeconomic inequalities in suicide in 15 European populations. The DEMETRIQ study collected and harmonised register-based data on suicide mortality follow-up of population censuses, from 1991 and 2001, in European populations aged 35-79. Absolute and relative inequalities of suicide according to education were computed on more than 300 million person-years. In the 1990s, people in the lowest educational group had 1.82 times more suicides than those in the highest group. In the 2000s, this ratio increased to 2.12. Among men, absolute and relative inequalities were substantial in both periods and generally did not decrease over time, whereas among women inequalities were absent in the first period and emerged in the second. The World Health Organization (WHO) plan for 'Fair opportunity of mental wellbeing' is not likely to be met.Declaration of interestNone.


Top-down guidance of attention to food cues is enhanced in individuals with overweight/obesity and predicts change in weight at one-year follow up.
Changing eating behaviour may be challenging for individuals with obesity and this may be related to attentional bias towards food. Previous paradigms used to assess attentional bias to food stimuli have not distinguished between bottom-up processes related to assessment of rewarding stimuli versus top-down processes related to effects of mind-set on attention. We investigated whether attentional bias for food cues varies between individuals with overweight/obesity and healthy weight individuals, due to differential top-down control of attention. We also determined whether top-down biases predict food consumption in the lab and weight change in our sample over one-year. Forty-three participants with overweight/obesity and 49 healthy weight participants between the ages of 18 and 58 participated. Participants completed two attention tasks in a counterbalanced order: (i) a priming task assessing bottom-up control of attention and (ii) a working memory task assessing top-down control of attention. Eating behaviour was assessed by a taste test. At one-year follow-up participants returned to the laboratory to assess changes in their body mass index (BMI). The healthy weight and overweight/obese groups did not differ in demographics and baseline measures (appetite, food liking, taste test food intake). Participants with overweight/obesity showed greater top-down attentional bias towards food cues than did healthy weight participants but had no difference in bottom-up attentional bias. Top down attentional bias towards food cues predicted weight change over one-year but did not predict food intake in the taste test. The present findings illustrate that the relationship between attentional bias for food, food intake, and body weight is complex. Top-down effects of mind-set on attention, rather than bottom-up control of attention to food may contribute to patterns of eating that result in development and/or maintenance of overweight/obesity. Interventions targeted at top down biases could be effective in facilitating prevention of weight gain.


Multi-modal sexual displays in Australian humpback dolphins.
Sexual displays enriched by object carrying serve to increase individual male fitness, yet are uncommon phenomena in the animal kingdom. While they have been documented in a variety of taxa, primarily birds, they are rare outside non-human mammals. Here, we document marine sponge presenting associated with visual and acoustic posturing found in several, geographically widespread populations of Australian humpback dolphins (Sousa sahulensis) over ten years of observation. Only adult males presented marine sponges, typically doing so in the presence of sexually mature females, although social groups predominantly consisted of mixed age and sex classes. Male humpback dolphins appear to be using sponges for signalling purposes in multi-modal sexual displays. Further, based on limited behavioural and genetic data, we hypothesise that pairs of adult male Sousa form at least temporary coalitions or alliances. The use of objects in sexual displays by non-human mammals is rare and, moreover, cooperation between males in the pursuit of an indivisible resource is an evolutionary hurdle relatively few species have overcome. These findings suggest a hitherto unrecognised level of social complexity in humpback dolphins.


Effect of phosphorus depletion on intestinal calcium and phosphorus absorption.
Intestinal calcium (Ca) hyperabsorption is a well-documented feature of experimental phosphorus depletion (PD). To further evaluate the effect of PD on Ca absorption we studied metabolic balance and in vitro everted duodenal sac uptake of Ca and phosphorus (P) in weanling male rats. Animals were assigned to three dietary groups: normal, 0.3% P ad libitum (NP); low, 0.03% P ad libitum (LP); and normal, 0.3% P but pair-fed with assigned LP mates (NP-PF). Results indicate that although PD led to an early but unsustained increase in 45Ca uptake by the everted duodenal sac in vitro, net intestinal Ca retention is consistently decreased in rats on the LP diet compared with rats eating either the NP or NP-PF diet. The reduction in net intestinal Ca absorption is reflected by an increase in fecal Ca, both in absolute quantities and in proportion to dietary Ca intake. The initial negative P balance after the initiation of the LP diet was promptly, albeit precariously, corrected. This was associated with a sustained increase in duodenal 32P uptake in vitro and virtual cessation of growth. Because the biosynthesis of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and its accumulation in intestinal mucosa have been reported to increase with PD, our study represents an example in which the physiological interrelationship between the activity of 1,25(OH)2D3 and intestinal Ca absorption may be dissociated.


Transsphenoidal surgery for a life-threatening prolactinoma apoplexy during pregnancy.
Prolactinoma is the most common secreting pituitary adenoma. It is typically diagnosed in women of reproductive age and is common cause of infertility. Currently the treatment of choice is pharmacotherapy with dopamine agonists, whereas surgical treatment is reserved for a selected group of patients. Pituitary-tumor apoplexy is a rare, life-threatening condition associated with significant morbidity and mortality. The authors present the case of a 25-year-old woman with prolactinoma treated with dopamine agonist. In course of such a treatment the patient became pregnant. The bromocriptine was gradually withdrawn. In the 14th week of pregnancy she was admitted for symptoms suggesting pituitary tumor apoplexy. The treatment with bromocriptine was reinitiated. In the 20th week of pregnancy further deterioration of the patient's neurological condition and visual-field abnormalities were observed. The patient was qualified for surgical treatment - selective transsphenoidal adenomectomy. The successful surgery led to improvement of neurological condition. The early postoperative PRL level decreased significantly and hormonal function of the pituitary was preserved. The pregnancy ended in 38th week with a caesarean section. Endocrinological evaluation conducted after the uneventful delivery confirmed normal function of the pituitary. Magnetic resonance imaging (MRI) did not reveal tumor re-growth. The patient is kept under constant medical care. In this case study the authors discussed therapeutic management and reviewed literature regarding gestational pituitary-tumor apoplexy with particular emphasis on surgical treatment.


What an anticardiovascular diet should be in 2015.
Given scientific and public debate about optimal diet to prevent cardiovascular disease, and interest in diet and other chronic diseases, we propose that following a few simple dietary principles would reduce chronic disease incidence. Nutrition research has been criticized for focusing on individual nutrients and foods, treated like drug therapy. With a few important exceptions, clinical trials of supplemental nutrients have not shown benefit. Although highly specific nutrition information is elusive, diet patterns have provided consistent answers, important for public health. Observational cohort studies have found that some dietary patterns are reported with high reliability over long periods and predict future cardiovascular and other inflammatory-related diseases. Two randomized clinical trials confirmed this finding. There are many common features of Mediterranean and prudent diets, particularly the plant-centered aspect, coupled with variety of foods eaten. A dietary pattern characterized by high fruit, vegetable, legume, whole grain, nut, berry, seed, and fish intakes, and possibly by intakes of dairy, coffee, tea, chocolate, and alcohol (not in excess), but low meat and detrimentally processed foods is associated with reduced incidence of cardiovascular disease and rates of noncardiovascular, noncancer chronic inflammatory-related mortality. A plant-centered diet may be broadly recommended.


The human delta-opioid receptor: genomic organization, cDNA cloning, functional expression, and distribution in human brain.
We have used the mouse delta-opioid receptor (mDOR) cDNA to isolate the mDOR gene and its human homologue. In both species the coding region is interrupted by two introns with conserved exon-intron boundaries located after transmembrane domains 1 and 4. Using the polymerase chain reaction and primers based on the sequence of the cloned human delta-opioid receptor (hDOR) gene, we have obtained a full length cDNA encoding the hDOR from SH-SY5Y neuroblastoma cells. The cDNA sequence is 100% identical to the cloned human genomic sequence and 94% identical to the mouse sequence at the protein level. When expressed in COS cells, hDOR displays nanomolar affinities for delta-selective ligands, whereas the affinities for mu- and kappa-selective ligands are in the micromolar range. The delta agonists [D-Ala2, D-Leu5]enkephalin, cyclic [D-penicillamine2,D-penicillamine5]enkephalin, and BW373U86 efficiently decrease forskolin-induced cAMP levels in hDOR-expressing COS cells, indicating functional coupling of the receptor. The distribution of hDOR mRNA in human brain was investigated using delta-selective reverse transcription-polymerase chain reaction amplification, followed by Southern hybridization with a delta-specific probe. The transcript is found in cortical areas, including olfactory bulb, hippocampus, and amygdala, as well as in basal ganglia and hypothalamus. No expression is detected in internal globus pallidus, thalamus, any investigated brainstem structure, or pituitary gland. Taken together, our results indicate similar structural, pharmacological, functional, and anatomical properties for the hDOR and the mDOR and therefore support the use of rodent models for the study of these receptors in opioid function.


Diabetes-prone NOD mice show an expanded subpopulation of mature circulating monocytes, which preferentially develop into macrophage-like cells in vitro.
In the nonobese diabetic (NOD) mouse, a model of autoimmune diabetes, dendritic cells (DC), and macrophages (Mphi) is important for the initiation and progression of autoimmunity and the final destruction of beta-cells. Previous studies suggested that an aberrant development of DC and Mphi is related to their pathogenic function. To study this in vivo, we investigated NOD mouse monocytes, the direct precursors of DC, and Mphi. The recently described discrimination between immature (Ly-6C(high)) and mature (Ly-6C(low)) monocytes enabled us to investigate the apportioning between blood monocyte populations in the NOD mouse, which had an abnormally high number of mature monocytes in circulation, and this phenomenon appeared to be intrinsic to the NOD background, as nonobese resistant (NOR) and NOD-H2b mice also showed this altered balance. After depletion by apoptosis-inducing liposomes, the reappearance and transition of immature-to-mature monocytes had similar kinetics as control mice but led again to the presence of a larger, mature monocyte compartment in the blood. In addition, although monocytes from C57BL mice down-regulated their capability to adhere to fibronectin and intercellular adhesion molecule-1 upon maturation, the mature NOD monocytes retained their high adhesion capacity, characteristic of immature cells. Furthermore, both monocyte subpopulations of NOD mice showed enhanced differentiation into Mphi-like F4/80(high) cells in vitro. In conclusion, mice with the NOD background have raised numbers of mature monocytes in the circulation and a proinflammatory, Mphi-directed monocyte development.


Risk and protective factors underlying depression and suicidal ideation in Autism Spectrum Disorder.
People with Autism Spectrum Disorder (ASD) are at significantly increased risk of suicidal thoughts and behavior. Given that social difficulties in ASD often lead to social isolation, which can in turn increase the risk for depression, this study examined loneliness and social support as potential risk and protective factors associated with depression and suicidal ideation. The sample comprised 185 people (92 females) with ASD aged 14 to 80 years who were participating in a national survey. Forty-nine percent of participants returned scores in the clinical range for depression and 36% reported recent suicidal ideation. Females, comprising almost 50% of the sample, returned higher depression scores than males, however no differences were identified between males and females in terms of suicidal ideation. Regression analyses revealed that loneliness, satisfaction with social support, and ASD traits predicted depression scores. Satisfaction with social support predicted suicidal ideation, however, it was no longer a significant predictor after the effects of depression were taken into account. Path analysis showed that ASD trait severity was independently related to depression, that the effect of number of social supports on depression was mediated by loneliness and satisfaction with social support, and that effects of loneliness and satisfaction with social support on suicidal ideation were mediated by depression. The pattern of relationships was nearly identical for males and females. This study supports a model whereby loneliness and social support operate respectively as protective and risk factors for depression and suicidal ideation in ASD.


Teaching undergraduates the process of peer review: learning by doing.
An active approach allowed undergraduates in Health Sciences to learn the dynamics of peer review at first hand. A four-stage process was used. In stage 1, students formed self-selected groups to explore specific issues. In stage 2, each group posted their interim reports online on a specific date. Each student read all the other reports and prepared detailed critiques. In stage 3, each report was discussed at sessions where the lead discussant was selected at random. All students participated in the peer review process. The written critiques were collated and returned to each group, who were asked to resubmit their revised reports within 2 wk. In stage 4, final submissions accompanied by rebuttals were graded. Student responses to a questionnaire were highly positive. They recognized the individual steps in the standard peer review, appreciated the complexities involved, and got a first-hand experience of some of the inherent variabilities involved. The absence of formal presentations and the opportunity to read each other's reports permitted them to study issues in greater depth.


A Follow-Up of the Multicenter Collaborative Study on HIV-1 Drug Resistance and Tropism Testing Using 454 Ultra Deep Pyrosequencing.
Ultra deep sequencing is of increasing use not only in research but also in diagnostics. For implementation of ultra deep sequencing assays in clinical laboratories for routine diagnostics, intra- and inter-laboratory testing are of the utmost importance. A multicenter study was conducted to validate an updated assay design for 454 Life Sciences' GS FLX Titanium system targeting protease/reverse transcriptase (RTP) and env (V3) regions to identify HIV-1 drug-resistance mutations and determine co-receptor use with high sensitivity. The study included 30 HIV-1 subtype B and 6 subtype non-B samples with viral titers (VT) of 3,940-447,400 copies/mL, two dilution series (52,129-1,340 and 25,130-734 copies/mL), and triplicate samples. Amplicons spanning PR codons 10-99, RT codons 1-251 and the entire V3 region were generated using barcoded primers. Analysis was performed using the GS Amplicon Variant Analyzer and geno2pheno for tropism. For comparison, population sequencing was performed using the ViroSeq HIV-1 genotyping system. The median sequencing depth across the 11 sites was 1,829 reads per position for RTP (IQR 592-3,488) and 2,410 for V3 (IQR 786-3,695). 10 preselected drug resistant variants were measured across sites and showed high inter-laboratory correlation across all sites with data (P<0.001). The triplicate samples of a plasmid mixture confirmed the high inter-laboratory consistency (mean% ± stdev: 4.6 ±0.5, 4.8 ±0.4, 4.9 ±0.3) and revealed good intra-laboratory consistency (mean% range ± stdev range: 4.2-5.2 ± 0.04-0.65). In the two dilutions series, no variants >20% were missed, variants 2-10% were detected at most sites (even at low VT), and variants 1-2% were detected by some sites. All mutations detected by population sequencing were also detected by UDS. This assay design results in an accurate and reproducible approach to analyze HIV-1 mutant spectra, even at variant frequencies well below those routinely detectable by population sequencing.


Practice Of Endodontic Re-Treatment In Four Cities Of Pakistan.
Root canal re-treatment is the procedure of choice when the primary root treatment fails but patient is inclined toward salvage of the tooth. The re-treatment is often a challenging procedure owing to lack to the predictability in the outcomes. Since, there is a no single way of planning and executing such procedure, a study was planned to assess the knowledge, attitude and practice regarding endodontic re-treatment among Pakistani dentists. The effect of clinical experience on the re-treatment planning was also determined. A survey was conducted by distributing a questionnaire among 240 dentists practicing in four major cities of Pakistan. Frequency distribution of the gender, experience, designation of the participants etc. was determined. A case scenario was also shared and responses upon decision making were noted. Chi square test was applied to see if re-treatment decision of experienced dentists (>5 years' practice) was significantly different than less experienced dentists. Out of 240 forms, 160 were received (response rate of 66.67%). The most commonly reported reason for endodontic re-treatment was under prepared/ under filled canals. Nearly 40% participants reported doing re-treatment with hand instruments only and 15% did not employ any solvent during re-treatment. There were no significant differences between the less experienced and the more experienced dentists on re-treatment decisions. Almost half of the dentists reported inappropriate decision making in re-treatment. This shows that in endodontic re-treatment practice in major cities of Pakistan falls short of internationally accepted standards. There is a significant difference in treatment planning done by more experienced dentists compared to ones with <5 years' clinical experience.


Regional patterns in prevalence of principal external diseases of dab Limanda limanda in the North Sea and adjacent areas 1992-1997.
The prevalence and spatial distribution of major diseases of dab Limanda limanda in the North Sea and adjacent areas were studied in the summers 1992 to 1997. Areas covered were the North Sea, Irish Sea, northern and northeastern British Waters and the English Channel. The diseases studied were lymphocystis, epidermal hyperplasia/papilloma and skin ulceration. To standardise data, results were analysed for females >15 cm (>3 yr old). Data were subjected to median polish, and additive, extended and additive plus multiplicative models were applied to best account for effects of region and year. Annual differences in disease prevalence were low whilst differences between areas were pronounced. For lymphocystis higher prevalence was observed in the northwestern sector of the North Sea, at the northern tip of Scotland and in an area south of Iceland. Prevalence was low in the Irish Sea, the English Channel and the southern North Sea, and intermediate in the German Bight. For epidermal hyperplasia/papilloma, levels were low at Icelandic stations, in the northern Irish Sea, in the southern North Sea and the English Channel, whilst levels were high in the northwestern part of the North Sea and the German Bight. Elevated levels of skin ulceration were found on the Dogger, at 1 station in the Irish Sea (off Sellafield) and at 1 station to the south of Iceland. Lower levels were detected west of Iceland. Prevalence in all other areas was intermediate. It is concluded that a detailed analysis of available data on disease prevalence and putative causative factors is desirable and, given the good availability of data, would be a promising step forward toward elucidating possible cause and effect relationships between diseases and anthropogenic factors.


Comparative Evaluation of Tissue Response of MTA and Portland Cement with Three Radiopacifying Agents: An Animal Study.
This study compared the tissue reaction of 80 wt% of White Portland cement (WPC) mixed with 20 wt% of three radiopacifying agents: Bismuth oxide/Iodoform/Zirconium oxide with MTA in rat subcutaneous connective tissue. The study was performed in 18 albino rats by implanting the WPC mixed with radiopacifying agents loaded in a polyethylene tube. Empty tubes were used as a control. At the end of 7, 30 and 60 days excisional biopsy of the implant along with surrounding tissues was done and sent for histological examination. In the 7 days experimental period there was no significant difference between groups in terms of the tissue response. In 30 and 60 days period significant difference was seen between the control (empty tube) and the other groups. But there was no significant difference between WPC mixed with radiopacifiers BiO/Iodoform/ZrO2and MTA. The tissue reaction of the tested materials, White Portland cement (WPC) + Bismuth oxide, WPC + Iodoform, and WPC + Zirconium dioxide were similar to MTA (Pro Root MTA) in all experimental periods 7 days, 30 days and 60 days.


Pharmacokinetics and pharmacodynamics of antifungals in children: clinical implications.
Invasive fungal disease (IFD) remains life threatening in premature infants and immunocompromised children despite the recent development of new antifungal agents. Optimal dosing of antifungals is one of the few factors clinicians can control to improve outcomes of IFD. However, dosing in children cannot be extrapolated from adult data because IFD pathophysiology, immune response, and drug disposition differ from adults. We critically examined the literature on pharmacokinetics (PK) and pharmacodynamics (PD) of antifungal agents and highlight recent developments in treating pediatric IFD. To match adult exposure in pediatric patients, dosing adjustment is necessary for almost all antifungals. In young infants, the maturation of renal and metabolic functions occurs rapidly and can significantly influence drug exposure. Fluconazole clearance doubles from birth to 28 days of life and, beyond the neonatal period, agents such as fluconazole, voriconazole, and micafungin require higher dosing than in adults because of faster clearance in children. As a result, dosing recommendations are specific to bracketed ranges of age. PD principles of antifungals mostly rely on in vitro and in vivo models but very few PD studies specifically address IFD in children. The exposure-response relationship may differ in younger children compared with adults, especially in infants with invasive candidiasis who are at higher risk of disseminated disease and meningoencephalitis, and by extension severe neurodevelopmental impairment. Micafungin is the only antifungal agent for which a specific target of exposure was proposed based on a neonatal hematogenous Candida meningoencephalitis animal model. In this review, we found that pediatric data on drug disposition of newer triazoles and echinocandins are lacking, dosing of older antifungals such as fluconazole and amphotericin B products still need optimization in young infants, and that target PK/PD indices need to be clinically validated for almost all antifungals in children. A better understanding of age-specific PK and PD of new antifungals in infants and children will help improve clinical outcomes of IFD by informing dosing and identifying future research areas.


Defectors cannot be detected during"small talk" with strangers.
To account for the widespread human tendency to cooperate in one-shot social dilemmas, some theorists have proposed that cooperators can be reliably detected based on ethological displays that are difficult to fake. Experimental findings have supported the view that cooperators can be distinguished from defectors based on "thin slices" of behavior, but the relevant cues have remained elusive, and the role of the judge's perspective remains unclear. In this study, we followed triadic conversations among unacquainted same-sex college students with unannounced dyadic one-shot prisoner's dilemmas, and asked participants to guess the PD decisions made toward them and among the other two participants. Two other sets of participants guessed the PD decisions after viewing videotape of the conversations, either with foreknowledge (informed), or without foreknowledge (naïve), of the post-conversation PD. Only naïve video viewers approached better-than-chance prediction accuracy, and they were significantly accurate at predicting the PD decisions of only opposite-sexed conversation participants. Four ethological displays recently proposed to cue defection in one-shot social dilemmas (arms crossed, lean back, hand touch, and face touch) failed to predict either actual defection or guesses of defection by any category of observer. Our results cast doubt on the role of "greenbeard" signals in the evolution of human prosociality, although they suggest that eavesdropping may be more informative about others' cooperative propensities than direct interaction.


The impact of hypocrisy on opinion formation: A dynamic model.
Humans have a demonstrated tendency to copy or imitate the behavior and attitude of others and actively influence each other's opinions. In plenty of empirical contexts, publicly revealed opinions are not necessarily in line with internal opinions, causing complex social influence dynamics. We study to what extent hypocrisy is sustained during opinion formation and how hidden opinions change the convergence to consensus in a group. We build and analyze a modified version of the voter model with hypocrisy in a complete graph with a neutral competition between two alternatives. We compare the process from various initial conditions, varying the proportions between the two opinions in the external (revealed) and internal (hidden) layer. According to our results, hypocrisy always prolongs the time needed for reaching a consensus. In a complete graph, this time span increases linearly with group size. We find that the group-level opinion emerges in two steps: (1) a fast and directional process, during which the number of the two kinds of hypocrites equalizes; and (2) a slower, random drift of opinions. During stage (2), the ratio of opinions in the external layer is approximately equal to the ratio in the internal layer; that is, the hidden opinions do not differ significantly from the revealed ones at the group level. We furthermore find that the initial abundances of opinions, but not the initial prevalence of hypocrisy, predicts the mean consensus time and determines the opinions' probabilities of winning. These insights highlight the unimportance of hypocrisy in consensus formation under neutral conditions. Our results have important societal implications in relation to hidden voter preferences in polls and improve our understanding of opinion formation in a more realistic setting than that of conventional voter models.


Uptake of different crystal structures of TiO₂ nanoparticles by Caco-2 intestinal cells.
The gastrointestinal uptake of different crystal structures of TiO2 was investigated using Caco-2 intestinal cells. Caco-2 monolayers exhibited time-dependent, saturable uptake of Ti from TiO2 exposures of 1 mgl(-1) over 24h, which was influenced by crystal type. Initial uptake rates were 5.3, 3.73, 3.58 and 4.48 nmol mg(-1)protein h(-1) for bulk, P25, anatase and rutile forms respectively. All exposures caused elevations of Ti in the cells relative to the control (ANOVA P<0.05). Electron micrographs of the Caco-2 monolayer showed the presence of particles inside the cells, and energy dispersive spectroscopy (EDS) confirmed the composition as TiO2. Incubating the cells with 120 IU nystatin (putative endocytosis inhibitor) or 100 μmol l(-1) vanadate (ATPase inhibitor) caused large increases in Ti accumulation for all crystal types relative to controls (ANOVA P<0.05), except for the rutile form with vanadate. Incubating the cells with 90 μmol l(-1) genistein (tyrosine kinase inhibitor) or 27 μmol l(-1) chloropromazine (clathrin-mediated endocytosis inhibitor) caused a large decrease in Ti accumulation relative to the controls (ANOVA P<0.05). Cell viability measures were generally good (low LDH leak, normal cell morphology), but there were some changes in the electrolyte composition (K(+), Na(+), Ca(2+), Mg(2+)) of exposed cells relative to controls. A rise in total Ca(2+) concentration in the cells was observed for all TiO2 crystal type exposures. Overall, the data shows that Ti accumulation for TiO2 NP exposure in Caco-2 cells is crystal structure-dependent, and that the mechanism(s) involves endocytosis of intact particles.


Economic valuation of informal care. An overview of methods and applications.
Informal care makes up a significant part of the total amount of care provided to care recipients with chronic and terminal diseases. Still, informal care is often neglected in economic evaluations of health care programs. Probably this is related to the fact that the costs of informal care are to an important extent related to time inputs by relatives and friends of care recipients and time is not easy to value. Development of theoretically sound, yet easily applicable valuation methods is therefore important since ignoring the costs of informal care may lead to undesirable shifts between formal and informal care. Moreover, there is increasing evidence that providing informal care may lead to health problems for the caregiver, both in terms of morbidity and mortality. Until now these health effects have not been incorporated in economic evaluations. More attention for the identification and valuation of the full costs and (health) effects of informal care for the informal caregiver seems needed therefore. This contribution presents a critical evaluation of the available methods to incorporate informal care in economic evaluations.


A root-knot nematode-secreted protein is injected into giant cells and targeted to the nuclei.
Root-knot nematodes (RKNs) are obligate endoparasites that maintain a biotrophic relationship with their hosts over a period of several weeks and induce the differentiation of root cells into specialized feeding cells. Nematode effectors synthesized in the oesophageal glands and injected into the plant tissue through the syringe-like stylet certainly play a central role in these processes. In a search for nematode effectors, we used comparative genomics on expressed sequence tag (EST) datasets to identify Meloidogyne incognita genes encoding proteins potentially secreted upon the early steps of infection. We identified three genes specifically expressed in the oesophageal glands of parasitic juveniles that encode predicted secreted proteins. One of these genes, Mi-EFF1 is a pioneer gene that has no similarity in databases and a predicted nuclear localization signal. We demonstrate that RKNs secrete Mi-EFF1 within the feeding site and show Mi-EFF1 targeting to the nuclei of the feeding cells. RKNs were previously shown to secrete proteins in the apoplasm of infected tissues. Our results show that nematodes sedentarily established at the feeding site also deliver proteins within plant cells through their stylet. The protein Mi-EFF1 injected within the feeding cells is targeted at the nuclei where it may manipulate nuclear functions of the host cell.


The impact of short- and long-range perception on population movements.
Navigation of cells and organisms is typically achieved by detecting and processing orienteering cues. Occasionally, a cue may be assessed over a much larger range than the individual's body size, as in visual scanning for landmarks. In this paper we formulate models that account for orientation in response to short- or long-range cue evaluation. Starting from an underlying random walk movement model, where a generic cue is evaluated locally or nonlocally to determine a preferred direction, we state corresponding macroscopic partial differential equations to describe population movements. Under certain approximations, these models reduce to well-known local and nonlocal biological transport equations, including those of Keller-Segel type. We consider a case-study application: "hilltopping" in Lepidoptera and other insects, a phenomenon in which populations accumulate at summits to improve encounter/mating rates. Nonlocal responses are shown to efficiently filter out the natural noisiness (or roughness) of typical landscapes and allow the population to preferentially accumulate at a subset of hilltopping locations, in line with field studies. Moreover, according to the timescale of movement, optimal responses may occur for different perceptual ranges.


Water-Soluble Flexible Organic Frameworks That Include and Deliver Proteins.
Four water-soluble hydrazone-based three-dimensional (3D) flexible organic frameworks FOF-1-4 have been synthesized from a semirigid tetracationic tetraaldehyde and four flexible dihydrazides. 1H NMR spectroscopy indicated the quantitative formation of FOF-1-4 in D2O, while dynamic light scattering experiments revealed that, depending on the concentration, these porous frameworks display hydrodynamic diameters ranging from 50 to 120 nm. The porosity of the frameworks is confirmed by ethanol vapor adsorption experiments of the solid samples as well as the high loading capacity for a 2.3 nm porphyrin guest in water. The new water-soluble frameworks exhibit low cytotoxicity and form inherent pores with diameters of 5.3 or 6.7 nm, allowing rapid inclusion of proteins such as bovine serum albumin and green and orange fluorescent proteins, and efficient delivery of the proteins into normal and cancer cells. Flow cytometric analysis reveals percentages of the delivered cells up to 99.8%.


'Nicotine deprivation effect' in rats with intermittent 23-hour access to intravenous nicotine self-administration.
Our previous work demonstrates that rats allowed extended 23-hour access to intravenous nicotine self-administration (IVSA) display voluntary, dose-related levels of nicotine intake (i.e., higher doses result in higher intake) that remain stable across 40 days. This study examined whether an escalating dose regimen with intermittent abstinence periods produces different levels of nicotine intake relative to those observed during continuous access to a fixed unit dose. Rats were trained to nose-poke for food and water in 23-hour sessions prior to and after recovery from surgical implantation of jugular catheters. Animals (n=12) then were given access to nicotine IVSA in 4-day cycles, each separated by three intervening days of abstinence in their home cage. The unit dose available for nicotine IVSA was increased between cycles as follows: 0.015, 0.03, 0.06, 0.09 mg/kg/0.1 ml infusion/1 s, fixed ratio 1. Control rats (n=6) were given access to saline for five 4-day IVSA periods. Nicotine dependence was assessed by examining physical signs of withdrawal following an injection of the nicotinic antagonist mecamylamine (1.5 mg/kg, i.p.). Nicotine intake dose-dependently increased between cycles. Within each cycle, nicotine intake was highest on the first day after abstinence and decreased over the next 3 days of continuous access. Mecamylamine produced a significant increase in overt signs of withdrawal in the 23-hour access animals comparable to that observed in previous studies of nicotine dependence. Our findings suggest that abstinence from nicotine may produce a "deprivation effect" in nicotine-dependent rats. In addition, intermittent access to increasing unit doses appears to produce higher levels of nicotine intake than continuous access to a constant unit nicotine dose.


Physicochemical properties correlated with drug resistance and the reversal of drug resistance in Plasmodium falciparum.
At high molar excess, verapamil can selectively increase the accumulation and cytotoxicity of structurally dissimilar natural product drugs in many multidrug-resistant tumor cell lines. Such concentrations of verapamil are also capable of increasing the accumulation and activity of chloroquine in chloroquine-resistant strains of the human malaria parasite Plasmodium falciparum. Despite such similarities, it is not clear why chloroquine-resistant P. falciparum is often susceptible to closely related compounds such as amodiaquine, whereas cancer cells are cross-resistant to many structurally unrelated drugs. For 13 aminoquinoline and aminoacridine compounds, relative drug resistance was negatively correlated with lipid solubility at physiological pH (r2 = 0.90, p < 0.0001). The ability of verapamil (5 microM) to reverse drug resistance was also negatively correlated with lipid solubility (r2 = 0.88, p < 0.0001). Furthermore, molar refractivity was weakly correlated with relative drug resistance (r2 = 0.46, p < 0.05) and reversal of drug resistance (r2 = 0.52, p < 0.005). Verapamil increases chloroquine accumulation by resistant parasites, a mechanism suggested to account for its selective chemosensitization effect. We show that the initial rate of chloroquine accumulation by resistant parasites is increased by verapamil. This effect of verapamil is abolished when deoxy-glucose is substituted for glucose. Therefore, verapamil produces an energy-dependent increase in the permeability of resistant parasites to chloroquine. For a panel of four chloroquine-resistant and two chloroquine-susceptible isolates, the effect of verapamil on the accumulation of chloroquine and monodesethyl amodiaquine was found to be correlated (r2 = 0.96, p < 0.001). Verapamil chemosensitization was also correlated for the two drugs (r2 = 0.92, p < 0.005), suggesting a common mechanism. In summary, the degree of drug resistance and the extent of verapamil chemosensitization for a particular drug seem to be dependent on general physical features such as lipid solubility and molar refractivity rather than on closely defined structural parameters. These studies provide insight into this important resistance mechanism of malaria parasites and may provide direction for the development of new drugs that are effective against resistant parasites.


Ionizing radiation biomarkers for potential use in epidemiological studies.
Ionizing radiation is a known human carcinogen that can induce a variety of biological effects depending on the physical nature, duration, doses and dose-rates of exposure. However, the magnitude of health risks at low doses and dose-rates (below 100mSv and/or 0.1mSvmin(-1)) remains controversial due to a lack of direct human evidence. It is anticipated that significant insights will emerge from the integration of epidemiological and biological research, made possible by molecular epidemiology studies incorporating biomarkers and bioassays. A number of these have been used to investigate exposure, effects and susceptibility to ionizing radiation, albeit often at higher doses and dose rates, with each reflecting time-limited cellular or physiological alterations. This review summarises the multidisciplinary work undertaken in the framework of the European project DoReMi (Low Dose Research towards Multidisciplinary Integration) to identify the most appropriate biomarkers for use in population studies. In addition to logistical and ethical considerations for conducting large-scale epidemiological studies, we discuss the relevance of their use for assessing the effects of low dose ionizing radiation exposure at the cellular and physiological level. We also propose a temporal classification of biomarkers that may be relevant for molecular epidemiology studies which need to take into account the time elapsed since exposure. Finally, the integration of biology with epidemiology requires careful planning and enhanced discussions between the epidemiology, biology and dosimetry communities in order to determine the most important questions to be addressed in light of pragmatic considerations including the appropriate population to be investigated (occupationally, environmentally or medically exposed), and study design. The consideration of the logistics of biological sample collection, processing and storing and the choice of biomarker or bioassay, as well as awareness of potential confounding factors, are also essential.


Impact of clinical decision support on receipt of antibiotic prescriptions for acute bronchitis and upper respiratory tract infection.
Antibiotics are commonly recognized as non-indicated for acute bronchitis and upper respiratory tract infection (URI), yet their widespread use persists. Clinical decision support in the form of electronic warnings is hypothesized to prevent non-indicated prescriptions. The purpose of this study was to identify the effect of clinical decision support on a common type of non-indicated prescription. Using National Ambulatory Medical Care Survey data from 2006 to 2010, ambulatory visits with a primary diagnosis of acute bronchitis or URI and orders for antibiotic prescriptions were identified. Visits were classified on the basis of clinician report of decision-support use. Generalized estimating equations were used to assess the effect of decision support on likelihood of antibiotic prescription receipt, controlling for patient, provider, and practice characteristics. Clinician use of decision support increased sharply between 2006 (16% of visits) and 2010 (55%). Antibiotic prescribing for acute bronchitis and URI increased from ∼35% of visits in 2006 to ∼45% by 2010. Use of decision support was associated with a 19% lower likelihood of receiving an antibiotic prescription, controlling for patient, provider, and practice characteristics. In spite of the increased use of decision-support systems and the relatively fewer non-indicated antibiotic prescriptions resulting from the use of decision support, a secular upward trend in non-indicated antibiotic prescribing offset these improvements. The overall effect of decision support suggests an important role for technology in reducing non-indicated prescriptions. Decision support alone may not be sufficient to eliminate non-indicated prescriptions given secular trends.


Neuroimaging predictors of functional outcomes in schizophrenia at baseline and 6-month follow-up.
Studies show that deficit syndrome schizophrenia patients, characterized by primary negative symptoms and poor functional outcome, have impairment in specific neural circuits. We assessed whether these same neural circuits are directly linked to functional outcomes across schizophrenia patients. T1- and diffusion-weighted MR images were obtained for schizophrenia (n=30) and matched healthy control participants (n=30). Negative symptoms and functional outcome were assessed at baseline and 6-month follow-up. Cortical thickness and tract-wise fractional anisotropy (FA) were compared between groups. To assess relationships of neuroimaging measures with functional outcome, principal component analysis (PCA) was performed on tract-wise FA values and components were entered into a multiple regression model for schizophrenia participants. Consistent with the literature, schizophrenia participants showed frontotemporal reductions in cortical thickness and tract-wise FA compared to controls. The top two components from PCA explained 71% of the variance in tract-wise FA values. The second component (associated with inferior longitudinal and arcuate fasciculus FA) was significantly correlated with functional outcome (baseline: β=0.54, p=0.03; follow-up: β=0.74, p=0.047); further analysis revealed this effect was mediated by negative symptoms. Post-hoc network analysis revealed increased cortical coupling between right inferior frontal and supramarginal gyri (connected by the arcuate fasciculus) in schizophrenia participants with poorer functional outcome. Our findings indicate that impairment in the same neural circuitry susceptible in deficit syndrome schizophrenia predicts functional outcome in a continuous manner in schizophrenia participants. This relationship was mediated by negative symptom burden. Our findings provide novel evidence for brain-based biomarkers of longitudinal functional outcome in people with schizophrenia.


Physicians' use of key functions in electronic health records from 2005 to 2007: a statewide survey.
OBJECTIVE Electronic health records (EHRs) have potential to improve quality and safety, but many physicians do not use these systems to full capacity. The objective of this study was to determine whether this usage gap is narrowing over time. DESIGN Follow-up mail survey of 1,144 physicians in Massachusetts who completed a 2005 survey. MEASUREMENTS Adoption of EHRs and availability and use of 10 EHR functions. RESULTS The response rate was 79.4%. In 2007, 35% of practices had EHRs, up from 23% in 2005. Among practices with EHRs, there was little change between 2005 and 2007 in the availability of nine of ten EHR features; the notable exception was electronic prescribing, reported as available in 44.7% of practices with EHRs in 2005 and 70.8% in 2007. Use of EHR functions changed inconsequentially, with more than one out of five physicians not using each available function regularly in both 2005 and 2007. Only electronic prescribing increased substantially: in 2005, 19.9% of physicians with this function available used it most or all the time, compared with 42.6% in 2007 (p < 0.001). CONCLUSIONS By 2007, more than one third of practices in Massachusetts reported having EHRs; the availability and use of electronic prescribing within these systems has increased. In contrast, physicians reported little change in the availability and use of other EHR functions. System refinements, certification efforts, and health policies, including standards development, should address the gaps in both EHR adoption and the use of key functions.


Trans-ethnic gut microbiota signatures of type 2 diabetes in Denmark and India.
Type 2 diabetes (T2D), a multifactorial disease influenced by host genetics and environmental factors, is the most common endocrine disease. Several studies have shown that the gut microbiota as a close-up environmental mediator influences host physiology including metabolism. The aim of the present study is to examine the compositional and functional potential of the gut microbiota across individuals from Denmark and South India with a focus on T2D. Many earlier studies have investigated the microbiome aspects of T2D, and it has also been anticipated that such microbial associations would be dependent on diet and ethnic origin. However, there has been no large scale trans-ethnic microbiome study earlier in this direction aimed at evaluating any "universal" microbiome signature of T2D. 16S ribosomal RNA gene amplicon sequencing was performed on stool samples from 279 Danish and 294 Indian study participants. Any differences between the gut microbiota of both populations were explored using diversity measures and negative binomial Wald tests. Study samples were stratified to discover global and country-specific microbial signatures for T2D and treatment with the anti-hyperglycemic drug, metformin. To identify taxonomical and functional signatures of the gut microbiota for T2D and metformin treatment, we used alpha and beta diversity measures and differential abundances analysis, comparing metformin-naive T2D patients, metformin-treated T2D patients, and normoglycemic individuals. Overall, the gut microbial communities of Danes and Indians are compositionally very different. By analyzing the combined study materials, we identify microbial taxonomic and functional signatures for T2D and metformin treatment. T2D patients have an increased relative abundance of two operational taxonomic units (OTUs) from the Lachnospiraceae family, and a decreased abundance of Subdoligranulum and Butyricicoccus. Studying each population per se, we identified T2D-related microbial changes at the taxonomic level within the Danish population only. Alpha diversity indices show that there is no significant difference between normoglycemic individuals and metformin-naive T2D patients, whereas microbial richness is significantly decreased in metformin-treated T2D patients compared to metformin-naive T2D patients and normoglycemic individuals. Enrichment of two OTUs from Bacteroides and depletion of Faecalibacterium constitute a trans-ethnic signature of metformin treatment. We demonstrate major compositional differences of the gut microbiota between Danish and South Indian individuals, some of which may relate to differences in ethnicity, lifestyle, and demography. By comparing metformin-naive T2D patients and normoglycemic individuals, we identify T2D-related microbiota changes in the Danish and Indian study samples. In the present trans-ethnic study, we confirm that metformin changes the taxonomic profile and functional potential of the gut microbiota.


GeneFriends: an online co-expression analysis tool to identify novel gene targets for aging and complex diseases.
Although many diseases have been well characterized at the molecular level, the underlying mechanisms are often unknown. Nearly half of all human genes remain poorly studied, yet these genes may contribute to a number of disease processes. Genes involved in common biological processes and diseases are often co-expressed. Using known disease-associated genes in a co-expression analysis may help identify and prioritize novel candidate genes for further study. We have created an online tool, called GeneFriends, which identifies co-expressed genes in over 1,000 mouse microarray datasets. GeneFriends can be used to assign putative functions to poorly studied genes. Using a seed list of disease-associated genes and a guilt-by-association method, GeneFriends allows users to quickly identify novel genes and transcription factors associated with a disease or process. We tested GeneFriends using seed lists for aging, cancer, and mitochondrial complex I disease. We identified several candidate genes that have previously been predicted as relevant targets. Some of the genes identified are already being tested in clinical trials, indicating the effectiveness of this approach. Co-expressed transcription factors were investigated, identifying C/ebp genes as candidate regulators of aging. Furthermore, several novel candidate genes, that may be suitable for experimental or clinical follow-up, were identified. Two of the novel candidates of unknown function that were co-expressed with cancer-associated genes were selected for experimental validation. Knock-down of their human homologs (C1ORF112 and C12ORF48) in HeLa cells slowed growth, indicating that these genes of unknown function, identified by GeneFriends, may be involved in cancer. GeneFriends is a resource for biologists to identify and prioritize novel candidate genes involved in biological processes and complex diseases. It is an intuitive online resource that will help drive experimentation. GeneFriends is available online at: http://genefriends.org/.


Taking the fungal highway: mobilization of pollutant-degrading bacteria by fungi.
The capacity of fungi to serve as vectors for the dispersion of pollutant-degrading bacteria was analyzed in laboratory model systems mimicking water-saturated (agar surfaces) and unsaturated soil environments (glass-bead-filled columns). Two common soil fungi (Fusarium oxysporum and Rhexocercosporidium sp.) forming hydrophilic and hydrophobic mycelia, respectively, and three polycyclic aromatic hydrocarbon degrading bacteria (Achromobacter sp. SK1, Mycobacterium frederiksbergense LB501TG, and Sphingomonas sp. L138) were selected based on the absence of mutual antagonistic effects. It was shown that fungal hyphae act as vectors for bacterial transport with mobilization strongly depending on the specific microorganisms chosen: The motile strain Achromobacter sp. SK1 was most efficiently spread along hyphae of hydrophilic F. oxysporum in both model systems with transport velocities of up to 1 cm d(-1), whereas no dispersion of the two nonmotile strains was observed in the presence of F. oxysporum. By contrast, none of the bacteria was mobilized along the hydrophobic mycelia of Rhexocercosporidium sp. growing on agar surfaces. In column experiments however, strain SK1 was mobilized by Rhexocercosporidium sp. It is hypothesized that bacteria may move by their intrinsic motilitythrough continuous (physiological) liquid films forming around fungal hyphae. The results of this study suggest that the specific stimulation of indigenous fungi may be a strategy to mobilize pollutant-degrading bacteria leading to their homogenization in polluted soil thereby improving bioremediation.


Cross-cultural comparisons of Irish and American adolescent drinking practices and beliefs.
The drinking behavior and alcohol expectancies of 168 Irish adolescents aged 15-18 were compared with those of a group of American adolescents matched on age and sex. The Irish adolescents reported less frequent social drinking and less problematic drinking. However, unlike American adolescents, those Irish youth who did drink in a social, frequent manner also reported drinking-related problems Irish adolescents expect less social benefit, less improvement of cognitive and motor functioning and less sexual enhancement, but greater increase in aggression as a consequence of drinking. These findings are discussed as possible etiological clues to established differences between Irish adult drinking and drinking by adults in other countries.


Halothane genotype and pork quality. 2. Cured meat products of three halothane genotypes.
The effect of the halothane gene on cured meat products was investigated using the meat from 60 Landrace×Large White pigs of known halothane genotype (NN=25, Nn=19, nn=16). The backs and hams were used to prepare cured, smoked bacon and canned hams. Initial bacon gain in pumped weight was significantly higher (P<0.001) for the NN (15.2%) and Nn (14.9%) compared to the nn pigs (8.9%). Similarly, the total gain in bacon yield was the highest for the Nn (11.5%) and NN pigs (10.0%), and significantly higher (P<0.05) than the bacon from nn pigs (3.4%). Differences between sexes were not significant. Canned hams (no phosphate) from the NN genotype had a significantly (P<0.001) lower percentage cooking loss (27.9%) compared to the Nn (30.1%) and nn pigs (31.1%), which did not differ statistically. Although addition of phosphates (0.3% on final product) led to a decrease in percentage cooking loss, the genotypes gave a similar response, with the NN genotype having 13.8% cooking loss, significantly lower (P<0.001) than the Nn (16.9%) and nn genotypes (17.7%). The results indicate reduced product quality with the inclusion of the halothane gene.


Residual human immunodeficiency virus (HIV) Type 1 RNA and DNA in lymph nodes and HIV RNA in genital secretions and in cerebrospinal fluid after suppression of viremia for 2 years.
Residual viral replication persists in a significant proportion of human immunodeficiency virus (HIV)-infected patients receiving potent antiretroviral therapy. To determine the source of this virus, levels of HIV RNA and DNA from lymphoid tissues and levels of viral RNA in serum, cerebrospinal fluid (CSF), and genital secretions in 28 patients treated for < or =2.5 years with indinavir, zidovudine, and lamivudine were examined. Both HIV RNA and DNA remained detectable in all lymph nodes. In contrast, HIV RNA was not detected in 20 of 23 genital secretions or in any of 13 CSF samples after 2 years of treatment. HIV envelope sequence data from plasma and lymph nodes from 4 patients demonstrated sequence divergence, which suggests varying degrees of residual viral replication in 3 and absence in 1 patient. In patients receiving potent antiretroviral therapy, the greatest virus burden may continue to be in lymphoid tissues rather than in central nervous system or genitourinary compartments.


MADEx: A System for Detecting Medications, Adverse Drug Events, and Their Relations from Clinical Notes.
Early detection of adverse drug events (ADEs) from electronic health records is an important, challenging task to support pharmacovigilance and drug safety surveillance. A well-known challenge to use clinical text for detection of ADEs is that much of the detailed information is documented in a narrative manner. Clinical natural language processing (NLP) is the key technology to extract information from unstructured clinical text. We present a machine learning-based clinical NLP system-MADEx-for detecting medications, ADEs, and their relations from clinical notes. We developed a recurrent neural network (RNN) model using a long short-term memory (LSTM) strategy for clinical name entity recognition (NER) and compared it with baseline conditional random fields (CRFs). We also developed a modified training strategy for the RNN, which outperformed the widely used early stop strategy. For relation extraction, we compared support vector machines (SVMs) and random forests on single-sentence relations and cross-sentence relations. In addition, we developed an integrated pipeline to extract entities and relations together by combining RNNs and SVMs. MADEx achieved the top-three best performances (F1 score of 0.8233) for clinical NER in the 2018 Medication and Adverse Drug Events (MADE1.0) challenge. The post-challenge evaluation showed that the relation extraction module and integrated pipeline (identify entity and relation together) of MADEx are comparable with the best systems developed in this challenge. This study demonstrated the efficiency of deep learning methods for automatic extraction of medications, ADEs, and their relations from clinical text to support pharmacovigilance and drug safety surveillance.


Dilemmas in the reliable estimation of the in-vitro cell viability in magnetic nanoparticle engineering: which tests and what protocols?
Magnetic nanoparticles [MNPs] made from iron oxides have many applications in biomedicine. Full understanding of the interactions between MNPs and mammalian cells is a critical issue for their applications. In this study, MNPs were coated with poly(ethylenimine) [MNP-PEI] and poly(ethylene glycol) [MNP-PEI-PEG] to provide a subtle difference in their surface charge and their cytotoxicity which were analysed by three standard cell viability assays: 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium [MTS], CellTiter-Blue and CellTiter-Glo (Promega, Southampton, UK) in SH-SY5Y and RAW 264.7 cells The data were validated by traditional trypan blue exclusion. In comparison to trypan blue manual counting, the MTS and Titer-Blue assays appeared to have consistently overestimated the viability. The Titer-Glo also experienced a small overestimation. We hypothesise that interactions were occurring between the assay systems and the nanoparticles, resulting in incorrect cell viability evaluation. To further understand the cytotoxic effect of the nanoparticles on these cells, reactive oxygen species production, lipid peroxidation and cell membrane integrity were investigated. After pegylation, the MNP-PEI-PEG possessed a lower positive surface charge and exhibited much improved biocompatibility compared to MNP-PEI, as demonstrated not only by a higher cell viability, but also by a markedly reduced oxidative stress and cell membrane damage. These findings highlight the importance of assay selection and of dissection of different cellular responses in in-vitro characterisation of nanostructures.


Energy transfer and enhanced 1.54 μm emission in Erbium-Ytterbium disilicate thin films.
α-(Yb1-xErx)2Si2O7 thin films on Si substrates were synthesized by magnetron co-sputtering. The optical emission from Er3+ ions has been extensively investigated, evidencing the very efficient role of Yb-Er coupling. The energy-transfer coefficient was evaluated for an extended range of Er content (between 0.2 and 16.5 at.%) reaching a maximum value of 2 × 10⁻¹⁶ cm⁻³s⁻¹. The highest photoluminescence emission at 1535 nm is obtained as a result of the best compromise between the number of Yb donors (16.4 at.%) and Er acceptors (1.6 at.%), for which a high population of the first excited state is reached. These results are very promising for the realization of 1.54 μm optical amplifiers on a Si platform.


Association between a germline OCA2 polymorphism at chromosome 15q13.1 and estrogen receptor-negative breast cancer survival.
Traditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted two-stage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival. We evaluated possible associations between overall survival after a breast cancer diagnosis and 10 621 germline single-nucleotide polymorphisms (SNPs) from up to 3761 patients with invasive breast cancer (including 647 deaths and 26 978 person-years at risk) that were genotyped previously in the SEARCH study with high-density oligonucleotide microarrays (ie, hypothesis-generating set). Associations with all-cause mortality were assessed for each SNP by use of Cox regression analysis, generating a per rare allele hazard ratio (HR). To validate putative associations, we used patient genotype information that had been obtained with 5' nuclease assay or mass spectrometry and overall survival information for up to 14 096 patients with invasive breast cancer (including 2303 deaths and 70 019 person-years at risk) from 15 international case-control studies (ie, validation set). Fixed-effects meta-analysis was used to generate an overall effect estimate in the validation dataset and in combined SEARCH and validation datasets. All statistical tests were two-sided. In the hypothesis-generating dataset, SNP rs4778137 (C>G) of the OCA2 gene at 15q13.1 was statistically significantly associated with overall survival among patients with estrogen receptor-negative tumors, with the rare G allele being associated with increased overall survival (HR of death per rare allele carried = 0.56, 95% confidence interval [CI] = 0.41 to 0.75, P = 9.2 x 10(-5)). This association was also observed in the validation dataset (HR of death per rare allele carried = 0.88, 95% CI = 0.78 to 0.99, P = .03) and in the combined dataset (HR of death per rare allele carried = 0.82, 95% CI = 0.73 to 0.92, P = 5 x 10(-4)). The rare G allele of the OCA2 polymorphism, rs4778137, may be associated with improved overall survival among patients with estrogen receptor-negative breast cancer.


Allele frequency changes due to hitch-hiking in genomic selection programs.
Genomic selection makes it possible to reduce pedigree-based inbreeding over best linear unbiased prediction (BLUP) by increasing emphasis on own rather than family information. However, pedigree inbreeding might not accurately reflect loss of genetic variation and the true level of inbreeding due to changes in allele frequencies and hitch-hiking. This study aimed at understanding the impact of using long-term genomic selection on changes in allele frequencies, genetic variation and level of inbreeding. Selection was performed in simulated scenarios with a population of 400 animals for 25 consecutive generations. Six genetic models were considered with different heritabilities and numbers of QTL (quantitative trait loci) affecting the trait. Four selection criteria were used, including selection on own phenotype and on estimated breeding values (EBV) derived using phenotype-BLUP, genomic BLUP and Bayesian Lasso. Changes in allele frequencies at QTL, markers and linked neutral loci were investigated for the different selection criteria and different scenarios, along with the loss of favourable alleles and the rate of inbreeding measured by pedigree and runs of homozygosity. For each selection criterion, hitch-hiking in the vicinity of the QTL appeared more extensive when accuracy of selection was higher and the number of QTL was lower. When inbreeding was measured by pedigree information, selection on genomic BLUP EBV resulted in lower levels of inbreeding than selection on phenotype BLUP EBV, but this did not always apply when inbreeding was measured by runs of homozygosity. Compared to genomic BLUP, selection on EBV from Bayesian Lasso led to less genetic drift, reduced loss of favourable alleles and more effectively controlled the rate of both pedigree and genomic inbreeding in all simulated scenarios. In addition, selection on EBV from Bayesian Lasso showed a higher selection differential for mendelian sampling terms than selection on genomic BLUP EBV. Neutral variation can be shaped to a great extent by the hitch-hiking effects associated with selection, rather than just by genetic drift. When implementing long-term genomic selection, strategies for genomic control of inbreeding are essential, due to a considerable hitch-hiking effect, regardless of the method that is used for prediction of EBV.


Adherence of Borrelia burgdorferi to the proteoglycan decorin.
Lyme disease is a tick-borne infection that can develop into a chronic, multisystemic disorder. The causative agent, Borrelia burgdorferi, is initially deposited by the tick into the host dermis, where it associates with collagen fibers, replicates, and eventually disseminates to other tissues. We have examined the adherence of the spirochete to different components of the collagen fiber and demonstrated that decorin, a proteoglycan which decorates collagen fibers, can support the attachment of B. burgdorferi. No significant direct attachment to isolated type I or III collagens could be detected. Attachment of the spirochetes to decorin was highly specific, and the process could be inhibited by soluble decorin but not by various unlabeled, unrelated components. B. burgdorferi also bound soluble 125I-labeled decorin in a time- and concentration-dependent manner. Spirochete binding of soluble 125I-labeled decorin required intact proteoglycan and could not be inhibited by either isolated core protein or glycosaminoglycan chain. B. burgdorferi expresses two decorin-binding proteins with apparent molecular masses of 19 and 20 kDa as revealed in a Western blot (immunoblot)-type assay. Our results indicate that decorin may mediate the adherence of B. burgdorferi to collagen fibers in skin and other tissues.


Hearing loss in the developing world: evaluating the iPhone mobile device as a screening tool.
Developing countries have the world's highest prevalence of hearing loss, and hearing screening programmes are scarce. Mobile devices such as smartphones have potential for audiometric testing. To evaluate the uHear app using an Apple iPhone as a possible hearing screening tool in the developing world, and to determine accuracy of certain hearing thresholds that could prove useful in early detection of hearing loss for high-risk populations in resource-poor communities. This was a quasi-experimental study design. Participants recruited from the Otolaryngology Clinic, Groote Schuur Hospital, Cape Town, South Africa, completed a uHear test in three settings--waiting room (WR), quiet roon (QR) and soundproof room (SR). Thresholds were compared with formal audiograms. Twenty-five patients were tested (50 ears). The uHear test detected moderate or worse hearing loss (pure-tone average (PTA) > 40 dB accurately with a sensitivity of 100% in all three environments. Specificity was 88% (SR), 73% (QR) and 68% (WR). Its was highly accurate in detecting high-frequency hearing loss (2 000, 4 000, 6 000 Hz) in the QR and SR with 'good' and 'very good' kappa values, showing statistical significance (p < 0.05). It was moderately accurate in low-frequency hearing loss (250, 500, 1 000 Hz) in the SR, and poor in the QR and WR. Using the iPhone, uHear is a feasible screening test to rule out significant hearing loss (PTA > 40 dB). It is highly sensitive for detecting threshold changes at high frequencies, making it reasonably well suited to detect presbycusis and ototoxic hearing loss from HIV, tuberculosis therapy and chemotherapy. Portability and ease of use make it appropriate to use in developing world communities that lack screening programmes.


GFAJ-1 is an arsenate-resistant, phosphate-dependent organism.
The bacterial isolate GFAJ-1 has been proposed to substitute arsenic for phosphorus to sustain growth. We have shown that GFAJ-1 is able to grow at low phosphate concentrations (1.7 μM), even in the presence of high concentrations of arsenate (40 mM), but lacks the ability to grow in phosphorus-depleted (<0.3 μM), arsenate-containing medium. High-resolution mass spectrometry analyses revealed that phosphorylated central metabolites and phosphorylated nucleic acids predominated. A few arsenylated compounds, including C6 sugar arsenates, were detected in extracts of GFAJ-1, when GFAJ-1 was incubated with arsenate, but further experiments showed they formed abiotically. Inductively coupled plasma mass spectrometry confirmed the presence of phosphorus in nucleic acid extracts, while arsenic could not be detected and was below 1 per mil relative to phosphorus. Taken together, we conclude that GFAJ-1 is an arsenate-resistant, but still a phosphate-dependent, bacterium.


Clinical Features of Heterosexual Intimate Partner Violence Victims With Escalating Injury Severity.
Intimate partner violence (IPV) is largely recognized to have a cyclical pattern and violence escalation in terms of frequency and intensity over time. However, there is a lack of systematic investigation of the profiles of victims and quantification of the patterns of injury of the victims associated with the first time versus repeated violence episodes. This study aimed to fill this knowledge gap by medical chart review of 878 victims in a 5-year period from 2010 to 2014 in Accident and Emergency Department (AED) of two public general hospitals in Hong Kong. The differences in injury patterns between the first IPV episode (FE) and recurrent IPV episodes (REs) experienced by male and female victims in heterosexual relationship were evaluated. The results indicated the violence escalation occurred in recurrent IPV in both genders. In female victims, there was significant increase in the number of injury locations (mean [M] = 2.0 vs. 2.2, p < .05), number of causes of injury (M = 1.7 vs. 2.2, p < .001) and police escort (15.2% vs. 22.1%, p < .05) in RE compared to FE. In male victims, however, only the increase in the number of causes of injury was significant (M = 1.6 vs. 2.1, p < .05) in RE compared to FE. In summary, our results highlight the escalation in the severity of harm of IPV victims in heterosexual relationship, and the gender differences in severity aggression and injury and help-seeking behavior change in recurrent IPV. Preventive measures are indicated to intervene the IPV occurrence and recurrence with rising morbidity and a potential of mortality.


The replicability of QTLs for murine alcohol preference drinking behavior across eight independent studies.
On the basis of eight independent quantitative trait loci (QTL) studies of ethanol (alcohol) preference drinking in mice, a meta-analysis was carried out to examine the replicability of QTLs across studies and to enhance the power of QTL detection and parameter estimation. To avoid genetic heterogeneity, we analyzed only studies of mapping populations derived from the C57BL/6 (B6) and DBA/2 (D2) inbred progenitor strains. Because these studies were carried out in five different laboratories, there were substantial differences in testing procedure, data analysis, and especially in the choice of mapping population (BXD recombinant inbred strains, F2, backcross, selected lines, or congenic strains). Despite this, we found several QTLs that were sufficiently robust as to appear consistently across studies given the strengths and weaknesses of the mapping populations employed. These were on Chromosomes (Chrs) 2 (proximal to mid), 3 (mid to distal), 4 (distal), and 9 (proximal to mid). The P value for each of these QTLs, combined across all applicable studies, ranged from 10(-7) to 10(-15), with the additive effect of each QTL accounting for 3-5% of the trait variance extrapolated to an F2 population. Two other QTLs on Chrs 1 (distal) and 11 (mid) were less consistent, but still reached overall significance (P <.0001).


Autosomal recessive mesoaxial synostotic syndactyly with phalangeal reduction maps to chromosome 17p13.3.
Previously we have described a novel and distinct form of non-syndromic osseous syndactyly segregating in an autosomal recessive pattern in a consanguineous Pakistani family. The limb findings include mesoaxial reduction of the fingers, synostoses of the third and fourth metacarpals with associated single phalanges, fifth finger clinodactyly, and preaxial webbing of toes. We identified another published report of this phenotype in a large, inbred Turkish family. In the present study we mapped the phenotype in the Pakistani and Turkish families to chromosome 17p13.3 (multipoint LOD score 5.1). The identification of a single locus for this complex limb malformation in two families with distinct ethnic backgrounds supports the hypothesis that this is a distinct form of syndactyly. Since this form of syndactyly is phenotypically distinct from the previously described eight types, we propose to name this phenotype mesoaxial synostotic syndactyly with phalangeal reduction (MSSD, type IX syndactyly, Malik-Percin type).


Add-on omalizumab in children with severe allergic asthma: a 1-year real life survey.
Omalizumab has been shown to reduce exacerbation rates in moderate to severe allergic asthma. Our aim was to evaluate omalizumab efficacy and safety in a real-life setting in severe asthmatic children. 104 children (aged 6-18 years), followed up in paediatric pulmonary tertiary care centres, were included at the beginning of omalizumab treatment. Asthma control levels, exacerbations, inhaled corticosteroid dose, lung function and adverse events were evaluated over 1 year. Children were characterised by allergic sensitisation to three or more allergens (66%), high IgE levels (mean 1125 kU · L(-1)), high rate of exacerbations (4.4 per year) and healthcare use during the previous year, and high inhaled corticosteroid dose (mean 703 μg equivalent fluticasone per day). Asthma control levels defined as good, partial or poor, improved from 0%, 18% and 82% at entry to 53%, 30% and 17% at week 20, and to 67%, 25% and 8% at week 52, respectively (p<0.0001). Exacerbation and hospitalisation rates dropped by 72% and 88.5%, respectively. At 12 months, forced expiratory volume in 1 s improved by 4.9% (p=0.023), and inhaled corticosteroid dose decreased by 30% (p<0.001). Six patients stopped omalizumab for related significant adverse events. Omalizumab improved asthma control in children with severe allergic asthma and was generally well tolerated. The observed benefit was greater than that reported in clinical trials.


A systematic literature review analysis of ultrasound joint count and scoring systems to assess synovitis in rheumatoid arthritis according to the OMERACT filter.
The OMERACT Ultrasound Task Force is currently developing a global synovitis score (GLOSS) with the objective of feasibly measuring global disease activity in patients with rheumatoid arthritis (RA). In order to determine the minimal number of joints to be included in such a scoring system, and to analyze the metric properties of proposed global (i.e., patient level) ultrasound (US) scoring systems of synovitis in RA, a systematic analysis of the literature was performed. A systematic literature search of Pubmed and Embase was performed (January 1, 1984, to March 31, 2010). Original research reports written in English including RA, ultrasound, Doppler, and scoring systems were included. The design, subjects, methods, imaging protocols, and performance characteristics studied were analyzed, as well as the ultrasound definition of synovitis. Of 3004 reports identified, 14 articles were included in the review. We found a lack of clear definition of synovitis as well as varying validity data with respect to the proposed scores. Scoring systems included a wide range and number of joints. All analyzed studies assessed construct validity and responsiveness by using clinical examination, laboratory findings, and other imaging modalities as comparators. Both construct validity and responsiveness varied according to the number and size of joints examined and according to the component of synovitis measured [i.e., gray-scale (GS) or power Doppler (PD) alone or in combination]. With regard to feasibility, time of evaluation varied from 15 to 60 min and increased with the number of joints involved in the examination. Ultrasound can be regarded as a valuable tool for globally examining the extent of synovitis in RA. However, it is presently difficult to determine a minimal number of joints to be included in a global ultrasound score. Further validation of proposed scores is needed.


Pathophysiological Mechanisms of Cognitive Impairment and Neurodegeneration by Toxoplasma gondii Infection.
Toxoplasma gondii is an obligate intracellular parasite considered one of the most successful pathogens in the world, owing to its ability to produce long-lasting infections and to persist in the central nervous system (CNS) in most warm-blooded animals, including humans. This parasite has a preference to invade neurons and affect the functioning of glial cells. This could lead to neurological and behavioral changes associated with cognitive impairment. Although several studies in humans and animal models have reported controversial results about the relationship between toxoplasmosis and the onset of dementia as a causal factor, two recent meta-analyses have shown a relative association with Alzheimer's disease (AD). AD is characterized by amyloid-β (Aβ) peptide accumulation, neurofibrillary tangles, and neuroinflammation. Different authors have found that toxoplasmosis may affect Aβ production in brain areas linked with memory functioning, and can induce a central immune response and neurotransmitter imbalance, which in turn, affect the nervous system microenvironment. In contrast, other studies have revealed a reduction of Aβ plaques and hyperphosphorylated tau protein formation in animal models, which might cause some protective effects. The aim of this article is to summarize and review the newest data in regard to different pathophysiological mechanisms of cerebral toxoplasmosis and their relationship with the development of AD and cognitive impairment. All these associations should be investigated further through clinical and experimental studies.


Identifying and assisting the impaired physician.
An impaired physician is one unable to fulfill professional or personal responsibilities because of psychiatric illness, alcoholism, or drug dependency. Current estimates are that approximately 15% of physicians will be impaired at some point in their careers. Although physicians may not have higher rates of impairment compared with other professionals, factors in their background, personality, and training may contribute and predispose them to drug abuse and mental illness, particularly depression. Many physicians possess a strong drive for achievement, exceptional conscientiousness, and an ability to deny personal problems. These attributes are advantageous for "success" in medicine; ironically, however, they may also predispose to impairment. Identifying impairment is often difficult because the manifestations are varied and physicians will typically suppress and deny any suggestion of a problem. Identification is essential because patient well-being may be at stake, and untreated impairment may result in loss of license, health problems, and even death. Fortunately, once identified and treated, physicians often do better in recovery than others and typically can return to a productive career and a satisfying personal and family life.


Canada's global health role: supporting equity and global citizenship as a middle power.
Canada's history of nation building, combined with its status as a so-called middle power in international affairs, has been translated into an approach to global health that is focused on equity and global citizenship. Canada has often aspired to be a socially progressive force abroad, using alliance building and collective action to exert influence beyond that expected from a country with moderate financial and military resources. Conversely, when Canada has primarily used economic self-interest to define its global role, the country's perceived leadership in global health has diminished. Current Prime Minister Justin Trudeau's Liberal federal government has signalled a return to progressive values, driven by appreciation for diversity, equality, and Canada's responsibility to be a good global citizen. However, poor coordination of efforts, limited funding, and the unaddressed legacy of Canada's colonisation of Indigenous peoples weaken the potential for Canadians to make meaningful contributions to improvement of global health equity. Amid increased nationalism and uncertainty towards multilateral commitments by some major powers in the world, the Canadian federal government has a clear opportunity to convert its commitments to equity and global citizenship into stronger leadership on the global stage. Such leadership will require the translation of aspirational messages about health equity and inclusion into concrete action at home and internationally.