DropSOAC: Stabilizing Microfluidic Drops for Time-Lapse Quantification of Single-Cell Bacterial Physiology.
The physiological heterogeneity of cells within a microbial population imparts resilience to stresses such as antimicrobial treatments and nutrient limitation. This resilience is partially due to a subpopulation of cells that can survive such stresses and regenerate the community. Microfluidic approaches now provide a means to study microbial physiology and bacterial heterogeneity at the single cell level, improving our ability to isolate and examine these subpopulations. Drop-based microfluidics provides a high-throughput approach to study individual cell physiology within bacterial populations. Using this approach, single cells are isolated from the population and encapsulated in growth medium dispersed in oil using a 15 μm diameter drop making microfluidic device. The drops are arranged as a packed monolayer inside a polydimethylsiloxane (PDMS) microfluidic device. Growth of thousands of individual cells in identical microenvironments can then be imaged using confocal laser scanning microscopy (CLSM). A challenge for this approach has been the maintenance of drop stability during extended time-lapse imaging. In particular, the drops do not maintain their volume over time during incubation in PDMS devices, due to fluid transport into the porous PDMS surroundings. Here, we present a strategy for PDMS device preparation that stabilizes drop position and volume within a drop array on a microfluidic chip for over 20 h. The stability of water-in-oil drops is maintained by soaking the device in a reservoir containing both water and oil in thermodynamic equilibrium. This ensures that phase equilibrium of the drop emulsion fluids within the porous PDMS material is maintained during drop incubation and imaging. We demonstrate the utility of this approach, which we label DropSOAC (Drop Stabilization On A Chip), for time-lapse studies of bacterial growth. We characterize growth of Pseudomonas aeruginosa and its Δhpf mutant derivative during resuscitation and growth following starvation. We demonstrate that growth rate and lag time heterogeneity of hundreds of individual bacterial cells can be determined starting from single isolated cells. The results show that the DropSOAC capsule provides a high-throughput approach toward studies of microbial physiology at the single cell level, and can be used to characterize physiological differences of cells from within a larger population.


The effect of orally and rectally administered delta 9-tetrahydrocannabinol on spasticity: a pilot study with 2 patients.
Multiple doses of delta 9-tetrahydrocannabinol (THC) capsules (Marinol) and THC hemisuccinate suppositories were administered in 24-hour intervals to 2 patients with organically caused spasticity. After oral doses of 10-15 mg THC, peak plasma levels from 2.1 to 16.9 ng/ml THC and 74.5 to 244.0 ng/ml 11-nor-9-carboxy-delta 9-tetrahydrocannabinol (THC-COOH, major THC metabolite) were measured by GC/MS within 1-8 h and 2-8 h, respectively. After rectal doses of 2.5-5 mg THC, peak plasma levels from 1.1 to 4.1 ng/ml THC and 6.1 to 42.0 ng/ml THC-COOH were measured within 2-8 h and 1-8 h, respectively. The bioavailability resulting from the oral formulation was 45-53% relative to the rectal route of administration, due to a lower absorption and higher first-pass metabolism. The effect of THC on spasticity, rigidity, and pain was estimated by objective neurological tests (Ashworth scale, walking ability) and patient self-rating protocols. Oral and rectal THC reduced at a progressive stage of illness the spasticity, rigidity, and pain, resulting in improved active and passive mobility. The relative effectiveness of the oral vs. the rectal formulation was 25-50%. Physiological and psychological parameters were used to monitor psychotropic and somatic side-effects of THC. No differences in the concentration ability, mood, and function of the cardiovascular system could be observed after administration of THC.


A rapid burst in hotspot motion through the interaction of tectonics and deep mantle flow.
Volcanic hotspot tracks featuring linear progressions in the age of volcanism are typical surface expressions of plate tectonic movement on top of narrow plumes of hot material within Earth's mantle. Seismic imaging reveals that these plumes can be of deep origin--probably rooted on thermochemical structures in the lower mantle. Although palaeomagnetic and radiometric age data suggest that mantle flow can advect plume conduits laterally, the flow dynamics underlying the formation of the sharp bend occurring only in the Hawaiian-Emperor hotspot track in the Pacific Ocean remains enigmatic. Here we present palaeogeographically constrained numerical models of thermochemical convection and demonstrate that flow in the deep lower mantle under the north Pacific was anomalously vigorous between 100 million years ago and 50 million years ago as a consequence of long-lasting subduction systems, unlike those in the south Pacific. These models show a sharp bend in the Hawaiian-Emperor hotspot track arising from the interplay of plume tilt and the lateral advection of plume sources. The different trajectories of the Hawaiian and Louisville hotspot tracks arise from asymmetric deformation of thermochemical structures under the Pacific between 100 million years ago and 50 million years ago. This asymmetric deformation waned just before the Hawaiian-Emperor bend developed, owing to flow in the deepest lower mantle associated with slab descent in the north and south Pacific.


Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes.
To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.


Urodynamic study of ileocystoplasty in the treatment of idiopathic detrusor instability.
Enterocystoplasty is being used with increasing frequency in the treatment of patients with idiopathic detrusor instability. We have performed a prospective clinical and urodynamic study of this procedure in 11 patients using both conventional (CMG) and ambulatory monitoring techniques (AM). Nine of 11 patients were satisfied with the symptomatic outcome, but 7 relied on clean intermittent self-catheterisation (CISC) to achieve a good result. Urodynamic studies demonstrated a significant increase in residual urine volume from 48 +/- 72 ml before to 347 +/- 298 ml after operation, but there was only a small and statistically insignificant increase in cystometric capacity. Detrusor instability, present before operation in all patients, could still be demonstrated in over half of them after operation. However, a significant decrease in the severity of instability was found after operation as assessed by an increased volume at first unstable contraction. The bladder volume before operation at which the first unstable contraction occurred was smaller in those who still had persistent instability after enterocystoplasty compared with those in whom instability could not be identified after operation. These results suggest that all patients about to undergo ileocystoplasty should be trained in the use of CISC. In selected patients with idiopathic detrusor instability refractory to other treatment, this procedure can yield satisfactory results.


Drugs of dependence though not of abuse: fenfluramine and imipramine.
Measures of subjective feeling used by five patients indicated that depression of mood occurred about four days after fenfluramine withdrawal. An experiment in which another 11 patients took fenfluramine 80 mg for 28 days confirmed the depression, maximal on the fourth withdrawal day. It also indicated that in the first week of administration there was some mood elevation, but with feelings of impaired ability to concentrate. The drug reduced appetite and weight. A comparison is drawn with imipramine, which was found to induce initial and withdrawal changes of subjective experience (of dreaming) in six volunteers. It is suggested that certain mood-influencing drugs may not be drugs of abuse because of some unpleasant initial effects, though they can be drugs of dependence.


A Study on Health Hazards to Employees near Main Streets.
In order to evaluate the physical and psychological health effects from automobile air pollution, 99 employees who worked near a main street were given a general health questionnaire, and the prevalence of their subjective complaints was measured. The collected data were classified according to gender, sleep time, degree of regular exercise, self-consciousness of symptoms, length of employment, work time, rest time, and smoking status. The results obtained were summarized as follows: The scores related to health complaints regarding physical and psychological items were higher in females than in males. THI scores were higher for the < 4 hour sleep time group. The health complaint scores for physical items were higher in the regular exercise group, whereas most scores for mental items were higher in the irregular exercise groups. The health complaints scores for physical and psychological items were higher in the unhealthy symptom group than in other groups. Those employees who had worked for > 4 years showed significantly higher rates of complaints regarding the eyes and skin. THI scores were higher for the < 6 hour working time group. The smoking group showed higher scores regarding health complaints related to physical items. The THI scores of the respiratory organs, mouth, anus, and digestive organs were significantly higher for the smoking group than for the non-smoking group. In summary, this study shows that the health complaint scores regarding physical and psychological symptoms tended to be higher among the unhealthy group, the less sleep time group, the less work time group, smokers, and females. These results can be used to improve the psychosomatic health status and working environments of employees who work near a main street.


The changing nature of paediatric otomycosis in the mid-west of Ireland.
Fungal otitis externa is prevalent in tropical and sub-tropical climates; however, over the past two decades, there has been a reported increase in the prevalence of otomycosis in paediatric patients from more temperate climates. This study aimed to review the children diagnosed with otomycosis at the University Hospital Limerick with reference to frequency, causative organism, predisposing factors and management. A retrospective review was conducted of paediatric patients from 2001 to 2015. Patients with positive fungal ear swabs and a diagnosis of otomycosis were identified. Ninety-three patients were positive for candida (mean age, 5.8 years), 10 patients were positive for aspergillus (mean age, 9.1 years) and 1 patient had mixed fungal infection containing both fungi. There was a positive correlation between a diagnosis of otomycosis and prior treatment with topical fluoroquinolones (r = 0.8; p < 0.01). The incidence of otomycosis has been increasing since 2001, which correlates with an increase in the use of topical fluoroquinolones. Previous studies identify aspergillus as the commonest causative fungi; however, this study found that candida was the commonest isolated fungi in the paediatric population.


Low levels of urinary epidermal growth factor predict chronic kidney disease progression in children.
Urinary epidermal growth factor (uEGF) has recently been identified as a promising biomarker of chronic kidney disease (CKD) progression in adults with glomerular disease. Low levels of uEGF predict CKD progression and appear to reflect the extent of tubulointerstitial damage. We investigated the relevance of uEGF in pediatric CKD. We performed a post hoc analysis of the Cardiovascular Comorbidity in Children with CKD (4C) study, which prospectively follows children aged 6-17 years with baseline estimated glomerular filtration rate (eGFR) of 10-60 ml/min/1.73 m2. uEGF levels were measured in archived urine collected within 6 months of enrollment. Congenital abnormalities of the kidney and urinary tract were the most common cause of CKD, with glomerular diseases accounting for <10% of cases. Median eGFR at baseline was 28 ml/min/1.73 m2, and 288 of 623 participants (46.3%) reached the composite endpoint of CKD progression (50% eGFR loss, eGFR < 10 ml/min/1.73 m2, or initiation of renal replacement therapy). In a Cox proportional hazards model, higher uEGF/Cr was associated with a decreased risk of CKD progression (HR 0.76; 95% CI 0.69-0.84) independent of age, sex, baseline eGFR, primary kidney disease, proteinuria, and systolic blood pressure. The addition of uEGF/Cr to a model containing these variables resulted in a significant improvement in C-statistics, indicating better prediction of the 1-, 2- and 3-year risk of CKD progression. External validation in a prospective cohort of 222 children with CKD demonstrated comparable results. Thus, uEGF may be a useful biomarker to predict CKD progression in children with CKD.


NK cells from an AML patient have recovered in remission and reached comparable cytolytic activity to that of a healthy monozygotic twin mediated by the single-chain triplebody SPM-2.
The capacity of patient's Natural Killer cells (NKs) to be activated for cytolysis is an important prerequisite for the success of antibody-derived agents such as single-chain triplebodies (triplebodies) in cancer therapy. NKs recovered from AML patients at diagnosis are often found to be reduced in peripheral blood titers and cytolytic activity. Here, we had the unique opportunity to compare blood titers and cytolytic function of NKs from an AML patient with those of a healthy monozygotic twin. The sibling's NKs were compared with the patient's drawn either at diagnosis or in remission after chemotherapy. The cytolytic activities of NKs from these different sources for the patient's autologous AML blasts and other leukemic target cells in conjunction with triplebody SPM-2, targeting the surface antigens CD33 and CD123 on the AML cells, were compared. Patient NKs drawn at diagnosis were compared to NKs drawn in remission after chemotherapy and a sibling's NKs, all prepared from PBMCs by immunomagnetic beads (MACS). Redirected lysis (RDL) assays using SPM-2 and antibody-dependent cellular cytotoxicity (ADCC) assays using the therapeutic antibody RituximabTM were performed with the enriched NKs. In addition, MACS-sorted NKs were analyzed for NK cell activating receptors (NCRs) by flow cytometry, and the release of TNF-alpha and IFN-gamma from blood samples of both siblings after the addition of the triplebody were measured in ELISA-assays. Patient NKs isolated from peripheral blood drawn in remission produced comparable lysis as NKs from the healthy twin against the patient's autologous bone marrow (BM) blasts, mediated by SPM-2. The NCR receptor expression profiles on NKs from patient and twin were similar, but NK cell titers in peripheral blood were lower for samples drawn at diagnosis than in remission. Peripheral blood NK titers and ex vivo cytolytic activities mediated by triplebody SPM-2 were comparable for cells drawn from an AML patient in remission and a healthy twin. If these results can be generalized, then NKs from AML patients in remission are sufficient in numbers and cytolytic activity to make triplebodies promising new agents for the treatment of AML.


Automatically classifying question types for consumer health questions.
We present a method for automatically classifying consumer health questions. Our thirteen question types are designed to aid in the automatic retrieval of medical answers from consumer health resources. To our knowledge, this is the first machine learning-based method specifically for classifying consumer health questions. We demonstrate how previous approaches to medical question classification are insufficient to achieve high accuracy on this task. Additionally, we describe, manually annotate, and automatically classify three important question elements that improve question classification over previous techniques. Our results and analysis illustrate the difficulty of the task and the future directions that are necessary to achieve high-performing consumer health question classification.


Multicentre controlled trial of parenting groups for childhood antisocial behaviour in clinical practice.
To see whether a behaviourally based group parenting programme, delivered in regular clinical practice, is an effective treatment for antisocial behaviour in children. Controlled trial with permuted block design with allocation by date of referral. Four local child and adolescent mental health services. 141 children aged 3-8 years referred with antisocial behaviour and allocated to parenting groups (90) or waiting list control (51). Webster-Stratton basic videotape programme administered to parents of six to eight children over 13-16 weeks. This programme emphasises engagement with parental emotions, rehearsal of behavioural strategies, and parental understanding of its scientific rationale. Semistructured parent interview and questionnaires about antisocial behaviour in children administered 5-7 months after entering trial; direct observation of parent-child interaction. Referred children were highly antisocial (above the 97th centile on interview measure). Children in the intervention group showed a large reduction in antisocial behaviour; those in the waiting list group did not change (effect size between groups 1.06 SD (95% confidence interval 0.71 to 1.41), P<0.001). Parents in the intervention group increased the proportion of praise to ineffective commands they gave their children threefold, while control parents reduced it by a third (effect size between groups 0.76 (0.16 to 1.36), P=0.018). If the 31 children lost to follow up were included in an intention to treat analysis the effect size on antisocial behaviour was reduced by 16%. Parenting groups effectively reduce serious antisocial behaviour in children in real life conditions. Follow up is needed to see if the children's poor prognosis is improved and criminality prevented.


Factors Associated With Reoperation After Fixation of Displaced Olecranon Fractures.
Surgery for fixation of olecranon fractures is associated with reoperation, mostly for implant removal. A study of a large cohort of patients treated by many different surgeons allows us to determine if specific techniques or implants are associated with a higher rate of reoperation. After open reduction and internal fixation of isolated olecranon fractures, what factors are associated with (1) reoperation and (2) implant removal? Three hundred ninety-two adult patients who had operative treatment of a displaced olecranon fracture not associated with other fractures, dislocation, or subluxation at two area hospitals between January 2002 and May 2014 were analyzed to determine factors associated with reoperation. One hundred thirty-eight (35%) patients had plate and screw fixation and 254 (65%) tension band wiring. Nearly 100% of patients with displaced olecranon fractures are currently treated operatively at our hospitals. All patients were followed for at least four months. Two hundred three of the 392 (52%) patients were followed for one year or more. Ninety-nine patients (25%) had a second operation, 92 (93%) at least in part for implant removal (12 for wire migration [3% of all fractures, 12% of reoperations]). We considered patient-related, fracture-related, and implant-related endpoints as possible factors associated with reoperation. With a total sample size of 99 reoperations, an α of 0.05, and an effect size of 0.3, we had 87% power. Reoperation was less common in men (36 [36%], women: 63 [64%]; adjusted odds ratio, 0.32; 95% confidence interval, 0.18-0.56; p < 0.001) and older patients (adjusted odds ratio, 0.75; 95% confidence interval, 0.65-0.87; p < 0.001). Similarly, request for implant removal was less in men (33 [36%], women: 59 [64%], adjusted odds ratio, 0.31; 95% confidence interval, 0.18-0.56; p < 0.001) and older patients (adjusted odds ratio, 0.75; 95% confidence interval, 0.65-0.87; p < 0.001). Patients who have operative fixation of a fracture of the olecranon can be counseled that most patients keep their implants, that only 3% experience implant migration, and that technical factors such as the type or configuration of an implant seem less important than personal factors in determining who requests a second surgery for implant removal. Level III, prognostic study.


Predictors of prostate-specific antigen progression among men with seminal vesicle invasion at the time of radical prostatectomy.
Seminal vesicle (SV) invasion at the time of radical prostatectomy (RP) generally is considered to be indicative of poor outcome. The authors examined whether there was a subset of men with SV invasion who had long-term prostate-specific antigen (PSA) progression-free survival. Data were examined from 1687 men who underwent RP between 1988 and 2002 at 5 equal-access medical centers. Patients were grouped based on the presence or absence of SV invasion at the time of RP. Clinical and pathologic variables as well as biochemical outcome data were compared across the groups using rank-sum, chi-square, and log-rank tests. Multivariate Cox proportional hazards analysis was used to determine the significant predictors of time to PSA failure among men with SV invasion. Men with SV invasion had significantly higher PSA values, higher clinical stage, higher grade tumors, and were more likely to have concomitant extracapsular extension or a positive surgical margin. The 5-year PSA progression-free rates for men who had SV invasion was 36%, compared with 70% among men who had no SV invasion. Among men who had SV invasion, using multivariate analysis, only age (P = 0.023), pathologic Gleason score (P = 0.041), and surgical margin status (P = 0.019) were found to be independent predictors of PSA failure. By combining significant prognostic variables, the authors identified a subset of men with SV invasion, low-grade tumors (Gleason score 2-6), and negative surgical margins who had a 5-year PSA progression-free rate of 69%. Men with SV invasion, Gleason scores 2-6 tumors, negative surgical margins, and age > or = 60 years (n = 11; 8%) had a 5-year PSA progression-free rate of 100%. Although the majority of men with SV invasion have high-grade disease and a short time to biochemical failure, the authors identified a subset of men with low-grade disease, negative surgical margins, and older age who, despite SV invasion, had an extremely favorable clinical course. Thus, SV invasion does not uniformly suggest an unfavorable prognosis. prognosis.


Imaging the effects of castration on bone turnover and hormone-independent prostate cancer colonization of bone.
Tumor populations may selectively colonize bone that is being actively remodeled. In prostate cancer patients, androgen deprivation directly inhibits tumor growth initially, whilst induced bone loss may facilitate tumor colonization of bone by androgen-insensitive cells. We have tested this hypothesis using a xenograft model of early growth of prostate cancer in bone. PC3 cells transfected with Green fluorescent protein (GFP) were injected into castrated and non-castrated athymic mice via intrabial and intracardiac routes. In vivo tumor growth was monitored daily and animals sacrificed 6-9 days following initial GFP-based detection of tumors. Tumor bearing and contra-lateral non-tumor bearing tibias were analyzed extensively by micro-CT and histology/immunohistochemistry for the presence of tumor cells and the effects of tumor and/or castration on bone cells and bone structure evaluated. GFP-positive tumors in bone were visible from 12 days post-injection following intratibial injection, allowing tumors <1 mm diameter to be monitored in live animals. Castration did not affect tumor frequency, tumor volume, or time to initial appearance of tumors injected via intratibial or intracardiac routes. Castration decreased trabecular bone volume in all mice. Significant tumor-induced suppression of numbers of osteoblasts, coupled with increased numbers of activated osteoclasts, was evident in both intact animals and castrated animals. In vivo GFP imaging allows the detection of early tumor growth at intra-osseous sites. Castration induces bone loss, but PC3-GFP cells are also capable of inducing bone remodeling in intact animals at early time points, independently of pre-existing castration-induced alterations to bone.


A biological rationale for musical scales.
Scales are collections of tones that divide octaves into specific intervals used to create music. Since humans can distinguish about 240 different pitches over an octave in the mid-range of hearing, in principle a very large number of tone combinations could have been used for this purpose. Nonetheless, compositions in Western classical, folk and popular music as well as in many other musical traditions are based on a relatively small number of scales that typically comprise only five to seven tones. Why humans employ only a few of the enormous number of possible tone combinations to create music is not known. Here we show that the component intervals of the most widely used scales throughout history and across cultures are those with the greatest overall spectral similarity to a harmonic series. These findings suggest that humans prefer tone combinations that reflect the spectral characteristics of conspecific vocalizations. The analysis also highlights the spectral similarity among the scales used by different cultures.


Private Sector An Important But Not Dominant Provider Of Key Health Services In Low- And Middle-Income Countries.
There is debate about the role of the private sector in providing services in the health systems of low- and middle-income countries and about how the private sector could help achieve the goal of universal health coverage. Yet the role that the private sector plays in the delivery of health services is poorly understood. Using data for the period 1990-2013 from 205 Demographic and Health Surveys in seventy low- and middle-income countries, I analyzed the use of the private sector for the treatment of diarrhea and of fever or cough in children, for antenatal care, for institutional deliveries, and as a source of modern contraception for women. I found that private providers were the dominant source of treatment for childhood illnesses but not for the other services. I also found no evidence of increased use of the private sector over time. There is tremendous variation in use of the private sector across countries and health services. Urban and wealthier women disproportionately use the private sector, compared to rural and poorer women. The private sector plays an important role in providing coverage, but strategies to further engage the sector, if they are to be effective, will need to take into consideration the variation in its use.


A new mouse model of autoimmune ocular myasthenia gravis.
To establish a novel model of autoimmune ocular myasthenia gravis (oMG) in mice and study the pathogenic mechanisms of oMG. oMG was induced in HLA-DQ8 transgenic, HLA-DR3 transgenic, major histocompatibility complex (MHC) class II-deficient, C57BL/6, and C57BL/10 mice by immunization with an Escherichia coli plasmid expressing the recombinant human acetylcholine receptor (AChR) alpha subunit. All strains of immunized mice developed ocular myasthenia gravis with varying disease incidence and severity. HLA-DQ8 transgenic mice were highly susceptible to oMG. Mice with oMG had serum autoantibodies to the mouse extraocular AChR, pathologic deposits of IgG, C3, and C5b-C9 in their extraocular and limb neuromuscular junctions, and droopiness of eyelids. HLA-DR3 transgenic and MHC class II-deficient mice were relatively resistant to oMG induced by AChR alpha subunit immunization and had minimal ocular abnormalities. These findings suggest that oMG pathogenesis could be triggered by immunity to the human AChR alpha subunit and that MHC class II molecule is required for human AChR alpha subunit presentation and CD4 cell-mediated anti-AChR antibody class switching. Differential oMG susceptibility observed in DQ8 and DR3 transgenic mice correlated with the intensity of lymphocytes to respond to the human AChR alpha subunit. This new model of oMG will be a valuable tool for studying the mechanism of oMG and gMG pathogenesis in humans and for preclinical therapeutic analysis.


A mutation in the nuclear pore complex gene Tmem48 causes gametogenesis defects in skeletal fusions with sterility (sks) mice.
Skeletal fusions with sterility (sks) is an autosomal recessive mutation of mouse that results in male and female sterility because of defects in gametogenesis. The mutants also have skeletal malformations with fused vertebrae and ribs. We examined testicular phenotypes of sks/sks mice to investigate the defects in spermatogenesis. Histological and immunocytochemical analyses and expression analyses of the marker genes demonstrated that spermatogenesis is arrested at mid to late pachytene stage of meiotic prophase with defective synapsis of the homologous chromosomes. Next, we determined the precise chromosomal localization of the sks locus on a 0.3-Mb region of mouse chromosome 4 by linkage analysis. By sequencing the positional candidate genes in this region and whole exome sequencing, we found a GG to TT nucleotide substitution in exon 6 of the Tmem48 gene that encodes a putative transmembrane protein with six transmembrane domains. The nucleotide substitution causes aberrant splicing, which deletes exon 6 of the Tmem48 transcript. Specific expression of TMEM48 was observed in germ cells of males and females. Furthermore, the phenotypes of the sks mutant were completely rescued by the transgenesis of a genomic fragment containing the wild-type Tmem48 gene. These findings indicate that the Tmem48 mutation is responsible for the gametogenesis defects and skeletal malformations in the sks mice. The TMEM48 protein is a nuclear membrane protein comprising the nuclear pore complex; its exact function in the nuclear pore complex is still unknown. Our finding suggested that the nuclear pore complex plays an important role in mammalian gametogenesis and skeletal development.


Berberine Inhibits Invasion and Metastasis of Colorectal Cancer Cells via COX-2/PGE2 Mediated JAK2/STAT3 Signaling Pathway.
Berberin, extracted from Chinese herbal medicine Coptis chinensis, has been found to have anti-tumor activities. However, the underlying mechanisms have not been fully elucidated. Our current study demonstrated that berberin inhibited the in vitro and in vivo growth, migration/invasion of CRC cells, via attenuating the expression levels of COX-2/PGE2, following by reducing the phosphorylation of JAK2 and STAT3, as well as the MMP-2/-9 expression. We further clarified that an increase of COX-2/PGE2 expression offset the repressive activity of Berberin on JAK2/STAT3 signaling, and a JAK2 inhibitor AZD1480 blocked the effect of COX-2/PGE2 on MMP-2/-9 expression. In summary, Berberin inhibited CRC invasion and metastasis via down-regulation of COX-2/PGE2- JAK2/STAT3 signaling pathway.


Hamster-to-rat heart and liver xenotransplantation with FK506 plus antiproliferative drugs.
Heterotopic hamster hearts transplanted to unmodified LEW rats underwent humoral rejection in 3 days. Survival was prolonged to a median of 4 days with 2 mg/kg/day FK506. As monotherapy, 15 mg/kg/day cyclophosphamide greatly prolonged graft survival--far more than could be accomplished with RS-61443, brequinar (BQR), mizoribine, methotrexate, or deoxyspergualin. However, when FK506 treatment, which was ineffective alone, was combined with a short induction course (14 or 30 days) of subtherapeutic BQR, RS-61443, or cyclophosphamide, routine survival of heart xenografts was possible for as long as the daily FK506 was continued. In addition, a single large dose of 80 mg/kg cyclophosphamide 10 days preoperatively allowed routine cardiac xenograft survival under FK506. The ability of these antimetabolites to unmask the therapeutic potential of FK506 correlated, although imperfectly, with the prevention of rises of preformed heterospecific cytotoxic antibodies immediately postoperatively. As an adjunct to FK506, azathioprine was of marginal value, whereas mizoribine, methotrexate, and deoxyspergualin (DSPG) were of intermediate efficacy. After orthotopic hepatic xenotransplantation, the perioperative survival of the liver with its well-known resistance to antibodies was less dependent than the heart on the antimetabolite component of the combined drug therapy, but the unsatisfactory results with monotherapy of FK506, BQR, RS-61443, or cyclophosphamide were changed to routine success by combining continuous FK506 with a short course of any of the other drugs. Thus, by breaking down the antibody barrier to xenotransplantation with these so-called antiproliferative drugs, it has been possible with FK506 to transplant heart and liver xenografts with consistent long-term survival of healthy recipients.


The role of AGG interruptions in the transcription of FMR1 premutation alleles.
Fragile X associated disorders are caused by a premutation allele in the fragile X mental retardation 1 gene (FMR1) and are hypothesized to result from the toxic effect of elevated levels of expanded FMR1 transcripts. Increased levels of FMR1 mRNA have indeed been reported in premutation carriers; however the mechanism by which expanded alleles lead to elevated levels of FMR1 mRNA in premutation carriers is unknown. Within the CGG repeat tract AGG interruptions are found, generally 1-3 present in normal/intermediate alleles (6-54 CGG repeats) and usually 0-1 in premutation alleles (55-200 CGG repeats). They are present at specific locations, generally occurring after 9 or 10 uninterrupted CGG repeats [(CGG)(9)AGG(CGG)(9)AGG(CGG)(n)]. We evaluated both the number of AGG interruptions and the resulting length of the uninterrupted 3' CGG repeat pure tract in premutation alleles derived from two large cohorts of male and female carriers to determine whether the presence of AGG interruptions or the length of a pure stretch of CGG repeats influence the levels of FMR1 mRNA in blood. Our findings indicate that neither the number of AGG interruptions, nor their position along the CGG tract have a significant affect on mRNA levels in premutation carriers. We also, as expected based on previous findings, observed a highly significant correlation between CGG repeat number (as both total length and length of pure CGG stretch) and FMR1 mRNA expression levels, in both males and females. Importantly, we did not observe any significant difference in FMR1 mRNA levels in premutation carriers based on age.


Young patients' views about provided psychiatric care.
Psychiatric illness is common among young adults, but there are only a few studies examining their views about the care they receive. There is a paradigm shift towards person-centred care and, therefore, a need for patients' perspectives in the development of clinical guidelines. The aim of this study was to examine the views about provided psychiatric care in a group of young adult psychiatric patients. This study was part of a larger study. Patients between the ages of 19-29 years old (n = 127) diagnosed with bipolar disorder, borderline personality disorder, and/or attention deficit hyperactivity disorder were interviewed. Participants answered open-ended questions concerning their views about provided psychiatric care in six different areas. The results were categorized into six themes: (1) Wish for better diagnostic assessments, (2) Dissatisfaction with treatment, (3) Inadequate information, (4) Lack of professional attitude, (5) Feeling abandoned, and (6) Satisfaction with care. Young psychiatric patients expressed a need for improvement of services that, if implemented, could make psychiatric care more person-centred.


PAM-Dependent Target DNA Recognition and Cleavage by C2c1 CRISPR-Cas Endonuclease.
C2c1 is a newly identified guide RNA-mediated type V-B CRISPR-Cas endonuclease that site-specifically targets and cleaves both strands of target DNA. We have determined crystal structures of Alicyclobacillus acidoterrestris C2c1 (AacC2c1) bound to sgRNA as a binary complex and to target DNAs as ternary complexes, thereby capturing catalytically competent conformations of AacC2c1 with both target and non-target DNA strands independently positioned within a single RuvC catalytic pocket. Moreover, C2c1-mediated cleavage results in a staggered seven-nucleotide break of target DNA. crRNA adopts a pre-ordered five-nucleotide A-form seed sequence in the binary complex, with release of an inserted tryptophan, facilitating zippering up of 20-bp guide RNA:target DNA heteroduplex on ternary complex formation. Notably, the PAM-interacting cleft adopts a "locked" conformation on ternary complex formation. Structural comparison of C2c1 ternary complexes with their Cas9 and Cpf1 counterparts highlights the diverse mechanisms adopted by these distinct CRISPR-Cas systems, thereby broadening and enhancing their applicability as genome editing tools.


An international survey indicated that unpublished systematic reviews exist.
To determine the frequency of unpublished systematic reviews (SRs) and explore factors contributing to their occurrence. First or corresponding authors from a sample of SRs published in 2005 were asked to participate in a 26-item survey administered through the Internet, facsimile, and postal mail. Outcomes included median and range of published and unpublished SRs, and barriers, facilitators, and reasons for not publishing SRs. Descriptive analyses were performed. 55.7% (348 of 625) of those invited participated, half of which were from Europe and 22.7% were from the United States. Participants reported 1,405 published (median: 2.0, range: 1-150) and 199 unpublished (median: 2.0, range: 1-33) SRs. Lack of time and lack of funding and organizational support were barriers, whereas time availability and self-motivation were facilitators to publishing reviews. For most recent unpublished SRs (n=52), the reasons for not publishing included lack of time (12 of 52, 23.0%), the manuscript being rejected (10 of 52, 19.0%), and operational issues (six of 52, 11.5%). Unpublished SRs do exist. Lack of time, funding, and organizational support were consistent reasons for not publishing SRs. Statistical significance of SR results was not reported as being a major barrier or reason for not publishing. Further research on unpublished SRs is warranted.


Garcinia cambogia extract ameliorates visceral adiposity in C57BL/6J mice fed on a high-fat diet.
The aim of present study is to evaluate the effects of Garcinia cambogia on the mRNA levels of the various genes involved in adipogenesis, as well as on body weight gain, visceral fat accumulation, and other biochemical markers of obesity in obesity-prone C57BL/6J mice. Consumption of the Garcinia cambogia extract effectively lowered the body weight gain, visceral fat accumulation, blood and hepatic lipid concentrations, and plasma insulin and leptin levels in a high-fat diet (HFD)-induced obesity mouse model. The Garcinia cambogia extract reversed the HFD-induced changes in the expression pattern of such epididymal adipose tissue genes as adipocyte protein aP2 (aP2), sterol regulatory element-binding factor 1c (SREBP1c), peroxisome proliferator-activated receptor gamma2 (PPARgamma2), and CCAT/enhancer-binding protein alpha (C/EBPalpha). These findings suggest that the Garcinia cambogia extract ameliorated HFD-induced obesity, probably by modulating multiple genes associated with adipogenesis, such as aP2, SREBP1c, PPARgamma2, and C/EBPalpha in the visceral fat tissue of mice.


Jugular vein distensibility predicts fluid responsiveness in septic patients.
The purpose of the study was to verify the efficacy of using internal jugular vein (IJV) size and distensibility as a reliable index of fluid responsiveness in mechanically ventilated patients with sepsis. Hemodynamic data of mechanically ventilated patients with sepsis were collected through a radial arterial indwelling catheter connected to continuous hemodynamic monitoring system (Most Care®, Vytech Health, Padova, Italy), including cardiac index (CI) (L/min/M(2)), heart rate (beats/min), mean arterial pressure (MAP) (mmHg), central venous pressure (CVP) (mmHg) and arterial pulse pressure variation (PPV), coupled with ultrasound evaluation of IJV distensibility (%), defined as a ratio of the difference between IJV maximal antero-posterior diameter during inspiration and minimum expiratory diameter to minimum expiratory diameter x100. Patients were retrospectively divided into two groups; fluid responders (R), if CI increase of more than or equal to 15% after a 7 ml/kg crystalloid infusion, and non-responders (NR) if CI increased more than 15%. We compared differences in measured variables between R and NR groups and calculated receiver-operator-characteristic (ROC) curves of optimal IJV distensibility and PPV sensitivity and specificity to predicting R. We also calculated a combined inferior vena cava distensibility-PPV ROC curve to predict R. We enrolled 50 patients, of these, 30 were R. Responders presented higher IJV distensibility and PPV before fluid challenge than NR (P <0.05). An IJV distensibility more than 18% prior to volume challenge had an 80% sensitivity and 85% specificity to predict R. Pairwise comparison between IJV distensibility and PPV ROC curves revealed similar ROC area under the curve results. Interestingly, combining IJV distensibility more than 9.7% and PPV more than 12% predicted fluid responsiveness with a sensitivity of 100% and specificity of 95%. IJV distensibility is an accurate, easily acquired non-invasive parameter of fluid responsiveness in mechanically ventilated septic patients with performance similar to PPV. The combined use of IJV distensibility with left-sided indexes of fluid responsiveness improves their predictive value.


High-power MIXSEL: an integrated ultrafast semiconductor laser with 6.4 W average power.
High-power ultrafast lasers are important for numerous industrial and scientific applications. Current multi-watt systems, however, are based on relatively complex laser concepts, for example using additional intracavity elements for pulse formation. Moving towards a higher level of integration would reduce complexity, packaging, and manufacturing cost, which are important requirements for mass production. Semiconductor lasers are well established for such applications, and optically-pumped vertical external cavity surface emitting lasers (VECSELs) are most promising for higher power applications, generating the highest power in fundamental transverse mode (>20 W) to date. Ultrashort pulses have been demonstrated using passive modelocking with a semiconductor saturable absorber mirror (SESAM), achieving for example 2.1-W average power, sub-100-fs pulse duration, and 50-GHz pulse repetition rate. Previously the integration of both the gain and absorber elements into a single wafer was demonstrated with the MIXSEL (modelocked integrated external-cavity surface emitting laser) but with limited average output power (<200 mW). We have demonstrated the power scaling concept of the MIXSEL using optimized quantum dot saturable absorbers in an antiresonant structure design combined with an improved thermal management by wafer removal and mounting of the 8-µm thick MIXSEL structure directly onto a CVD-diamond heat spreader. The simple straight cavity with only two components has generated 28-ps pulses at 2.5-GHz repetition rate and an average output power of 6.4 W, which is higher than for any other modelocked semiconductor laser.


Factor VIII ectopically targeted to platelets is therapeutic in hemophilia A with high-titer inhibitory antibodies.
Inhibitory immune response to exogenously infused factor VIII (FVIII) is a major complication in the treatment of hemophilia A. Generation of such inhibitors has the potential to disrupt gene therapy for hemophilia A. We explore what we believe to be a novel approach to overcome this shortcoming. Human B-domain-deleted FVIII (hBDDFVIII) was expressed under the control of the platelet-specific alphaIIb promoter in platelets of hemophilic (FVIIInull) mice to create 2bF8trans mice. The FVIII transgene product was stored in platelets and released at the site of platelet activation. In spite of the lack of FVIII in the plasma of 2bF8trans mice, the bleeding phenotype of FVIIInull mice was corrected. More importantly, the bleeding phenotype was corrected in the presence of high inhibitory antibody titers introduced into the mice by infusion or by spleen cell transfer from recombinant hBDDFVIII-immunized mice. Our results demonstrate that this approach to the targeted expression of FVIII in platelets has the potential to correct hemophilia A, even in the presence of inhibitory immune responses to infused FVIII.


Staphylococcus aureus proteins Sbi and Efb recruit human plasmin to degrade complement C3 and C3b.
Upon host infection, the human pathogenic microbe Staphylococcus aureus (S. aureus) immediately faces innate immune reactions such as the activated complement system. Here, a novel innate immune evasion strategy of S. aureus is described. The staphylococcal proteins surface immunoglobulin-binding protein (Sbi) and extracellular fibrinogen-binding protein (Efb) bind C3/C3b simultaneously with plasminogen. Bound plasminogen is converted by bacterial activator staphylokinase or by host-specific urokinase-type plasminogen activator to plasmin, which in turn leads to degradation of complement C3 and C3b. Efb and to a lesser extend Sbi enhance plasmin cleavage of C3/C3b, an effect which is explained by a conformational change in C3/C3b induced by Sbi and Efb. Furthermore, bound plasmin also degrades C3a, which exerts anaphylatoxic and antimicrobial activities. Thus, S. aureus Sbi and Efb comprise platforms to recruit plasmin(ogen) together with C3 and its activation product C3b for efficient degradation of these complement components in the local microbial environment and to protect S. aureus from host innate immune reactions.


The relationship between nociceptive brain activity, spinal reflex withdrawal and behaviour in newborn infants.
Measuring infant pain is complicated by their inability to describe the experience. While nociceptive brain activity, reflex withdrawal and facial grimacing have been characterised, the relationship between these activity patterns has not been examined. As cortical and spinally mediated activity is developmentally regulated, it cannot be assumed that they are predictive of one another in the immature nervous system. Here, using a new experimental paradigm, we characterise the nociceptive-specific brain activity, spinal reflex withdrawal and behavioural activity following graded intensity noxious stimulation and clinical heel lancing in 30 term infants. We show that nociceptive-specific brain activity and nociceptive reflex withdrawal are graded with stimulus intensity (p < 0.001), significantly correlated (r = 0.53, p = 0.001) and elicited at an intensity that does not evoke changes in clinical pain scores (p = 0.55). The strong correlation between reflex withdrawal and nociceptive brain activity suggests that movement of the limb away from a noxious stimulus is a sensitive indication of nociceptive brain activity in term infants. This could underpin the development of new clinical pain assessment measures.


Management recommendations for metabolic complications associated with second-generation antipsychotic use in children and youth.
Second-generation antipsychotics are commonly associated with metabolic complications. These medications are being used more frequently for the treatment of mental health disorders in children, which has stimulated the need for creating formal guidelines on monitoring their safety and effectiveness. Previous guidelines have been developed for monitoring metabolic and neurological complications. To assist practitioners who perform these monitoring procedures, a complementary set of treatment recommendations have been created for situations in which abnormal measurements or results are encountered. To create evidence-based recommendations to assist in managing metabolic complications in children being treated with second-generation antipsychotics. A systematic review of the literature on metabolic complications of second-generation antipsychotic medications in children was conducted. Members of the consensus group evaluated the information gathered from the systematic review of the literature and used a nominal group process to reach a consensus on treatment recommendations. Wherever possible, references were made to existing guidelines on the evaluation and treatment of metabolic abnormalities in children. Evidence-based recommendations are presented to assist in managing metabolic complications including weight gain; increased waist circumference; elevation in prolactin, cholesterol, triglyceride and glucose levels; abnormal liver function tests and abnormal thyroid studies. The use of second-generation antipsychotics requires proper monitoring procedures. The present treatment guideline provides guidance to clinicians on the clinical management of metabolic complications if they occur.


The serotonin transporter gene-linked polymorphic region (5-HTTLPR) and the sleep-promoting effects of tryptophan: A randomized placebo-controlled crossover study.
The low-expressive short (S) allele of a functional polymorphism (5-HTTLPR) within the serotonin (5-hydroxytriptamine; 5-HT) transporter gene (SLC6A4) has been associated with a reduced functioning of the brain 5-HT system relative to the long (L) allele. As a consequence, the S-allele is found to predispose individuals to a higher risk of sleep quality reduction and clinical insomnia. The present study investigated whether subchronic pre-sleep tryptophan administration could compensate for this predisposition by improving sleep in 5-HTTLPR S-allele carriers. In a double-blind placebo-controlled crossover design a sample of homozygous 5-HTTLPR S-allele (n = 47) and L-allele (n = 51) carriers were assessed for subjective (sleep diary) and objective (actigraphy) sleep during a treatment protocol consisting of 1 week of placebo (1000 mg/day) and 1 week of tryptophan administration (1000 mg/day). The results support the sleep-promoting effects of tryptophan. Tryptophan improved objective sleep efficiency and objective wake after sleep onset irrespective of allelic variation. There was a marginally significant improvement of subjective sleep quality in the 5-HTTLPR S-allele group but not in the L-allele group following tryptophan relative to placebo intake. In contrast, a significantly poorer sleep quality in the S-allele as opposed to the L-allele group in the placebo condition was not observed in the tryptophan condition. Tryptophan augmentation promises to be a valuable treatment strategy for sleep impairments related to genetic deficiencies in 5-HT functioning.


First Direct Search for Inelastic Boosted Dark Matter with COSINE-100.
A search for inelastic boosted dark matter (IBDM) using the COSINE-100 detector with 59.5 days of data is presented. This relativistic dark matter is theorized to interact with the target material through inelastic scattering with electrons, creating a heavier state that subsequently produces standard model particles, such as an electron-positron pair. In this study, we search for this electron-positron pair in coincidence with the initially scattered electron as a signature for an IBDM interaction. No excess over the predicted background event rate is observed. Therefore, we present limits on IBDM interactions under various hypotheses, one of which allows us to explore an area of the dark photon parameter space that has not yet been covered by other experiments. This is the first experimental search for IBDM using a terrestrial detector.


Effects of zinc transporters on Cryptococcus gattii virulence.
Zinc is an essential nutrient for all living organisms because it is a co-factor of several important proteins. Furthermore, zinc may play an essential role in the infectiousness of microorganisms. Previously, we determined that functional zinc metabolism is associated with Cryptococcus gattii virulence. Here, we characterized the ZIP zinc transporters in this human pathogen. Transcriptional profiling revealed that zinc levels regulated the expression of the ZIP1, ZIP2 and ZIP3 genes, although only the C. gattii zinc transporter Zip1 was required for yeast growth under zinc-limiting conditions. To associate zinc uptake defects with virulence, the most studied cryptococcal virulence factors (i.e., capsule, melanin and growth at 37 °C) were assessed in ZIP mutant strains; however, no differences were detected in these classical virulence-associated traits among the mutant and WT strains. Interestingly, higher levels of reactive oxygen species were detected in the zip1Δ and in the zip1Δ zip2Δ double mutants. In line with these phenotypic alterations, the zip1Δ zip2Δ double mutant displayed attenuated virulence in a murine model of cryptococcosis. Together, these results indicate that adequate zinc uptake is necessary for cryptococcal fitness and virulence.


Social outcomes of young adults with childhood-onset epilepsy: A case-sibling-control study.
We aimed to compare long-term social outcomes in young adults with childhood-onset epilepsy (cases) with neurologically normal sibling controls. Long-term social outcomes were assessed at the 15-year follow-up of the Connecticut Study of Epilepsy, a community-based prospective cohort study of children with newly diagnosed epilepsy. Young adults with childhood-onset epilepsy with complicated (abnormal neurologic exam findings, abnormal brain imaging with lesion referable to epilepsy, intellectual disability (ID; IQ < 60) or informative history of neurologic insults to which the occurrence of epilepsy might be attributed), and uncomplicated epilepsy presentations were compared to healthy sibling controls. Age, gender, and matched-pair adjusted generalized linear models stratified by complicated epilepsy and 5-year seizure-free status estimated adjusted odds ratios (aORs) and 95% confidence intervals [CIs] for each outcome. The 15-year follow-up included 361 individuals with epilepsy (59% of initial cases; N = 291 uncomplicated and N = 70 complicated epilepsy; mean age 22 years [standard deviation, SD 3.5]; mean epilepsy onset 6.2 years [SD 3.9]) and 173 controls. Social outcomes for cases with uncomplicated epilepsy with ≥5 years terminal remission were comparable to controls; cases with uncomplicated epilepsy <5 years seizure-free were more likely to be less productive (school/employment < 20 h/week) (aOR 3.63, 95% CI 1.83-7.20) and not to have a driver's license (aOR 6.25, 95% CI 2.85-13.72). Complicated cases with epilepsy <5 years seizure-free had worse outcomes across multiple domains; including not graduating high school (aOR 24.97, 95% CI 7.49-83.30), being un- or underemployed (<20 h/week) (aOR 11.06, 95% CI 4.44-27.57), being less productively engaged (aOR 15.71, 95% CI 6.88-35.88), and not living independently (aOR 10.24, 95% CI 3.98-26.36). Complicated cases without ID (N = 36) had worse outcomes with respect to productive engagement (aOR 6.02; 95% CI 2.48-14.58) compared to controls. Cases with complicated epilepsy were less likely to be driving compared to controls, irrespective of remission status or ID. In individuals with uncomplicated childhood-onset epilepsy presentations and 5-year terminal remission, young adult social outcomes are comparable to those of sibling controls. Complicated epilepsy, notable for intellectual disability, and seizure remission status are important prognostic indicators for long-term young adult social outcomes in childhood-onset epilepsy.


What are we injecting with our drugs?
In preparation for a case, an anaesthetist opened a 20 ml glass vial of propofol and aspirated the propofol into a syringe via a blunt drawing-up needle. Increased resistance was felt with aspiration. On inspection, a shard of glass was found at the tip of the drawing-up needle. The shard was presumed to be from the propofol ampoule, and to have fallen into the solution upon snapping open its glass tip. This illustrative case raises the issue of contamination of drugs by particles introduced during the drawing-up process. It also highlights the possibility that during the drawing-up process, intravenous drugs may become contaminated not just with particles, but with microorganisms on the surface of the particles. In this article, we discuss relevant recent research of the implications of this type of drug contamination. We draw attention to the need for meticulous care in drawing up and administering intravenous drugs during anaesthesia, particularly propofol.


Disrupted Fear and Sadness Recognition in Binge Drinking: A Combined Group and Individual Analysis.
Binge drinking is a harmful pattern of alcohol consumption, associated with cognitive and cerebral impairments. Indeed, various cognitive processes have been identified as disrupted in binge drinking, ranging from perceptive to executive functions, but emotional processes have conversely been little investigated. Particularly, it is unclear to what extent binge drinkers (BD) present difficulties to recognize and categorize the emotions expressed by other individuals. Such an exploration would, however, offer a more comprehensive view of the deficits associated with alcohol-related disorders and potentially involved in the maintenance of this harmful habit. Fifty-two BD and 42 control participants performed an emotional task assessing the ability to recognize 6 basic emotions (i.e., anger, contempt, disgust, fear, happiness, and sadness). Accuracy score and detection threshold were collected for each emotion. To explore the extent of emotion recognition difficulties, 2 analyses were conducted: (i) classical repeated measures analyses of variance, to compare groups' performance, and (ii) multiple single-case analyses (i.e., Crawford's t-tests), to determine the percentage of BD presenting genuine emotion recognition deficits. Correlations were also performed between alcohol consumption characteristics and emotional recognition scores. BD presented reduced performance for the recognition of fear and sadness. Multiple single cases highlighted that these deficits respectively concerned 21.15 and 15.38% of the binge drinking sample, and the relation between binge drinking and reduced sadness detection was supported by correlational analyses. These findings show that binge drinking is associated with a disrupted processing of emotional stimuli. By identifying heterogeneity in the impairments presented by BD, the present results also underline the usefulness of a combined group and individual Analysis.


Disrupted dynamic network reconfiguration of the language system in temporal lobe epilepsy.
Temporal lobe epilepsy tends to reshape the language system causing maladaptive reorganization that can be characterized by task-based functional MRI, and eventually can contribute to surgical decision making processes. However, the dynamic interacting nature of the brain as a complex system is often neglected, with many studies treating the language system as a static monolithic structure. Here, we demonstrate that as a specialized and integrated system, the language network is inherently dynamic, characterized by rich patterns of regional interactions, whose transient dynamics are disrupted in patients with temporal lobe epilepsy. Specifically, we applied tools from dynamic network neuroscience to functional MRI data collected from 50 temporal lobe epilepsy patients and 30 matched healthy controls during performance of a verbal fluency task, as well as during rest. By assigning 16 language-related regions into four subsystems (i.e. bilateral frontal and temporal), we observed regional specialization in both the probability of transient interactions and the frequency of such changes, in both healthy controls and patients during task performance but not rest. Furthermore, we found that both left and right temporal lobe epilepsy patients displayed reduced interactions within the left frontal 'core' subsystem compared to the healthy controls, while left temporal lobe epilepsy patients were unique in showing enhanced interactions between the left frontal 'core' and the right temporal subsystems. Also, both patient groups displayed reduced flexibility in the transient interactions of the left temporal and right frontal subsystems, which formed the 'periphery' of the language network. Importantly, such group differences were again evident only during task condition. Lastly, through random forest regression, we showed that dynamic reconfiguration of the language system tracks individual differences in verbal fluency with superior prediction accuracy compared to traditional activation-based static measures. Our results suggest dynamic network measures may be an effective biomarker for detecting the language dysfunction associated with neurological diseases such as temporal lobe epilepsy, specifying both the type of neuronal communications that are missing in these patients and those that are potentially added but maladaptive. Further advancements along these lines, transforming how we characterize and map language networks in the brain, have a high probability of altering clinical decision making in neurosurgical centres.10.1093/brain/awy042_video1awy042media15754656112001.


Signal changes on T2*-weighted magnetic resonance imaging from the acute to chronic phases in patients with subarachnoid hemorrhage.
Timing of the onset of subarachnoid hemorrhage (SAH) is important for treatment decision-making, especially as some patients visit hospital several weeks after the onset of SAH. T2*-weighted (T2*W) magnetic resonance (MR) imaging is regarded as a sensitive method for the detection of deoxyhemoglobin or hemosiderin deposits. This study investigated the characteristics of the abnormal low intensity changes on T2*W imaging in patients with SAH, how long the abnormal low intensity persisted, and whether the day of onset could be predicted based on the T2*W imaging changes. The study included patients treated for SAH associated with ruptured cerebral aneurysms, or who had previously suffered such SAH and were followed up at our hospital, between 2006 and 2007. MR imaging was performed using a whole-body 3.0-tesla MR scanner. All patients underwent gradient recalled echo (GRE) and echo planar (EP) T2*W imaging. The strength of the low intensity areas was evaluated as the following 5 grades: grade 0, no abnormal low intensity on both GRE and EP T2*W images; grade 1, no abnormal intensity on GRE T2*W images and low intensity on EP T2*W images; grade 2, spotty abnormal low intensity on both GRE and EP T2*W images; grade 3, medium abnormal low intensity (<5 mm) on both GRE and EP T2*W images, and grade 4, large abnormal low intensity (≥5 mm) on both GRE and EP T2*W images. A total of 50 patients with 74 MR images were included during the study period. Abnormal low intensity on T2*W imaging was observed in all patients. The T2* score gradually decreased from the onset of SAH until day 90, showing a significant negative linear correlation (R(2) = 0.25, p = 0.0002). On the other hand, the T2* score did not change after 1 year. The square correlation coefficient between the recorded and calculated days from the onset of SAH was 0.29 (p = 0.0107). The pure error was ±10 days. The T2* score gradually decreased until 90 days from the onset of SAH, but persisted for 16 years after the onset. We could predict the day of onset with pure error ±10 days in patients with SAH within 90 days of onset using our grading system for T2*W images.


Kluyveromyces marxianus and Saccharomyces boulardii Induce Distinct Levels of Dendritic Cell Cytokine Secretion and Significantly Different T Cell Responses In Vitro.
Interactions between members of the intestinal microbiota and the mucosal immune system can significantly impact human health, and in this context, fungi and food-related yeasts are known to influence intestinal inflammation through direct interactions with specialized immune cells in vivo. The aim of the present study was to characterize the immune modulating properties of the food-related yeast Kluyveromyces marxianus in terms of adaptive immune responses indicating inflammation versus tolerance and to explore the mechanisms behind the observed responses. Benchmarking against a Saccharomyces boulardii strain with probiotic effects documented in clinical trials, we evaluated the ability of K. marxianus to modulate human dendritic cell (DC) function in vitro. Further, we assessed yeast induced DC modulation of naive T cells toward effector responses dominated by secretion of IFNγ and IL-17 versus induction of a Treg response characterized by robust IL-10 secretion. In addition, we blocked relevant DC surface receptors and investigated the stimulating properties of β-glucan containing yeast cell wall extracts. K. marxianus and S. boulardii induced distinct levels of DC cytokine secretion, primarily driven by Dectin-1 recognition of β-glucan components in their cell walls. Upon co-incubation of yeast exposed DCs and naive T cells, S. boulardii induced a potent IFNγ response indicating TH1 mobilization. In contrast, K. marxianus induced a response dominated by Foxp3+ Treg cells, a characteristic that may benefit human health in conditions characterized by excessive inflammation and positions K. marxianus as a strong candidate for further development as a novel yeast probiotic.


Health information search to deal with the exploding amount of health information produced.
This focus theme deals with the various aspects of health information search that are necessary to cope with the challenges of an increasing amount and complexity of medical information currently produced. This editorial reviews the main challenges of health information search and summarizes the five papers of this focus theme. The five papers of the focus theme cover a large part of the current challenges in health information search such as coding standards, information extraction from complex data, user requirements analysis, multimedia data analysis and the access to big data. Several future challenges are identified such as the combination of visual and textual data for information search and the difficulty to scale when analyzing big data.


Identification of a Novel Non-desmoglein Autoantigen in Pemphigus Vulgaris.
Pemphigus vulgaris (PV) is an autoimmune bullous disease of the skin and mucous membranes characterized by the presence of circulating and tissue-bound autoantibodies against keratinocyte cell surface antigens, specifically desmoglein (Dsg) 1 and 3. The pathogenic role of anti-Dsg antibodies is well-established, while the mechanism of blister formation is only partly defined. We have applied a previously developed method for the efficient immortalization of IgG+ memory B cells to identify novel target antigens in PV. A human monoclonal antibody reactive with a hitherto unreported non-Dsg antigen was isolated. Immunoprecipitation and immunoblotting studies with keratinocyte extracts indicated α-catenin as the putative antigen, then confirmed by immunoblotting on the recombinant protein. Four of ten PV sera reacted with recombinant α-catenin. Although the isolated human monoclonal antibody was per se unable to dissociate keratinocyte monolayers and also to synergize with a pathogenic antibody in vitro, further studies are warranted to assess its possible in vivo contribution in the multifactorial pathogenesis and heterogeneous manifestations of PV disease.


Fruit and vegetable intake and risk of wheezing and asthma: a systematic review and meta-analysis.
Major bibliographic databases were searched for studies examining the relationship between fruit and vegetable consumption and the risk of wheezing and asthma. Random-effects models were used to pool study results. Subgroup analyses were conducted by fruit and vegetable categories, study design, and age group. Twelve cohorts, 4 population-based case-control studies, and 26 cross-sectional studies published between January 1990 and July 2013 were identified. For the meta-analysis of adults and children, the relative risk (RR) and confidence intervals (CI) when comparing the highest intake group with the lowest intake group were 0.78 (95%CI, 0.70-0.87) for fruit and 0.86 (95%CI, 0.75-0.98) for vegetables. High intake of fruit and vegetables (RR = 0.76; 95%CI, 0.68-0.86 and RR = 0.83; 95%CI, 0.72-0.96) reduced the risk of childhood wheezing. Total intake of fruit and vegetables had a negative association with risk of asthma in adults and children (RR = 0.54; 95%CI, 0.41-0.69). Consuming fruit and vegetables during pregnancy had no association with the risk of asthma in offspring. High intake of fruit and vegetables may reduce the risk of asthma and wheezing in adults and children.


Exploring workplace violence among home care workers in a consumer-driven home health care program.
Nominal research has examined sexual harassment and workplace violence against home care workers within consumer-driven home care models such as those offered in Oregon. This study examined home care workers' experiences of violence while providing care to consumer employers, the patients who hire and manage home care workers. Focus groups and interviews were conducted in Oregon with 83 home care workers, 99 Oregon Department of Human Services (DHS) employees, and 11 consumer employers. Home care workers reported incidents of workplace physical violence (44%), psychological abuse (65%), sexual harassment (41%), and sexual violence (14%). Further, three themes were identified that may increase the risk of workplace violence: (1) real and perceived barriers to reporting violence; (2) tolerance of violence; and (3) limited training to prevent violence. To ensure worker safety while maintaining quality care, safety policies and training for consumer employers, state DHS employees, and home care workers must be developed.


Root hair phenotypes influence nitrogen acquisition in maize.
The utility of root hairs for nitrogen (N) acquisition is poorly understood. We explored the utility of root hairs for N acquisition in the functional-structural model SimRoot and with maize genotypes with variable root hair length (RHL) in greenhouse and field environments. Simulation results indicate that long, dense root hairs can improve N acquisition under varying N availability. In the greenhouse, ammonium availability had no effect on RHL and low nitrate availability increased RHL, while in the field low N reduced RHL. Longer RHL was associated with 216 % increase in biomass and 237 % increase in plant N content under low-N conditions in the greenhouse and a 250 % increase in biomass and 200 % increase in plant N content in the field compared with short-RHL phenotypes. In a low-N field environment, genotypes with long RHL had 267 % greater yield than those with short RHL. We speculate that long root hairs improve N capture by increased root surface area and expanded soil exploration beyond the N depletion zone surrounding the root surface. We conclude that root hairs play an important role in N acquisition. We suggest that root hairs merit consideration as a breeding target for improved N acquisition in maize and other crops.


Clinical significance of serum p53 antigen in patients with pancreatic carcinomas.
Alterations in the p53 gene are often found in pancreatic cancer, and accumulation of the p53 protein has been noted in tumour cells. To investigate whether serum p53 protein concentrations could be used as markers for p53 gene mutations in neoplasms of the pancreas. Serum p53 protein concentrations were determined by an enzyme linked immunosorbent assay (ELISA) in 104 cases of pancreatic adenocarcinoma, and 61 matched formalin fixed tissue sections were also stained by an anti-p53 DO-7 monoclonal antibody. The mean serum concentration of p53 protein in the adenocarcinoma patients was 0.27 (SEM 0.02) ng/ml, and was significantly higher than in 35 healthy blood donors (0.15 (0.02) ng/ml, SD = 0.11) or in 15 cases of chronic pancreatitis (0.15 (0.02) ng/ml). Adopting an arbitrary cut off value for the serum p53 protein concentration of 0.37 ng/ml, which corresponded to a value 2 SD above the mean value from the healthy blood donors, positive serum p53 protein concentrations were found in 23 out of 104 (22.1%) patients with adenocarcinomas examined, 16 out of 47 (34.0%) patients with carcinomas with distant metastases, but only seven of 57 patients (12.3%) with carcinomas without metastases (p < 0.05). In 11 patients with pancreatic adenocarcinomas, the mean serum p53 protein concentration after tumour resection was 0.21 (0.05) ng/ml, and had decreased compared with the preoperative concentrations (0.25 (0.05) ng/ml) (P < 0.05). There were no significant associations between the serum concentrations of p53 protein and serum concentrations of markers such as CA19-9 or CEA; however, serum concentrations of p53 protein demonstrated a potential role as an additional tumour marker. Immunohistochemical studies disclosed that the p53 protein was expressed in 28 out of 61 pancreatic adenocarcinomas (45.9%). Serum p53 protein concentrations in the positively immunostained cases were significantly higher than in the negatively immunostained cases (0.35 (0.05) ng/ml v 0.15 (0.01) ng/ml; p < 0.005). Furthermore, positive immunostaining for p53 protein was found in eight out of 10 (80%) serum positive p53 protein cases with adenocarcinomas. An increase in serum p53 protein concentrations appears during the progression of pancreatic adenocarcinoma and correlates with the accumulation of p53 protein as a result of a mutation of the p53 gene. An analysis of p53 antigen concentrations can detect p53 gene alterations, which could be useful for the selection of treatment regimens.


Arrangement of electron transport chain components in bovine mitochondrial supercomplex I1III2IV1.
The respiratory chain in the inner mitochondrial membrane contains three large multi-enzyme complexes that together establish the proton gradient for ATP synthesis, and assemble into a supercomplex. A 19-Å 3D map of the 1.7-MDa amphipol-solubilized supercomplex I(1)III(2)IV(1) from bovine heart obtained by single-particle electron cryo-microscopy reveals an amphipol belt replacing the membrane lipid bilayer. A precise fit of the X-ray structures of complex I, the complex III dimer, and monomeric complex IV indicates distances of 13 nm between the ubiquinol-binding sites of complexes I and III, and of 10-11 nm between the cytochrome c binding sites of complexes III and IV. The arrangement of respiratory chain complexes suggests two possible pathways for efficient electron transfer through the supercomplex, of which the shorter branch through the complex III monomer proximal to complex I may be preferred.


The effects of acute tryptophan depletion on brain activation during cognition and emotional processing in healthy volunteers.
Acute tryptophan depletion (ATD), a method to temporarily lower central serotonin levels, has been used to study the functioning of the serotonergic system. Relatively recent studies that examined the effects of ATD on brain activation associated with cognitive and emotional processing in healthy volunteers are reviewed. An overview of the findings in healthy volunteers is important for the interpretation of the effect of ATD on brain activation in patients with an affective disorder, such as major depression. These studies show that during response control and negative feedback processing ATD modulates the BOLD response in the inferior/orbitofrontal cortex, the anterior cingulate cortex and the dorsomedial prefrontal cortex. During emotional processing, it is consistently found that ATD modulates the BOLD response in the amygdala. These brain regions also show abnormal activation in depressed patients. However, at the moment it remains unclear if the changes induced by ATD are related to decreased basal serotonin (5-HT) release or the result of other biochemical changes that are mediated by ATD. Future studies should implement methodological improvements, explore the possibilities of new promising imaging techniques and expand investigations into the effects of ATD on basal 5-HT release and other biochemical mechanisms that might be modulated by ATD.


A collaboration investigating endocannabinoid signalling in brain and bone.
Investigations into the cellular and molecular mechanisms underlying the psychoactive effects of cannabis preparations have led to the discovery of the endocannabinoid system. Interest in the central nervous system effects was initially the main focus of the research, but it soon became evident that the endocannabinoid system affects virtually every organ. The research field has therefore experienced a tremendous growth over the last decade and is now truly interdisciplinary. This short review provides a personal account of an interdisciplinary collaboration between Itai Bab from the Hebrew University of Jerusalem and the author. It describes the discovery of the endocannabinoid system in bone and the analysis of its functions. I am summarising the role of CB1 signalling as a modulator of sympathetic inhibition of bone formation. Thus, activation of CB1 receptors on sympathetic nerve terminals in bone, presumably from endocannabinoids released from apposing osteoblasts, reduces the inhibition of bone formation of sympathetic norepinephrine. CB2 receptors on osteoblasts and osteoclasts also modulate the proliferation and functions of these cells. Thus, activation of CB2 stimulates bone formation and represses bone resorption, whereas the genetic disruption of CB2 results in an osteoporosis-like phenotype. This signalling mechanism is clinically relevant, as shown by the association of polymorphisms in the CB2 receptor gene, CNR2, with bone density and osteoporosis. Finally, the review provides a summary of the recently discovered role of endocannabinoid signalling in one elongation. This review will also discuss the benefits of interdisciplinary and international collaborations.


Effect of PEEP on discharge of pulmonary C-fibers in dogs.
Although positive end-expiratory pressure (PEEP) is believed to depress cardiac output and arterial pressure by compressing the vena cava and the heart, it is unclear whether PEEP also depresses these variables by a reflex arising from an inflation-induced stimulation of pulmonary C-fibers. We therefore recorded the impulse activity of 17 pulmonary C-fibers in barbiturate-anesthetized dogs with closed chests, while we placed the expiratory outlet of a ventilator under 5-30 cmH2O. Increasing PEEP in a ramp-like manner stimulated 12 of the 17 pulmonary C-fibers, with activity increasing from 0.0 +/- 0.1 to 0.9 +/- 0.2 imp/s when end-expiratory pressure equaled 15 cmH2O. When PEEP was increased in a stepwise manner to 15-20 cmH2O and maintained at this pressure for 15 min, pulmonary C-fibers increased their firing rates, but the effect was small averaging 0.2-0.3 imp/s after the 1st min of this maneuver. We conclude that pulmonary C-fibers are unlikely to be responsible for causing much of the decreases in cardiac output and arterial pressure evoked by sustained periods of PEEP in both patients and laboratory animals. These C-fibers, however, are likely to be responsible for causing the reflex decreases in these variables evoked by sudden application of PEEP.


Blood loss in patients for total knee arthroplasty.
Ninety-four patients with osteoarthritis (OA) and 180 with rheumatoid arthritis (RA) undergoing unilateral total knee arthroplasty (TKA) were analyzed to clarify the necessity for preoperative autogenous blood deposition or homologous blood transfusion. Two hundred and twenty-four and 50 patients underwent TKA with cement and without cement, respectively. The difference in average blood loss in patients between with (372 ml) and without cementation (449 ml) was significant. In the OA group the average blood loss significantly decreased after cementation but not in the RA group. Although the rate of avoiding transfusion in the OA group did not significantly decrease with the use of cement (92.4% vs. 93.3%), that in the RA group did (80% to 57.1%). Eight of 159 patients with hemoglobin level (Hb) of 11.0 g/dl or higher received homologous blood transfusion. Of these eight patients five had associated disorders. Only one patient with Hb of 12.0 g/dl or higher underwent homologous blood transfusion. Patients with Hb of 12.0 g/dl or higher are not indicated for preoperative autologous blood deposition. In patients with Hb between 11.0 and 12.0 g/dl preoperative blood deposition may be planned after consideration of general condition and complication. Patients with Hb lower than 11.0 g/dl should undergo preoperative blood deposition.


Brinicles as a case of inverse chemical gardens.
Brinicles are hollow tubes of ice from centimeters to meters in length that form under floating sea ice in the polar oceans when dense, cold brine drains downward from sea ice to seawater close to its freezing point. When this extremely cold brine leaves the ice, it freezes the water it comes into contact with: a hollow tube of ice-a brinicle-growing downward around the plume of descending brine. We show that brinicles can be understood as a form of the self-assembled tubular precipitation structures termed chemical gardens, which are plantlike structures formed on placing together a soluble metal salt, often in the form of a seed crystal, and an aqueous solution of one of many anions, often silicate. On one hand, in the case of classical chemical gardens, an osmotic pressure difference across a semipermeable precipitation membrane that filters solutions by rejecting the solute leads to an inflow of water and to its rupture. The internal solution, generally being lighter than the external solution, flows up through the break, and as it does so, a tube grows upward by precipitation around the jet of internal solution. Such chemical-garden tubes can grow to many centimeters in length. In the case of brinicles, on the other hand, in floating sea ice we have porous ice in a mushy layer that filters out water, by freezing it, and allows concentrated brine through. Again there is an osmotic pressure difference leading to a continuing ingress of seawater in a siphon pump mechanism that is sustained as long as the ice continues to freeze. Because the brine that is pumped out is denser than the seawater and descends rather than rises, a brinicle is a downward-growing tube of ice, an inverse chemical garden.


Adapting the IDEAL Framework and Recommendations for medical device evaluation: A modified Delphi survey.
Current regulatory systems for medical device marketing approval lack adequate requirements for evidence of safety and efficacy. The Total Product Life Cycle (TPLC) concept, with clinical use and marketing expanding as evidence develops, has won support, but lacks a template to define evidence requirements at different stages. The IDEAL Framework & Recommendations, originally developed for new surgical procedures, might provide such a template, but may require modification. We conducted a Delphi expert consensus exercise to determine how IDEAL might be modified to accommodate the needs of device regulation. 34 experts were invited to participate in 3 rounds of questioning, with feedback of the results of each round to participants before the next. 27 of 34 experts responded in at least one survey round. Experts agreed that, after appropriate modifications, IDEAL could form an evidence template for a TPLC-based regulatory system. Necessary modifications include a new Stage 0 should guide reporting of pre-clinical studies, expansion of registries to all stages, and omission of IDEAL stages 2 and 3 for "successor" devices under certain conditions. A standard approach to TPLC evaluation of medical devices does not currently exist. The IDEAL Framework, if modified appropriately, could fill such a void and improve the safety of new medical devices.


Neurohumoral and hemodynamic responses to dietary calcium supplementation in deoxycorticosterone-salt hypertensive dogs.
We determined whether dietary calcium supplementation can influence the development and maintenance of hypertension in deoxycorticosterone (DOC)-salt-treated dogs. Dogs on normal dietary calcium (0.4%) had significant increases in mean arterial pressure (from 92 +/- 2 to 131 +/- 3 mm Hg, p less than 0.01); those given high dietary calcium (1.7%) had attenuated but significant increases in mean arterial pressure (from 90 +/- 2 to 107 +/- 1, p less than 0.01). The elevation of blood pressure in dogs on normal dietary calcium was primarily due to increased calculated total peripheral resistance, which was prevented by the high calcium diet. The increases in blood pressure could not be attributed to any changes in cardiac output, blood volume, or plasma norepinephrine. These results suggest that mineralocorticoid hypertension in the dog is associated with abnormalities not only in sodium, but also in calcium metabolism. Further, they suggest a direct link between sodium and calcium metabolism and may thus have implications for the pathogenesis and management of salt-dependent hypertension.


The Tinkerbell (Tink) Mutation Identifies the Dual-Specificity MAPK Phosphatase INDOLE-3-BUTYRIC ACID-RESPONSE5 (IBR5) as a Novel Regulator of Organ Size in Arabidopsis.
Mitogen-activated dual-specificity MAPK phosphatases are important negative regulators in the MAPK signalling pathways responsible for many essential processes in plants. In a screen for mutants with reduced organ size we have identified a mutation in the active site of the dual-specificity MAPK phosphatase indole-3-butyric acid-response5 (IBR5) that we named tinkerbell (tink) due to its small size. Analysis of the tink mutant indicates that IBR5 acts as a novel regulator of organ size that changes the rate of growth in petals and leaves. Organ size and shape regulation by IBR5 acts independently of the KLU growth-regulatory pathway. Microarray analysis of tink/ibr5-6 mutants identified a likely role for this phosphatase in male gametophyte development. We show that IBR5 may influence the size and shape of petals through auxin and TCP growth regulatory pathways.


The effects of ovariectomy and estrogen replacement on trkA and choline acetyltransferase mRNA expression in the basal forebrain of the adult female Sprague-Dawley rat.
Cognitive deficits associated with aging and with neurodegenerative diseases such as Alzheimer's disease have been attributed to degeneration of cholinergic neurons in the basal forebrain. Estrogen is known to provide trophic support to cholinergic neurons, although the mechanisms underlying the actions of estrogen have yet to be determined. Because cholinergic neurons require neurotrophic growth factors for their survival, it is possible that the trophic effects of estrogen on basal forebrain systems are caused by enhanced expression of neurotrophins or their receptors. To begin to examine this hypothesis, we used in situ hybridization analysis to determine the effects of ovariectomy (ovx) and estrogen replacement on trkA mRNA levels in the rat basal forebrain. Ten days of estrogen deprivation after ovx resulted in significant decreases in trkA mRNA levels in the horizontal limb of the diagonal band of Broca and the nucleus basalis of Meynert. Short-term estrogen replacement therapy restored trkA mRNA expression to a level comparable with ovary-intact animals. No changes in trkA mRNA levels were observed in the vertical limb of the diagonal band of Broca after ovx or estrogen replacement. To assess the functional status of cholinergic neurons in the absence and presence of estrogen, the effects of ovx and estrogen replacement on ChAT mRNA levels were also examined and found to reflect the changes observed in trkA mRNA expression. These studies suggest that the trophic effects of estrogen on basal forebrain cholinergic systems may be mediated, in part, through the signaling of neurotrophic growth factors through their receptors.


Improving Pediatric Rapid Response Team Performance Through Crew Resource Management Training of Team Leaders.
Rapid response teams (RRTs) improve the detection of and response to deteriorating patients. Professional hierarchies and the multidisciplinary nature of RRTs hinder team performance. This study assessed whether an intervention involving crew resource management training of team leaders could improve team performance. In situ observations of RRT activations were performed pre- and post-training intervention. Team performance and dynamics were measured by observed adherence to an ideal task list and by the Team Emergency Assessment Measure tool, respectively. Multiple quartile (median) and logistic regression models were developed to evaluate change in performance scores or completion of specific tasks. Team leader and team introductions (40% to 90%, P = .004; 7% to 45%, P = .03), floor team presentations in Situation Background Assessment Recommendation format (20% to 65%, P = .01), and confirmation of the plan (7% to 70%, P = .002) improved after training in patients transferred to the ICU (n = 35). The Team Emergency Assessment Measure metric was improved in all 4 categories: leadership (2.5 to 3.5, P < .001), teamwork (2.7 to 3.7, P < .001), task management (2.9 to 3.8, P < .001), and global scores (6.0 to 9.0, P < .001) for teams caring for patients who required transfer to the ICU. Targeted crew resource management training of the team leader resulted in improved team performance and dynamics for patients requiring transfer to the ICU. The intervention demonstrated that training the team leader improved behavior in RRT members who were not trained.


A randomized trial of long-term remote monitoring of pacemaker recipients (the COMPAS trial).
Professional practice guidelines recommend that pacemaker recipients be followed regularly. However, the majority of scheduled ambulatory visits is unproductive and imposes a heavy burden on the health-care system. The COMPAS randomized, multicentre, non-inferiority trial examined the safety of long-term remote monitoring of pacemakers. Between December 2005 and January 2008, 538 patients were randomly assigned to remote monitoring follow-up (active group) vs. standard care (control group). The primary objective was to confirm that the proportion of patients who experienced at least one major adverse event (MAE), including all-cause death and hospitalizations for device-related or cardiovascular adverse events, was not >7% higher in the active than in the control group. MAE-free survivals and quality of life were compared in both groups. The characteristics of the study groups were similar. Over a follow-up of 18.3 months, 17.3% of patients in the active and 19.1% in the control group experienced at least one MAE (P < 0.01 for non-inferiority). Hospitalizations for atrial arrhythmias (6 vs. 18) and strokes (2 vs. 8) were fewer (P < 0.05), and the number of interim ambulatory visits was 56% lower (P < 0.001) in the active than the control group. Changes in pacemaker programming or drug regimens were made in 62% of visits in the active vs. 29% in the control group (P < 0.001). Quality of life remained unchanged in both groups. Remote monitoring was a safe alternative to conventional care and significantly lowered the number of ambulatory visits during long-term follow-up of permanently paced patients. ClinicalTrials.gov identifier: NCT00989326.


Development and initial testing of a measure of person-directed care.
The purpose of the study was to empirically test items of a new measure designed to assess person-directed care (PDC) practices in long-term care. After reviewing the literature, we identified five areas related to PDC: personhood, comfort care, autonomy, knowing the person, and support for relationships. We also identified an additional component of environmental support. We developed items to reflect the constructs, and then a series of lay and professional experts in the field reviewed the items for face validity. We distributed the resulting 64-item PDC and Environmental Support for PDC measure to direct care workers and nursing, administrative, and other staff from a range of long-term settings across Oregon, culminating in a sample size of 430 participants from eight sites. We employed exploratory factor analyses to reveal the underlying structure of the measure. After we dropped 14 items from the measure, it attained good simple structure, revealing five PDC constructs as previously theorized and three Environmental Support constructs: Support for Work With Residents; Person-Directed Environment for Residents, and Management/Structural Support. All constructs were conceptually distinct and internally consistent, and, as expected, all were positively correlated. The PDC measurement tool developed through the Better Jobs Better Care demonstration program funded by the Atlantic Philanthropies and Robert Wood Johnson Foundation is an important step toward operationalizing the philosophies inherent in the concepts of PDC and is expected to be a useful tool in evaluating successes in meeting PDC goals and in prompting further research regarding PDC and its consequences for resident and client outcomes.


Rural doctors' attitudes to and knowledge of medicinal cannabis.
The use of cannabis for medical purposes remains controversial. Since support from general practitioners would be needed for the successful operation of a legalised prescription regime, New South Wales Northern Rivers general practitioners were surveyed on their attitudes to and knowledge of medicinal cannabis. A representative random sample of general practitioners, stratified by age and gender, was derived and interviewed. Results indicated generally high levels of knowledge of cannabis's medical uses. The mean number of patients seen in 2004 with medicinal cannabis-treatable conditions was 66.8, with chronic pain patients accounting for 36.7. Overwhelming majorities of respondents reported they would prescribe medicinal cannabis if it were legal, professionally supported and backed by research and that they would approve of clinical trials and a legalised regulatory scheme under such conditions. These results suggest the need to conduct a Statewide general practitioners' survey to confirm or refute the present findings.