Longitudinal patterns of β-amyloid deposition in nondemented older adults.
High levels of β-amyloid (Aβ) characterize Alzheimer disease. To investigate whether longitudinal changes in Aβ deposition can be detected in vivo in older adults without dementia (hereafter referred to as nondemented). Prospective study. Community-dwelling older adults. Twenty-four nondemented participants (4 with a baseline Clinical Dementia Rating Scale score of 0.5; mean [SD] age, 79.2 [8.1] years) in the Baltimore Longitudinal Study of Aging underwent serial carbon 11-labeled Pittsburgh Compound B-positron emission tomography ([(11)C]PiB-PET) (follow-up at a mean [SD] of 1.5 [0.5] years), with 5 participants undergoing a third [(11)C]PiB-PET examination. Annual changes in distribution volume ratio (DVR) were evaluated using a global index of cortical DVR (cDVR) and region-of-interest analyses. Given the variability of cDVR at the initial PiB-PET, annual changes in cDVR in those with minimal vs those with elevated initial cDVR were compared. In nondemented older adults, annual increase in [(11)C]PiB retention is 0.011 DVR per year (0.9%; P = .01), which localizes to the prefrontal, parietal, lateral temporal, occipital, and anterior and posterior cingulate cortices. Annual change in cDVR is greater in older adults with elevated cDVR than in those with a minimal initial cDVR (P = .006). Fibrillar Aβ detected by [(11)C]PiB-PET increases over time even in nondemented older adults. Individuals with higher initial [(11)C]PiB retention have greater rates of Aβ deposition, providing evidence of differential rates of Aβ deposition. Moreover, regional vulnerabilities to Aβ deposition allow for more targeted investigation of early Aβ changes.


Quality-adjusted survival with combination nal-IRI+5-FU/LV vs 5-FU/LV alone in metastatic pancreatic cancer patients previously treated with gemcitabine-based therapy: a Q-TWiST analysis.
In the NAPOLI-1 Phase 3 trial, nal-IRI+5-fluorouracil and leucovorin (5-FU/LV) significantly improved median overall survival (6.1 vs 4.2 months, P=0.012) and progression-free survival (3.1 vs 1.5 months, P=0.0001) vs 5-FU/LV alone in metastatic pancreatic adenocarcinoma patients previously treated with gemcitabine-based therapy. This analysis evaluated between treatment differences in quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST). Overall survival was partitioned into time with grade ⩾3 toxicity (TOX), disease progression (REL), and time without disease progression symptoms or grade ⩾3 toxicity (TWiST). Mean Q-TWiST was calculated by weighting time spent by a utility of 1.0 for TWiST and 0.5 for TOX and REL. In threshold analyses, utility for TOX and REL were varied from 0.0 to 1.0. Patients in nal-IRI+5-FU/LV (n=117) vs 5-FU/LV (n=119) had significantly more mean time in TWiST (3.4 vs 2.4 months) and TOX (1.0 vs 0.3 months) but similar REL (2.5 vs 2.7 months). In the base case, nal-IRI+5-FU/LV patients had 1.3 months (95% CI, 0.4-2.1; 5.1 vs 3.9) greater Q-TWiST (threshold analyses range: 0.9-1.6 months). Within NAPOLI-1, nal-IRI+5-FU/LV resulted in statistically significant and clinically meaningful gains in quality-adjusted survival vs 5-FU/LV alone.


Scaling laws of strategic behavior and size heterogeneity in agent dynamics.
We consider the financial market as a model system and study empirically how agents strategically adjust the properties of large orders in order to meet their preference and minimize their impact. We quantify this strategic behavior by detecting scaling relations between the variables characterizing the trading activity of different institutions. We also observe power-law distributions in the investment time horizon, in the number of transactions needed to execute a large order, and in the traded value exchanged by large institutions, and we show that heterogeneity of agents is a key ingredient for the emergence of some aggregate properties characterizing this complex system.


Energy Balance-Related Behaviors and Body Mass Index in Asian School-Aged Children With Congenital Heart Disease.
Overweight/obesity is a substantial global public health concern, which can be caused by genetic factors and energy balance-related behaviors (EBRBs). If it occurs in children with congenital heart disease (CCHD), it can yield an extra burden on their health. Most studies on CCHD have taken place in Western societies, leaving Asian populations understudied, especially children. We sought (1) to determine body mass index distribution among school-aged CCHD in Taiwan, (2) to ascertain whether the body mass index of CCHD differs from that of the general population, (3) to describe EBRBs in CCHD, and (4) to identify factors associated with underweight and overweight/obesity among CCHD. In this cross-sectional study, 97 child-parent dyads (53.6% boys; mean age, 9.73 years; 25.8% moderate-to-severe heart conditions) were enrolled. Self-administered questionnaires were used to collect demographics, medical factors, food frequency, physical activity, and sedentary behaviors. Anthropometric measurements were taken in the hospital. Independent predictors of EBRBs and health conditions were calculated through logistic regression analysis. Among Taiwanese CCHD, 19.6% were underweight and 14.4% were overweight/obese. Children with moderate-to-severe heart defects were more often underweight. Body mass index did not differ between CCHD and children in the general population. More complex heart defects and asthma were associated with being underweight, whereas sedentary behaviors, cardiomegaly, and the New York Heart Association classification II to IV were associated with being overweight/obese. Sedentary lifestyle is seemingly the only EBRB correlated with being overweight. Physical activity programs for children may help prevent and treat overweight or obesity in Asian CCHD, similar to Western countries.


Feasibility, double-blind, randomised, placebo-controlled, multi-centre trial of hand-held NB-UVB phototherapy for the treatment of vitiligo at home (HI-Light trial: Home Intervention of Light therapy).
Hand-held NB-UVB units are lightweight devices that may overcome the need to treat vitiligo in hospital-based phototherapy cabinets, allowing early treatment at home that may enhance the likelihood of successful repigmentation. The pilot Hi-Light trial examined the feasibility of conducting a large multi-centre randomised controlled trial (RCT) on the use of such devices by exploring recruitment, adherence, acceptability, and patient education. This was a feasibility, double-blind, multi-centre, parallel group randomised placebo-controlled trial of hand-held NB-UVB phototherapy for the treatment of vitiligo at home. The overall duration of the trial was seven months; three months recruitment and four months treatment. Participants were randomly allocated to active or placebo groups (2:1 ratio). The primary outcome measure was the proportion of eligible participants who were willing to be randomised. The secondary outcomes included proportion of participants expressing interest in the trial and fulfilling eligibility criteria, withdrawal rates and missing data, proportion of participants adhering to and satisfied with the treatment, and incidence of NB-UVB short-term adverse events. Eighty-three percent (45/54) of vitiligo patients who expressed interest in the trial were willing to be randomised. Due to time and financial constraints, only 29/45 potential participants were booked to attend a baseline hospital visit. All 29 (100%) potential participants were confirmed as being eligible and were subsequently randomised. Willingness to participate in the study for General Practice (family physicians) surgeries and hospitals were 40% and 79%, respectively; 86% (25/29) of patients adhered to the treatment and 65% (7/11) of patients in the active group had some degree of repigmentation. Only one patient in the active group reported erythema grade 3 (3%). Both devices (Dermfix 1000 NB-UVB and Waldmann NB-UVB 109) were acceptable to participants. Hand-held NB-UVB devices need evaluation in a large, pragmatic RCT. This pilot trial has explored many of the uncertainties that need to be overcome before embarking on a full scale trial, including the development of a comprehensive training package and treatment protocol. The study has shown strong willingness of participants to be randomised, very good treatment adherence and repigmentation rates, and provided evidence of feasibility for a definitive trial. NCT01478945.


The effectiveness of a pendulum swing for the development of leg strength and counter-movement jump performance.
Various training devices have been developed to facilitate 'plyometric' training, one such device being the 'pendulum swing'. To assess the effectiveness of the pendulum swing, the results of a 3 week training programme using a combination of pendulum swing and weight-training exercises were compared to those of a weight-training programme. Subjects were assigned to one of two groups (n = 9) for weight-training only or for combined pendulum and weight-training. Both groups performed the same number of exercise repetitions. Measurements of isometric knee and hip extension-flexion, 1-RM squat weight, maximum jump height and power for a counter-movement jump were taken pre-training, 2 days after the end of the programme and 2 weeks after the end of the programme. The data were analysed using two-way MANOVA and MANCOVA techniques. Both methods showed significant (P < 0.05) increases in knee and hip extension strength. Hip and knee flexion strength increased only for the weight-trained group. Counter-movement jump height increased for both groups (weight-trained, P < 0.05; combined, P < 0.01). Maximum power increased only for the combined group (P < 0.05). When the pre-training scores were used as a covariate, the weight-trained group showed a greater increase in hip flexion and extension strength and knee flexion strength than the combined training group (P < 0.05). The combined group showed the greatest increase in knee extensor strength. It is concluded that the pendulum system induces a training effect which could be used to supplement weight-training for improving vertical jump performance.


Enhanced spontaneous DNA twisting/bending fluctuations unveiled by fluorescence lifetime distributions promote mismatch recognition by the Rad4 nucleotide excision repair complex.
Rad4/XPC recognizes diverse DNA lesions including ultraviolet-photolesions and carcinogen-DNA adducts, initiating nucleotide excision repair. Studies have suggested that Rad4/XPC senses lesion-induced helix-destabilization to flip out nucleotides from damaged DNA sites. However, characterizing how DNA deformability and/or distortions impact recognition has been challenging. Here, using fluorescence lifetime measurements empowered by a maximum entropy algorithm, we mapped the conformational heterogeneities of artificially destabilized mismatched DNA substrates of varying Rad4-binding specificities. The conformational distributions, as probed by FRET between a cytosine-analog pair exquisitely sensitive to DNA twisting/bending, reveal a direct connection between intrinsic DNA deformability and Rad4 recognition. High-specificity CCC/CCC mismatch, free in solution, sampled a strikingly broad range of conformations from B-DNA-like to highly distorted conformations that resembled those observed with Rad4 bound; the extent of these distortions increased with bound Rad4 and with temperature. Conversely, the non-specific TAT/TAT mismatch had a homogeneous, B-DNA-like conformation. Molecular dynamics simulations also revealed a wide distribution of conformations for CCC/CCC, complementing experimental findings. We propose that intrinsic deformability promotes Rad4 damage recognition, perhaps by stalling a diffusing protein and/or facilitating 'conformational capture' of pre-distorted damaged sites. Surprisingly, even mismatched DNA specifically bound to Rad4 remains highly dynamic, a feature that may reflect the versatility of Rad4/XPC to recognize many structurally dissimilar lesions.


Identification of a candidate prognostic gene signature by transcriptome analysis of matched pre- and post-treatment prostatic biopsies from patients with advanced prostate cancer.
Although chemotherapy for prostate cancer (PCa) can improve patient survival, some tumours are chemo-resistant. Tumour molecular profiles may help identify the mechanisms of drug action and identify potential prognostic biomarkers. We performed in vivo transcriptome profiling of pre- and post-treatment prostatic biopsies from patients with advanced hormone-naive prostate cancer treated with docetaxel chemotherapy and androgen deprivation therapy (ADT) with an aim to identify the mechanisms of drug action and identify prognostic biomarkers. RNA sequencing (RNA-Seq) was performed on biopsies from four patients before and ~22 weeks after docetaxel and ADT initiation. Gene fusion products and differentially-regulated genes between treatment pairs were identified using TopHat and pathway enrichment analyses undertaken. Publically available datasets were interrogated to perform survival analyses on the gene signatures identified using cBioportal. A number of genomic rearrangements were identified including the TMPRSS2/ERG fusion and 3 novel gene fusions involving the ETS family of transcription factors in patients, both pre and post chemotherapy. In total, gene expression analyses showed differential expression of at least 2 fold in 575 genes in post-chemotherapy biopsies. Of these, pathway analyses identified a panel of 7 genes (ADAM7, FAM72B, BUB1B, CCNB1, CCNB2, TTK, CDK1), including a cell cycle-related geneset, that were differentially-regulated following treatment with docetaxel and ADT. Using cBioportal to interrogate the MSKCC-Prostate Oncogenome Project dataset we observed a statistically-significant reduction in disease-free survival of patients with tumours exhibiting alterations in gene expression of the above panel of 7 genes (p = 0.015). Here we report on the first "real-time" in vivo RNA-Seq-based transcriptome analysis of clinical PCa from pre- and post-treatment TRUSS-guided biopsies of patients treated with docetaxel chemotherapy plus ADT. We identify a chemotherapy-driven PCa transcriptome profile which includes the down-regulation of important positive regulators of cell cycle progression. A 7 gene signature biomarker panel has also been identified in high-risk prostate cancer patients to be of prognostic value. Future prospective study is warranted to evaluate the clinical value of this panel.


[Effect of acupuncture on quality of life in post-ischemic stroke patients with dysphagia].
To observe the effect of acupuncture on quality of life (QOL) in post-ischemic stroke patients with dysphagia. Sixty-six patients with dysphagia were randomly assigned to 3 groups, the 23 patients in the electro-acupuncture (EA) group treated by EA, 18 in the control group received rehabilitation training combined with acupoint percutaneous electric stimulation, and 25 in the acupoint token puncturing (TP) group received rehabilitation training combined with acupoint TP, once every day for 20 days in total. Changes in QOL scale specified for dysphagia of patients before and after treatment were compared. The total effective rate was 69.6% in the EA group, 50.0% in the control group and 64.0% in the TP group with insignificant difference among them (P > 0.05), but the improvements dealing with patients' general condition, time for taking food, frequency of uneasiness, emotion, appetite, social intercourse ability, fatigue, sleep and mental health, etc. in the EA group were superior to those in the other two groups (P < 0.05). Acupuncture could improve the QOL of patients with dysphagia after ischemic stroke.


Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung cancer: a Southwest Oncology Group trial.
This randomized trial was designed to determine whether paclitaxel plus carboplatin (PC) offered a survival advantage over vinorelbine plus cisplatin (VC) for patients with advanced non--small-cell lung cancer. Secondary objectives were to compare toxicity, tolerability, quality of life (QOL), and resource utilization. Two hundred two patients received VC (vinorelbine 25 mg/m(2)/wk and cisplatin 100 mg/m(2)/d, day 1 every 28 days) and 206 patients received PC (paclitaxel 225 mg/m(2) over 3 hours with carboplatin area under the curve of 6, day 1 every 21 days). Patients completed QOL questionnaires at baseline, 13 weeks, and 25 weeks. Resource utilization forms were completed at five time points through 24 months. Patient characteristics were similar between the groups. The objective response rate was 28% in the VC arm and 25% in the PC arm. Median survival was 8 months in both arms, with 1-year survival rates of 36% and 38%, respectively. Grade 3 and 4 leukopenia (P =.002) and neutropenia (P =.008) occurred more frequently on the VC arm. Grade 3 nausea and vomiting were higher on the VC arm (P =.001, P =.007), and grade 3 peripheral neuropathy was higher on the PC arm (P <.001). More patients on the VC arm discontinued therapy because of toxicity (P =.001). No difference in QOL was observed. Overall costs on the PC arm were higher than on the VC arm because of drug costs. PC is equally efficacious as VC for the treatment of advanced non--small-cell lung cancer. PC is less toxic and better tolerated but more expensive than VC. New treatment strategies should be pursued.


Regulatory T cells.
Regulatory T (TR) cells are a subset of T cells that function to control immune responses. Different populations of TR cells have been described, including thymically derived CD4(+)CD25+ TR cells and Tr1 cells induced in the periphery through exposure to antigen. A transcription factor, Foxp3, has been identified that is essential for CD4(+)CD25+ TR cell development and function. There is now evidence that transforming growth factor-beta might play a role in this pathway. CD4(+)CD25+ TR cells proliferate extensively in vivo in an antigen-specific manner, and can respond to both self and foreign peptides. By suppressing excessive immune responses, TR cells play a key role in the maintenance of self-tolerance, thus preventing autoimmune disease, as well as inhibiting harmful inflammatory diseases such as asthma and inflammatory bowel disease.


Visually Evoked Potential Markers of Concussion History in Patients with Convergence Insufficiency.
We investigated whether differences in the pattern visual evoked potentials exist between patients with convergence insufficiency and those with convergence insufficiency and a history of concussion using stimuli designed to differentiate between magnocellular (transient) and parvocellular (sustained) neural pathways. Sustained stimuli included 2-rev/s, 85% contrast checkerboard patterns of 1- and 2-degree check sizes, whereas transient stimuli comprised 4-rev/s, 10% contrast vertical sinusoidal gratings with column width of 0.25 and 0.50 cycles/degree. We tested two models: an a priori clinical model based on an assumption of at least a minimal (beyond instrumentation's margin of error) 2-millisecond lag of transient response latencies behind sustained response latencies in concussed patients and a statistical model derived from the sample data. Both models discriminated between concussed and nonconcussed groups significantly above chance (with 76% and 86% accuracy, respectively). In the statistical model, patients with mean vertical sinusoidal grating response latencies greater than 119 milliseconds to 0.25-cycle/degree stimuli (or mean vertical sinusoidal latencies >113 milliseconds to 0.50-cycle/degree stimuli) and mean vertical sinusoidal grating amplitudes of less than 14.75 mV to 0.50-cycle/degree stimuli were classified as having had a history of concussion. The resultant receiver operating characteristic curve for this model had excellent discrimination between the concussed and nonconcussed (area under the curve = 0.857; P < .01) groups with sensitivity of 0.92 and specificity of 0.80. The results suggest a promising electrophysiological approach to identifying individuals with convergence insufficiency and a history of concussion.


Mesoporous bioactive glass composition effects on degradation and bioactivity.
Mesoporous bioactive glasses (MBGs) are promising materials for regenerative medicine, due to their favorable properties including bioactivity and degradability. These key properties, but also their surface area, pore structure and pore volume are strongly dependent on synthesis parameters and glass stoichiometry. However, to date no systematic study on MBG properties covering a broad range of possible compositions exists. Here, 24 MBG compositions in the SiO2-CaO-P2O5 system were synthesized by varying SiO2 (60-90 mol %), CaO and P2O5 content (both 0 to 40 mol-%), while other synthesis parameters were kept constant. Mesopore characteristics, degradability and bioactivity were analysed. The results showed that, within the tested range of compositions, mesopore formation required a molar SiO2 content above 60% but was independent of CaO and P2O5 content. While mesopore size did not depend on glass stoichiometry, mesopore arrangement was influenced by the SiO2 content. Specific surface area and pore volume were slightly altered by the SiO2 content. All materials were degradable; however, degradation as well as bioactivity, i.e. the ability to form a CaP mineral on the surface, depended on stoichiometry. Major differences were found in early surface reactions in simulated body fluid: where some MBGs induced direct hydroxyapatite crystallization, high release of calcium in others resulted in calcite formation. In summary, degradation and bioactivity, both key parameters of MBGs, can be controlled by glass stoichiometry over a broad range while leaving the unique structural parameters of MBGs relatively unaffected. This allows targeted selection of material compositions for specific regenerative medicine applications.


Vaccine research for gonococcal infections: where are we?
Gonorrhoea continues to seriously impact human society with an estimated 106 million new infections occurring annually. The consequence of gonorrhoea on reproductive and neonatal health is especially concerning as is its role in the spread of HIV. Current control measures rely on the identification and treatment of infected individuals and their sexual contacts. The success of this strategy, which is already inadequate, is lessened by poor diagnostic capabilities in many parts of the world and challenged by the rapid emergence of antibiotic-resistant strains. The potential of untreatable gonorrhoea is now real, and a gonorrhoea vaccine is seriously needed. Historically, gonorrhoea vaccine research has been hampered by the antigenic variability of the gonococcal surface, a lack of known protective mechanisms, and the absence of a small laboratory animal model for testing candidate vaccines and manipulating host responses. Here we discuss recent advances that have rekindled research efforts towards a gonorrhoea vaccine. Several conserved and semiconserved vaccine antigens have been identified that elicit bactericidal antibodies or inhibit target function. A mouse genital tract infection model is available for systematic testing of vaccines, and transgenic mice have been developed to relieve host restrictions. Additionally, several immunological advances have been made including the identification of mechanisms by which Neisseria gonorrhoeae suppresses the adaptive response and the demonstration that Th1 responses clear experimental infection in mice and induce a protective memory response. We also discuss important issues with respect to product development that must be considered when entering the vaccine pipeline.


Nasal reconstruction with articulated irradiated rib cartilage.
Nasal structural reconstruction is a formidable task in cases where there is loss of support to both the nasal dorsum and tip. A multitude of surgical approaches and materials have been used for the correction of the saddle-nose deformity with varying degrees of success. Articulated irradiated rib cartilage inserted through an external rhinoplasty approach was used to reconstruct nasal deformities in 18 patients over a 6-year period. Simultaneous use of a midline forehead flap to reconstruct the overlying soft tissue was required in four cases. Follow-up ranged from 1 to 6 years (mean, 2.8 years). Results were rewarding in most cases with marked improvement in nasal support and airway. Revision and/or replacement secondary to trauma or warping of the graft was required in four cases. None of the patients exhibited infection, extrusion, or noticeable resorption. A description of the surgical technique, review of all the cases, and recommendation for continued use of this graft material are discussed.


Centrifugal step emulsification applied for absolute quantification of nucleic acids by digital droplet RPA.
Aqueous microdroplets provide miniaturized reaction compartments for numerous chemical, biochemical or pharmaceutical applications. We introduce centrifugal step emulsification for the fast and easy production of monodisperse droplets. Homogenous droplets with pre-selectable diameters in a range from 120 μm to 170 μm were generated with coefficients of variation of 2-4% and zero run-in time or dead volume. The droplet diameter depends on the nozzle geometry (depth, width, and step size) and interfacial tensions only. Droplet size is demonstrated to be independent of the dispersed phase flow rate between 0.01 and 1 μl s(-1), proving the robustness of the centrifugal approach. Centrifugal step emulsification can easily be combined with existing centrifugal microfluidic unit operations, is compatible to scalable manufacturing technologies such as thermoforming or injection moulding and enables fast emulsification (>500 droplets per second and nozzle) with minimal handling effort (2-3 pipetting steps). The centrifugal microfluidic droplet generation was used to perform the first digital droplet recombinase polymerase amplification (ddRPA). It was used for absolute quantification of Listeria monocytogenes DNA concentration standards with a total analysis time below 30 min. Compared to digital droplet polymerase chain reaction (ddPCR), with processing times of about 2 hours, the overall processing time of digital analysis was reduced by more than a factor of 4.


Analysis of the C-value paradox by molecular hybridization.
Poly(A)-containing RNA was isolated from ovaries of Xenopus laevis laevis and Triturus cristatus carnifex and used as a template for the synthesis of radioactive complementary DNA with RNA-dependent DNA polymerase. When annealed with an excess of homologous DNA, the complementary DNA is rendered double-stranded with kinetics that suggest that the coding sequences are single-copy in both these organisms. In Triturus, these sequences are distinct from the majority of the genome, which consists of repeated sequences, and distinct from the ribosomal cistrons, which are present in proportion to the increase in C-value relative to the Xenopus genome. Moreover, the number of different poly(A)-containing molecules in the ovary (sequence complexity) is the same in Xenopus and in Triturus.


Endothelial cell proliferation during angiogenesis. In vitro modulation by basement membrane components.
Modulation of the behavior of microvascular endothelial cells during angiogenesis has been observed to correlate with changes in the extracellular matrix. These reports prompted a comparison of the growth of microvascular endothelial cells on monolayers of various matrix components in vitro. Over a 5 day period, the proliferation of these cells was significantly greater on laminin than on either plasma fibronectin, the interstitial collagen types I and III, or on the basement membrane collagen type IV. Proliferation of the microvascular endothelial cells was compared with that of bovine aortic endothelial cells and bovine aortic smooth muscle cells on the same matrices. All three cell types grew significantly more rapidly on laminin than on fibronectin. The aortic endothelial cells differed from their microvascular counterparts in that the growth of these large vessel endothelial cells on the collagenous matrices (types I and III, or type IV) was not significantly different from that observed for laminin, but was greater than the relatively slow growth seen on plasma fibronectin. Further comparison of the growth of the microvascular endothelial cells on the two basement membrane components, laminin and type IV collagen, demonstrated that the growth of these cells on laminin can be modulated by the presence of type IV collagen. This was true either if the two matrices were combined as a mixed layer, or if the laminin was specifically bound to a layer of type IV collagen, more closely simulating the distribution of these molecules in a basement membrane. Examination by immunoperoxidase of in vivo model of neovascularization in the murine cornea revealed a temporally staggered appearance of basement membrane components. The appearance of laminin was found to occur throughout the newly formed vessels, as well as in individual cells at the migrating, proliferating tips. In contrast, the appearance of type IV collagen correlated with lumen formation and was not detected at the vessel tips. The results of this study suggest that the temporally ordered synthesis of specific matrix components plays a significant role in orchestrating the growth and differentiation of endothelial cells during the highly integrated set of responses known as angiogenesis.


Changing patterns of medical practice: protein restriction for chronic renal failure.
The use of dietary protein restriction for renal failure has fluctuated during the past 125 years. These fluctuations reflect not only the state of medical knowledge but also social, economic, and cultural factors. Factors inhibiting use of dietary treatment have been its status as an aspect of hygiene rather than as active therapy; the opinions of dominant practitioners and scientists around midcentury, including a presumption that renal adaptation to a high-protein diet must be appropriate; fear of malnutrition and a cultural belief in the virtue of dietary protein; unwillingness by physicians and patients to restrict consumption or lifestyle; and professional identification with the technologies of dialysis and renal transplantation. Factors promoting dietary treatment have been rediscovery of previous work on protein-induced renal injury; a sense that homeostatic compensations could have adverse consequences; federal incentives to curb consumption of scarce resources such as renal dialysis; and the integration of research on, and therapeutic use of diet into scientific medicine. A large ongoing study of dietary protein restriction to limit renal injury will add to our knowledge of this treatment; its application will surely be informed by social and cultural considerations.


Gels composed of sodium-aluminium silicate, lake magadi, kenya.
Sodium-aluminum silicate gels are found in surficial deposits as thick as 5 centimeters in the Magadi area of Kenya. Chemical data indicate they are formed by the interaction of hot alkaline springwaters (67 degrees to 82 degrees C; pH, about 9) with alkali trachyte flows and their detritus, rather than by direct precipitation. In the process, Na(2)O is added from and silica is released to the saline waters of the springs. Algal mats protect the gels from erosion and act as thermal insulators. The gels are probably yearly accumulates that are washed into the lakes during floods. Crystallization of these gels in the laboratory yields analcite; this fact suggests that some analcite beds in lacustrine deposits may have formed from gels. Textural evidence indicates that cherts of rocks of the Pleistocene chert series in the Magadi area may have formed from soft sodium silicate gels. Similar gels may have acted as substrates for the accumulation and preservation of prebiological organic matter during the Precambrian.


Wolbachia-driven selective sweep in a range expanding insect species.
Evolutionary processes can cause strong spatial genetic signatures, such as local loss of genetic diversity, or conflicting histories from mitochondrial versus nuclear markers. Investigating these genetic patterns is important, as they may reveal obscured processes and players. The maternally inherited bacterium Wolbachia is among the most widespread symbionts in insects. Wolbachia typically spreads within host species by conferring direct fitness benefits, and/or by manipulating its host reproduction to favour infected over uninfected females. Under sufficient selective advantage, the mitochondrial haplotype associated with the favoured maternally-inherited symbiotic strains will spread (i.e. hitchhike), resulting in low mitochondrial genetic variation across the host species range. The common bluetail damselfly (Ischnura elegans: van der Linden, 1820) has recently emerged as a model organism for genetics and genomic signatures of range expansion during climate change. Although there is accumulating data on the consequences of such expansion on the genetics of I. elegans, no study has screened for Wolbachia in the damselfly genus Ischnura. Here, we present the biogeographic variation in Wolbachia prevalence and penetrance across Europe and Japan (including samples from 17 populations), and from close relatives in the Mediterranean area (i.e. I. genei: Rambur, 1842; and I. saharensis: Aguesse, 1958). Our data reveal (a) multiple Wolbachia-strains, (b) potential transfer of the symbiont through hybridization, (c) higher infection rates at higher latitudes, and (d) reduced mitochondrial diversity in the north-west populations, indicative of hitchhiking associated with the selective sweep of the most common strain. We found low mitochondrial haplotype diversity in the Wolbachia-infected north-western European populations (Sweden, Scotland, the Netherlands, Belgium, France and Italy) of I. elegans, and, conversely, higher mitochondrial diversity in populations with low penetrance of Wolbachia (Ukraine, Greece, Montenegro and Cyprus). The timing of the selective sweep associated with infected lineages was estimated between 20,000 and 44,000 years before present, which is consistent with the end of the last glacial period about 20,000 years. Our findings provide an example of how endosymbiont infections can shape spatial variation in their host evolutionary genetics during postglacial expansion. These results also challenge population genetic studies that do not consider the prevalence of symbionts in many insects, which we show can impact geographic patterns of mitochondrial genetic diversity.


Divergent ontogenies of trophic morphology in two closely related haplochromine cichlids.
Fish develop morphological specializations in their trophic and locomotor systems as a result of varying functional demands in response to environmental pressures at different life stages. These specializations should maximize particular performances in specialists, adapting them to their trophic and habitat niches at each ontogenetic stage. Because differential growth rates of the structural components comprised in the head are likely to be linked to the diet of a fish throughout its development, we investigated the ontogenetic development of two haplochromine cichlid species belonging to different trophic guilds. We employed geometric morphometric techniques to evaluate whether starting from morphologically similar fry they diverge into phenotypes that characterize trophic guilds and locomotor types. Our examination of overall body shape shows that certain specialized morphological features are already present in fry, whereas other traits diverge through ontogeny due to differences in species-specific allometric variation. Allometric shape variation was found to be more relevant for the biter specialist than for the sucker morphotype. Our results confirm that phenotypic changes during ontogeny can be linked to dietary and habitat shifts in these fish. Furthermore, evidence for an integrated development of trophic and locomotor specializations in morphology was observed.


'It's like a personal motivator that you carried around wi' you': utilising self-determination theory to understand men's experiences of using pedometers to increase physical activity in a weight management programme.
Self-monitoring using pedometers is an effective behaviour change technique to support increased physical activity (PA). However, the ways in which pedometers operate as motivational tools in adoption and maintenance of PA is not well understood. This paper investigates men's experiences of pedometers as motivational tools both during and after their participation in a 12-week group-based, weight management programme for overweight/obese men, Football Fans in Training (FFIT). Semi-structured telephone interviews were conducted with 28 men, purposively sampled to include men who did and did not achieve 5% weight loss during the programme. Data were analysed thematically utilising the framework approach, using Self-Determination Theory (SDT) - namely concepts of behavioural regulation and the basic needs of relatedness, competence and autonomy - as an analytical lens. During the programme, FFIT's context and fellow participants supported relatedness and encouraged use of the pedometer. The pedometer was seen to provide tangible proof of progress, thus increasing competence for change, whilst the ability to monitor one's own progress and take remedial action supported autonomy; these men portrayed the pedometer as an 'ally'. However, a minority found the pedometer 'dispiriting' or controlling when it evidenced their inability to meet their PA targets. After the programme, some men no longer used the device as they had fully internalised their motivations for increased PA. In contrast, others continued to use pedometers or progressed to other self-monitoring technologies because it was enjoyable and facilitated maintenance of their increased PA. However, the minority of men who experienced the pedometer as controlling no longer used it. They were less successful in achieving 5% weight loss and appeared reliant on external factors, including support from coach and group members, to maintain motivation. These findings show how self-monitoring using pedometers and associated goal setting supported the development of autonomous motivation for PA, during and after participation in a group-based programme. They also suggest that programmes could focus on early identification of participants who remain motivated by extrinsic factors or express negative experiences of self-monitoring tools, to offer greater support to identify the benefits of PA based on a person's own values.


NUP214-ABL1-mediated cell proliferation in T-cell acute lymphoblastic leukemia is dependent on the LCK kinase and various interacting proteins.
The NUP214-ABL1 fusion protein is a constitutively active protein tyrosine kinase that is found in 6% of patients with T-cell acute lymphoblastic leukemia and that promotes proliferation and survival of T-lymphoblasts. Although NUP214-ABL1 is sensitive to ABL1 kinase inhibitors, development of resistance to these compounds is a major clinical problem, underlining the need for additional drug targets in the sparsely studied NUP214-ABL1 signaling network. In this work, we identify and validate the SRC family kinase LCK as a protein whose activity is absolutely required for the proliferation and survival of T-cell acute lymphoblastic leukemia cells that depend on NUP214-ABL1 activity. These findings underscore the potential of SRC kinase inhibitors and of the dual ABL1/SRC kinase inhibitors dasatinib and bosutinib for the treatment of NUP214-ABL1-positive T-cell acute lymphoblastic leukemia. In addition, we used mass spectrometry to identify protein interaction partners of NUP214-ABL1. Our results strongly support that the signaling network of NUP214-ABL1 is distinct from that previously reported for BCR-ABL1. Moreover, we found that three NUP214-ABL1-interacting proteins, MAD2L1, NUP155, and SMC4, are strictly required for the proliferation and survival of NUP214-ABL1-positive T-cell acute lymphoblastic leukemia cells. In conclusion, this work identifies LCK, MAD2L1, NUP155 and SMC4 as four new potential drug targets in NUP214-ABL1-positive T-cell acute lymphoblastic leukemia.


Serologic markers of Chlamydia trachomatis and other sexually transmitted infections and subsequent ovarian cancer risk: Results from the EPIC cohort.
A substantial proportion of epithelial ovarian cancer (EOC) arises in the fallopian tube and other epithelia of the upper genital tract; these epithelia may incur damage and neoplastic transformation after sexually transmitted infections (STI) and pelvic inflammatory disease. We investigated the hypothesis that past STI infection, particularly Chlamydia trachomatis, is associated with higher EOC risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort including 791 cases and 1669 matched controls. Serum antibodies against C. trachomatis, Mycoplasma genitalium, herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) 16, 18 and 45 were assessed using multiplex fluorescent bead-based serology. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) comparing women with positive vs. negative serology. A total of 40% of the study population was seropositive to at least one STI. Positive serology to C. trachomatis Pgp3 antibodies was not associated with EOC risk overall, but with higher risk of the mucinous histotype (RR = 2.30 [95% CI = 1.22-4.32]). Positive serology for chlamydia heat shock protein 60 (cHSP60-1) was associated with higher risk of EOC overall (1.36 [1.13-1.64]) and with the serous subtype (1.44 [1.12-1.85]). None of the other evaluated STIs were associated with EOC risk overall; however, HSV-2 was associated with higher risk of endometrioid EOC (2.35 [1.24-4.43]). The findings of our study suggest a potential role of C. trachomatis in the carcinogenesis of serous and mucinous EOC, while HSV-2 might promote the development of endometrioid disease.


Osteoblast de- and redifferentiation are controlled by a dynamic response to retinoic acid during zebrafish fin regeneration.
Zebrafish restore amputated fins by forming tissue-specific blastema cells that coordinately regenerate the lost structures. Fin amputation triggers the synthesis of several diffusible signaling factors that are required for regeneration, raising the question of how cell lineage-specific programs are protected from regenerative crosstalk between neighboring fin tissues. During fin regeneration, osteoblasts revert from a non-cycling, mature state to a cycling, preosteoblastic state to establish a pool of progenitors within the blastema. After several rounds of proliferation, preosteoblasts redifferentiate to produce new bone. Blastema formation and proliferation are driven by the continued synthesis of retinoic acid (RA). Here, we find that osteoblast dedifferentiation and redifferentiation are inhibited by RA signaling, and we uncover how the bone regenerative program is achieved against a background of massive RA synthesis. Stump osteoblasts manage to contribute to the blastema by upregulating expression of the RA-degrading enzyme cyp26b1. Redifferentiation is controlled by a presumptive gradient of RA, in which high RA levels towards the distal tip of the blastema suppress redifferentiation. We show that this might be achieved through a mechanism involving repression of Bmp signaling and promotion of Wnt/β-catenin signaling. In turn, cyp26b1(+) fibroblast-derived blastema cells in the more proximal regenerate serve as a sink to reduce RA levels, thereby allowing differentiation of neighboring preosteoblasts. Our findings reveal a mechanism explaining how the osteoblast regenerative program is protected from adverse crosstalk with neighboring fibroblasts that advances our understanding of the regulation of bone repair by RA.


Patient-centered medical home model: do school-based health centers fit the model?
School-based health centers (SBHCs) are an important component of health care reform. The SBHC model of care offers accessible, continuous, comprehensive, family-centered, coordinated, and compassionate care to infants, children, and adolescents. These same elements comprise the patient-centered medical home (PCMH) model of care being promoted by the Affordable Care Act with the hope of lowering health care costs by rewarding clinicians for primary care services. PCMH survey tools have been developed to help payers determine whether a clinician/site serves as a PCMH. Our concern is that current survey tools will be unable to capture how a SBHC may provide a medical home and therefore be denied needed funding. This article describes how SBHCs might meet the requirements of one PCMH tool. SBHC stakeholders need to advocate for the creation or modification of existing survey tools that allow the unique characteristics of SBHCs to qualify as PCMHs.


Efficacy of an internet program for smoking cessation during and after inpatient rehabilitation treatment: a quasi-randomized controlled trial.
To test the feasibility and efficacy of an internet program for smoking cessation during and after inpatient treatment in rehabilitation centers. A total of 7574 consecutively admitted inpatients from three German rehabilitation centers were assessed for smoking status. Daily smokers or former daily smokers who regularly used the internet and e-mail were proactively invited for study participation. Out of 749 eligible patients, 477 (64%) participated in the study and were randomly assigned to an intervention or an assessment only control group based on the calendar week of admission. Patients of the intervention group had the possibility to use an internet program for smoking cessation for a period of six months. The program provided at least one but up to seven individual counseling sessions through a computer expert system, informational websites and a message board. At six-months follow-up, seven-day point prevalence smoking abstinence was twice as high in the intervention group as in the control group (OR=2.0; CI 1.1-3.8; p=.02). Proactive recruitment of smokers in combination with the provision of an internet program for smoking cessation allow for an inexpensive and effective smoking cessation support during and after inpatient rehabilitation treatment.


Femoral neck fracture after Birmingham Hip Resurfacing Arthroplasty: prevalence, time to fracture, and outcome after revision.
A consecutive cohort of 3076 Birmingham Hip Resurfacings from a single institution was analyzed. The prevalence of femoral neck fracture, the time to fracture, and the outcome after revision were investigated. Fractures occurred in 34 hips (prevalence, 1.1%). Median time to fracture was 0.27 year (range, 0.014-11.2 years). Mean operation time for revision was 59 minutes, and 71% underwent isolated femoral component revision. At a mean follow-up of 5.5 years since revision, 3 patients required re-revision (2 aseptic loosening, 1 for sepsis) giving a survival of 95.7% (confidence interval, 86.9%-100%) at 5 years for the revision. Median Oxford Hip Score was 12.5% (interquartile range, 3.2%-32.3%). There were no cases of radiologic failure during follow-up. Most fractures occur early after hip resurfacing and were straightforward to revise.


Outcomes After Coronary Stenting or Bypass Surgery for Men and Women With Unprotected Left Main Disease: The EXCEL Trial.
The aim of the present study was to assess outcomes after coronary artery bypass grafting surgery (CABG) and percutaneous coronary intervention (PCI) according to sex in a large randomized trial of patients with unprotected left main disease. In the SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) trial, sex had a significant interaction effect with revascularization strategy, and women had an overall higher mortality when treated with PCI than CABG. The EXCEL (Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial was a multinational randomized trial that compared PCI with everolimus-eluting stents and CABG in patients with unprotected left main disease. The primary endpoint was the composite of all-cause death, myocardial infarction, or stroke at 3 years. Of 1,905 patients randomized, 1,464 (76.9%) were men and 441 (23.1%) were women. Compared with men, women were older; had higher prevalence rates of hypertension, hyperlipidemia, and diabetes; and were less commonly smokers but had lower coronary anatomic burden and complexity (mean SYNTAX score 24.2 vs. 27.2, p < 0.001). By multivariate analysis, sex was not independently associated with either the primary endpoint (hazard ratio [HR]: 1.10; 95% confidence interval [CI]: 0.82 to 1.48; p = 0.53) or all-cause death (HR: 1.39; 95% CI: 0.92 to 2.10; p = 0.12) at 3 years. At 30 days, all-cause death, myocardial infarction, or stroke had occurred in 8.9% of woman treated with PCI, 6.2% of women treated with CABG, 3.6% of men treated with PCI, and 8.4% of men treated with CABG (p for interaction = 0.003). The 3-year rate of the composite primary endpoint was 19.7% in women treated with PCI, 14.6% in women treated with CABG, 13.8% in men treated with PCI, and 14.7% in men treated with CABG (p for interaction = 0.06). These differences were driven by higher periprocedural rates of myocardial infarction in women after PCI and in men after CABG. In patients with unprotected left main disease in the EXCEL trial, sex was not an independent predictor of adverse outcomes after revascularization. However, women undergoing PCI had a trend toward worse outcomes, a finding related to associated comorbidities and increased periprocedural complications. Further studies are required to determine the optimal revascularization modality in women with complex coronary artery disease.


Abl kinase constructs expressed in bacteria: facilitation of structural and functional studies including segmental labeling by expressed protein ligation.
A great portion of tyrosine kinases are involved in cell development and their structural alteration is intimately involved in associated pathologies of development and oncology. These kinases are one of the major groups of targets under investigation for molecular therapeutics. To carry out biochemical and structural biological studies on these kinases, economical production of their purified forms is highly desirable. However over-expressing tyrosine kinases as recombinant forms in bacterial systems and their purification is a significant challenge. Abelson kinase (Abl) has previously been expressed on a large scale to facilitate X-ray crystallography and NMR structure studies mainly in baculovirus infected insect cells. Even though success has been achieved in expression of soluble tyrosine kinases in E. coli with chaperones to improve correct folding, low expression levels of kinases are intrinsic in such systems because of diversion of resources to produce chaperones. Here we present a straightforward method to express and purify isolated Abl kinase domain and SH3-SH2-kinase multi-domain structures. The expressed Abl protein retains its correct folding and biological function. The yield of soluble protein is in a several mg L(-1) range in minimal media. Furthermore we demonstrate that segmental isotopic labelling using expressed protein ligation can be achieved using bacterial expressed Abl kinase domain constructs, which is especially useful in NMR structure-activity studies.


Ab initio study of free-radical polymerization: polyethylene propagation kinetics.
The chain-length dependence of the propagation rate coefficient for the free-radical polymerization of ethylene was investigated on an ab initio basis. Polyethylene was chosen as a test system because of its structural simplicity. Ab initio density functional theory at the B3LYP/6-31g(d) level was applied to study the kinetics of a set of addition reactions of a systematically growing radical alkyl chain to ethylene. These reactions are propagation steps in the free-radical polymerization of ethylene. Special attention was paid to low normal modes corresponding to internal rotations (IR), since the latter are important for an accurate description of the partition functions. The effect of coupling of the IR modes is also discussed. A comparison is made with the propagation rate constant derived from experiment. The results indicate that the propagation rate coefficient has largely converged by the hexyl radical stage, though a weaker chain-length dependence of k(p) for longer chains was detected.


Research priority setting in organ transplantation: a systematic review.
Barriers to access and long-term complications remain a challenge in transplantation. Further advancements may be achieved through research priority setting with patient engagement to strengthen its relevance. We evaluated research priority setting in solid organ transplantation and described stakeholder priorities. Databases were searched to October 2016. We synthesized the findings descriptively. The 28 studies (n = 2071 participants) addressed kidney [9 (32%)], heart [7 (25%)], liver [3 (11%)], lung [1 (4%)], pancreas [1 (4%)], and nonspecified organ transplantation [7 (25%)] using consensus conferences, expert panel meetings, workshops, surveys, focus groups, interviews, and the Delphi technique. Nine (32%) reported patient involvement. The 336 research priorities addressed the following: organ donation [43 priorities (14 studies)]; waitlisting and allocation [43 (10 studies)]; histocompatibility and immunology [31 (8 studies)]; immunosuppression [21 (10 studies)]; graft-related complications [38 (13 studies)]; recipient (non-graft-related) complications [86 (14 studies)]; reproduction [14 (1 study)], psychosocial and lifestyle [49 (7 studies)]; and disparities in access and outcomes [10 (4 studies)]. The priorities identified were broad but only one-third of initiatives engaged patients/caregivers, and details of the process were lacking. Setting research priorities in an explicit manner with patient involvement can guide investment toward the shared priorities of patients and health professionals.


A Cold Suboceanic Mantle Belt at the Earth's Equator.
An exceptionally low degree of melting of the upper mantle in the equatorial part of the mid-Atlantic Ridge is indicated by the chemical composition of mantle-derived mid-ocean ridge peridotites and basalts. These data imply that mantle temperatures below the equatorial Atlantic are at least approximately 150 degrees C cooler than those below the normal mid-Atlantic Ridge, suggesting that isotherms are depressed and the mantle is downwelling in the equatorial Atlantic. An equatorial minimum of the zero-age crustal elevation of the East Pacific Rise suggests a similar situation in the Pacific. If so, an oceanic upper mantle cold equatorial belt separates hotter mantle regimes and perhaps distinct chemical and isotopic domains in the Northern and Southern hemispheres. Gravity data suggest the presence of high density material in the oceanic equatorial upper mantle, which is consistent with its inferred low temperature and undepleted composition. The equatorial distribution of cold, dense upper mantle may be ultimately an effect of the Earth's rotation.


Three Eras in Global Tobacco Control: How Global Governance Processes Influenced Online Tobacco Control Networking.
Online networks can serve as a platform to diffuse policy innovations and enhance global health governance. This study focuses on how shifts in global health governance may influence related online networks. We compare social network metrics (average degree centrality [AVGD], density [D] and clustering coefficient [CC]) of Globalink, an online network of tobacco control advocates, across three eras in global tobacco control governance; pre-Framework Convention on Tobacco Control (FCTC) policy transfer (1992-1998), global regime formation through the FCTC negotiations (1999-2005), and philanthropic funding through the Bloomberg Initiative (2006-2012). Prior to 1999, Globalink was driven by a handful of high-income countries (AVGD=1.908 D=0.030, CC=0.215). The FCTC negotiations (1999-2005) corresponded with a rapid uptick in the number of countries represented within Globalink and new members were most often brought into the network through relationships with regional neighbors (AVGD=2.824, D=0.021, CC=0.253). Between 2006 and 2012, the centrality of the US in the network increases significantly (AVGD=3.414, D=0.023, CC=0.310). The findings suggest that global institutionalization through WHO, as with the FCTC, can lead to the rapid growth of decentralized online networks. Alternatively, private initiatives, such as the Bloomberg Initiative, can lead to clustering in which a single source of information gains increasing influence over an online network.


Transcriptional activation of the miR-17-92 cluster is involved in the growth-promoting effects of MYB in human Ph-positive leukemia cells.
MicroRNAs, non-coding regulators of gene expression, are likely to function as important downstream effectors of many transcription factors including MYB. Optimal levels of MYB are required for transformation/maintenance of BCR-ABL-expressing cells. We investigated whether MYB silencing modulates microRNA expression in Philadelphia-positive (Ph+) leukemia cells and if MYB-regulated microRNAs are important for the "MYB addiction" of these cells. Thirty-five microRNAs were modulated by MYB silencing in lymphoid and erythromyeloid chronic myeloid leukemia-blast crisis BV173 and K562 cells; 15 of these were concordantly modulated in both lines. We focused on the miR-17-92 cluster because of its oncogenic role in tumors and found that: i) it is a direct MYB target; ii) it partially rescued the impaired proliferation and enhanced apoptosis of MYB-silenced BV173 cells. Moreover, we identified FRZB, a Wnt/β-catenin pathway inhibitor, as a novel target of the miR-17-92 cluster. High expression of MYB in blast cells from 2 Ph+leukemia patients correlated positively with the miR-17-92 cluster and inversely with FRZB. This expression pattern was also observed in a microarray dataset of 122 Ph+acute lymphoblastic leukemias. In vivo experiments in NOD scid gamma mice injected with BV173 cells confirmed that FRZB functions as a Wnt/β-catenin inhibitor even as they failed to demonstrate that this pathway is important for BV173-dependent leukemogenesis. These studies illustrate the global effects of MYB expression on the microRNAs profile of Ph+cells and supports the concept that the "MYB addiction" of these cells is, in part, caused by modulation of microRNA-regulated pathways affecting cell proliferation and survival.


Influence of STRO-1 selection on osteogenic potential of human tooth germ derived mesenchymal stem cells.
Mesenchymal stem cells derived from the human tooth germ (hTGSCs) are a heterogeneous cell population that can differentiate into osteogenic, neurogenic, and adipogenic lineages. The aim of this study was to compare the osteogenic differentiation capacity of STRO-1 positive (STRO-1+) hTGSCs and unsorted heterogeneous hTGSCs and to establish if STRO-1+ cells are more committed to osteogenic differentiation. HTGSCs were isolated from impacted third molar tooth germ tissues of adolescents, and a subpopulation of STRO-1+ hTGSCs was obtained by fluorescence-activated cell sorting. STRO-1+, STRO-1 negative (STRO-1-), and unsorted cells were cultured in osteogenic and standard culture media to compare their capacity to differentiate towards osteoblastic lineage. Cells were tested for proliferation rates, alkaline phosphatase activity, and amounts of accumulated calcium. Gene expression levels of the RUNX2, osteocalcin, and osteonectin genes were analyzed with real time PCR. Mineralization and osteogenic protein expression were examined by using von Kossa staining and confocal microscopy. Our results indicated that osteogenically induced cell populations showed greater mineralization capacity than non-induced cells. However, expression levels of early and late osteogenic markers were not significantly different between STRO-1+ and unsorted cells. In conclusion, the selection by STRO-1 expression does not yield cells with osteogenic capacity higher than that of the heterogeneous hTGSC population. Cell sorting using osteogenic markers other than STRO-1 might be beneficial in obtaining a more sensitive osteogenic sub-population from unsorted heterogenous hTGSCs.


Effect of herpes simplex suppression on incidence of HIV among women in Tanzania.
Infection with herpes simplex virus type 2 (HSV-2) is associated with an increased risk of acquiring infection with the human immunodeficiency virus (HIV). This study tested the hypothesis that HSV-2 suppressive therapy reduces the risk of HIV acquisition. Female workers at recreational facilities in northwestern Tanzania who were 16 to 35 years of age were interviewed and underwent serologic testing for HIV and HSV-2. We enrolled female workers who were HIV-seronegative and HSV-2-seropositive in a randomized, double-blind, placebo-controlled trial of suppressive treatment with acyclovir (400 mg twice daily). Participants attended mobile clinics every 3 months for a follow-up period of 12 to 30 months, depending on enrollment date. The primary outcome was the incidence of infection with HIV. We used a modified intention-to-treat analysis; data for participants who became pregnant were censored. Adherence to treatment was estimated by a tablet count at each visit. A total of 821 participants were randomly assigned to receive acyclovir (400 participants) or placebo (421 participants); 679 (83%) completed follow-up. Mean follow-up for the acyclovir and placebo groups was 1.52 and 1.62 years, respectively. The incidence of HIV infection was 4.27 per 100 person-years (27 participants in the acyclovir group and 28 in the placebo group), and there was no overall effect of acyclovir on the incidence of HIV (rate ratio for the acyclovir group, 1.08; 95% confidence interval, 0.64 to 1.83). The estimated median adherence was 90%. Genital HSV was detected in a similar proportion of participants in the two study groups at 6, 12, and 24 months. No serious adverse events were attributable to treatment with acyclovir. These data show no evidence that acyclovir (400 mg twice daily) as HSV suppressive therapy decreases the incidence of infection with HIV. (Current Controlled Trials number, ISRCTN35385041 [controlled-trials.com].).


Attentional selection of location and modality in vision and touch modulates low-frequency activity in associated sensory cortices.
Selective attention allows us to focus on particular sensory modalities and locations. Relatively little is known about how attention to a sensory modality may relate to selection of other features, such as spatial location, in terms of brain oscillations, although it has been proposed that low-frequency modulation (α- and β-bands) may be key. Here, we investigated how attention to space (left or right) and attention to modality (vision or touch) affect ongoing low-frequency oscillatory brain activity over human sensory cortex. Magnetoencephalography was recorded while participants performed a visual or tactile task. In different blocks, touch or vision was task-relevant, whereas spatial attention was cued to the left or right on each trial. Attending to one or other modality suppressed α-oscillations over the corresponding sensory cortex. Spatial attention led to reduced α-oscillations over both sensorimotor and occipital cortex contralateral to the attended location in the cue-target interval, when either modality was task-relevant. Even modality-selective sensors also showed spatial-attention effects for both modalities. The visual and sensorimotor results were generally highly convergent, yet, although attention effects in occipital cortex were dominant in the α-band, in sensorimotor cortex, these were also clearly present in the β-band. These results extend previous findings that spatial attention can operate in a multimodal fashion and indicate that attention to space and modality both rely on similar mechanisms that modulate low-frequency oscillations.


High-throughput single-cell ChIP-seq identifies heterogeneity of chromatin states in breast cancer.
Modulation of chromatin structure via histone modification is a major epigenetic mechanism and regulator of gene expression. However, the contribution of chromatin features to tumor heterogeneity and evolution remains unknown. Here we describe a high-throughput droplet microfluidics platform to profile chromatin landscapes of thousands of cells at single-cell resolution. Using patient-derived xenograft models of acquired resistance to chemotherapy and targeted therapy in breast cancer, we found that a subset of cells within untreated drug-sensitive tumors share a common chromatin signature with resistant cells, undetectable using bulk approaches. These cells, and cells from the resistant tumors, have lost chromatin marks-H3K27me3, which is associated with stable transcriptional repression-for genes known to promote resistance to treatment. This single-cell chromatin immunoprecipitation followed by sequencing approach paves the way to study the role of chromatin heterogeneity, not just in cancer but in other diseases and healthy systems, notably during cellular differentiation and development.


Dobutamine-stress magnetic resonance microimaging in mice : acute changes of cardiac geometry and function in normal and failing murine hearts.
The aim of this study was to assess the capability of MRI to characterize systolic and diastolic function in normal and chronically failing mouse hearts in vivo at rest and during inotropic stimulation. Applying an ECG-gated FLASH-cine sequence, MRI at 7 T was performed at rest and after administration of 1.5 microgram/g IP dobutamine. There was a significant increase of heart rate, cardiac output, and ejection fraction and significant decrease of end-diastolic and end-systolic left ventricular (LV) volumes (P<0.01 each) in normal mice during inotropic stimulation. In mice with heart failure due to chronic myocardial infarction (MI), MRI at rest revealed gross LV dilatation. There was a significant decrease of LV ejection fraction in infarcted mice (29%) versus sham mice (58%). Mice with MI showed a significantly reduced maximum LV ejection rate (P<0.001) and LV filling rate (P<0.01) and no increase of LV dynamics during dobutamine action, indicating loss of contractile and relaxation reserve. In 4-month-old transgenic mice with cardiospecific overexpression of the beta(1)-adrenergic receptor, which at this early stage do not show abnormalities of resting cardiac function, LV filling rate failed to increase after dobutamine stress (transgenic, 0.19+/-0.03 microL/ms; wild type, 0.36+/-0.01 microL/ms; P<0.01). Thus, MRI unmasked diastolic dysfunction during dobutamine stress. Dobutamine-stress MRI allows noninvasive assessment of systolic and diastolic components of heart failure. This study shows that MRI can demonstrate loss of inotropic and lusitropic response in mice with MI and can unmask diastolic dysfunction as an early sign of cardiac dysfunction in a transgenic mouse model of heart failure.


Sports Dietitians Australia position statement: sports nutrition for the adolescent athlete.
It is the position of Sports Dietitians Australia (SDA) that adolescent athletes have unique nutritional requirements as a consequence of undertaking daily training and competition in addition to the demands of growth and development. As such, SDA established an expert multidisciplinary panel to undertake an independent review of the relevant scientific evidence and consulted with its professional members to develop sports nutrition recommendations for active and competitive adolescent athletes. The position of SDA is that dietary education and recommendations for these adolescent athletes should reinforce eating for long term health. More specifically, the adolescent athlete should be encouraged to moderate eating patterns to reflect daily exercise demands and provide a regular spread of high quality carbohydrate and protein sources over the day, especially in the period immediately after training. SDA recommends that consideration also be given to the dietary calcium, Vitamin D and iron intake of adolescent athletes due to the elevated risk of deficiency of these nutrients. To maintain optimal hydration, adolescent athletes should have access to fluids that are clean, cool and supplied in sufficient quantities before, during and after participation in sport. Finally, it is the position of SDA that nutrient needs should be met by core foods rather than supplements, as the recommendation of dietary supplements to developing athletes over-emphasizes their ability to manipulate performance in comparison with other training and dietary strategies.


How to measure the impact of premenstrual symptoms? Development and validation of the German PMS-Impact Questionnaire.
With 75% of women of reproductive age affected, premenstrual symptoms are very common, ranging from emotional and cognitive to physical symptoms. Premenstrual Syndrome and Premenstrual Dysphoric Disorder can lead to substantial functional interference and psychological distress comparable to that of dysthymic disorders. The assessment of this impact is required as a part of the diagnostic procedure in the DSM-5. In the absence of a specific measure, the authors developed the PMS-Impact Questionnaire. A sample of 101 women reporting severe premenstrual complaints was assessed with the twenty-two items in the questionnaire during their premenstrual phase in an ongoing intervention study at the Philipps-University Marburg from August 2013 until January 2015. An exploratory factor analysis revealed a two-factor solution (labeled Psychological Impact and Functional Impact) with 18 items. A Cronbach's alpha of 0.90 for Psychological Impact and of 0.90 for Functional Impact indicated good reliability. Convergent construct validity was demonstrated by moderate to high correlations with the Pain Disability Index. Low correlations with the Big Five Inventory-10 indicated good divergent validity. The PMS-Impact Questionnaire was found to be a valid, reliable, and an economic measure to assess the impact of premenstrual symptoms. In future research, cross validations and confirmatory factor analyses should be conducted.


Effectiveness of quality physical education in improving students' manipulative skill competency.
This study aimed to examine the extent to which the quality physical education teaching (QPET) practices contributed to improving 4th- and 5th-grade students' manipulative skill competency. Participants were 9 elementary physical education (PE) teachers and their 4th- and 5th-grade students (n = 2709-3420). The students' skill competency was assessed with 3 manipulative skills using PE metrics assessment rubrics. The PE teachers' levels of QPET were assessed by coding 63 videotaped lessons using the assessing quality teaching rubrics (AQTR), which consisted of 4 essential dimensions including task design, task presentation, class management, and instructional guidance. Codes were confirmed through inter-rater reliability (82.4%, 84.5%, and 94%). Data were analyzed through descriptive statistics, multiple R 2 regression models, and independent sample t tests. This study indicated that the 4 essential dimensions of QPET were all significant contributors to students' manipulative skill competency. These predictors were significantly higher for boys than for girls in soccer and striking skills, while they were significantly higher for girls than for boys in throwing skill competency. Of the 4 essential dimensions of QPET, task presentation played the most significant role in contributing to all 3 skill competencies for both boys and girls. Further, students who experienced high QPET were significantly more skillfully competent than those students who did not have this experience. It was concluded that the QPET practices played a significantly critical role in contributing to students' manipulative skill competency.


Effects of protein energy supplementation during pregnancy on fetal growth: a review of the literature focusing on contextual factors.
Maternal diet during pregnancy is one of the most important factors associated with adequate fetal growth. There are many complications associated with fetal growth restriction that lead to lifelong effects. The aim of this review was to describe the studies examining the effects of protein energy supplementation during pregnancy on fetal growth focusing on the contextual differences. Relevant articles published between 2007 and 2012 were identified through systematic electronic searches of the PubMed, Science Direct, and EBSCO database and the examination of the bibliographies of retrieved articles. The search aimed to identify studies examining pregnant women receiving protein and/or energy during pregnancy and to assess fetal growth measures. Data of effectiveness and practical aspects of protein energy supplementation during pregnancy were extracted and compiled. Twenty studies (11 randomized controlled trials, 8 controlled before and after, and 1 prospective study) were included in this review. Positive outcomes in infants and women cannot be expected if the supplementation is not needed. Therefore, it is essential to correctly select women who will benefit from dietary intervention programs during pregnancy. However, there is currently no consensus on the most effective method of identifying these women. The content of protein in the supplements considering total diet is also an important determinant of fetal growth. Balanced protein energy supplementation (containing up to 20% of energy as protein) given to pregnant women with energy or protein deficit appears to improve fetal growth, increase birth weight (by 95-324 g) and height (by 4.6-6.1 mm), and decrease the percentage of low birth weight (by 6%). Supplements with excess protein (>20% of energy as protein) provided to women with a diet already containing adequate protein may conversely impair fetal growth. There is also no consensus on the best time to start supplementation. Strong quality studies examining adequate criteria to screen women who would benefit from supplementation, time to start supplementation, and type of supplements are warranted.


Morpholino antisense oligonucleotide-mediated gene knockdown during thymocyte development reveals role for Runx3 transcription factor in CD4 silencing during development of CD4-/CD8+ thymocytes.
During thymic T cell development, immature CD4(+)/CD8(+) thymocytes develop into either CD4(+)/CD8(-) helper or CD4(-)/CD8(+) CTLs. The molecular mechanisms governing the complex selection and differentiation steps during thymic T cell development are not well understood. Here we developed a novel approach to investigate gene function during thymocyte development. We transfected ex vivo isolated immature thymocytes with gene-specific morpholino antisense oligonucleotides and induced differentiation in cell or organ cultures. A morpholino oligonucleotide specific for CD8alpha strongly reduces CD8 expression. To our knowledge, this is the first demonstrated gene knockdown by morpholino oligonucleotides in primary lymphocytes. Using this approach, we show here that the transcription factor Runx3 is involved in silencing of CD4 expression during CD8 T cell differentiation. Runx3 protein expression appears late in thymocyte differentiation and is confined to mature CD8 single-positive thymocytes, whereas Runx3 mRNA is transcribed in mature CD4 and CD8 thymocytes. Therefore, Runx3 protein expression is regulated at a post-transcriptional level. The knockdown of Runx3 protein expression through morpholino oligonucleotides inhibited the development of CD4(-)/CD8(+) T cells. Instead, mature cells with a CD4(+)/CD8(+) phenotype accumulated. Potential Runx binding sites were identified in the CD4 gene silencer element, which are bound by Runx protein in EMSAs. Mutagenesis of potential Runx binding sites in the CD4 gene silencer abolished silencing activity in a reporter gene assay, indicating that Runx3 is involved in CD4 gene silencing. The experimental approach developed here should be valuable for the functional analysis of other candidate genes in T cell differentiation.


Viral gametocytic hypertrophy of Crassostrea gigas in France: from occasional records to disease emergence?
Viral gametocytic hypertrophy was reported for the first time in 2001 in Pacific oyster Crassostrea gigas in France. Since this date, the number of reported cases and the distribution area have increased every year; however, the cases are not associated with macroscopic signs or increased mortality rates. Both male and female gametes were hypertrophied and basophilic inclusions were observed in gamete nuclei. Transmission electron microscopy revealed the presence of viral particles in these intranuclear basophilic inclusions. These particles had characteristics similar to those of the Papillomaviridae and Polyoma viridae families: they were small, non-enveloped, icosahedral, and 44 to 56 nm in diameter. The viral particles were found in male, female and hermaphrodite oysters and no significant difference in viral infection was observed between those groups. The frequency of detection and the intensity of infection were low and no host defence reaction was recognised, suggesting that the viral particles had a weak impact on C. gigas. The viral particles described in the present study seem to be similar to these described in C. virginica in the USA and Canada and in C. gigas in Korea, but further studies are required to confirm their identity. The issue of a possible emergence of this infection is discussed.


Comparison of headless screws used in the treatment of proximal nonunion of scaphoid bone.
Screws with different levels of compression force are available for scaphoid fixation and it is known that the Acutrak screw generates greater compression than the Herbert screw. We retrospectively compared two types of headless compression screw for their effectiveness in the repair of scaphoid nonunion. Twenty-nine cases of proximal scaphoid nonunion were surgically treated with non-vascularised bone graft: the Acutrak screw was used in 17 patients and the cannulated Herbert screw in 12 patients. Wrist range of motion, Mayo wrist score, grip strength and QuickDASH scores were indicators used for the functional evaluation. Radiographic findings were assessed for consolidation of nonunion and signs of arthrosis. The mean follow-up time was 49.2 months (range 12-96). Statistically, there was no significant difference between the Acutrak and Herbert screw types in terms of functional evaluation and time required for consolidation. Greater compression did not influence the functional outcome, consolidation rate or time to consolidation. The need for greater compression in the treatment of proximal scaphoid nonunions is thus questionable because it may increase the risk of proximal fragment communition.


What happened to life expectancy in Spain in the 1980s?
Life expectancy at birth in Spain improved between 1972 and 1982, by 2.5 years for males and 3.2 years for females. This slowed considerably in the following decade, with increases of only 0.5 and 1.7 years respectively. To determine the causes of death that have been responsible for the failure by Spain to maintain in the 1980s and 1990s the rate of improvement in life expectancy seen during the 1970s. Data from WHO mortality tapes grouped in a series of clinically meaningful categories were used to calculate the contribution of each category, in five year age groups, to the changing life expectancy at birth in the two periods. Spain. The trend in life expectancy at birth in Spain over this 20 year period can be considered to have two components, both with important consequences for public health policy. Underlying trends include a steady negative contribution from respiratory cancer in men and a reduction in cardiovascular disease. More recent trends include a considerable deterioration in deaths among young adults, most notably from accidents and, possibly, AIDS. The failure to maintain the rate of earlier gains in life expectancy in Spain can be attributed largely to a few conditions, although these may indicate less obvious underlying problems. These findings have important consequences for prioritising public health policies.


Contextual influences on health worker motivation in district hospitals in Kenya.
Organizational factors are considered to be an important influence on health workers' uptake of interventions that improve their practices. These are additionally influenced by factors operating at individual and broader health system levels. We sought to explore contextual influences on worker motivation, a factor that may modify the effect of an intervention aimed at changing clinical practices in Kenyan hospitals. Franco LM, et al's (Health sector reform and public sector health worker motivation: a conceptual framework. Soc Sci Med. 2002, 54: 1255-66) model of motivational influences was used to frame the study Qualitative methods including individual in-depth interviews, small-group interviews and focus group discussions were used to gather data from 185 health workers during one-week visits to each of eight district hospitals. Data were collected prior to a planned intervention aiming to implement new practice guidelines and improve quality of care. Additionally, on-site observations of routine health worker behaviour in the study sites were used to inform analyses. Study settings are likely to have important influences on worker motivation. Effective management at hospital level may create an enabling working environment modifying the impact of resource shortfalls. Supportive leadership may foster good working relationships between cadres, improve motivation through provision of local incentives and appropriately handle workers' expectations in terms of promotions, performance appraisal processes, and good communication. Such organisational attributes may counteract de-motivating factors at a national level, such as poor schemes of service, and enhance personally motivating factors such as the desire to maintain professional standards. Motivation is likely to influence powerfully any attempts to change or improve health worker and hospital practices. Some factors influencing motivation may themselves be influenced by the processes chosen to implement change.


Can FDG PET predict radiation treatment outcome in head and neck cancer? Results of a prospective study.
In head and neck cancer (HNC) various treatment strategies have been developed to improve outcome, but selecting patients for these intensified treatments remains difficult. Therefore, identification of novel pretreatment assays to predict outcome is of interest. In HNC there are indications that pretreatment tumour (18)F-fluorodeoxyglucose (FDG) uptake may be an independent prognostic factor. The aim of this study was to assess the prognostic value of FDG uptake and CT-based and FDG PET-based primary tumour volume measurements in patients with HNC treated with (chemo)radiotherapy. A total of 77 patients with stage II-IV HNC who were eligible for definitive (chemo)radiotherapy underwent coregistered pretreatment CT and FDG PET. The gross tumour volume of the primary tumour was determined on the CT (GTV(CT)) and FDG PET scans. Five PET segmentation methods were applied: interpreting FDG PET visually (PET(VIS)), applying an isocontour at a standardized uptake value (SUV) of 2.5 (PET(2.5)), using fixed thresholds of 40% and 50% (PET(40%), PET(50%)) of the maximum intratumoral FDG activity (SUV(MAX)) and applying an adaptive threshold based on the signal-to-background (PET(SBR)). Mean FDG uptake for each PET-based volume was recorded (SUV(mean)). Subsequently, to determine the metabolic volume, the integrated SUV was calculated as the product of PET-based volume and SUV(mean). All these variables were analysed as potential predictors of local control (LC), regional recurrence-free survival (RRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS). In oral cavity/oropharynx tumours PET(VIS) was the only volume-based method able to predict LC. Both PET(VIS) and GTV(CT) were able to predict DMFS, DFS and OS in these subsites. Integrated SUVs were associated with LC, DMFS, DFS and OS, while SUV(mean) and SUV(MAX) were not. In hypopharyngeal/laryngeal tumours none of the variables was associated with outcome. There is no role yet for pretreatment FDG PET as a predictor of (chemo)radiotherapy outcome in HNC in daily routine. However, this potential application needs further exploration, focusing both on FDG PET-based primary tumour volume, integrated SUV and SUV(MAX) of the primary tumour.


G-CSF-dependent neutrophil differentiation requires downregulation of MAPK activities through the Gab2 signaling pathway.
Granulocyte colony-stimulating factor (G-CSF) stimulation of myeloid cells induced tyrosine-phosphorylation of cellular proteins. One of the tyrosine-phosphorylated proteins was found to be a scaffold protein, Grb2-associated binding protein 2 (Gab2). Another member of Gab family protein, Gab3, was exogenously overexpressed in neutrophil progenitor cells to make the Gab3 protein to compete with the endogenous Gab2 for the G-CSF-dependent signaling. In Gab3-overexpressed cells, the level of tyrosine phosphorylation of endogenous Gab2 by G-CSF stimulation was markedly downregulated, while the phosphorylation of Gab3 was significantly enhanced. The Gab3-overexpressed cells continuously proliferated in the medium containing G-CSF and lost the ability to differentiate to the mature neutrophil, characterized by the lobulated nucleus. The G-CSF stimulation-dependent tyrosine phosphorylation of Gab3, the association of SHP2 to Gab3 and the following mitogen-activated protein kinase (MAPK) activation were prolonged in the Gab3-overexpressed cells, compared to the parental cells, where the binding of SHP2 to Gab2 protein and thereby the activation of MAPK were not sustained after G-CSF stimulation. Inhibition of MAPK by pharmaceutical inhibitor restored the Gab3-overexpressed cells to the ability to differentiate to mature neutrophil. Therefore, G-CSF-dependent Gab2 phosphorylation and following its downregulation led the short-term MAPK activation. The downregulation of MAPK after transient Gab2 phosphorylation was necessary for the consequent neutrophil differentiation induced by G-CSF stimulation.


Science and the management of coral reefs.
Increasing accessibility of coral reefs from the latter third of the 20th century led quickly to recognition of the vulnerability of coral reef communities to a combination of direct and indirect human impacts. Coral reefs are confronted by the stark threats of climate and ocean changes from the increasing number, intensity and forms of human use impacting global and marine systems. Management, particularly of accessible coral reefs, occurs in the context of multiple scale transboundary water column linkages of lifecycle processes and increasing human use of coastal and marine space. Four decades of experience have demonstrated the combined importance of biophysical and socio-economic sciences and sharing knowledge with communities for developing implementing effective management. In the face of environmental and socio-economic change the challenge for science and management is to develop knowledge and management responses that can better understand and increase resilience to improve he outlook for coral reef communities.


Intersession repeatability of visual acuity scores in age-related macular degeneration.
To describe the intersession repeatability of visual acuity measures obtained with Early Treatment of Diabetic Retinopathy Study (ETDRS) charts in patients with age-related macular degeneration. Visual acuity was measured in four sessions over 12 weeks using a standardized protocol with ETDRS charts in 107 nontreated eyes of 107 patients with age-related macular degeneration enrolled in an ongoing clinical trial. Data from 90 patients were included in the analysis. The 95% coefficient of repeatability (CR) was 12 ETDRS letters and ranged from 9 letters for 29 eyes with small to intermediate drusen only to 17 letters for 25 eyes with late AMD (macular scars or geographic atrophy). Ten (11%) eyes had a 5-letter reduction or more in visual acuity at the week 1 visit compared with baseline. Excluding seven eyes with visual acuity measurements potentially affected by measurement-related factors (a change in testing distance between visits) the revised CR was 10 letters for the cohort (n = 83) and 11 letters for the late-AMD subgroup (n = 18). Intersession ETDRS visual acuity measurements are subject to considerable variability in patients with AMD. The variability may be due to both measurement- and disease-related factors. The variable readings have implications for AMD clinical trial design and for the assessment and treatment of patients with neovascular AMD. Further work is needed to determine both the sources of variability in visual acuity measurements and the optimal change criterion for visual acuity measurements in this important group of patients.


Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial.
Pulmonary artery catheters (PACs) have been used to guide therapy in multiple settings, but recent studies have raised concerns that PACs may lead to increased mortality in hospitalized patients. To determine whether PAC use is safe and improves clinical outcomes in patients hospitalized with severe symptomatic and recurrent heart failure. The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) was a randomized controlled trial of 433 patients at 26 sites conducted from January 18, 2000, to November 17, 2003. Patients were assigned to receive therapy guided by clinical assessment and a PAC or clinical assessment alone. The target in both groups was resolution of clinical congestion, with additional PAC targets of a pulmonary capillary wedge pressure of 15 mm Hg and a right atrial pressure of 8 mm Hg. Medications were not specified, but inotrope use was explicitly discouraged. The primary end point was days alive out of the hospital during the first 6 months, with secondary end points of exercise, quality of life, biochemical, and echocardiographic changes. Severity of illness was reflected by the following values: average left ventricular ejection fraction, 19%; systolic blood pressure, 106 mm Hg; sodium level, 137 mEq/L; urea nitrogen, 35 mg/dL (12.40 mmol/L); and creatinine, 1.5 mg/dL (132.6 micromol/L). Therapy in both groups led to substantial reduction in symptoms, jugular venous pressure, and edema. Use of the PAC did not significantly affect the primary end point of days alive and out of the hospital during the first 6 months (133 days vs 135 days; hazard ratio [HR], 1.00 [95% confidence interval {CI}, 0.82-1.21]; P = .99), mortality (43 patients [10%] vs 38 patients [9%]; odds ratio [OR], 1.26 [95% CI, 0.78-2.03]; P = .35), or the number of days hospitalized (8.7 vs 8.3; HR, 1.04 [95% CI, 0.86-1.27]; P = .67). In-hospital adverse events were more common among patients in the PAC group (47 [21.9%] vs 25 [11.5%]; P = .04). There were no deaths related to PAC use, and no difference for in-hospital plus 30-day mortality (10 [4.7%] vs 11 [5.0%]; OR, 0.97 [95% CI, 0.38-2.22]; P = .97). Exercise and quality of life end points improved in both groups with a trend toward greater improvement with the PAC, which reached significance for the time trade-off at all time points after randomization. Therapy to reduce volume overload during hospitalization for heart failure led to marked improvement in signs and symptoms of elevated filling pressures with or without the PAC. Addition of the PAC to careful clinical assessment increased anticipated adverse events, but did not affect overall mortality and hospitalization. Future trials should test noninvasive assessments with specific treatment strategies that could be used to better tailor therapy for both survival time and survival quality as valued by patients.


MO-D-218-02: Ultrasound Phantoms in Image Quality Measurements and Performance Assessment.
Agreement has recently emerged for measurement of only three parameters in routine quality assurance. These include element or channel failure (EOCF), maximum depth of penetration (MDOP) and distance measurement accuracy (DMA). The related study leading to this agreement was done at the Mayo Clinic ["Four-year experience with a clinical ultrasound quality control program," Hangiandreou et al. Ultrasound Med & Biol, vol. 37, pp. 1350-1357 (2011)]. A variety of phantoms have been proposed for performing these measurements. These include: 1) a phantom with both flat and cone-shaped scanning windows, tissue-mimicking material and parallel nylon fibers for measuring all three parameters; 2) a starch suspension in water phantom for assessing ECOF; 3) polyurethane phantom for determining ECOF and estimating MDOP; 4) a silicone phantom for determining ECOF. Determination of ECOF and MDOP requires acquisition of image cine loops including many statistically independent versions; analysis of the data requires averaging of the images in the cine loops, and software is being tested at the time of this writing for user-friendly downloading and averaging of the cine images. The phantoms will be described and examples of procedures and results for making measurements. One method for assessing imaging performance involves quantifying the detectability of small low-echo spheres as a function of depth; detectability will depend on sphere size and on depth. It can be argued that the smaller the sphere and the greater the detectability, the better the scanner can delineate the boundary of an inclusion such as a spiculated cancer. Phantoms and software will be described which allow quantitative determination of detectability of low-echo spheres ( 40 dB) as a function of depth; one phantom has a spatially random distribution of 4-mm diameter low-echo spheres for lower frequencies, and the other 2-mm diameter spheres for higher frequencies. The parameter that is quantified is the mean lesion signal-to-noise ratio (LSNR) as described for cylinders by Lopez H et al. IEEE Trans Med Imaging, 1992 and for spheres by Kofler et al. Ultrasound Med & Biol, 2005. The phantoms accommodate any size and shape transducer. Note that spheres have no preferred orientation; therefore, phased arrays and convex (curved) arrays with a broad range of radii of curvature and sector angles can be can be assessed. Phantoms for assessing other aspects of performance such as quantitative determination of the contrast of large objects in a background will also be discussed.


What are the factors associated with short prostate specific antigen doubling time after radical prostatectomy? A report from the SEARCH database group.
Short prostate specific antigen doubling time following recurrence after radical prostatectomy portends a poor prognosis in men with prostate cancer. We determined which demographic and clinicopathological variables were predictive of a short prostate specific antigen doubling time in a cohort of men with clinically localized prostate cancer treated with radical prostatectomy. Data on 856 men from the Shared Equal Access Regional Cancer Hospital database who underwent radical prostatectomy for node negative prostate cancer between 1988 and 2003 were included in the analysis. We used logistic regression analysis to determine the independent factors associated with a short prostate specific antigen doubling time of less than 9 months vs a longer doubling time of 9 months or greater, or no recurrence. The variables analyzed were patient age, race, logarithmically transformed preoperative prostate specific antigen, body mass index, year of surgery, pathological Gleason sum, extraprostatic extension, surgical margin status and seminal vesicle invasion. On multivariate analysis higher preoperative prostate specific antigen (OR 2.20, 95% CI 1.52-3.19, p <0.001), pathological Gleason sum 8-10 (OR 4.70, 95% CI 2.11-10.43, p <0.001) and 7 (OR 2.11, 95% CI 1.09-4.08, p = 0.026), tumors with extraprostatic extension and/or positive surgical margins (OR 2.08, 95% CI 1.48-3.91, p = 0.023), and seminal vesicle invasion (OR 3.26, 95% CI 1.48-7.21, p = 0.003) were independent predictors of a short prostate specific antigen doubling time. Based on these risk factors we developed a table to estimate the risk of recurrence with a prostate specific antigen doubling time of less than 9 months. The factors that are invariably used to predict overall biochemical recurrence following radical prostatectomy, including high prostate specific antigen, high grade and adverse pathological findings, also predict aggressive recurrence.