Scotland's GP Rural Fellowship: an initiative that has impacted on rural recruitment and retention.
In Scotland 20% of the population live in a remote or rural area spread across 94% of the land mass that is defined as remote and rural. NHS Education for Scotland (NES), NHS Scotland's training and education body, works in partnership with territorial health boards and medical schools to address rural recruitment and retention through a variety of initiatives. The longest established of these is the GP Rural Fellowship, which has been in place since 2002. This article describes this program and reports on a survey of the output of the Fellowship from 2002 to 2013. The Fellowship is aimed at newly qualified GPs, who are offered a further year of training in and exposure to rural medicine. The Fellowship has grown and undergone several modifications since its inception. The current model involves co-funding arrangements between NES and participating boards, supporting a maximum of 12 fellows per year. The Health Boards' investment in the Fellowship is returned through the service commitment that the Fellows provide, and the funding share from NES allows Fellows to have protected educational time to meet their educational needs in relation to rural medicine. Given this level of funding support it is important that the outcome of the Fellowship experience is understood, in particular its influence on recruitment to and retention in general practice in rural Scotland. To address this need a survey of all previous rural Fellows was undertaken in the first quarter of 2014, including all Fellows that had undertaken the Fellowship between 2002-03 and 2012-13. A total of 69 GPs were recruited to the Fellowship in this period, of which 66 were able to be included in the survey. There was a response rate of 98% to the survey and 63 of those that responded (97%) were working currently in general practice, 53 of whom were doing so in Scotland. A total of 46 graduates of the Fellowship in the period surveyed (71%) were working in rural areas or accessible small towns in Scotland, 39 in substantive general practice roles (60%). Scotland's GP Rural Fellowship program represents a successful collaboration between education and service, and the results of the survey reported in this article underline previously unpublished data that suggest that approximately three-quarters of graduates are retained in important roles in rural Scotland. It is unclear however whether the Fellowship confirms a prior intention to work in rural practice, or whether it provides a new opportunity through protected exposure. This will form the basis of further evaluation.


Identification and characterization of secondary neural tube-derived embryonic neural stem cells in vitro.
Secondary neurulation is an embryonic progress that gives rise to the secondary neural tube, the precursor of the lower spinal cord region. The secondary neural tube is derived from aggregated Sox2-expressing neural cells at the dorsal region of the tail bud, which eventually forms rosette or tube-like structures to give rise to neural tissues in the tail bud. We addressed whether the embryonic tail contains neural stem cells (NSCs), namely secondary NSCs (sNSCs), with the potential for self-renewal in vitro. Using in vitro neurosphere assays, neurospheres readily formed at the rosette and neural-tube levels, but less frequently at the tail bud tip level. Furthermore, we identified that sNSC-generated neurospheres were significantly smaller in size compared with cortical neurospheres. Interestingly, various cell cycle analyses revealed that this difference was not due to a reduction in the proliferation rate of NSCs, but rather the neuronal commitment of sNSCs, as sNSC-derived neurospheres contain more committed neuronal progenitor cells, even in the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). These results suggest that the higher tendency for sNSCs to spontaneously differentiate into progenitor cells may explain the limited expansion of the secondary neural tube during embryonic development.


Divergent morphological and acoustic traits in sympatric communities of Asian barbets.
The opposing effects of environmental filtering and competitive interactions may influence community assembly and coexistence of related species. Competition, both in the domain of ecological resources, and in the sensory domain (for example, acoustic interference) may also result in sympatric species evolving divergent traits and niches. Delineating these scenarios within communities requires understanding trait distributions and phylogenetic structure within the community, as well as patterns of trait evolution. We report that sympatric assemblages of Asian barbets (frugivorous canopy birds) consist of a random phylogenetic sample of species, but are divergent in both morphological and acoustic traits. Additionally, we find that morphology is more divergent than expected under Brownian evolution, whereas vocal frequency evolution is close to the pattern expected under Brownian motion (i.e. a random walk). Together, these patterns are consistent with a role for competition or competitive exclusion in driving community assembly. Phylogenetic patterns of morphological divergence between related species suggest that these traits are key in species coexistence. Because vocal frequency and size are correlated in barbets, we therefore hypothesize that frequency differences between sympatric barbets are a by-product of their divergent morphologies.


Surgical treatment for tubal disease in women due to undergo in vitro fertilisation.
Tubal disease, and particularly hydrosalpinx, has a detrimental effect on the outcome of in-vitro fertilisation (IVF). Performing a surgical intervention such as salpingectomy, tubal occlusion, aspiration of the hydrosalpinx fluid, or salpingostomy, prior to the IVF procedure in women with hydrosalpinges is thought improve the likelihood of successful outcome. To assess and compare the value of surgical treatments for tubal disease prior to IVF. Trials were sought in the Cochrane Menstrual Disorders and Subfertility Group trials register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PSYCHMED and in Conference proceedings and reference lists up until Ocober 28 2009. Researchers in the field were contacted to reveal unpublished studies. All trials comparing a surgical treatment for tubal disease with a control group generated by randomisation were considered for inclusion in the review. Two reviewers independently assessed trial quality and extracted data. The studied outcomes were live birth, ongoing pregnancy, viable-, clinical- and biochemical pregnancy, ectopic pregnancy, miscarriage, multiple pregnancy, ovarian function and complications. Five randomised controlled trials involving 646 women were included in this review. Four studies assessed salpingectomy versus no treatment, two of which also included a tubal occlusion arm, and one trial assessed aspiration versus no treatment. No trials reported on the primary outcome: live birth. The odds of ongoing pregnancy (Peto OR 2.14, 95%CI 1.23 to 3.73) and of clinical pregnancy (Peto OR 2.31, 95%CI 1.48 to 3.62) however were increased with laparoscopic salpingectomy for hydrosalpinges prior to IVF. Laparoscopic occlusion of the fallopian tube versus no intervention did not increase the odds of ongoing pregnancy significantly (Peto OR 7.24, 95%CI 0.87 to 59.57) but the odds of clinical pregnancy (Peto OR 4.66, 95%CI 2.47 to 10.01) had sufficient power to show a significant increase. Comparison of tubal occlusion to salpingectomy did not show a significant advantage of either surgical procedure in terms of ongoing pregnancy (Peto OR: 1.65, 95%CI 0.74, 3.71) or clinical pregnancy (Peto OR 1.28, 95%CI 0,76 to 2.14). One RCT reported efficacy of ultrasound guided aspiration, however the odds of pregnancy did not show a significant increase in the odds of clinical pregnancy (Peto OR 1.97, 95%CI 0.62 to 6.29), and confidence intervals were wide. Throughout the different comparisons no significant differences were seen in adverse effects of surgical treatments. Surgical treatment should be considered for all women with hydrosalpinges prior to IVF treatment. Previous evidence supported only unilateral salpingectomy for a unilateral hydrosalpinx (bilateral salpingectomy for bilateral hydrosalpinges). This review now provides evidence that laparoscopic tubal occlusion is an alternative to laparoscopic salpingectomy in improving IVF pregnancy rates in women with hydrosalpinges. Further research is required to assess the value of aspiration of hydrosalpinges prior to or during IVF procedures and also the value of tubal restorative surgery as an alternative (or as a preliminary) to IVF.


Increased serum malondialdehyde level in neonates with hypoxic-ischaemic encephalopathy: prediction of disease severity.
Increased serum level of malondialdehyde (sMDA) in neonates with hypoxic-ischaemic encephalopathy (HIE) was evaluated as a possible criterion for determining HIE severity. Mean body weight and gestational age in a healthy control group of neonates (n = 63) and in neonates with HIE (n = 69) were statistically similar. Apgar scores at 1 and 5 min for the HIE group were significantly lower than for the control group. The mean sMDA level for the HIE group was significantly higher than the control group. Within the HIE group, the sMDA level for neonates with Sarnat's grade II and III was significantly higher than for those with Sarnat's grade I. There was a significant correlation between Sarnat's grading and the sMDA level. The sMDA level was significantly higher for neonates who died (n = 20) compared with those who survived (n = 49). In conclusion, the sMDA level was highest in neonates with HIE and correlated with HIE severity. The sMDA concentration could, therefore, be used as a criterion for predicting disease severity.


Meta-analyses of the sensitivity and specificity of ante-mortem and post-mortem diagnostic tests for bovine tuberculosis in the UK and Ireland.
Bovine Tuberculosis (bTB) in cattle is a global health problem and eradication of the disease requires accurate estimates of diagnostic test performance to optimize their efficiency. The objective of this study was, through statistical meta-analyses, to obtain estimates of sensitivity (Se) and specificity (Sp), for 14 different ante-mortem and post-mortem diagnostic tests for bTB in cattle. Using data from a systematic review of the scientific literature (published 1934-2009) diagnostic Se and Sp were estimated using Bayesian logistic regression models adjusting for confounding factors. Random effect terms were used to account for unexplained heterogeneity. Parameters in the models were implemented using Markov Chain Monte Carlo (MCMC), and posterior distributions for the diagnostic parameters with adjustment for covariates (confounding factors) were obtained using the inverse logit function. Estimates for Se and/or Sp of the tuberculin skin tests and the IFN-γ blood test were compared with estimates published 2010-2015. Median Se for the single intradermal comparative cervical tuberculin skin (SICCT) test (standard interpretation) was 0.50 and Bayesian credible intervals (CrI) were wide (95% CrI 0.26, 0.78). Median Sp for the SICCT test was 1.00 (95% CrI 0.99, 1.00). Estimates for the IFN-γ blood test Bovine Purified Protein Derivative (PPD)-Avian PPD and Early Secreted Antigen target 6 and Culture Filtrate Protein 10 (ESAT-6/CFP10) ESAT6/CFP10 were 0.67 (95% CrI 0.49, 0.82) and 0.78 (95% CrI 0.60, 0.90) respectively for Se, and 0.98 (95% CrI 0.96, 0.99) and 0.99 (95% CrI 0.99, 1.00) for Sp. The study provides an overview of the accuracy of a range of contemporary diagnostic tests for bTB in cattle. Better understanding of diagnostic test performance is essential for the design of effective control strategies and their evaluation.


The weight-specific adolescent instrument for economic evaluation (WAItE): psychometric evaluation using a Rasch model approach.
The Weight-specific Adolescent Instrument for Economic evaluation (WAItE) is a 7-item condition-specific tool assessing the impact of weight status on seven dimensions of quality of life. The content of the WAItE was developed with both treatment-seeking and non-treatment-seeking adolescents aged 11-18 years. The aim of this study was to assess the psychometric properties of the WAItE in adolescent and adult populations. Treatment-seeking adolescents with obesity (females n = 155; males n = 123; mean age = 13.3; 13.1 years, respectively) completed the WAItE twice. An adult general population sample completed the WAItE via an online survey (females n = 236; males n = 231; mean age = 41.2; 44.3 years, respectively). The Partial Credit Model was applied to the data and item fit evaluated against published criteria. The WAItE had a unidimensional structure both for adolescents and adults. There was no item misfit observed for either participant samples and no differential item functioning (DIF) was present by age or gender for the adolescents. Some DIF was observed across age groups for the adult sample. For the adolescent sample, stable item locations were observed over time. The aim of the WAItE is to assess the impact of weight status on the lives of adolescents in cost-effectiveness evaluation of weight management programmes. The results of this study demonstrated that the WAItE has reliable psychometric properties. The instrument may therefore be used to aid informed decision around the identification of cost-effective weight management programmes in both adolescent and adult populations.


Quantitative nuclease protection assay in paraffin-embedded tissue replicates prognostic microarray gene expression in diffuse large-B-cell lymphoma.
Gene expression profiling (GEP) has identified genes whose expression levels predict patient survival in diffuse large-B-cell lymphoma (DLBCL). Such discovery techniques generally require frozen samples unavailable for most patients. We developed a quantitative nuclease protection assay to measure expression levels of prognostic DLBCL genes using formalin-fixed, paraffin-embedded (FFPE) tissue. FFPE tissue was sectioned, permeabilized, denatured in the presence of specific probes, and hybridized to mRNA in situ. Nuclease subsequently destroyed non-hybridized probe. Alkaline hydrolysis freed mRNA-bound probes from tissue, which were transferred to ArrayPlates for probe capture and chemiluminescent quantification. We validated assay performance using frozen, fresh, and FFPE DLBCL samples, then used 39 archived DLBCL, previously microarray analyzed, to correlate GEP and ArrayPlate results. We compared old (>18 years) with new (<2 months) paraffin blocks made from previously frozen tissue from the original biopsy. ArrayPlate gene expression results were confirmed with immunohistochemistry for BCL2, BCL6, and HLA-DR, showing agreement between mRNA species and the proteins they encode. Assay performance was linear to approximately 1 mg sample/well. RNase and DNase treatments demonstrated assay specificity for RNA detection, both fixed and soluble RNA detection. Comparisons were excellent for lysate vs snap-frozen vs FFPE (R(2)>0.98 for all comparisons). Coefficients of variation for quadruplicates on FFPE were generally <20%. Correlation between new and old paraffin blocks from the same biopsy was good (R(2)=0.71). Comparison of ArrayPlate to Affymetrix and cDNA microarrays showed reasonable correlations. Insufficient power from small sample size prevented successfully correlating results with patient survival, although hazard ratios trended the expected directions. We developed an assay to quantify expression levels of survival prediction genes in DLBCL using FFPE, fresh, or frozen tissue. While this technique cannot replace GEP for discovery, it indicates that expression differences identified by GEP can be replicated on a platform applicable to archived FFPE samples.


Mood and appetite: Their relationship with discretionary and total daily energy intake.
Negative affect is shown consistently to promote unhealthy food choices and dietary intake in laboratory studies. However, this relationship in naturalistic settings is less clear and previous research is limited by dietary assessment methodology and neglects to account for several important moderating variables. This observational study aimed to examine the association of negative affect and other psychological factors associated with eating behaviour simultaneously with discretionary energy intake and total energy intake, and whether these were moderated by emotional eating predisposition or age, sex and weight status. One hundred adults completed a four-day food diary, a concurrent end-of-day questionnaire that assessed daily affect and experience of appetite, and the Three Factor Eating Questionnaire to assess trait eating behaviour. Food diaries provided data on participants' daily intake of total energy and of "discretionary items" (specific energy-dense and nutrient poor foods and beverages as defined by the Australian Guide to Healthy Eating). Stepwise random effects models were used to estimate the association of end-of-day ratings, trait eating behaviour and personal factors, and their interactions, with discretionary and total energy intake. Daily rated negative affect and appetite were significantly and positively associated with discretionary intake, such that a one unit increase in each scale was associated with eating 139 kJ/d [SE 61] and 194 kJ/d [SE 68] more discretionary energy, respectively. Negative affect and its interaction with emotional eating were consistently, positively associated with discretionary energy intake. This relationship was strongest in younger participants (β = -4.9 [SE 2.2], p < .05). There was no interaction with sex or weight status. Total energy intake was not associated with negative affect nor its interaction with emotional eating but was consistently associated with appetite. When personal factors (age, sex, BMI), trait eating behaviours and daily rated negative affect and appetite are considered simultaneously, daily discretionary intake is associated most strongly with negative affect. Individuals, particularly young adults, may be more likely to overeat discretionary energy on days that negative affect is rated more highly. However, this may not necessarily translate into greater total energy intake which was most consistently associated with daily rated appetite.


Improved survival of colon cancer due to improved treatment and detection: a nationwide population-based study in The Netherlands 1989-2006.
We described changes in treatment of colon cancer over time and the impact on survival in The Netherlands in the period 1989-2006. All 103,744 patients with invasive colon cancer during 1989-2006 in The Netherlands were included. Data were extracted from The Netherlands Cancer Registry. Trends in treatment over time were analysed and multivariable relative survival analysis was carried out. The administration of adjuvant chemotherapy in stage III patients <75 years increased from 19% in 1989-1993 to 79% in 2004-2006 and from 1% to 19% in stage III patients ≥75 years. Among stage IV patients, resection rates of the primary tumour decreased from 72% to 63%, while chemotherapy administration increased from 23% to 64% in those <75 years. Survival increased from 52% to 58% in males and from 55% to 58% among females. Stage III patients with adjuvant chemotherapy exhibited a relative excess risk of 0.4 (95% confidence interval 0.4-0.4) compared with those without. Among stage IV patients, resection of primary tumour, palliative chemotherapy, and metastasectomy were important prognostic factors. There were substantial improvements in management and survival of colon cancer from 1989 to 2006. Stage III disease patients with colon cancer experienced the largest improvement in survival, most likely related to the increased administration of adjuvant chemotherapy.


Self-assembling supramolecular complexes by single-stranded extension from plasmid DNA.
Self-assembling supramolecular complexes are of great interest for bottom-up research like nanotechnology. DNA is an inexpensive building block with sequence-specific self-assembling capabilities through Watson-Crick and/or Hoogsteen base pairing and could be used for applications in surface chemistry, material science, nanomechanics, nanoelectronics, nanorobotics, and of course in biology. The starting point is usually single-stranded DNA, which is rather easily accessible for base pairing and duplex formation. When long stretches of double-stranded DNA are desirable, serving either as genetic codes or electrical wires, bacterial expansion of plasmids is an inexpensive approach with scale-up properties. Here, we present a method for using double-stranded DNA of any sequence for generating simple structures, such as junctions and DNA lattices. It is known that supercoiled plasmids are strand-invaded by certain DNA analogs. Here we add to the complexity by using "Self-assembling UNiversal (SUN) anchors" formed by DNA analog oligonucleotides, synthesized with an extension, a "sticky-end" that can be used for further base pairing with single-stranded DNA. We show here how the same set of SUN anchors can be utilized for gene therapy, plasmid purification, junction for lattices, and plasmid dimerization through Watson-Crick base pairing. Using atomic force microscopy, it has been possible to characterize and quantify individual components of such supra-molecular complexes.


Control of plasmon emission and dynamics at the transition from classical to quantum coupling.
With nanosecond radiative lifetimes, quenching dominates over enhancement for conventional fluorescence emitters near metal interfaces. We explore the fundamentally distinct behavior of photoluminescence (PL) with few-femtosecond radiative lifetimes of a coupled plasmonic emitter. Controlling the emitter-surface distance with subnanometer precision by combining atomic force and scanning tunneling distance control, we explore the unique behavior of plasmon dynamics at the transition from long-range classical resonant energy transfer to quantum coupling. Because of the ultrafast radiative plasmon emission, classical quenching is completely suppressed. Field-enhanced behavior dominates until the onset of quantum coupling dramatically reduces emission intensity and field enhancement, as verified in concomitant tip-enhanced Raman measurements. The entire distance behavior from tens of nanometers to subnanometers can be described using a phenomenological rate equation model and highlights the new degrees of freedom in radiation control enabled by an ultrafast radiative emitter near surfaces.


The current state of endoscopic disc surgery: review of controlled studies comparing full-endoscopic procedures for disc herniations to standard procedures.
Neuropathic pain originating from spinal disc herniations is a very common problem. The majority of disc surgeries are performed to alleviate this pain once conservative measures and targeted injections have failed. Endoscopic spinal surgery is increasingly popular because it minimizes access trauma and hastens recovery from the intervention. This clinically oriented review evaluates controlled studies that investigate the clinical results and the complications of full-endoscopic lumbar and cervical procedures for symptomatic disc herniations in comparison to a microsurgical standard procedure. This review focuses exclusively on modern, full-endoscopic disc surgery irrespective of the specific access technique (e.g., interlaminar vs. transforaminal) and irrespective of the spinal region. Comprehensive review of the literature. To assess the clinical outcomes and complication rates of full-endoscopic disc surgery compared to the microsurgical standard procedures. A PubMed and Embase search was performed, considering entries up to January 2013. All 504 results were screened and categorized. Only 4 randomized controlled trials (RCTs) and one controlled studies (CS) could finally be considered for evaluation. All 5 manuscripts were meticulously analyzed with regards to randomization mode, inclusion/exclusion criteria, clinical results, and complication rates. Overall, the endoscopic techniques had shorter operating times, less blood loss, less operative site pain, and faster postoperative rehabilitation/shorter hospital stay/faster return to work than the microsurgical techniques. There were no significant differences in the main clinical outcome criteria between the endoscopic and the microsurgical techniques in any of the trials. All 5 studies had fewer complications with the endoscopic technique and this was statistically significant in 2 of the studies. One study showed a lower rate of revision surgeries requiring arthrodesis with the endoscopic technique. All 5 studies that could be considered originate from experienced investigators and all 4 RCTs came from one group. This limits the transferability of their results to surgeons less experienced in endoscopic disc surgery. The studies show that full-endoscopic disc surgery can achieve the same clinical results in symptomatic cervical and lumbar disc herniations as the microsurgical standard techniques. This does not appear to come at the price of higher complication rates.


Ecological effects on underdominance threshold drives for vector control.
Underdominance gene drives are frequency-dependent drives that aim to spread a desired homozygote genotype within a population. When the desired homozygote is released above a threshold frequency, heterozygote fitness disadvantage acts to drive the desired trait to fixation. Underdominance drives have been proposed as a way to control vector-borne disease through population suppression and replacement in a spatially contained and reversible way-benefits that directly address potential safety concerns with gene drives. Here, ecological and epidemiological dynamics are coupled to a model of mosquito genetics to investigate theoretically the impact of different types of underdominance gene drive on disease prevalence. We model systems with two engineered alleles carried either on the same pair of chromosomes at the same locus or homozygously on different pairs at different loci, genetic lethality that affects both sexes or only females, and bi-sex or male-only releases. Further, the different genetic and ecological fitness costs that can arise from genetic modification and artificial rearing are investigated through their effect on the population threshold frequency that is required to trigger the drive mechanism. We show that male-only releases must be significantly larger than bi-sex releases to trigger the underdominance drive. In addition, we find that female-specific lethality averts a higher percentage of disease cases over a control period than does bi-sex lethality. Decreases in the genetic fitness of the engineered homozygotes can increase the underdominance threshold substantially, but we find that the mating success of transgenic mosquitoes with wild-type females (influenced by a lack of competitiveness or the evolution of behavioural resistance in the form of active female mate preference) and the longevity of artificially-reared mosquitoes are vitally important to the success chances of underdominance based gene drive control efforts.


A Systematic Review and Standardized Comparison of Available Evidence for Outcome Measures Used to Evaluate Proximal Humerus Fracture Patients.
To summarize and appraise any patient-reported or clinician-measured outcome measures based on their measurement properties in proximal humerus fracture patients. MEDLINE, EMBASE, and CINAHL were searched from January 2000 to August 2018 to identify all studies of proximal humerus fracture patients that reported a measurement property evaluation of an outcome measure. Quality appraisal of each measure was completed using the Evaluating the Measurement of Patient-Reported Outcomes (EMPRO) tool. The EMPRO takes into account all studies of each measure, and the overall score is transformed linearly to a range of 0 (lowest) to 100 (best). Eleven instruments were identified. Intended concepts of the instruments included clinician-measured shoulder function, patient-reported function or disability, and patient-reported general health state. Only the Disabilities of the Arm, Shoulder and Hand (DASH), Oxford Shoulder Score, Constant Score, University of California, Los Angeles Shoulder Score, and EuroQol 5 Dimension (EQ5D) were evaluated in more than 1 study. The Shoulder Function Index (SFINX), DASH, and EQ5D had the highest EMPRO scores (80, 66, and 58, respectively). The SFINX and DASH consistently scored among the top 3 instruments for each attribute. Evidence on the measurement properties of outcome measures for proximal humerus fracture patients is limited. With the available evidence, the SFINX is recommended as a clinician-measured functional outcome measure, the DASH as a patient-reported functional outcome measure, and the EQ5D as a general health status measure.


Experience with ambulatory preoperative bowel preparation at the Johns Hopkins Hospital.
A transition to ambulatory preoperative antibiotic bowel preparation was carried out. The protocol included a liquid diet for 40 hours preceding surgery and coordination of purging with buffered oral saline laxative, 45 mL containing 8 g sodium phosphate and 22 g sodium biphosphate (Fleet Phospho-Soda, C.B. Fleet Co, Lynchburg, Va) and bisacodyl preparation with an oral erythromycin base-neomycin routine. Enemas were omitted. Personnel in the preoperative evaluation center had the responsibility of instructing patients, distributing directions and drugs, and reviewing for compliance and possible problems during the preoperative period. All patients scheduled for any of a variety of gastrointestinal procedures, as well as some other complex operations, were included in this study. Follow-up data were obtained. Surgeons' comments regarding efficacy were highly favorable. In only five cases was there comment regarding liquid stool, and this was no impediment to surgery. This incidence was comparable with that of the inpatient experience, as was the spectrum of postoperative complications. Transfer of responsibility to the department proceeded with ease. Results were entirely comparable with those of the former inpatient experience.


Tracing transgene expression in cancer gene therapy: a requirement for rational progress in the field.
This review summarizes the status of gene therapy in medicine and the role of molecular imaging in its development. In gene therapy, genetic material is introduced into cells in order to generate a specific biological effect. Natural (viruses) or artificial molecular constructs, named gene therapy vectors, are used to achieve efficient cell transduction. This new form of therapy can be used for treating a broad variety of conditions including hereditary diseases, infections, degenerative disorders and cancer. Monitoring transgene expression using noninvasive imaging techniques is a necessary complement for the development of clinical gene therapy. Recent developments in magnetic resonance imaging afford the possibility of detecting gene transfer in vivo, but the most promising results have been obtained with positron emission tomography (PET). PET allows imaging gene therapy products by administration of a labeled substrate when the transgene codes for an enzyme or by administration of a labeled ligand when the transgene codes for a receptor. In the latter strategy, a membrane molecule (somatostatin or dopamine receptors) is used to detect the selective trapping of its radiolabeled ligand in the transduced cells. One of the approaches for the genetic treatment of cancer consists in transferring the "suicide genes" into tumor cells, the most common being the thymidine kinase (tk) of herpes viruses. Different nucleoside analogs can be labeled for its use as PET reporter probes in order to visualize tk expression. The results of pre-clinical studies are extremely encouraging. Reliable methods for the in vivo tracing of transgene expression in humans have to be developed in order for the field of gene therapy to mature. PET has emerged as a powerful tool to assist in achieving this goal.


Genome structure and metabolic features in the red seaweed Chondrus crispus shed light on evolution of the Archaeplastida.
Red seaweeds are key components of coastal ecosystems and are economically important as food and as a source of gelling agents, but their genes and genomes have received little attention. Here we report the sequencing of the 105-Mbp genome of the florideophyte Chondrus crispus (Irish moss) and the annotation of the 9,606 genes. The genome features an unusual structure characterized by gene-dense regions surrounded by repeat-rich regions dominated by transposable elements. Despite its fairly large size, this genome shows features typical of compact genomes, e.g., on average only 0.3 introns per gene, short introns, low median distance between genes, small gene families, and no indication of large-scale genome duplication. The genome also gives insights into the metabolism of marine red algae and adaptations to the marine environment, including genes related to halogen metabolism, oxylipins, and multicellularity (microRNA processing and transcription factors). Particularly interesting are features related to carbohydrate metabolism, which include a minimalistic gene set for starch biosynthesis, the presence of cellulose synthases acquired before the primary endosymbiosis showing the polyphyly of cellulose synthesis in Archaeplastida, and cellulases absent in terrestrial plants as well as the occurrence of a mannosylglycerate synthase potentially originating from a marine bacterium. To explain the observations on genome structure and gene content, we propose an evolutionary scenario involving an ancestral red alga that was driven by early ecological forces to lose genes, introns, and intergenetic DNA; this loss was followed by an expansion of genome size as a consequence of activity of transposable elements.


Telemedicine at sea and onshore: divergences and convergences.
Telemedical Maritime Assistance Service (TMAS) is one of the fundamental components of medical assistance delivery at sea. However, while onshore telemedicine is undergoing a fast growth, these research and clinical investments unfortunately did not yet benefit for telemedicine at sea. While telemedicine aims at providing distant health care, telemedicine at sea and onshore bear major differences, particularly for merchant vessels, and to a lesser extent for passenger vessels, which can be divided between structural differences, differences of practices, and policy differences. Despite the existence of important divergences between telemedicine at sea and telemedicine onshore, these two major branches of distant health care delivery still converge in some respects. Identifying the convergences between telemedicine at sea and telemedicine onshore might contribute to increase and optimise the transfer from research on onshore telemedicine to maritime telemedicine, and to overcome the relatively low amount of research performed on telemedicine at sea compared to its onshore counterpart.


Leptin Raises Defended Body Temperature without Activating Thermogenesis.
Leptin has been believed to exert its weight-reducing action not only by inducing hypophagia but also by increasing energy expenditure/thermogenesis. Leptin-deficient ob/ob mice have correspondingly been thought to be thermogenically limited and to show hypothermia, mainly due to atrophied brown adipose tissue (BAT). In contrast to these established views, we found that BAT is fully functional and that leptin treatment did not increase thermogenesis in wild-type or in ob/ob mice. Rather, ob/ob mice showed a decreased but defended body temperature (i.e., were anapyrexic, not hypothermic) that was normalized to wild-type levels after leptin treatment. This was not accompanied by increased energy expenditure or BAT recruitment but, instead, was mediated by decreased tail heat loss. The weight-reducing hypophagic effects of leptin are, therefore, not augmented through a thermogenic effect of leptin; leptin is, however, pyrexic, i.e., it alters centrally regulated thresholds of thermoregulatory mechanisms, in parallel to effects of other cytokines.


The cancer burden in the United Kingdom in 2007 due to radiotherapy.
The number of long-term cancer survivors in the general population of the UK is substantial and increasing rapidly. Many cancer survivors have been treated with radiotherapy but the likely number of radiotherapy-related second cancers has not previously been estimated. We used estimates of the numbers of cancer survivors in the UK at the beginning of 2007, in conjunction with estimates of the relative risk of a second primary cancer associated with previous radiotherapy from the United States Surveillance Epidemiology and End Results (SEER) programme, to estimate the numbers of incident cancers in the UK in 2007 that were associated with radiotherapy for a previous cancer and that may have been caused by it. We estimated that 1,346 cases of cancer, or about 0.45% of the 298,000 new cancers registered in the UK in 2007, were associated with radiotherapy for a previous cancer. The largest numbers of radiotherapy-related second cancers were lung cancer (23.7% of the total), oesophageal cancer (13.3%), and female breast cancer (10.6%); 54% of radiotherapy-related second cancers were in individuals aged 75 or over. The highest percentages of second cancers related to radiotherapy were among survivors of Hodgkin's disease and cancers of the oral cavity and pharynx and cervix uteri; over 15% of second cancers among these survivors were associated with radiotherapy for the first cancer. These calculations, which involve a number of assumptions and approximations, provide a reasonable, if conservative, estimate of the fraction of incident cancers in the UK that are attributable to past radiation therapy.


Mid term functional results following surgical treatment of recto-urinary fistulas postprostate cancer treatment.
To evaluate the mid term functional results of patients treated for RUF and to determine an optimal treatment strategy to improve their quality of life. Recto-urinary Fistula (RUF) is a rare complication following prostate cancer treatment, and can have a major impact on patients' quality of life. There is a lack of consensus concerning the best approach and different techniques have been proposed: endoscopic, transrectal, perineal and transperitoneal (open, laparoscopic or robotic). We retrospectively reviewed the charts of patients who underwent RUF repair from January 2001 to December 2010 at our Institute. 16 patients who developed RUF following prostate cancer treatment were included in the study. The fistula had to be confirmed both clinically and by imaging. All patients had follow up consultation every 3 month for the first year and then annually. They were asked to fill questionnaires evaluating functional outcomes. The International Continence Society (ICS) score was used to assess the postoperative urinary continence. Fecal continence was evaluated with the Wexner score and sexual function was assessed with the International Index for erectile function (IIEF-5) score. Eighty-seven percent patients (14/16) in our series developed RUF as a consequence of prostate cancer surgery and 13% (2/16) postbrachytherapy (BT). All patients initially had a diversion colostomy and a supra pubic catheter. 69% (11/16) underwent primary YM repair and 73% (8/11) were successful. 2/3 primary failures were successfully retreated with graciloplasty. Primary gracilis flap interposition (GFI), on 3 non-irradiated patients were successful (100%). Primary GFI postbrachytherapy, no patient had recover urinary and digestive continuity. In total primary GIF was successful in 60% (3/5). Over all long term, success rate with a urinary and digestive continuity and without recurrence of the fistula was 81% (13/16). Mid term functional results were evaluated at mean follow up of 40 months (14-92). 13% (2/16) achieved complete urinary continence, 48% (7/16) required single pad, 25% (4/16) developed major incontinence, 7% (1/16) required urinary diversion and 13% (2/16) developed complete urethral closure post BT requiring permanent suprapubic catheterization. Colostomy was reversed in 93% (15/16) cases. 75% (12/16) achieved complete faecal continence, minor incontinence (wexner score 3-4) was seen in 13% (2/16) and major incontinence (wexner score 14) in 7% (1/16) and 7% (1/16) required a long term colostomy. 19% (3/16) developed colostomy related complications. Only 13% (2/16) achieved adequate erections with the use of intra cavernosal prostaglandin injections. RUF following prostate cancer treatment is a serious complication with severe repercussion on patients' quality of life. Surgical repair with the York Mason technique or Gracilis Flap interposition is associated with good success rates. If available pediculed gracilis muscle should be used as it offers better success rates. 3.


A phase I study of an anti-CD22-deglycosylated ricin A chain immunotoxin in the treatment of B-cell lymphomas resistant to conventional therapy.
Twenty-six patients, whose B-cell lymphoma had relapsed after conventional therapies, were treated in a phase I dose escalation study with an immunotoxin consisting of a mouse CD22 monoclonal antibody (RFB4:IgG1K) coupled to chemically deglycosylated ricin A chain (dgA). Two to 12 doses of the immunotoxin were infused intravenously at 48-hour intervals. The peak serum concentration and half-life (T1/2) did not correlate directly with the dose and averaged 3.8 micrograms/mL and 7.8 hours, respectively. The main dose-limiting toxicity was caused by the vascular leak syndrome (VLS) consisting of weight gain, edema, serum albumin decrease, and critically by pulmonary edema. Myalgia occurred frequently and was only dose limiting in one patient who developed rhabdomyolysis. The presence of lymphoma cells in the blood (> or = 10(10)/L) and clinically detectable splenomegaly were associated with reduced toxicity and a shorter T1/2. Nine of 24 evaluable patients (37.5%) made antibody to either mouse Ig or dgA. There were five partial responses (PR) and one complete response (CR) lasting 30 to 78 days. High peak concentrations of immunotoxin in the serum, a long T1/2, and large areas under the curve (AUC) correlated with both clinical response and toxicity. None of three patients with CD5+ lymphomas (including two CLL patients) had more than mild toxicity or responded to the immunotoxin.


Reproducibility of subfoveal choroidal thickness measurements with enhanced depth imaging by spectral-domain optical coherence tomography.
To measure the interobserver reproducibility and intra-observer reproducibility of subfoveal choroidal thickness measurements performed by enhanced depth imaging of spectral-domain optical coherence tomography (EDI-OCT) in a population-based setting. The Beijing Eye Study 2011 was a population-based study performed in rural and urban regions of Greater Beijing. The study included 3468 individuals with a mean age of 64.6 ± 9.8 years (range, 50-93 years). The participants underwent EDI-OCT and the subfoveal choroidal thickness (SFCT) was measured. To examine the interobserver variability, all images were assessed by two examiners independently of each other within 2 months. To examine the intra-observer reproducibility, a smaller study sample consisting of 21 eyes of 21 healthy subjects from the Tongren Eye Center was included in the study. These latter subjects were scanned 10 times with 1 minute breaks between each examination. The SFCT was measured by the same observer within 2 weeks. The intrasession within subject SD, the coefficient of variation, and the intraclass correlation coefficient (ICC) were calculated. EDI-OCTs were performed for 3233 subjects. Mean SFCT measured by grader one and grader two were 254.6 ± 107.3 μm and 253.8 ± 107.4 μm, respectively, with a mean difference of 3.14 ± 13.1 μm (95% confidence interval, 0.0, 24.0). Bland-Altman plot showed 1.9% (61/3233) points outside the 95% limits of agreement. For the assessment of the intra-observer reproducibility, the ICC was 1.00 (P < 0.001, and the mean coefficient of variation was 0.85% ± 1.48%). Under routine examination conditions, SFCT measurements by EDI-OCT showed a high intra-observer reproducibility and interobserver reproducibility.


Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa.
Patients with Lynch syndrome (LS) are at markedly increased risk for colorectal cancer. It is being increasingly recognised that the immune system plays an essential role in LS tumour development, thus making an ideal target for cancer prevention. Our objective was to evaluate the safety, assess the activity and discover novel molecular pathways involved in the activity of naproxen as primary and secondary chemoprevention in patients with LS. We conducted a Phase Ib, placebo-controlled, randomised clinical trial of two dose levels of naproxen sodium (440 and 220 mg) administered daily for 6 months to 80 participants with LS, and a co-clinical trial using a genetically engineered mouse model of LS and patient-derived organoids (PDOs). Overall, the total number of adverse events was not different across treatment arms with excellent tolerance of the intervention. The level of prostaglandin E2 in the colorectal mucosa was significantly decreased after treatment with naproxen when compared with placebo. Naproxen activated different resident immune cell types without any increase in lymphoid cellularity, and changed the expression patterns of the intestinal crypt towards epithelial differentiation and stem cell regulation. Naproxen demonstrated robust chemopreventive activity in a mouse co-clinical trial and gene expression profiles induced by naproxen in humans showed perfect discrimination of mice specimens with LS and PDOs treated with naproxen and control. Naproxen is a promising strategy for immune interception in LS. We have discovered naproxen-induced gene expression profiles for their potential use as predictive biomarkers of drug activity. gov Identifier: NCT02052908.


NR4A nuclear receptors support memory enhancement by histone deacetylase inhibitors.
The formation of a long-lasting memory requires a transcription-dependent consolidation period that converts a short-term memory into a long-term memory. Nuclear receptors compose a class of transcription factors that regulate diverse biological processes, and several nuclear receptors have been implicated in memory formation. Here, we examined the potential contribution of nuclear receptors to memory consolidation by measuring the expression of all 49 murine nuclear receptors after learning. We identified 13 nuclear receptors with increased expression after learning, including all 3 members of the Nr4a subfamily. These CREB-regulated Nr4a genes encode ligand-independent "orphan" nuclear receptors. We found that blocking NR4A activity in memory-supporting brain regions impaired long-term memory but did not impact short-term memory in mice. Further, expression of Nr4a genes increased following the memory-enhancing effects of histone deacetylase (HDAC) inhibitors. Blocking NR4A signaling interfered with the ability of HDAC inhibitors to enhance memory. These results demonstrate that the Nr4a gene family contributes to memory formation and is a promising target for improving cognitive function.


Dynamics of HIV-containing compartments in macrophages reveal sequestration of virions and transient surface connections.
During HIV pathogenesis, infected macrophages behave as "viral reservoirs" that accumulate and retain virions within dedicated internal Virus-Containing Compartments (VCCs). The nature of VCCs remains ill characterized and controversial. Using wild-type HIV-1 and a replication-competent HIV-1 carrying GFP internal to the Gag precursor, we analyzed the biogenesis and evolution of VCCs in primary human macrophages. VCCs appear roughly 14 hours after viral protein synthesis is detected, initially contain few motile viral particles, and then mature to fill up with virions that become packed and immobile. The amount of intracellular Gag, the proportion of dense VCCs, and the density of viral particles in their lumen increased with time post-infection. In contrast, the secretion of virions, their infectivity and their transmission to T cells decreased overtime, suggesting that HIV-infected macrophages tend to pack and retain newly formed virions into dense compartments. A minor proportion of VCCs remains connected to the plasma membrane overtime. Surprisingly, live cell imaging combined with correlative light and electron microscopy revealed that such connections can be transient, highlighting their dynamic nature. Together, our results shed light on the late phases of the HIV-1 cycle and reveal some of its macrophage specific features.


Managed care and the diffusion of endoscopy in fee-for-service Medicare.
To determine whether Medicare managed care penetration impacted the diffusion of endoscopy services (sigmoidoscopy, colonoscopy) among the fee-for-service (FFS) Medicare population during 2001-2006. We model utilization rates for colonoscopy or sigmoidoscopy as impacted by both market supply and demand factors. We use spatial regression to perform ecological analysis of county-area utilization rates over two time intervals (2001-2003, 2004-2006) following Medicare benefits expansion in 2001 to cover colonoscopy for persons of average risk. We examine each technology in separate cross-sectional regressions estimated over early and later periods to assess differential effects on diffusion over time. We discuss selection factors in managed care markets and how failure to control perfectly for market selection might impact our managed care spillover estimates. Areas with worse socioeconomic conditions have lower utilization rates, especially for colonoscopy. Holding constant statistically the socioeconomic factors, we find that managed care spillover effects onto FFS Medicare utilization rates are negative for colonoscopy and positive for sigmoidoscopy. The spatial lag estimates are conservative and interpreted as a lower bound on true effects. Our findings suggest that managed care presence fostered persistence of the older technology during a time when it was rapidly being replaced by the newer technology.


A Fungal Arrestin Protein Contributes to Cell Cycle Progression and Pathogenesis.
Arrestins, a structurally specialized and functionally diverse group of proteins, are central regulators of adaptive cellular responses in eukaryotes. Previous studies on fungal arrestins have demonstrated their capacity to modulate diverse cellular processes through their adaptor functions, facilitating the localization and function of other proteins. However, the mechanisms by which arrestin-regulated processes are involved in fungal virulence remain unexplored. We have identified a small family of four arrestins, Ali1, Ali2, Ali3, and Ali4, in the human fungal pathogen Cryptococcus neoformans Using complementary microscopy, proteomic, and reverse genetics techniques, we have defined a role for Ali1 as a novel contributor to cytokinesis, a fundamental cell cycle-associated process. We observed that Ali1 strongly interacts with proteins involved in lipid synthesis, and that ali1Δ mutant phenotypes are rescued by supplementation with lipid precursors that are used to build cellular membranes. From these data, we hypothesize that Ali1 contributes to cytokinesis by serving as an adaptor protein, facilitating the localization of enzymes that modify the plasma membrane during cell division, specifically the fatty acid synthases Fas1 and Fas2. Finally, we assessed the contributions of the C. neoformans arrestin family to virulence to better understand the mechanisms by which arrestin-regulated adaptive cellular responses influence fungal infection. We observed that the C. neoformans arrestin family contributes to virulence, and that the individual arrestin proteins likely fulfill distinct functions that are important for disease progression.IMPORTANCE To survive under unpredictable conditions, all organisms must adapt to stressors by regulating adaptive cellular responses. Arrestin proteins are conserved regulators of adaptive cellular responses in eukaryotes. Studies that have been limited to mammals and model fungi have demonstrated that the disruption of arrestin-regulated pathways is detrimental for viability. The human fungal pathogen Cryptococcus neoformans causes more than 180,000 infection-related deaths annually, especially among immunocompromised patients. In addition to being genetically tractable, C. neoformans has a small arrestin family of four members, lending itself to a comprehensive characterization of its arrestin family. This study serves as a functional analysis of arrestins in a pathogen, particularly in the context of fungal fitness and virulence. We investigate the functions of one arrestin protein, Ali1, and define its novel contributions to cytokinesis. We additionally explore the virulence contributions of the C. neoformans arrestin family and find that they contribute to disease establishment and progression.


Observation of pressure wave generated by focusing a femtosecond laser pulse inside a glass.
The pressure (or stress) wave generated by focusing a femtosecond laser pulse inside a glass has been considered one of the important factors in determining structures created in the laser focal region. In this paper, a method of the transient lens (TrL) analysis was proposed to characterize the pressure wave. Experimentally, the TrL signal exhibited damping oscillation within 2 ns. Simulations of the TrL signal showed that the shape of the oscillating signal depended on the width and amplitude of the pressure wave. Comparing the observed TrL signal with the simulated one, we estimated these properties of the pressure wave generated after femtosecond laser focusing inside a soda-lime glass.


Increased frontal and paralimbic activation following ayahuasca, the pan-Amazonian inebriant.
Ayahuasca is a South American psychoactive plant tea which contains the serotonergic psychedelic N,N-dimethyltryptamine (DMT) and monoamine-oxidase inhibitors that render DMT orally active. Previous investigations with ayahuasca have highlighted a psychotropic effect profile characterized by enhanced introspective attention, with individuals reporting altered somatic perceptions and intense emotional modifications, frequently accompanied by visual imagery. Despite recent advances in the study of ayahuasca pharmacology, the neural correlates of acute ayahuasca intoxication remain largely unknown. To investigate the effects of ayahuasca administration on regional cerebral blood flow. Fifteen male volunteers with prior experience in the use of psychedelics received a single oral dose of encapsulated freeze-dried ayahuasca equivalent to 1.0 mg DMT/kg body weight and a placebo in a randomized double-blind clinical trial. Regional cerebral blood flow was measured 100-110 min after drug administration by means of single photon emission tomography (SPECT). Ayahuasca administration led to significant activation of frontal and paralimbic brain regions. Increased blood perfusion was observed bilaterally in the anterior insula, with greater intensity in the right hemisphere, and in the anterior cingulate/frontomedial cortex of the right hemisphere, areas previously implicated in somatic awareness, subjective feeling states, and emotional arousal. Additional increases were observed in the left amygdala/parahippocampal gyrus, a structure also involved in emotional arousal. The present results suggest that ayahuasca interacts with neural systems that are central to interoception and emotional processing and point to a modulatory role of serotonergic neurotransmission in these processes.


Are dentists interested in the oral-systemic disease connection? A qualitative study of an online community of 450 practitioners.
Dentists in the US see an increasing number of patients with systemic conditions. These patients are challenging to care for when the relationship between oral and systemic disease is not well understood. The prevalence of professional isolation exacerbates the problem due to the difficulty in finding expert advice or peer support. This study aims to identify whether dentists discuss the oral-systemic connection and what aspects they discuss; to understand their perceptions of and attitudes toward the connection; and to determine what information they need to treat patients with systemic conditions. We retrieved 14,576 messages posted to the Internet Dental Forum from April 2008 to May 2009. Using natural language processing and human classification, we identified substantive phrases and keywords and used them to retrieve 141messages on the oral-systemic connection. We then conducted coding and thematic analysis to identify recurring themes on the topic. Dentists discuss a variety of topics on oral diseases and systemic health, with the association between periodontal and systemic diseases, the effect of dental materials or procedures on general health, and the impact of oral-systemic connection on practice behaviors as the leading topics. They also disseminate and share research findings on oral and systemic health with colleagues online. However, dentists are very cautious about the nature of the oral-systemic linkage that may not be causal. Nonetheless, they embrace the positive association as a motivating point for patients in practice. When treating patients with systemic conditions, dentists enquire about the cause of less common dental diseases potentially in relation to medical conditions in one-third of the cases and in half of the cases seek clinical guidelines and evidence-based interventions on treating dental diseases with established association with systemic conditions. Dentists' unmet information needs call for more research into the association between less studied dental conditions and systemic diseases, and more actionable clinical guidelines for well-researched disease connections. To improve dissemination and foster behavioral change, it is imperative to understand what information clinicians need and in which situations. Leveraging peer influence via social media could be a useful strategy to achieve the goal.


Self-Reported Reasons for Smoking: Predicting Abstinence and Implications for Smoking Cessation Treatments Among Those With a Psychotic Disorder.
People living with a psychotic illness have higher rates of cigarette smoking and face unique barriers to quitting compared to the general population. We examined whether self-reported reasons for smoking are useful predictors of successful quit attempts among people with psychosis. As part of a randomized controlled trial addressing smoking and cardiovascular disease risk behaviors among people with psychosis, self-reported reasons for smoking were assessed at baseline (n = 235), 15 weeks (n = 151), and 12 months (n = 139). Three factors from the Reasons for Smoking Questionnaire (Coping, Physiological, and Stimulation/Activation) were entered into a model to predict short- and long-term abstinence. The relationship between these factors and mental health symptoms were also assessed. Participants scoring higher on the Stimulation/Activation factor (control of weight, enjoyment, concentration, and "peps me up") at baseline were just less than half as likely to be abstinent at 15 weeks. Female participants were five times more likely to abstinent at 15 weeks, and those with a higher global functioning at baseline were 5% more likely to be abstinent. There was a positive correlation between changes over time in the Stimulation/Activation factor from baseline to 12-month follow-up and the Brief Psychiatric Rating Scale total score at 12-month follow-up. This indicates that increasingly higher endorsement of the factor was associated with more psychological symptoms. There was also a negative correlation between the change over time in the Stimulation/Activation factor and global functioning at 12 months, indicating that increasingly higher endorsement of the factor led to lower global assessment of functioning. The Stimulation/Activation factor may be particularly important to assess and address among smokers with psychosis. It is recommended that further research use the Reasons for Smoking Questionnaire among smokers with psychosis as a clinical tool to identify specific quit barriers. Further research into why females have higher smoking cessation rates in the short term and relapse prevention interventions seem worthy of further investigation.


Use of myocardial perfusion imaging and estimation of associated radiation doses in Germany from 2005 to 2012.
For several years the Working Group Cardiovascular Nuclear Medicine of the German Society of Nuclear Medicine has been performing a regular survey to obtain information on technique, utilization and development of myocardial perfusion scintigraphy (MPS). Currently, data of six surveys from 2005 to 2012 are available. The aim of this paper is to deliver a general and comprehensive overview of all surveys documenting the course of patient doses over time and the development of the method. A one-page questionnaire with number of MPS patients, number of stress and rest MPS, referral structure and several technical issues was sent to all centres performing MPS in Germany and evaluated. With the data on protocol utilization, effective MPS patient doses were estimated. MPS per million population (pmp) varied between 2,380 and 2,770. In 2012, MPS pmp showed a slight increase for the first time. From 2005 to 2009 the angiography to MPS ratio increased from 3.4 to 4.4, and the revascularization to MPS ratio decreased from 0.66 to 0.53. In 2012, both indices demonstrated an opposite trend for the first time (4.1 and 0.55). A total of 108 centres participated in all surveys. They showed an increase in MPS patients of 4.0 % over the reporting period. In 2012, more than 50 % of the centres experienced no change or an increase in MPS numbers. The leading single competitor was MRI, followed by angiography and stress echocardiography. (201)Tl studies have decreased since 2005 from 20 to 5 %. (99m)Tc MPS studies showed a mild increase in 2-day protocols. In 2012, the average effective dose per patient was estimated at 7.4 mSv. Due to the decreasing use of (201)Tl, a mild decline over the observation period can be documented. Dynamic exercise stress was the most common stress test and adenosine the leading pharmacological stress agent, with a growing percentage. In 2012, the regadenoson percentage was 9 %. Gated single photon emission computed tomography (SPECT) noted an increasing acceptance with >70 % in 2012. The segmental scoring of perfusion studies had a low acceptance. Ambulatory care cardiologists represented the major referral group. Germany has a moderate to moderate-high MPS utilization rate. Nevertheless, coronary artery disease (CAD) diagnosis and disease management are dominated by angiography. The survey data reveal a positive trend in MPS and a decrease in average patient dose reflecting good practice with guideline adherence, the implementation of technical improvements and success in training.


Model selection for the North American Breeding Bird Survey.
The North American Breeding Bird Survey (BBS) provides data that can be used in complex, multiscale analyses of population change, while controlling for scale-specific nuisance factors. Many alternative models can be fit to the data, but most model selection procedures are not appropriate for hierarchical models. Leave-one-out cross-validation (LOOCV), in which relative model fit is assessed by omitting an observation and assessing the prediction of a model fit using the remainder of the data, provides a reasonable approach for assessing models, but is time consuming and not feasible to apply for all observations in large data sets. We report the first large-scale formal model selection for BBS data, applying LOOCV to stratified random samples of observations from BBS data. Our results are for 548 species of North American birds, comparing the fit of four alternative models that differ in year effect structures and in descriptions of extra-Poisson overdispersion. We use a hierarchical model among species to evaluate posterior probabilities that models are best for individual species. Models in which differences in year effects are conditionally independent (D models) were generally favored over models in which year effects are modeled by a slope parameter and a random year effect (S models), and models in which extra-Poisson overdispersion effects are independent and t-distributed (H models) tended to be favored over models where overdispersion was independent and normally distributed. Our conclusions lead us to recommend a change from the conventional S model to D and H models for the vast majority of species (544/548). Comparison of estimated population trends based on the favored model relative to the S model currently used for BBS summaries indicates no consistent differences in estimated trends. Of the 18 species that showed large differences in estimated trends between models, estimated trends from the default S model were more extreme, reflecting the influence of the slope parameter in that model for species that are undergoing large population changes. WAIC, a computationally simpler alternative to LOOCV, does not appear to be a reliable alternative to LOOCV.


Excess thermopower and the theory of thermopower waves.
Self-propagating exothermic chemical reactions can generate electrical pulses when guided along a conductive conduit such as a carbon nanotube. However, these thermopower waves are not described by an existing theory to explain the origin of power generation or why its magnitude exceeds the predictions of the Seebeck effect. In this work, we present a quantitative theory that describes the electrical dynamics of thermopower waves, showing that they produce an excess thermopower additive to the Seebeck prediction. Using synchronized, high-speed thermal, voltage, and wave velocity measurements, we link the additional power to the chemical potential gradient created by chemical reaction (up to 100 mV for picramide and sodium azide on carbon nanotubes). This theory accounts for the waves' unipolar voltage, their ability to propagate on good thermal conductors, and their high power, which is up to 120% larger than conventional thermopower from a fiber of all-semiconducting SWNTs. These results underscore the potential to exceed conventional figures of merit for thermoelectricity and allow us to bound the maximum power and efficiency attainable for such systems.


A comparison study of antidepressants and structured intensive group psychotherapy in the treatment of bulimia nervosa.
Previous research on the treatment of outpatients with bulimia nervosa has focused on two treatment strategies: (1) drug therapy, primarily using tricyclic antidepressants, and (2) psychotherapy, often employing behavioral and cognitive behavioral techniques. We report here the short-term treatment outcome of a 12-week comparison trial of bulimic outpatients who were randomly assigned to one of four treatment cells: (1) imipramine hydrochloride treatment, (2) placebo treatment, (3) imipramine treatment combined with intensive group psychotherapy, and (4) placebo treatment combined with intensive group psychotherapy. All three active treatment cells resulted in significant reductions in target-eating behaviors and in a significant improvement in mood relative to placebo treatment. However, the results also suggested that the amount of improvement obtained with the intensive group psychotherapy component was superior to that obtained with antidepressant treatment alone. The addition of antidepressant treatment to the intensive group psychotherapy component did not significantly improve outcome over intensive group psychotherapy combined with placebo treatment in terms of eating behavior, but did result in more improvement in the symptoms of depression and anxiety.


Persistence of Borrelia burgdorferi following antibiotic treatment in mice.
The effectiveness of antibiotic treatment was examined in a mouse model of Lyme borreliosis. Mice were treated with ceftriaxone or saline solution for 1 month, commencing during the early (3 weeks) or chronic (4 months) stages of infection with Borrelia burgdorferi. Tissues from mice were tested for infection by culture, PCR, xenodiagnosis, and transplantation of allografts at 1 and 3 months after completion of treatment. In addition, tissues were examined for the presence of spirochetes by immunohistochemistry. In contrast to saline solution-treated mice, mice treated with antibiotic were consistently culture negative, but tissues from some of the mice remained PCR positive, and spirochetes could be visualized in collagen-rich tissues. Furthermore, when some of the antibiotic-treated mice were fed on by Ixodes scapularis ticks (xenodiagnosis), spirochetes were acquired by the ticks, as determined based upon PCR results, and ticks from those cohorts transmitted spirochetes to naïve SCID mice, which became PCR positive but culture negative. Results indicated that following antibiotic treatment, mice remained infected with nondividing but infectious spirochetes, particularly when antibiotic treatment was commenced during the chronic stage of infection.


De novo assembly and characterization of the transcriptome of seagrass Zostera marina using Illumina paired-end sequencing.
The seagrass Zostera marina is a monocotyledonous angiosperm belonging to a polyphyletic group of plants that can live submerged in marine habitats. Zostera marina L. is one of the most common seagrasses and is considered a cornerstone of marine plant molecular ecology research and comparative studies. However, the mechanisms underlying its adaptation to the marine environment still remain poorly understood due to limited transcriptomic and genomic data. Here we explored the transcriptome of Z. marina leaves under different environmental conditions using Illumina paired-end sequencing. Approximately 55 million sequencing reads were obtained, representing 58,457 transcripts that correspond to 24,216 unigenes. A total of 14,389 (59.41%) unigenes were annotated by blast searches against the NCBI non-redundant protein database. 45.18% and 46.91% of the unigenes had significant similarity with proteins in the Swiss-Prot database and Pfam database, respectively. Among these, 13,897 unigenes were assigned to 57 Gene Ontology (GO) terms and 4,745 unigenes were identified and mapped to 233 pathways via functional annotation against the Kyoto Encyclopedia of Genes and Genomes pathway database (KEGG). We compared the orthologous gene family of the Z. marina transcriptome to Oryza sativa and Pyropia yezoensis and 11,667 orthologous gene families are specific to Z. marina. Furthermore, we identified the photoreceptors sensing red/far-red light and blue light. Also, we identified a large number of genes that are involved in ion transporters and channels including Na+ efflux, K+ uptake, Cl- channels, and H+ pumping. Our study contains an extensive sequencing and gene-annotation analysis of Z. marina. This information represents a genetic resource for the discovery of genes related to light sensing and salt tolerance in this species. Our transcriptome can be further utilized in future studies on molecular adaptation to abiotic stress in Z. marina.


Anesthesia plus surgery in neonatal period impairs preference for social novelty in mice at the juvenile age.
Anesthetic sevoflurane could induce neurotoxicity in developing brain and cause adverse neurobehavioral outcomes in mice, including inattention, social interaction deficit, and learning and memory impairment. However, there is less data on the effect of anesthesia plus surgery on social interaction behavior. Therefore, we investigated whether the combination of anesthesia and surgical stimulation could induce behavioral and biochemical changes in mice. Firstly, the six-day-old mice were received either 3% sevoflurane anesthesia or abdominal surgery under sevoflurane anesthesia. Then, these mice were scheduled to social interaction test in three-chambered social paradigm at one-month-old. In addition, the brain tissues of neonatal mice were harvested at 24 h after treatment, for measuring the levels of OXTR and NMDAR1 in Western blot analysis. We found that neonatal anesthesia with sevoflurane in a clinically-relevant dosage could not induce social interaction deficit. Nevertheless, anesthesia plus surgery was able to impair preference for social novelty in mice. Moreover, anesthesia plus surgery decreased the levels of OXTR in hippocampus and cortex of mice, as well as NMDAR1 in hippocampus. Collectively, these results suggested that anesthesia plus surgery could impair social novelty preference, but not sociability in mice, and that social memory might be more vulnerable than social affiliation in biological property. Furthermore, reduction in the levels of cortex OXTR and hippocampus NMDAR1 could be associated with social recognition memory in mice.


Association of Dietary Inflammatory Potential With Colorectal Cancer Risk in Men and Women.
Inflammation is important in colorectal cancer development. Diet modulates inflammation and may thus be a crucial modifiable factor in colorectal cancer prevention. To examine whether proinflammatory diets are associated with increased colorectal cancer risk by using an empirical dietary inflammatory pattern (EDIP) score based on a weighted sum of 18 food groups that characterizes dietary inflammatory potential based on circulating levels of inflammation biomarkers. Cohort study of 46 804 men (Health Professionals Follow-up Study: 1986-2012) and 74 246 women (Nurses' Health Study: 1984-2012) followed for 26 years to examine associations between EDIP scores and colorectal cancer risk using Cox regression. We also examined associations in categories of alcohol intake and body weight. Data analysis began January 17, 2017, and was completed August 9, 2017. EDIP scores calculated from food frequency questionnaires administered every 4 years. Incident colorectal cancer. We documented 2699 incident colorectal cancer cases over 2 571 831 person-years of follow-up. Compared with participants in the lowest EDIP quintile (Q) who had a colorectal cancer incidence rate (per 100 000 person-years) of 113 (men) and 80 (women), those in the highest Q had an incidence rate of 151 (men) and 92 (women), leading to an unadjusted rate difference of 38 and 12 more colorectal cancer cases, respectively, among those consuming highly proinflammatory diets. Comparing participants in the highest vs lowest EDIP Qs in multivariable-adjusted analyses, higher EDIP scores were associated with 44% (men: hazard ratio [HR], 1.44; 95% CI, 1.19-1.74; P < .001 for trend), 22% (women: HR, 1.22; 95% CI, 1.02-1.45; P = .007 for trend), and 32% (men and women: pooled HR, 1.32; 95% CI, 1.12-1.55; P < .001 for trend) higher risk of developing colorectal cancer. In both men and women, associations were observed in all anatomic subsites except for the rectum in women. In subgroups (P ≤ .02 for all interactions), associations differed by alcohol intake level, with stronger associations among men (Q5 vs Q1 HR, 1.62; 95% CI, 1.05-2.49; P = .002 for trend) and women (Q5 vs Q1 HR, 1.33; 95% CI, 0.97-1.81; P = .03 for trend) not consuming alcohol; and by body weight, with stronger associations among overweight/obese men (Q5 vs Q1 HR, 1.48; 95% CI, 1.12-1.94; P = .008 for trend) and lean women (Q5 vs Q1 HR, 1.31; 95% CI, 0.99-1.74; P = .01 for trend). Findings suggest that inflammation is a potential mechanism linking dietary patterns and colorectal cancer development. Interventions to reduce the adverse role of proinflammatory diets may be more effective among overweight/obese men and lean women or men and women who do not consume alcohol.


Management of postoperative infections after spinal instrumentation.
The authors retrospectively reviewed 452 consecutively treated patients who underwent a spinal instrumentation procedure at a single institution to establish which patients and which surgical approaches might be associated with an increased risk of developing deep wound infections and to determine the efficacy with which the institution's current treatment strategy eradicates these infections. Wound infections occurred in 17 patients (10 men and seven women) with spinal instrumentation (incidence 3.8%). All infections occurred after posterior spinal instrumentation procedures (7.2%); there were no infections after anterior instrumentation procedures regardless of the level. Each patient was assigned an infection risk factor (RF) score depending on the number of RFs identified in an individual patient preoperatively. The mean RF score of patients who developed infections was 2.18, whereas the mean RF score for a procedure-matched, infection-free control group was 0.71. The mean number of days from surgery to clinical presentation was 27.6 days (range 4-120 days), and the mean increase in hospitalization time for the subset of patients who developed infections was 16.6 days. The most common organism isolated from wound cultures was Staphylococcus aureus (nine of 17 cases). Of the 17 patients, five had infections involving multiple organisms. All patients were infection free at a minimum of 8 months follow-up review. The current treatment regimen advocated at this institution consists of operative debridement of the infected wound, a course of intravenous followed by oral antibiotic medications, insertion of an antibiotic-containing irrigation-suction system for a mean of 5 days, and maintenance of the instrumentation system within the infected wound.


Total Synthesis of Verruculogen and Fumitremorgin A Enabled by Ligand-Controlled C-H Borylation.
Verruculogen and fumitremorgin A are bioactive alkaloids that contain a unique eight-membered endoperoxide. Although related natural products such as fumitremorgins B and C have been previously synthesized, we report the first synthesis of the more complex, endoperoxide-containing members of this family. A concise route to verruculogen and fumitremorgin A relied not only on a hydroperoxide/indole hemiaminal cyclization, but also on the ability to access the seemingly simple starting material, 6-methoxytryptophan. An iridium-catalyzed C-H borylation/Chan-Lam procedure guided by an N-TIPS group enabled the conversion of a tryptophan derivative into a 6-methoxytryptophan derivative, proving to be a general way to functionalize the C6 position of an N,C3-disubstituted indole for the synthesis of indole-containing natural products and pharmaceuticals.


Adaptive optics for optimization of image resolution.
Adaptive optics can be used to improve the quality of optical imaging instruments otherwise limited in resolution by atmospheric turbulence. To achieve a given level of resolution improvement at the lowest cost, design of adaptive mirrors must be carefully optimized. We have calculated the mean value of the optical transfer function (OTF) of an instrument corrected by adaptive optics using the OTF as a criterion for resolution optimization and describing perturbations through their phase structure function. A fourparameter numerical program has been written to compute the OTF. Assuming that the optics diameter and the perturbation Fried's parameter are known, it then becomes possible to optimize the system by a proper choice of the number of actuators and of the influence diameter, a parameter which characterizes the size of the required corrections.


Self-rated health (SRH) in young people and causes of death and mortality in young adulthood. A prospective registry-based Norwegian HUNT-study.
Self-rated health (SRH), which is frequently used in epidemiological research, has consistently been shown to be a strong predictor of morbidity and mortality, even after controlling for demographic, social and medical risk factors. However, less is known about the relationship between SRH and all-cause and cause-specific mortality in young adulthood. To investigate SRH in young people (13-35 years-old) as a predictor of all-cause mortality in young adulthood (deaths before age 54) and examine the associated causes of death. We used data from two large population-based cohort studies (N = 23,679): Young-HUNT1 (1995-1997, persons 13 to 20 years old, participation rate = 90%) and HUNT2 (1995-1997, persons 20 to 35 years old, participation rate = 70%). These data were linked to the Norwegian Cause of Death Registry up to 2014, and 247 deaths were identified. Other predictors we examined included age, gender, baseline smoking, physical activity and physical and mental disability. Participants reporting 'not so good'/'poor' SRH had approximately twice the risk of death compared to those reporting 'good' or 'very good' SRH at baseline. The association between low SRH and risk of death was attenuated when the models were adjusted for other predictors, but remained statistically significant. The causes of death differed somewhat between SRH levels. Most of the deaths for people reporting 'very good' SRH at baseline were mostly due to neoplasms (34%) and other external causes (30%). The causes of death were more varied for people reporting 'not so good'/'poor' SRH, with suicide (23%), other external causes (21%) and other/unknown causes of death (17%) being the most frequent causes. SRH predicts all-cause mortality in young adulthood, with poor SRH being associated with death in young adulthood. The findings also indicate different causes of death for different SRH. This knowledge is important for identifying groups at risk for later disease, which can potentially be used to prevent morbidity in the adult population.


Efficient patch-based approach for compressive depth imaging.
We present efficient camera hardware and algorithms to capture images with extended depth of field. The camera moves its focal plane via a liquid lens and modulates the scene at different focal planes by shifting a fixed binary mask, with synchronization achieved by using the same triangular wave to control the focal plane and the pizeoelectronic translator that shifts the mask. Efficient algorithms are developed to reconstruct the all-in-focus image and the depth map from a single coded exposure, and various sparsity priors are investigated to enhance the reconstruction, including group sparsity, tree structure, and dictionary learning. The algorithms naturally admit a parallel computational structure due to the independent patch-level operations. Experimental results on both simulation and real datasets demonstrate the efficacy of the new hardware and the inversion algorithms.


A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk.
Whether apolipoprotein B (apoB) or non-high-density lipoprotein cholesterol (HDL-C) adds to the predictive power of low-density lipoprotein cholesterol (LDL-C) for cardiovascular risk remains controversial. This meta-analysis is based on all the published epidemiological studies that contained estimates of the relative risks of non-HDL-C and apoB of fatal or nonfatal ischemic cardiovascular events. Twelve independent reports, including 233 455 subjects and 22 950 events, were analyzed. All published risk estimates were converted to standardized relative risk ratios (RRRs) and analyzed by quantitative meta-analysis using a random-effects model. Whether analyzed individually or in head-to-head comparisons, apoB was the most potent marker of cardiovascular risk (RRR, 1.43; 95% CI, 1.35 to 1.51), LDL-C was the least (RRR, 1.25; 95% CI, 1.18 to 1.33), and non-HDL-C was intermediate (RRR, 1.34; 95% CI, 1.24 to 1.44). The overall comparisons of the within-study differences showed that apoB RRR was 5.7%>non-HDL-C (P<0.001) and 12.0%>LDL-C (P<0.0001) and that non-HDL-C RRR was 5.0%>LDL-C (P=0.017). Only HDL-C accounted for any substantial portion of the variance of the results among the studies. We calculated the number of clinical events prevented by a high-risk treatment regimen of all those >70th percentile of the US adult population using each of the 3 markers. Over a 10-year period, a non-HDL-C strategy would prevent 300 000 more events than an LDL-C strategy, whereas an apoB strategy would prevent 500 000 more events than a non-HDL-C strategy. These results further validate the value of apoB in clinical care.


The possible role of cranio-cervical trauma and abnormal CSF hydrodynamics in the genesis of multiple sclerosis.
UPRIGHT Multi-Position MR scanning has uncovered a key set of new observations regarding Multiple Sclerosis (MS), which observations are likely to provide a new understanding of the origin of MS. The new findings may also lead to new forms of treatment for MS. The UPRIGHT MRI has demonstrated pronounced anatomic pathology of the cervical spine in five of the MS patients studied and definitive cervical pathology in the other three. The pathology was the result of prior head and neck trauma. All eight MS patients entered the study on a first come first serve basis without priority, and all but one were found to have a history of serious prior cervical trauma which resulted in significant cervical pathology. The cervical pathology was visualized by UPRIGHT MRI. Upright cerebrospinal fluid (CSF) cinematography and quantitative measurements of CSF velocity, CSF flow and CSF pressure gradients in the upright patient revealed that significant obstructions to CSF flow were present in all MS patients. The obstructions are believed to be responsible for CSF "leakages" of CSF from the ventricles into the surrounding brain parenchyma which "leakages" can be the source of the MS lesions in the brain that give rise to MS symptomatology. The CSF flow obstructions are believed to result in increases in intracranial pressure (ICP) that generate "leakages" of the CSF into the surrounding brain parenchyma. In all but one MS patient, anatomic pathologies were found to be more severe in the upright position than in the recumbent position. Similarly, CSF flow abnormalities were found to be more severe in the upright position than in the recumbent position in all but one MS patient. Images of the MS patient anatomic pathologies and CSF flow abnormalities are provided with comparison images from normal examinees in Figures 1-15.


Implementation of case management in long-term conditions in England: survey and case studies.
Our aim was to describe the current provision of case management arrangements in primary care for people with long-term conditions in England and identify the extent and nature of self-care support services within it. Cross-sectional survey of primary care trusts (PCTs) in England and four case studies using semi-structured interviews and focus groups. Services were predominantly nurse-led, typically by community matrons, and delivered on a geographical basis. Often multiple arrangements existed within a PCT but integration of services with local authority adult social care was not widespread. A range of self-care support services were utilized and often tuition was provided by case managers to patients in their own homes. Assessment, care coordination and direct support to patients were the principal tasks. Often care plans were limited to primary care services and did not include service costings. Links with nurse-led services within PCTs were evident but operational links with adult social care were poorly developed. This is consistent with previous research relating to the introduction of care management in social services in England which also resulted in a plethora of organizational arrangements. Case management for patients with long-term conditions is at an early stage of development. Effective links with a range of local services are required if care plans are going to be comprehensive.


Understanding factors influencing the adoption of mHealth by the elderly: An extension of the UTAUT model.
mHealth (mobile health) services are becoming an increasingly important form of information and communication technology (ICT) enabled delivery for healthcare, especially in low-resource environments such as developing countries like Bangladesh. Despite widespread adoption of mobile phones and the acknowledged potential of using them to improve healthcare services, the adoption and acceptance of this technology among the elderly is significantly low. However, little research has been done to draw any systematic study of the elderly's intention to adopt mHealth services. The aim of this study was to develop a theoretical model based on the Unified Theory of Acceptance and Use of Technology (UTAUT) and then empirically test it for determining the key factors influencing elderly users' intention to adopt and use the mHealth services. A face-to-face structured questionnaire survey method was used to collect data from nearly 300 participants of age 60 years and above from the capital city of Bangladesh. The data were analyzed using the Partial Least Squares (PLS) method, a statistical analysis technique based upon Structural Equation Modeling (SEM). The study determined that performance expectancy, effort expectancy, social influence, technology anxiety, and resistance to change (p<0.05) had a significant impact on the users' behavioral intention to adopt mHealth services. The study, however, revealed no significant relation between the facilitating condition and the users' behavioral intention to use the mHealth services (p>0.05). This study confirms the applicability of UTAUT model in the context of mHealth services among the elderly in developing countries like Bangladesh. It provides valuable information for mHealth service providers and policy makers in understanding the adoption challenges and the issues and also provides practical guidance for the successful implementation of mHealth services. Additionally the empirical findings identify implications related to the design and development of mHealth services that influence potential users. Furthermore, due to a generic approach, the findings of this study could be easily modified to assist other developing countries in the planning and up-take of mHealth services.


Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study.
FTY720, a novel immunomodulator, displays potent immunosuppressive activity in a variety of preclinical transplant models. This study examined the safety, pharmacodynamics, and pharmacokinetics of multiple doses of FTY720 in stable renal transplant patients. This randomized, multicenter, double-blind, placebo-controlled, phase I study included adults who had been maintained on a regimen of cyclosporine A (CsA) microemulsion and prednisone (or its equivalent) for at least 1 year after renal transplantation. Patients received once-daily doses of 0.125, 0.25, 0.5, 1.0, 2.5, or 5.0 mg FTY720, or placebo for 28 days. After completion of study drug administration, the patients were monitored until day 56 by serial laboratory tests, clinical examinations, and recording of adverse events. The study includes 76 treatment courses (61 FTY720 and 15 placebo), with 65 patients enrolled once and 11 reenrolled. FTY720 doses greater than or equal to 1.0 mg/day produced a significant reduction in peripheral blood lymphocyte count by up to 85%, which reversed within 3 days after discontinuation of study medication. Compared with placebo-treated patients, FTY720 subjects did not show a major increase in adverse events or a change in renal function. Pharmacokinetic measurements revealed that FTY720 displayed linear relations of doses and concentrations over a wide range, but had no effect on CsA exposure. At doses up to 5.0 mg/day for 28 days, stable renal transplant patients treated with FTY720 in combination with CsA and prednisone displayed a dose-dependent, reversible decline in peripheral blood lymphocytes without an enhanced incidence of collateral toxicities, except possibly bradycardia.


"A morning since eight of just pure grill": a multischool qualitative study of student abuse.
Previous medical student abuse research employed quantitative surveys that failed to explore factors thought to contribute to abuse and students' actions in the face of abuse. This study examined medical student abuse narratives to identify types of perceived abuse, factors cited by students as contributing to abuse, and students' actions at the time of abuse. A qualitative design was adopted employing 22 individual and 32 group interviews to elicit narratives of professionalism dilemmas from 200 medical students at two 5-year undergraduate programs and one 4-year graduate entry program (England, Wales, and Australia) between 2007 and 2009. Thematic analysis of abuse narratives was conducted. Of 833 professionalism dilemma narratives, 86 (10%) involved perceived medical student abuse. Within these narratives, students reported mostly covert, status-related abuse, direct verbal abuse, and sexual harassment and discrimination. Some narrators described multiple factors contributing to abuse (individual, work, and/or organization); most cited factors focusing on individuals. Despite the abuse typically recounted with negative emotion, few participants reported resisting at the time of abuse by challenging or reporting the perpetrator. Participants gave a variety of reasons for this inaction (e.g., anxiety about receiving bad marks from the perpetrator) and for resisting (e.g., the abuse was affecting their education negatively). Although narratives focused predominantly on individual factors contributing to abuse and responses to abuse, educators should focus on the dynamic interplay between individual and organizational factors to combat abuse. Several opportunities to mitigate this continuing blight on the conscience of the profession are described.


Validation of Neutrophil Count as An Algorithm-Based Predictive Factor of Progression-Free Survival in Patients with Metastatic Soft Tissue Sarcomas Treated with Trabectedin.
Introduction: Based on a mathematical model of trabectedin-induced neutropenia, we assessed the predictive value of absolute neutrophil count (ANC) on progression-free survival (PFS) in an independent validation cohort of patients treated with trabectedin. Methods: We collected data from 87 patients in two expert centers who received at least two cycles of trabectedin for soft tissue sarcomas (STS) treatment. Correlations between ANC, patients' characteristics, and survival were assessed, and a multivariate model including tumor grade, performance status, ANC, and hemoglobin level was developed. Results: Therapeutic ANC ≥ 7.5 G/L level was associated with shorter PFS: 3.22 months (95% confidence interval (CI), 1.57⁻4.87) in patients with ANC ≥ 7.5 G/L vs. 5.78 months (95% CI, 3.95⁻7.61) in patients with ANC < 7.5 G/L (p = 0.009). Age, primary localization, lung metastases, dose reduction, hemoglobin, and albumin rates were also associated with PFS. In multivariate analysis, ANC ≥ 7.5 G/L was independently associated with poor PFS and overall survival. Conclusion: We validated increased pre-therapeutic ANC as a predictive factor of short PFS in patients starting trabectedin for STS. ANC appears to have an impact on survival rates and may be used as a decision-making tool for personalizing second-line strategies in patients with metastatic STS.


Tetrahydrochromenoimidazoles as potassium-competitive acid blockers (P-CABs): structure-activity relationship of their antisecretory properties and their affinity toward the hERG channel.
Potassium-competitive acid blockers (P-CABs) constitute a new therapeutic option for the treatment of acid-related diseases that are widespread and constitute a significant economical burden. Enantiomerically pure tetrahydrochromenoimidazoles were prepared using the readily available candidate 4 (BYK 405879) as starting material or the Noyori asymmetric reduction of ketones as key reaction. A comprehensive SAR regarding the influence of the 5-carboxamide and the 8-aryl residue on in vitro activity, acid-suppression in the Ghosh Schild rat, and affinity toward the hERG channel was established. In addition, efficacy and duration of the antisecretory action was examined for the most promising target compounds by 24 h pH-metry in the fistula dog and a significantly different SAR was observed as compared to the Ghosh Schild rat. Several tetrahydrochromenoimidazoles were identified that possessed a comparable profile as the candidate 4.