Late seromas after breast implants: theory and practice.
Late seromas surrounding breast implants are becoming an increasingly important issue in breast surgery. The authors report their experience with late seromas and describe their previous management options. A multicenter retrospective review of patients who developed late seromas (clinically presenting seromas without evidence of overt or documented infection more than 1 year after implant operation) was performed. Management, surgical technique, outcomes, complications, culture findings, and cytology results were recorded. Between 2005 and 2010, 28 late seromas were identified in 25 patients. The average interval from the patient's last surgery to seroma onset was 4.7 years; 27 of 28 breasts (96 percent) had a Biocell textured device in place at the time of seroma development. The late seromas in the series were managed as follows: 15 (53.6 percent) by complete capsulectomy, seroma drainage, and new implant placement; three (10.7 percent) by seroma drainage and new implant placement but without capsulectomy; two (7.1 percent) by complete capsulectomy and seroma drainage but without implant replacement; five (17.9 percent) by only ultrasound-guided seroma drainage without the need for surgical intervention; and three (10.7 percent) by antibiotic therapy alone. All cultures and cytology studies were negative for malignancy or infection; 27 of 28 seromas (96 percent) were treated successfully by one of the described approaches. Biocell textured implants were more likely to be associated with late seromas than were smooth shell implants. The overwhelming majority of late seromas appear to be idiopathic, without clear evidence of infection or malignancy. A graduated approach, including several different management strategies, was used to successfully manage these patients. Therapeutic, IV.


Treatment strategies in primary vitreoretinal lymphoma: a 17-center European collaborative study.
The best treatment option for primary vitreoretinal lymphoma (PVRL) without signs of central nervous system lymphoma (CNSL) involvement determined on magnetic resonance imaging or in cerebrospinal fluid is unknown. To evaluate the outcomes of treatment regimens used for PVRL in the prevention of subsequent CNSL. A retrospective cohort study was conducted at 17 referral ophthalmologic centers in Europe. We reviewed clinical, laboratory, and imaging data on 78 patients with PVRL who did not have CNSL on presentation between January 1, 1991, and December 31, 2012, with a focus on the incidence of CNS manifestations during the follow-up period. The term extensive treatment was used for various combinations of systemic and intrathecal chemotherapy, whole-brain radiotherapy, and peripheral blood stem cell transplantation. Therapy to prevent CNSL included ocular radiotherapy and/or ocular chemotherapy (group A, 31 patients), extensive systemic treatment (group B, 21 patients), and a combination of ocular and extensive treatment (group C, 23 patients); 3 patients did not receive treatment. A total of 40 patients received systemic chemotherapy. Development of CNSL following the diagnosis of PVRL relative to the use or nonuse of systemic chemotherapy and other treatment regimens. Overall, CNSL developed in 28 of 78 patients (36%) at a median follow-up of 49 months. Specifically, CNSL developed in 10 of 31 (32%) in group A, 9 of 21 (43%) in group B, and 9 of 23 (39%) in group C. The 5-year cumulative survival rate was lower in patients with CNSL (35% [95% CI, 50% to 86%]) than in patients without CNSL (68% [95% CI, 19% to 51%]; P = .003) and was similar among all treatment groups (P = .10). Adverse systemic effects occurred in 9 of 40 (23%) patients receiving systemic chemotherapy; the most common of these effects was acute renal failure. In the present series of patients with isolated PVRL, the use of systemic chemotherapy was not proven to prevent CNSL and was associated with more severe adverse effects compared with local treatment.


Tumour-derived adhesion factor in colorectal cancer.
Tumour-derived adhesion factor (TAF) has been shown to be associated with breast, prostate and colorectal cancer (CRC), acting as tumour suppressor or tumour promoter by mechanisms not as yet understood. Here, we comparatively analyzed the expression profile of TAF in plasma, tumour and paired normal tissue from patients with CRC. In addition, we investigated the relationship between TAF and systemic inflammation, mirrored by the elevation of interleukin-6 (IL-6) and TAF levels in plasma. Levels of TAF and IL-6 were determined by ELISA. Immunohistochemistry was performed to investigate the site of TAF expression. We also used a TaqMan system to investigate a TAF single nucleotide polymorphism (rs2041437) with a potential effect on CRC. TAF protein levels were significantly (P<0.001) higher in colorectal tumours than in normal tissue, and were increased in patients with Dukes' stages B and C compared to A. Immunohistochemistry revealed heterogeneous TAF expression mainly in the epithelial cells of the cancer and normal tissue. The plasma TAF level was reduced in CRC patients compared with the controls (P=0.002), independent of the inflammatory marker IL-6. Regarding genotype and allelic distributions, significant differences between CRC patients and control subjects or associations between clinical characteristics and TAF levels in tissue and plasma were not observed. In conclusion, altered TAF protein expression in cancer tissue may be a potential biomarker in colorectal carcinogenesis. Further research exploring the regulation of TAF is required to evaluate whether TAF is linked to clinical outcome.


Photocatalytic inactivation of bioaerosols in a fixed-bed reactor with TiO2-coated glass rings.
The photocatalytic inactivation of Bacillus subtilis spores in air was evaluated employing a fixed-bed reactor with TiO2-coated glass rings, under artificial UV-A radiation. Calculations of the radiation effectively absorbed inside the reactor were carried out by Monte Carlo simulations. The photocatalytic inactivation was assessed by analyzing the viability of the microorganisms retained by the coated glass rings inside the reactor at different irradiation periods. The initial concentration of the spores was reduced by almost 55% at the end of the experiment (12 h). Complementary assays were carried out employing Bacillus subtilis vegetative cells, obtaining a reduction of more than 96% under the same conditions. Two efficiency parameters were computed to assess the reactor performance: the photonic efficiency and the quantum efficiency of inactivation. Results of the efficiency parameters allow an objective comparison of the reactor performance under different experimental conditions and configurations.


Heterogeneity of inter-rater reliabilities of grant peer reviews and its determinants: a general estimating equations approach.
One of the most important weaknesses of the peer review process is that different reviewers' ratings of the same grant proposal typically differ. Studies on the inter-rater reliability of peer reviews mostly report only average values across all submitted proposals. But inter-rater reliabilities can vary depending on the scientific discipline or the requested grant sum, for instance. Taking the Austrian Science Fund (FWF) as an example, we aimed to investigate empirically the heterogeneity of inter-rater reliabilities (intraclass correlation) and its determinants. The data consisted of N = 8,329 proposals with N = 23,414 overall ratings by reviewers, which were statistically analyzed using the generalized estimating equations approach (GEE). We found an overall intraclass correlation (ICC) of reviewer? ratings of ρ = .259 with a 95% confidence interval of [.249,.279]. In humanities the ICCs were statistically significantly higher than in all other research areas except technical sciences. The ICC in biosciences deviated statistically significantly from the average ICC. Other factors (besides the research areas), such as the grant sum requested, had negligible influence on the ICC. Especially in biosciences, the number of reviewers of each proposal should be increased so as to increase the ICC.


DNA cleavage specificity of a group of cationic metalloporphyrins.
The ability of a group of water-soluble metalloporphyrins to cleave DNA has been investigated. Incubation of Mn3+, Fe3+, or Co3+ complexes of meso-tetrakis(N-methyl-4-pyridiniumyl)porphine (H2T4MPyP) with DNA in the presence of ascorbate, superoxide ion, or iodosobenzene results in DNA breakage. Comparisons between the rates of porphyrin autodestruction with the rates of strand scission of covalently closed circular PM2 DNA indicate that the porphyrins remain intact during the cleavage process. Analysis of the porphyrin-mediated strand scissions on a 139-base-pair restriction fragment of pBR322 DNA using gel electrophoresis/autoradiography/microdensitometry reveals that the minimum porphyrin cleavage site is (A X T)3. The cleavage pattern within a given site was found to be asymmetric, indicating that porphyrin binding and the strand scission process are highly directional in nature. In addition to an analysis of the mechanism of porphyrin-mediated strand breakage in terms of the DNA cleavage mechanism of methidium-propyl-iron-EDTA and Fe-bleomycin, the potential of the cationic metalloporphyrins as footprinting probes and as new "reporter ligands" for DNA is presented and discussed.


Prediction of gene phenotypes based on GO and KEGG pathway enrichment scores.
Observing what phenotype the overexpression or knockdown of gene can cause is the basic method of investigating gene functions. Many advanced biotechnologies, such as RNAi, were developed to study the gene phenotype. But there are still many limitations. Besides the time and cost, the knockdown of some gene may be lethal which makes the observation of other phenotypes impossible. Due to ethical and technological reasons, the knockdown of genes in complex species, such as mammal, is extremely difficult. Thus, we proposed a new sequence-based computational method called kNNA-based method for gene phenotypes prediction. Different to the traditional sequence-based computational method, our method regards the multiphenotype as a whole network which can rank the possible phenotypes associated with the query protein and shows a more comprehensive view of the protein's biological effects. According to the prediction result of yeast, we also find some more related features, including GO and KEGG information, which are making more contributions in identifying protein phenotypes. This method can be applied in gene phenotype prediction in other species.


Next-Gen Sequencing Exposes Frequent MED12 Mutations and Actionable Therapeutic Targets in Phyllodes Tumors.
Phyllodes tumors are rare fibroepithelial tumors with variable clinical behavior accounting for a small subset of all breast neoplasms, yet little is known about the genetic alterations that drive tumor initiation and/or progression. Here, targeted next-generation sequencing (NGS) was used to identify somatic alterations in formalin-fixed paraffin-embedded (FFPE) patient specimens from malignant, borderline, and benign cases. NGS revealed mutations in mediator complex subunit 12 (MED12) affecting the G44 hotspot residue in the majority (67%) of cases spanning all three histologic grades. In addition, loss-of-function mutations in p53 (TP53) as well as deleterious mutations in the tumor suppressors retinoblastoma (RB1) and neurofibromin 1 (NF1) were identified exclusively in malignant tumors. High-level copy-number alterations (CNA) were nearly exclusively confined to malignant tumors, including potentially clinically actionable gene amplifications in IGF1R and EGFR. Taken together, this study defines the genomic landscape underlying phyllodes tumor development, suggests potential molecular correlates to histologic grade, expands the spectrum of human tumors with frequent recurrent MED12 mutations, and identifies IGF1R and EGFR as potential therapeutic targets in malignant cases. Integrated genomic sequencing and mutational profiling provides insight into the molecular origin of phyllodes tumors and indicates potential druggable targets in malignant disease. Visual Overview: http://mcr.aacrjournals.org/content/early/2015/04/02/1541-7786.MCR-14-0578/F1.large.jpg.


Species and ecological diversity within the Cladosporium cladosporioides complex (Davidiellaceae, Capnodiales).
The genus Cladosporium is one of the largest genera of dematiaceous hyphomycetes, and is characterised by a coronate scar structure, conidia in acropetal chains and Davidiella teleomorphs. Based on morphology and DNA phylogeny, the species complexes of C. herbarum and C. sphaerospermum have been resolved, resulting in the elucidation of numerous new taxa. In the present study, more than 200 isolates belonging to the C. cladosporioides complex were examined and phylogenetically analysed on the basis of DNA sequences of the nuclear ribosomal RNA gene operon, including the internal transcribed spacer regions ITS1 and ITS2, the 5.8S nrDNA, as well as partial actin and translation elongation factor 1-α gene sequences. For the saprobic, widely distributed species Cladosporium cladosporioides, both a neotype and epitype are designated in order to specify a well established circumscription and concept of this species. Cladosporium tenuissimum and C. oxysporum, two saprobes abundant in the tropics, are epitypified and shown to be allied to, but distinct from C. cladosporioides. Twenty-two species are newly described on the basis of phylogenetic characters and cryptic morphological differences. The most important phenotypic characters for distinguishing species within the C. cladosporioides complex, which represents a monophyletic subclade within the genus, are shape, width, length, septation and surface ornamentation of conidia and conidiophores; length and branching patterns of conidial chains and hyphal shape, width and arrangement. Many of the treated species, e.g., C. acalyphae, C. angustisporum, C. australiense, C. basiinflatum, C. chalastosporoides, C. colocasiae, C. cucumerinum, C. exasperatum, C. exile, C. flabelliforme, C. gamsianum, and C. globisporum are currently known only from specific hosts, or have a restricted geographical distribution. A key to all species recognised within the C. cladosporioides complex is provided.


PDX-1 protein is internalized by lipid raft-dependent macropinocytosis.
PDX-1 plays a central role in regulating insulin gene transcription and differentiation of insulin-producing cells. It was previously reported that, due to its own Antennapedia-like protein transduction domain (PTD), exogenous PDX-1 protein can permeate cells and induces insulin gene expression in pancreatic ducts, thought to be islet progenitor cells. These data suggest that PDX-1 protein transduction could be a safe and valuable strategy for facilitating differentiation of progenitor cells into insulin-producing cells without requiring gene transfer technology. Here it is shown that after an initial ionic cell-surface interaction, PDX-1 proteins are rapidly internalized by lipid raft-dependent macropinocytosis. HeLa cells were treated with both FITC-conjugated PDX-1 PTD and FM 4-64, a general fluorescent marker of endocytosis. A punctate cytoplasmic distribution of PDX-1 PTD, which colocalized with FM 4-64, was observed in treated cells. Because expression of dominant-negative dynamin-1 did not block PDX-1 PTD uptake, PDX-1 protein transduction is independent on phagocytosis and clathrin- or caveolar-mediated endocytosis. Cells were pretreated with amiloride, a specific inhibitor of the Na+/H+ exchange required for macropinocytosis, or cytochalasin D, an F-actin elongation inhibitor. Treatment of cells with both macropinosome inhibitors resulted in the reduction in PDX-1 PTD transduction into vesicles, suggesting that PDX-1 PTD-mediated cellular entry occurs by lipid raft-mediated macropinocytosis. Taken together, these observations provide the mechanism of PDX-1 protein transduction and suggest that the protein transduction system could work for experimental and therapeutic strategies.


Mucosal immunization against ovine lentivirus using PEI-DNA complexes and modified vaccinia Ankara encoding the gag and/or env genes.
Sheep were immunized against Visna/Maedi virus (VMV) gag and/or env genes via the nasopharynx-associated lymphoid tissue (NALT) and lung using polyethylenimine (PEI)-DNA complexes and modified vaccinia Ankara, and challenged with live virus via the lung. env immunization enhanced humoral responses prior to but not after VMV challenge. Systemic T cell proliferative and cytotoxic responses were generally low, with the responses following single gag gene immunization being significantly depressed after challenge. A transient reduction in provirus load in the blood early after challenge was observed following env immunization, whilst the gag gene either alone or in combination with env resulted in significantly elevated provirus loads in lung. However, despite this, a significant reduction in lesion score was observed in animals immunized with the single gag gene at post-mortem. Inclusion of IFN-gamma in the immunization mixture in general had no significant effects. The results thus showed that protective effects against VMV-induced lesions can be induced following respiratory immunization with the single gag gene, though this was accompanied by an increased pulmonary provirus load.


Natural Language Processing in Radiology: A Systematic Review.
Radiological reporting has generated large quantities of digital content within the electronic health record, which is potentially a valuable source of information for improving clinical care and supporting research. Although radiology reports are stored for communication and documentation of diagnostic imaging, harnessing their potential requires efficient and automated information extraction: they exist mainly as free-text clinical narrative, from which it is a major challenge to obtain structured data. Natural language processing (NLP) provides techniques that aid the conversion of text into a structured representation, and thus enables computers to derive meaning from human (ie, natural language) input. Used on radiology reports, NLP techniques enable automatic identification and extraction of information. By exploring the various purposes for their use, this review examines how radiology benefits from NLP. A systematic literature search identified 67 relevant publications describing NLP methods that support practical applications in radiology. This review takes a close look at the individual studies in terms of tasks (ie, the extracted information), the NLP methodology and tools used, and their application purpose and performance results. Additionally, limitations, future challenges, and requirements for advancing NLP in radiology will be discussed.


Benefits versus risks associated with consumption of fish and other seafood.
Fish provide nutrition for much of the world's population, and when not contaminated with chemicals, fish is a very good food. A major benefit of fish is that they are high in polyunsaturated fatty acids (PUFAs), low in saturated fat, and they contain other critical nutrients. Much of the benefit of fish consumption derives from their high levels of long chain omega-3 PUFAs, which are produced by aquatic microorganisms and bioconcentrate in the aquatic food supply. The PUFAs are essential, in that humans and other vertebrates are not able to synthesize them and therefore must obtain them from the diet. The PUFAs particularly concentrate in the nervous system, alter immune system function reduce serum triglyceride levels and have been reported to reduce the risk of sudden death after a myocardial infarction. But the problem is that most fish have at least some degree of chemical contamination with methylmercury, (which binds to muscle) and/or with persistent organic pollutants such as dioxins, polychlorinated biphenyls, polybrominated diphenyl ethers, chlorinated pesticides (which concentrate in fish fat). These chemicals have adverse effects on nervous system function, modulate the immune system, and are associated with elevations in risk of cardiovascular disease. Thus the question of benefits and risk from fish consumption is complex but very important.


Animal-assisted therapy in a Canadian psychiatric prison.
Prison-based animal programs are becoming increasingly common in North America. The majority focus on community and animal well-being, with less explicit therapeutic goals for human participants. The purpose of this paper is to measure the objectives of a canine animal-assisted therapy (AAT) program in a Canadian psychiatric prison and examine whether the program supports inmates' correctional plans. A modified instrumental case study design was applied with three inmates over a 24-AAT-session program. Quantitative and qualitative AAT session data were collected and mid- and end-of-program interviews were held with the inmates, their mental health clinicians and the therapy dog handlers. Inmates connected with the therapy dogs through the animals' perceived offering of love and support. This development of a human-animal bond supported inmates' correctional plans, which are largely situated within a cognitive-behavioral skill development framework. Specifically, inmates' connections with the therapy dogs increased recognition of their personal feelings and emotions and positively impacted their conduct. The findings suggest that prison-based AAT programs emphasizing inmate mental well-being, alongside that of animal and community well-being generally, merit further exploration. It would be worthwhile to assess this AAT program with a larger and more diverse sample of inmates and in a different institutional context and also to conduct a post-intervention follow-up. This is the first study of a prison-based AAT program in a Canadian psychiatric correctional facility.


Hybrid orthogonal junctions: wideband plasmonic slot-silicon waveguide couplers.
In this paper, novel ultra compact and ultra wide band couplers between silicon and plasmonic slot waveguides are analyzed, characterized, and fabricated. This novel coupling scheme is fabricated using silicon on insulator platform. An orthogonal junction configuration is designed to provide non-resonate wideband coupling from a 400 nm silicon waveguide to 50-nm wide air-filled plasmonic slot. The 1 μm wide full-width half-max coupling spectrum can theoretically reach high peak of 70% coupling to the plasmonic slot centered around the 1550 nm wavelength. This center wavelength can be controlled by varying the silicon waveguide width. Theoretical analysis is in good agreement with FDTD simulated results, and experimental results. The fabrication procedure is also presented and discussed.


Incorporating Known Genetic Variants Does Not Improve the Accuracy of PSA Testing to Identify High Risk Prostate Cancer on Biopsy.
Prostate-specific antigen (PSA) testing is a widely accepted screening method for prostate cancer, but with low specificity at thresholds giving good sensitivity. Previous research identified four single nucleotide polymorphisms (SNPs) principally associated with circulating PSA levels rather than with prostate cancer risk (TERT rs2736098, FGFR2 rs10788160, TBX3 rs11067228, KLK3 rs17632542). Removing the genetic contribution to PSA levels may improve the ability of the remaining biologically-determined variation in PSA to discriminate between high and low risk of progression within men with identified prostate cancer. We investigate whether incorporating information on the PSA-SNPs improves the discrimination achieved by a single PSA threshold in men with raised PSA levels. Men with PSA between 3-10 ng/mL and histologically-confirmed prostate cancer were categorised as high or low risk of progression (Low risk: Gleason score≤6 and stage T1-T2a; High risk: Gleason score 7-10 or stage T2C). We used the combined genetic effect of the four PSA-SNPs to calculate a genetically corrected PSA risk score. We calculated the Area under the Curve (AUC) to determine how well genetically corrected PSA risk scores distinguished men at high risk of progression from low risk men. The analysis includes 868 men with prostate cancer (Low risk: 684 (78.8%); High risk: 184 (21.2%)). Receiver operating characteristic (ROC) curves indicate that including the 4 PSA-SNPs does not improve the performance of measured PSA as a screening tool for high/low risk prostate cancer (measured PSA level AUC = 59.5% (95% CI: 54.7,64.2) vs additionally including information from the 4 PSA-SNPs AUC = 59.8% (95% CI: 55.2,64.5) (p-value = 0.40)). We demonstrate that genetically correcting PSA for the combined genetic effect of four PSA-SNPs, did not improve discrimination between high and low risk prostate cancer in men with raised PSA levels (3-10 ng/mL). Replication and gaining more accurate estimates of the effects of the 4 PSA-SNPs and additional variants associated with PSA levels and not prostate cancer could be obtained from subsequent GWAS from larger prospective studies.


Efficient Electrochemical Self-Catalytic Platform Based on l-Cys-hemin/G-quadruplex and Its Application for Bioassay.
Commonly, in the artificial enzyme-involved signal amplification approach, the catalytic efficiency was limited by the relatively low binding affinity between artificial enzyme and substrate. In this work, substrate l-cysteine (l-Cys) and hemin were combined into one molecule to form l-Cys-hemin/G-quadruplex as an artificial self-catalytic complex for the improvement of the binding affinity between l-Cys-hemin/G-quadruplex and l-Cys. The apparent Michaelis-Menten constant ( Km = 2.615 μM) on l-Cys-hemin/G-quadruplex for l-Cys was further investigated to assess the affinity, which was much lower than that of hemin/G-quadruplex ( Km = 8.640 μM), confirming l-Cys-hemin/G-quadruplex possessed better affinity to l-Cys compared with that of hemin/G-quadruplex. Meanwhile, l-Cys bilayer could be further assembled onto the surface of l-Cys-hemin/G-quadruplex based on hydrogen-bond and electrostatic interaction to concentrate l-Cys around the active center, which was beneficial to the catalytic enhancement. Through this efficient electrochemical self-catalytic platform, a sensitive thrombin aptasensor was constructed. The results exhibited good sensitivity from 0.1 pM to 80 nM and the detection limit was calculated to be 0.032 pM. This self-catalytic strategy with improved binding affinity between l-Cys-hemin/G-quadruplex and l-Cys could provide an efficient approach to improve artificial enzymatic catalytic efficiency.


How do surgeons think they learn about communication? A qualitative study.
Communication education has become integral to pre- and post-qualification clinical curricula, but it is not informed by research into how practitioners think that good communication arises. This study was conducted to explore how surgeons conceptualise their communication with patients with breast cancer in order to inform the design and delivery of communication curricula. We carried out 19 interviews with eight breast surgeons. Each interview centred on a specific consultation with a different patient. We analysed the transcripts of the surgeons' interviews qualitatively using a constant comparative approach. All of the surgeons described communication as central to their role. Communication could be learned to some extent, not from formal training, but by selectively incorporating practices they observed in other practitioners and by being mindful in consultations. Surgeons explained that their own values and character shaped how they communicated and what they wanted to achieve, and constrained what could be learned. These surgeons' understanding of communication is consistent with recent suggestions that communication education: (i) should place practitioners' goals at its centre, and (ii) might be enhanced by approaches that support 'mindful' practice. By contrast, surgeons' understanding diverged markedly from the current emphasis on 'communication skills'. Research that explores practitioners' perspectives might help educators to design communication curricula that engage practitioners by seeking to enhance their own ways of learning about communication.


Temporal accumulation and localization of isoflurane in the C57BL/6 mouse and assessment of its potential contamination in 19 F MRI with perfluoro-crown-ether-labeled cardiac progenitor cells at 9.4 Tesla.
To assess the uptake, accumulation, temporal stability, and spatial localization of isoflurane (ISO) in the C57BL/6 mouse, and to identify its potential interference with the detection of labeled cardiac progenitor cells using 19 F MRI/MR spectroscopy (MRS). Objectives are demonstrated using (a) in vitro ISO tests, (b) in vivo temporal accumulation/spatial localization C57BL/6 studies (n = 3), and (c) through injections of perfluoro-crown-ether (PFCE) labeled cardiac progenitor cells into femoral muscle areas of the murine hindlimb post-mortem (n = 1) using 1 H/19 F MRI/MRS at 9.4 Tesla. Data were acquired using double-gated spoiled gradient echo images and pulse-acquire spectra. For the in vivo study, the temporal stability of ISO resonances was quantified using coefficient of variability (CV) (5 min) estimates. Two ISO resonances were observed in vivo that correspond to the -CF3 and -OCHF2 moieties. CV values ranged between 3.2 and 6.4% (-CF3 ) and 6.4 and 11.2% (-OCHF2 ). Reductions of the ISO dose (2.0 to 1.7%) at 80 min postinduction had insignificant effects on ISO signals (P = 0.23; P = 0.71). PFCE-labeled cells exhibited a resonance at -16.25 ppm in vitro that did not overlap with the ISO resonances, a finding that is confirmed with MRS post-mortem using injected, labeled cells. Based on 19 F MRI, similar in vivo/post-mortem ISO compartmentalization was also confirmed in peripheral and thoracic skeletal muscles. Significant ISO accumulation was observed by 19 F MRS in vivo with temporally stable signals over 90 min postinduction. ISO effects on PFCE labels are anticipated to be minimal but may be more prominent for perfluoropolyether or perfluorooctyl bromide labels. 1 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;45:1659-1667.


Association of Ketamine With Psychiatric Symptoms and Implications for Its Therapeutic Use and for Understanding Schizophrenia: A Systematic Review and Meta-analysis.
Ketamine hydrochloride is increasingly used to treat depression and other psychiatric disorders but can induce schizophrenia-like or psychotomimetic symptoms. Despite this risk, the consistency and magnitude of symptoms induced by ketamine or what factors are associated with these symptoms remain unknown. To conduct a meta-analysis of the psychopathological outcomes associated with ketamine in healthy volunteers and patients with schizophrenia and the experimental factors associated with these outcomes. MEDLINE, Embase, and PsychINFO databases were searched for within-participant, placebo-controlled studies reporting symptoms using the Brief Psychiatric Rating Scale (BPRS) or the Positive and Negative Syndrome Scale (PANSS) in response to an acute ketamine challenge in healthy participants or patients with schizophrenia. Of 8464 citations retrieved, 36 studies involving healthy participants were included. Inclusion criteria were studies (1) including healthy participants; (2) reporting symptoms occurring in response to acute administration of subanesthetic doses of ketamine (racemic ketamine, s-ketamine, r-ketamine) intravenously; (3) containing a placebo condition with a within-subject, crossover design; (4) measuring total positive or negative symptoms using BPRS or PANSS; and (5) providing data allowing the estimation of the mean difference and deviation between the ketamine and placebo condition. Two independent investigators extracted study-level data for a random-effects meta-analysis. Total, positive, and negative BPRS and PANSS scores were extracted. Subgroup analyses were conducted examining the effects of blinding status, ketamine preparation, infusion method, and time between ketamine and placebo conditions. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. Standardized mean differences (SMDs) were used as effect sizes for individual studies. Standardized mean differences between ketamine and placebo conditions were calculated for total, positive, and negative BPRS and PANSS scores. The overall sample included 725 healthy volunteers (mean [SD] age, 28.3 [3.6] years; 533 [73.6%] male) exposed to the ketamine and placebo conditions. Racemic ketamine or S-ketamine was associated with a statistically significant increase in transient psychopathology in healthy participants for total (SMD = 1.50 [95% CI, 1.23-1.77]; P < .001), positive (SMD = 1.55 [95% CI, 1.29-1.81]; P < .001), and negative (SMD = 1.16 [95% CI, 0.96-1.35]; P < .001) symptom ratings relative to the placebo condition. The effect size for this association was significantly greater for positive than negative symptoms of psychosis (estimate, 0.36 [95% CI, 0.12-0.61]; P = .004). There was significant inconsistency in outcomes between studies (I2 range, 77%-83%). Bolus followed by constant infusion increased ketamine's association with positive symptoms relative to infusion alone (effect size, 1.63 [95% CI, 1.36-1.90] vs 0.84 [95% CI, 0.35-1.33]; P = .006). Single-day study design increased ketamine's ability to generate total symptoms (effect size, 2.29 [95% CI, 1.69-2.89] vs 1.39 [95% CI, 1.12-1.66]; P = .007), but age and sex did not moderate outcomes. Insufficient studies were available for meta-analysis of studies in schizophrenia. Of these studies, 2 found a statistically significant increase in symptoms with ketamine administration in total and positive symptoms. Only 1 study found an increase in negative symptom severity with ketamine. This study found that acute ketamine administration was associated with schizophrenia-like or psychotomimetic symptoms with large effect sizes, but there was a greater increase in positive than negative symptoms and when a bolus was used. These findings suggest that bolus doses should be avoided in the therapeutic use of ketamine to minimize the risk of inducing transient positive (psychotic) symptoms.


The Study of Environment on Aboriginal Resilience and Child Health (SEARCH): a long-term platform for closing the gap.
The full potential for research to improve Aboriginal health has not yet been realised. This paper describes an established long-term action partnership between Aboriginal Community Controlled Health Services (ACCHSs), the Aboriginal Health and Medical Research Council of New South Wales (AH&MRC), researchers and the Sax Institute, which is committed to using high-quality data to bring about health improvements through better services, policies and programs. The ACCHSs, in particular, have ensured that the driving purpose of the research conducted is to stimulate action to improve health for urban Aboriginal children and their families. This partnership established a cohort study of 1600 urban Aboriginal children and their caregivers, known as SEARCH (the Study of Environment on Aboriginal Resilience and Child Health), which is now having significant impacts on health, services and programs for urban Aboriginal children and their families. This paper describes some examples of the impacts of SEARCH, and reflects on the ways of working that have enabled these changes to occur, such as strong governance, a focus on improved health, AH&MRC and ACCHS leadership, and strategies to support the ACCHS use of data and to build Aboriginal capacity.


Oncogenesis and genome duplication maps (commentary).
Examples of activation of putative cancer genes belonging to multigene families are given. Their structure and chromosomal location helps in identifying genome duplications. Reciprocally, genome duplication maps may help in predicting the location and behaviour of putative cancer genes.


SDF-1α stiffens myeloma bone marrow mesenchymal stromal cells through the activation of RhoA-ROCK-Myosin II.
Multiple myeloma (MM) is a B lymphocyte malignancy that remains incurable despite extensive research efforts. This is due, in part, to frequent disease recurrences associated with the persistence of myeloma cancer stem cells (mCSCs). Bone marrow mesenchymal stromal cells (BMSCs) play critical roles in supporting mCSCs through genetic or biochemical alterations. Previously, we identified mechanical distinctions between BMSCs isolated from MM patients (mBMSCs) and those present in the BM of healthy individuals (nBMSCs). These properties of mBMSC contributed to their ability to preferentially support mCSCs. To further illustrate mechanisms underlying the differences between mBMSCs and nBMSCs, here we report that (i) mBMSCs express an abnormal, constitutively high level of phosphorylated Myosin II, which leads to stiffer membrane mechanics, (ii) mBMSCs are more sensitive to SDF-1α-induced activation of MYL2 through the G(i./o)-PI3K-RhoA-ROCK-Myosin II signaling pathway, affecting Young's modulus in BMSCs and (iii) activated Myosin II confers increased cell contractile potential, leading to enhanced collagen matrix remodeling and promoting the cell-cell interaction between mCSCs and mBMSCs. Together, our findings suggest that interfering with SDF-1α signaling may serve as a new therapeutic approach for eliminating mCSCs by disrupting their interaction with mBMSCs.


Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog.
Accumulation of polymorphonuclear neutrophils during the acute inflammatory response may exacerbate tissue injury through the release of activated oxygen products or proteolytic enzymes or both. To assess the role of neutrophils in acute myocardial infarction, circulating neutrophil levels in dogs were reduced by 77 +/- 2% (mean +/- SEM) by administering rabbit antiserum to dog neutrophils. Acute myocardial infarction was induced in open-chest anesthetized dogs by 90 minutes of left circumflex coronary artery occlusion followed by 6 hours of reperfusion. Dogs treated with neutrophil antiserum (n = 8) developed myocardial infarcts that were an average of 43% smaller than infarcts in dogs treated with nonimmune rabbit serum (n = 7) (27.0 +/- 4.5% vs 47.1% +/- 7.5% of the area at risk, p less than 0.05). In a saline-treated control group (n = 8), infarct size was 48.0 +/- 4.7% of the area at risk, a value not significantly different from that of the nonimmune serum group but significantly greater than that in the neutrophil antiserum dogs (p less than 0.05). There were no major hemodynamic differences between groups. Histopathologic examination revealed that infarcted myocardium from dogs given saline or treated with nonimmune serum had a substantial neutrophilic infiltrate, which was virtually absent in infarcted tissue from dogs treated with neutrophil antiserum. These observations suggest that neutrophil accumulation in response to myocardial ischemia may be responsible for a substantial portion of the irreversible myocardial injury resulting from temporary coronary artery occlusion.


Delivery and impact of the NHS Health Check in the first 8 years: a systematic review.
Since 2009, all eligible persons in England have been entitled to an NHS Health Check. Uncertainty remains about who attends, and the health-related impacts. To review quantitative evidence on coverage (the proportion of eligible individuals who attend), uptake (proportion of invitees who attend), and impact of NHS Health Checks. A systematic review and quantitative data synthesis. Included were studies or data reporting coverage or uptake and studies reporting any health-related impact that used an appropriate comparison group or before- and-after study design. Eleven databases and additional internet sources were searched to November 2016. Twenty-six observational studies and one additional dataset were included. Since 2013, 45.6% of eligible individuals have received a health check. Coverage is higher among older people, those with a family history of coronary heart disease, those living in the most deprived areas, and some ethnic minority groups. Just under half (48.2%) of those invited have taken up the invitation. Data on uptake and impact (especially regarding health-related behaviours) are limited. Uptake is higher in older people and females, but lower in those living in the most deprived areas. Attendance is associated with small increases in disease detection, decreases in modelled cardiovascular disease risk, and increased statin and antihypertensive prescribing. Published attendance, uptake, and prescribing rates are all lower than originally anticipated, and data on impact are limited, with very few studies reporting the effect of attendance on health-related behaviours. High-quality studies comparing matched attendees and non-attendees and health economic analyses are required.


Older Adults Accessing HIV Care and Treatment and Adherence in the IeDEA Central Africa Cohort.
Background. Very little is known about older adults accessing HIV care in sub-Saharan Africa. Materials and Methods. Data were obtained from 18,839 HIV-positive adults at 10 treatment programs in Burundi, Cameroon, and the Democratic Republic of Congo. We compared characteristics of those aged 50+ with those aged 18-49 using chi-square tests. Logistic regression was used to determine if age was associated with medication adherence. Results. 15% of adults were 50+ years. Those aged 50+ were more evenly distributed between women and men (56% versus 44%) as compared to those aged 18-49 (71% versus 29%) and were more likely to be hypertensive (8% versus 3%) (P < 0.05). Those aged 50+ were more likely to be adherent to their medications than those aged 18-49 (P < 0.001). Adults who were not heavy drinkers reported better adherence as compared to those who reported drinking three or more alcoholic beverages per day (P < 0.001). Conclusions. Older adults differed from their younger counterparts in terms of medication adherence, sociodemographic, behavioral, and clinical characteristics.


Formation of bromate during ferrate(VI) oxidation of bromide in water.
Ferrate (VI) is traditionally recognized as a safe oxidant without production of disinfection byproducts (DBPs). However, here we detected probable carcinogenic bromate (BrO3(-)) during ferrate(VI) oxidation of bromide (Br(-))-containing water, and evaluated the effects of pH, ferrate(VI) dose, initial Br(-) concentration, and co-existing anions on the BrO3(-) formation. BrO3(-) was produced at a moderately-weakly acidic pH condition and in the absence of phosphate that was commonly applied as a buffer and stabilizing agent in previous ferrate(VI) studies. At pH 5.0, the produced BrO3(-) was increased from 12.5 to 273.8 μg/L with the increasing initial Br(-) concentration from 200 to 1000 μg/L at 10 mg/L Fe(VI), corresponding to an increase in the molar conversion ([BrO3(-)]/initial [Br(-)]) from 2.3% to 10.3%, in a bicarbonate-buffered solution. As pH increased to 7.0, the BrO3(-) concentration gradually dropped. The BrO3(-) production appeared to be associated with the oxidation by high valence iron species (i.e. Fe(VI), Fe(V) and Fe(IV)). Two key intermediate products (i.e. hypobromous acid/hypobromite (HOBr/OBr(-)) and hydrogen peroxide (H2O2)) relevant to the bromate formation were identified. The production of HOBr, a requisite intermediate for the ensuing bromate formation, was indirectly validated through identification of bromine-containing trihalomethanes and haloacetic acids during ferrate oxidation in a natural water, though these bromo-organic DBPs produced were insignificant. Furthermore, the inhibition effects of various anions on the formation of BrO3(-) followed chloride < sulfate < silicate < phosphate. More H2O2 was detected at higher phosphate concentration. It could reduce HOBr to Br(-), thereby inhibiting the bromate formation.


Occupational health needs of universities: a review with an emphasis on the United Kingdom.
This study describes the needs of universities in relation to planning the provision of occupational health services, by detailing their occupational hazards and risks and other relevant factors. The paper presents the results of (1) an enquiry into publicly available data relevant to occupational health in the university sector in the United Kingdom, (2) a literature review on occupational health provision in universities, and (3) selected results from a survey of university occupational health services in the UK. Although the enquiry and survey, but not the literature review, were restricted to the UK, the authors consider that the results are relevant to other countries because of the broad similarities of the university sector between countries. These three approaches showed that the university sector is large, with a notably wide range of occupational hazards, and other significant factors which must be considered in planning occupational health provision for individual universities or for the sector as a whole.


Let physicians be physicians.
On a recent visit to his physician, a friend reported that the physician spent 95% of the visit hunched over a laptop computer, leaving it only for a quick listen to his heart and lungs. The remarkable thing is, in medical circles the story is unremarkable. Many consider it the norm now. Who thought it was a good idea to turn physicians into typists? Does it make sense that the most highly educated person in the building is doing data entry? How is patient care improved if the physician is hunched over a laptop computer in the exam room?


Genomic, Proteomic, and Metabolite Characterization of Gemfibrozil-Degrading Organism Bacillus sp. GeD10.
Gemfibrozil is a widely used hypolipidemic and triglyceride lowering drug. Excess of the drug is excreted and discharged into the environment primarily via wastewater treatment plant effluents. Bacillus sp. GeD10, a gemfibrozil-degrader, was previously isolated from activated sludge. It is the first identified bacterium capable of degrading gemfibrozil. Gemfibrozil degradation by Bacillus sp. GeD10 was here studied through genome sequencing, quantitative proteomics and metabolite analysis. From the bacterial proteome of Bacillus sp. GeD10 1974 proteins were quantified, of which 284 proteins were found to be overabundant by more than 2-fold (FDR corrected p-value ≤0.032, fold change (log2) ≥ 1) in response to gemfibrozil exposure. Metabolomic analysis identified two hydroxylated intermediates as well as a glucuronidated hydroxyl-metabolite of gemfibrozil. Overall, gemfibrozil exposure in Bacillus sp. GeD10 increased the abundance of several enzymes potentially involved in gemfibrozil degradation as well as resulted in the production of several gemfibrozil metabolites. The potential catabolic pathway/modification included ring-hydroxylation preparing the substrate for subsequent ring cleavage by a meta-cleaving enzyme. The identified genes may allow for monitoring of potential gemfibrozil-degrading organisms in situ and increase the understanding of microbial processing of trace level contaminants. This study represents the first omics study on a gemfibrozil-degrading bacterium.


Oncolytic effect of wild-type Newcastle disease virus isolates in cancer cell lines in vitro and in vivo on xenograft model.
Oncolyic virotherapy is one of the modern experimental techniques to treat human cancers. Here we studied the antitumor activity of wild-type Newcastle disease virus (NDV) isolates from Russian migratory birds. We showed that NDV could selectively kill malignant cells without affecting healthy cells. We evaluated the oncolytic effect of 44 NDV isolates in 4 histogenetically different human cell lines (HCT116, HeLa, A549, MCF7). The safety of the isolates was also tested in normal peripheral blood mononuclear (PBMC) cells. The viability of tumor cell lines after incubation with NDV isolates was evaluated by MTT. All cell lines, except for normal PBMC primary cells, had different degrees of susceptibility to NDV infection. Seven NDV strains had the highest oncolytic activity, and some NDV strains demonstrated oncolytic selectivity for different cell lines. In vivo, we described the intratumoral activity of NDV/Altai/pigeon/770/2011 against subcutaneous non-small cell lung carcinoma using xenograft SCID mice model. All animals were responsive to therapy. Histology confirmed therapy-induced destructive changes and growing necrotic bulk density in tumor tissue. Our findings indicate that wild-type NDV strains selectively kill tumor cells with no effect on healthy PBMC cells, and intratumoral virotherapy with NDV suppresses the subcutaneous tumor growth in SCID mice.


Lower limb movement symmetry cannot be assumed when investigating the stop-jump landing.
When investigating lower limb landing biomechanics, researchers often assume movement symmetry between a participant's right and left lower limbs for the simplicity of data collection and analysis, although landing tasks often involve dual-limb motion. However, whether lower limb symmetry can be assumed when investigating dynamic, sport-specific movements such as the stop-jump has not been investigated. Therefore, this study aimed to determine whether there were any significant differences in selected kinetic, kinematic, and muscle activation patterns characterizing lower limb biomechanics displayed by the dominant limb compared with the nondominant limb of participants during a stop-jump task. Sixteen male athletes with normal patellar tendons on diagnostic imaging performed five successful stop-jump trials. Patellar tendon forces (FPT), ground reaction forces, three-dimensional kinematics, and EMG activity of seven lower limb muscles were recorded for the dominant and nondominant lower limbs during each trial. During the horizontal landing phase, the dominant lower limb sustained a significantly higher FPT and peak net knee joint extension moment compared with the nondominant lower limb. Furthermore, during the vertical landing phase, the dominant lower limb sustained significantly lower vertical but higher posterior ground reaction forces compared with the nondominant lower limb. Other variables did not significantly vary as a function of lower limb dominance. It is recommended that researchers clearly identify their primary outcome variables and ensure that their experimental design, particularly in terms of lower limb dominance, provides an appropriate framework to investigate possible mechanics underlying unilateral and bilateral knee joint injuries during dual-limb movements such as the stop-jump task.


Catalytic Activity and Stability of Oxides: The Role of Near-Surface Atomic Structures and Compositions.
Electrocatalysts play an important role in catalyzing the kinetics for oxygen reduction and oxygen evolution reactions for many air-based energy storage and conversion devices, such as metal-air batteries and fuel cells. Although noble metals have been extensively used as electrocatalysts, their limited natural abundance and high costs have motivated the search for more cost-effective catalysts. Oxides are suitable candidates since they are relatively inexpensive and have shown reasonably high activity for various electrochemical reactions. However, a lack of fundamental understanding of the reaction mechanisms has been a major hurdle toward improving electrocatalytic activity. Detailed studies of the oxide surface atomic structure and chemistry (e.g., cation migration) can provide much needed insights for the design of highly efficient and stable oxide electrocatalysts. In this Account, we focus on recent advances in characterizing strontium (Sr) cation segregation and enrichment near the surface of Sr-substituted perovskite oxides under different operating conditions (e.g., high temperature, applied potential), as well as their influence on the surface oxygen exchange kinetics at elevated temperatures. We contrast Sr segregation, which is associated with Sr redistribution in the crystal lattice near the surface, with Sr enrichment, which involves Sr redistribution via the formation of secondary phases. The newly developed coherent Bragg rod analysis (COBRA) and energy-modulated differential COBRA are uniquely powerful ways of providing information about surface and interfacial cation segregation at the atomic scale for these thin film electrocatalysts. In situ ambient pressure X-ray photoelectron spectroscopy (APXPS) studies under electrochemical operating conditions give additional insights into cation migration. Direct COBRA and APXPS evidence for surface Sr segregation was found for La1-xSrxCoO3-δ and (La1-ySry)2CoO4±δ/La1-xSrxCoO3-δ oxide thin films, and the physical origin of segregation is discussed in comparison with (La1-ySry)2CoO4±δ/La1-xSrxCo0.2Fe0.8O3-δ. Sr enrichment in many electrocatalysts, such as La1-xSrxMO3-δ (M = Cr, Co, Mn, or Co and Fe) and Sm1-xSrxCoO3, has been probed using alternative techniques, including low energy ion scattering, secondary ion mass spectrometry, and X-ray fluorescence-based methods for depth-dependent, element-specific analysis. We highlight a strong connection between cation segregation and electrocatalytic properties, because cation segregation enhances oxygen transport and surface oxygen exchange kinetics. On the other hand, the formation of cation-enriched secondary phases can lead to the blocking of active sites, inhibiting oxygen exchange. With help from density functional theory, the links between cation migration, catalyst stability, and catalytic activity are provided, and the oxygen p-band center relative to the Fermi level can be identified as an activity descriptor. Based on these findings, we discuss strategies to increase a catalyst's activity while maintaining stability to design efficient, cost-effective electrocatalysts.


The reliability and quality of cognitive case formulation.
Limited research on the reliability of cognitive case formulation suggests cognitive therapists can agree about clients' presenting problems but show poor agreement about the inferential aspects of formulation. There has been no research examining the quality of practitioners' case formulations. This study assessed whether participants with different levels of experience could produce reliable cognitive formulations using a systematic cognitive therapy case formulation method: the J. Beck Case Conceptualization Diagram. As part of continuing education workshops on cognitive case formulation, 115 mental health practitioners were given the same case description and asked to provide case formulations. Inter-rater agreement and agreement with a "benchmark" formulation provided by J. Beck were measured. The results showed that participants were able to agree with each other and with the benchmark on most descriptive aspects of the formulation but rates of agreement decreased for aspects of the formulation requiring greater levels of theory-driven inference. Based on definitions and measurements of the quality of cognitive formulations derived in this study, the quality of formulations ranged from very poor to good, with only 44% rated as being at least good enough. Both reliability and quality of case formulations were associated with levels of clinical experience and accreditation status. Implications for training and supervision are discussed.


TSPO PET Using [18F]PBR111 Reveals Persistent Neuroinflammation Following Acute Diisopropylfluorophosphate Intoxication in the Rat.
Acute intoxication with organophosphates (OPs) can trigger status epilepticus followed by persistent cognitive impairment and/or electroencephalographic abnormalities. Neuroinflammation is widely posited to influence these persistent neurological consequences. However, testing this hypothesis has been challenging, in part because traditional biometrics preclude longitudinal measures of neuroinflammation within the same animal. Therefore, we evaluated the performance of noninvasive positron emission tomography (PET), using the translocator protein (TSPO) radioligand [18F]PBR111 against classic histopathologic measures of neuroinflammation in a preclinical model of acute intoxication with the OP diisopropylfluorophosphate (DFP). Adult male Sprague Dawley rats administered pyridostigmine bromide (0.1 mg/kg, im) 30 min prior to administration of DFP (4 mg/kg, sc), atropine sulfate (2 mg/kg, im) and 2-pralidoxime (25 mg/kg, im) exhibited moderate-to-severe seizure behavior. TSPO PET performed prior to DFP exposure and at 3, 7, 14, 21, and 28 days postexposure revealed distinct lesions, as defined by increased standardized uptake values (SUV). Increased SUV showed high spatial correspondence to immunohistochemical evidence of neuroinflammation, which was corroborated by cytokine gene and protein expression. Regional SUV metrics varied spatiotemporally with days postexposure and correlated with the degree of neuroinflammation detected immunohistochemically. Furthermore, SUV metrics were highly correlated with seizure severity, suggesting that early termination of OP-induced seizures may be critical for attenuating subsequent neuroinflammatory responses. Normalization of SUV values to a cerebellar reference region improved correlations to all outcome measures and seizure severity. Collectively, these results establish TSPO PET using [18F]PBR111 as a robust, noninvasive tool for longitudinal monitoring of neuroinflammation following acute OP intoxication.


An international dosimetry exchange for boron neutron capture therapy. Part I: Absorbed dose measurements.
An international collaboration was organized to undertake a dosimetry exchange to enable the future combination of clinical data from different centers conducting neutron capture therapy trials. As a first step (Part I) the dosimetry group from the Americas, represented by MIT, visited the clinical centers at Studsvik (Sweden), VTT Espoo (Finland), and the Nuclear Research Institute (NRI) at Rez (Czech Republic). A combined VTT/NRI group reciprocated with a visit to MIT. Each participant performed a series of dosimetry measurements under equivalent irradiation conditions using methods appropriate to their clinical protocols. This entailed in-air measurements and dose versus depth measurements in a large water phantom. Thermal neutron flux as well as fast neutron and photon absorbed dose rates were measured. Satisfactory agreement in determining absorbed dose within the experimental uncertainties was obtained between the different groups although the measurement uncertainties are large, ranging between 3% and 30% depending upon the dose component and the depth of measurement. To improve the precision in the specification of absorbed dose amongst the participants, the individually measured dose components were normalized to the results from a single method. Assuming a boron concentration of 15 microg g(-1) that is typical of concentrations realized clinically with the boron delivery compound boronophenylalanine-fructose, systematic discrepancies in the specification of the total biologically weighted dose of up to 10% were apparent between the different groups. The results from these measurements will be used in future to normalize treatment plan calculations between the different clinical dosimetry protocols as Part II of this study.


Acute bronchiolitis in infants, a review.
Acute viral bronchiolitis is one of the most common medical emergency situations in infancy, and physicians caring for acutely ill children will regularly be faced with this condition. In this article we present a summary of the epidemiology, pathophysiology and diagnosis, and focus on guidelines for the treatment of bronchiolitis in infants. The cornerstones of the management of viral bronchiolitis are the administration of oxygen and appropriate fluid therapy, and overall a "minimal handling approach" is recommended. Inhaled adrenaline is commonly used in some countries, but the evidences are sparse. Recently, inhalation with hypertonic saline has been suggested as an optional treatment. When medical treatment fails to stabilize the infants, non-invasive and invasive ventilation may be necessary to prevent and support respiratory failure. It is important that relevant treatment algorithms exist, applicable to all levels of the treatment chain and reflecting local considerations and circumstances.


Solution Blow Spinning of High-Performance Submicron Polyvinylidene Fluoride Fibres: Computational Fluid Mechanics Modelling and Experimental Results.
Computational fluid dynamics (CFD) was used to investigate characteristics of high-speed air as it is expelled from a solution blow spinning (SBS) nozzle using a k-ε turbulence model. Air velocity, pressure, temperature, turbulent kinetic energy and density contours were generated and analysed in order to achieve an optimal attenuation force for fibre production. A bespoke convergent nozzle was used to produce polyvinylidene fluoride (PVDF) fibres at air pressures between 1 and 5 bar. The nozzle comprised of four parts: a polymer solution syringe holder, an air inlet, an air chamber, and a cap that covers the air chamber. A custom-built SBS setup was used to produce PVDF submicron fibres which were consequently analysed using scanning electron microscope (SEM) for their morphological features. Both theoretical and experimental observations showed that a higher air pressure (4 bar) is more suitable to achieve thin fibres of PVDF. However, fibre diameter increased at 5 bar and intertwined ropes of fibres were also observed.


Levels of CD56+TIM-3- effector CD8 T cells distinguish HIV natural virus suppressors from patients receiving antiretroviral therapy.
Prolonged antiretroviral therapy (ART) with effective HIV suppression and reconstitution of CD4 T cells, fails to restore CD8 T cell lytic effector function that is needed to eradicate the viral reservoir. Better understanding of the phenotype and function of circulating CD8 cells in HIV patients will contribute to new targeted therapies directed at increasing CD8 T cell lytic effector function and destruction of the viral reservoir. We show that CD8 T cells from ART treated patients had sharply reduced expression of CD56 (neural cell adhesion molecule-1), a marker associated with cytolytic function whereas elite patients who control HIV in the absence of ART had CD56+ CD8 T cell levels similar to uninfected controls. The CD56+ CD8 T cells had higher perforin upregulation as well as degranulation following stimulation with HIV gag peptides compared with CD56 negative CD8 T cells. Elite patients had the highest frequencies of perforin producing CD56+ CD8 T cells among all HIV+ groups. In patients receiving ART we noted high levels of the exhaustion marker TIM-3 on CD56+ CD8 T cells, implying that defective effector function was related to immune exhaustion. CD56+ CD8 T cells from elite or treated HIV patients responded to PMA plus ionomycin stimulation, and expressed transcription factors T-bet and EOMES at levels similar to uninfected controls. Consequently, the lytic effector defect in chronic HIV disease is due to immune exhaustion and quantitative loss of CD56+ CD8 T cells and this defect is not repaired in patients where viremia is suppressed and CD4 T cells are recovered after ART. Reconstituting the cytotoxic CD56+ subset of CD8+ T cells through new interventions might improve the lytic effector capacity and contribute to reducing the viral reservoir. Our initial studies indicate that IL-15 treatment partly reverses the CD56 defect, implying that myeloid cell defects could be targeted for immune therapy during chronic HIV disease.


Dynamic reorganization of intrinsic functional networks in the mouse brain.
Functional connectivity (FC) derived from resting-state functional magnetic resonance imaging (rs-fMRI) allows for the integrative study of neuronal processes at a macroscopic level. The majority of studies to date have assumed stationary interactions between brain regions, without considering the dynamic aspects of network organization. Only recently has the latter received increased attention, predominantly in human studies. Applying dynamic FC (dFC) analysis to mice is attractive given the relative simplicity of the mouse brain and the possibility to explore mechanisms underlying network dynamics using pharmacological, environmental or genetic interventions. Therefore, we have evaluated the feasibility and research potential of mouse dFC using the interventions of social stress or anesthesia duration as two case-study examples. By combining a sliding-window correlation approach with dictionary learning, several dynamic functional states (dFS) with a complex organization were identified, exhibiting highly dynamic inter- and intra-modular interactions. Each dFS displayed a high degree of reproducibility upon changes in analytical parameters and across datasets. They fluctuated at different degrees as a function of anesthetic depth, and were sensitive indicators of pathology as shown for the chronic psychosocial stress mouse model of depression. Dynamic functional states are proposed to make a major contribution to information integration and processing in the healthy and diseased brain.


Cancer-associated glycoforms of gelatinase B exhibit a decreased level of binding to galectin-3.
Gelatinase B (MMP-9) and galectin-3 are widely known to participate in tumor cell invasion and metastasis. Glycans derived from MMP-9 expressed in MCF-7 breast cancer and THP-1 myeloid leukemia cells were compared with those from MMP-9 expressed in natural neutrophils. The many O-linked glycans of neutrophil gelatinase B presented a cluster of mainly galactosylated core II structures, 46% of which were ligands for galectin-3; 11% contained two to three N-acetyllactosamine repeating units that are high-affinity ligands for the lectin. The glycan epitopes thus provide MMP-9 with both high-affinity and (presumably) high-avidity interactions with galectin-3. In contrast, the O-glycans released from MMP-9 expressed in MCF-7 and THP-1 cells were predominantly sialylated core I structures. Only 10% of MCF-7 and THP-1 gelatinase B O-glycans were ligands for galectin-3 and contained only a maximum single N-acetyllactosamine repeat. Consistent with the glycan analysis, surface plasmon resonance binding assays indicated that the cancer-associated glycoforms of MMP-9 bound galectin-3 with an affinity and avidity significantly reduced compared with those of the natural neutrophil MMP-9. Galectin-3 exists as a multimer that also binds laminin, providing a means of localizing neutrophil MMP-9 in the extracellular matrix (ECM). The analytical data presented here suggest that MMP-9 glycoforms secreted by tumor cells are unlikely to be tethered at the site of secretion, thus promoting more extensive cleavage of the ECM and providing a rationale for the contribution that gelatinase B makes to cancer cell metastasis.


Stable overexpression of the type-1 inositol 1,4,5-trisphosphate receptor in L fibroblasts: subcellular distribution and functional consequences.
InsP3 receptor (InsP3R)/Ca(2+)-release channels differ markedly in abundance in different tissues/cell types and InsP3R expression levels may be modulated in response to a variety of external cues. Cell lines overexpressing InsP3Rs will provide useful models for the study of the influence of receptor density and subtype on InsP3-mediated Ca2+ signalling. We have investigated the properties of InsP3Rs in mouse L fibroblast cell lines transfected with either type-1 InsP3R cDNA (L15) or vector control (Lvec). L15 cells express approximately eightfold higher levels of the type-1 InsP3R protein than Lvec cells, as assessed by radioligand binding and immunoblotting. Increased expression was stable since it did not alter over ten cell passages. Both L15 and Lvec cells express predominantly the type-1 InsP3R isoform, indicating that functional differences in the InsP3-mediated Ca2+ signalling in these cell lines are due to alteration in the levels of receptor rather than changes in the isoform expressed. Type-1 InsP3R in L15 cells is largely associated with subcellular membrane fractions bearing the sarco/endoplasmic reticulum Ca2+ ATPase pump, appropriate for rapidly exchanging Ca2+ pools. Functionally, there is an approximately fourfold increase in the sensitivity of permeabilized L15-cell Ca2+ mobilization in response to increasing concentrations of Ins(1,4,5)P3. This study indicates that L15/ Lvec cells provide a suitable model for studying the effects of InsP3R expression level on InsP3-induced Ca2+ mobilization.


Energetic radiation belt electron precipitation: a natural depletion mechanism for stratospheric ozone.
During geomagnetically disturbed periods the precipitational loss of energetic electrons from the outer radiation belt of the earth can readily provide the major ionization source for the mesosphere and upper stratosphere. One particularly intense manifestation of this interaction between the radiation belts and the lower atmosphere is the relativistic electron precipitation (REP) event which occurs at subauroral latitudes during magnetospheric substorm activity. At relativistic energies the precipitating electrons produce copious fluxes of energetic bremsstrahlung x-rays, the major portion of which penetrate deep into the stratosphere before undergoing excitation and ionization collisions with the neutral atmosphere. If such REP events occur more than a few percent of the time, they can, on an annual basis, provide a local source of upper stratospheric nitric oxide molecules (via the dissociation of molecular nitrogen) comparable to that from either galactic cosmic rays or energetic solar proton events. Since nitric oxide plays a major role in the removal of stratospheric ozone, it appears that the influence of REP events must also be considered in future photochemical modeling of the terrestrial ozone layer.


Dog ownership and health-related physical activity among Japanese adults.
Dog ownership appears to have associated health benefits as a result of increased physical activity through dog walking. This study examined the association between dog ownership and health-related physical activity among Japanese adults. Male and female respondents to an Internet-based cross-sectional survey were divided into the following groups: dog owner (DOG), nondog pet owner (NDOG), and nonpet owner (NPOG). Moderate and vigorous physical activity amount (MVPA), walking amount (Walking), and sedentary behavior time (SB) were estimated from the International Physical Activity Questionnaire. Analyses of covariance and logistic regression analysis were used. The differences in MVPA, Walking, and SB were statistically significant among the three groups. DOG had a significantly greater amount of MVPA than NDOG and NPOG. DOG also had a significantly greater amount of Walking and less SB time than NPOG, and DOG was 1.5 times more likely to meet the physical activity recommendation than NDOG and NPOG. The dog owners had higher physical activity levels than owners of other kinds of pets and those without any pets, suggesting that dogs may play a major role in promoting physical activity. However, only 30% of the dog owners met the recommended criteria for physical activity.


Responsiveness in rheumatoid arthritis. a report from the OMERACT 11 ultrasound workshop.
To summarize the work performed by the Outcome Measures in Rheumatology (OMERACT) Ultrasound (US) Task Force on the validity of different US measures in rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) presented during the OMERACT 11 Workshop. The Task Force is an international group aiming to iteratively improve the role of US in arthritis clinical trials. Recently a major focus of the group has been the assessment of responsiveness of a person-level US synovitis score in RA: the US Global Synovitis Score (US-GLOSS) combines synovial hypertrophy and power Doppler signal in a composite score detected at joint level. Work has also commenced examining assessment of tenosynovitis in RA and the role of US in JIA. The US-GLOSS was tested in a large RA cohort treated with biologic therapy. It showed early signs of improvement in synovitis starting at Day 7 and increasing to Month 6, and demonstrated sensitivity to change of the proposed grading. Subsequent voting questions concerning the application of the US-GLOSS were endorsed by > 80% of OMERACT delegates. A standardized US scoring system for detecting and grading severity of RA tenosynovitis and tendon damage has been developed, and acceptable reliability data were presented from a series of exercises. A preliminary consensus definition of US synovitis in pediatric arthritis has been developed and requires further testing. At OMERACT 11, consensus was achieved on the application of the US-GLOSS for evaluating synovitis in RA; and work continues on development of RA tenosynovitis scales as well as in JIA synovitis.


Reduction of polarization effects in interference coatings.
A design procedure is developed which yields layer combinations having a polarization independent effective index of refraction. A method of transforming massive media to nonpolarizing effective massive media is shown. These two design techniques are then applied to the problem of making polarization independent metal-dielectric-metal interference filters and polarization independent beam splitters.


High protein diets are associated with increased bacterial translocation in septic guinea pigs.
During sepsis, body protein stores are decreased due to an increase in protein catabolism. The utilization of nutritional support with high-protein diets has been used as a solution to the problem of sepsis-induced protein loss. Work from our laboratory, however, has shown that diets low in protein (5% of total calories) improve survival in septic animals as compared to high protein (20%) diets. The present study investigated the relationship between low-protein diets and improved survival by determining whether septic animals receiving high-protein diets have increased bacterial translocation. Sepsis was induced in guinea pigs by the implantation of an osmotic minipump into the peritoneal cavity containing an equal mixture of Escherichia coli (10(8)) and Staphylococcus aureus (10(8)) or saline. On Day 3 postlaparotomy, the animals were randomized to one of four groups. The groups consisted of septic and nonseptic animals that received a diet with 5 or 20% of total calories as protein. Following 4 days of diet all animals received an instillation of 14C labeled E. coli (10(10)). Four hours later the animals were sacrificed and blood, mesenteric lymph nodes, spleen, lungs, and liver were removed for determination of radionuclide counts. Results indicated that the septic animals that received the high protein diet had more bacterial translocation, as indexed by higher radionuclide counts in the MLN, liver, lung and blood. These findings suggest that a low protein, enterally fed diet may improve survival in septic patients by decreasing the incidence of bacterial translocation.


Trajectories of PTSD: a 20-year longitudinal study.
This study assessed the psychopathological effects of combat in veterans with and without combat stress reaction. Veterans (N=214) from the 1982 Lebanon War were assessed in a prospective longitudinal design: 131 suffered from combat stress reaction during the war, and 83 did not. They were evaluated 1, 2, 3, and 20 years after the war. Combat stress reaction is an important vulnerability marker. Veterans with combat stress reaction were 6.6 times more likely to endorse posttraumatic stress disorder (PTSD) at all four measurements, their PTSD was more severe, and they were at increased risk for exacerbation/reactivation. A qualitative analysis of the profile of PTSD symptoms revealed some time-related changes in the symptom configuration of veterans who did not suffer from combat stress reaction. In both groups, the course fluctuated; PTSD rates dropped 3 years postwar and rose again 17 years later; 23% of veterans without combat stress reaction reported delayed PTSD. These findings suggest that the detrimental effects of combat are deep and enduring and follow a complex course, especially in combat stress reaction casualties. The implications of aging and ongoing terror in impeding recovery from the psychological wounds of war are discussed.


Integrating online communities and social networks with computerised treatment for insomnia: a qualitative study.
Insomnia is a common psychological complaint. Cognitive behavioural therapy for insomnia (CBT-I), although effective, is little used because of lack of trained providers. Computerised CBT-I (CCBT-I) may be a solution to this shortfall in access. To explore patient and health professional perspectives and the role of social networking, to develop a novel CCBT-I programme to increase access to this form of intervention. Qualitative methods underpinned by the theory of planned behaviour in primary care in Lincolnshire and Nottinghamshire. Semi-structured interviews and focus groups with a purposive sample of health professionals and adults with insomnia. A total of 23 health professionals and 28 patients were interviewed. Features designed to engender trust and improve functionality were perceived to improve uptake and adherence to CCBT-I. Trust lay in programme accreditation; for professionals, trust derived from evidence of effectiveness; for patients, trust depended on the doctor-patient relationship, professional support, the quality of online peer support, and perceptions of risk. Patients wanted mobile applications; access in short periods; self-assessment; interactive, personalised information on sleep; and moderated contact with other users. Patients and practitioners differed over whether useful information could be distinguished from less useful or potentially incorrect information. Improving uptake and adherence to online programmes for insomnia requires design features focusing on trust and functionality. Enabling greater patient control and interaction with other users and professionals may stimulate positive experiences of online therapy. CCBT-I would enable greater access to treatment but is limited by lack of online access or poor computer literacy.


Poly(ethylene glycol)-conjugated phospholipids in aqueous micellar solutions: hydration, static structure, and interparticle interactions.
By means of dielectric relaxation spectroscopy (DRS) and small-angle X-ray scattering (SAXS), we have investigated hydration behavior, solvent dynamics, and static structures of aqueous solutions of poly(ethylene glycol)-conjugated distearoyl phosphatidylethanolamine (DSPE-PEG) (molecular weight of PEG: M(PEG)= 2000, 5000, and 12,000 Da). A quantitative analysis of the bulk-water relaxation amplitude revealed the effective hydration number of a DSPE-PEG molecule per ethylene oxide monomer unit to be approximately 5.0-5.5, virtually independent of M(PEG). The overall hydration number of a DSPE-PEG molecule is ca. 20% higher than that of the corresponding normal PEG (without DSPE). This is attributed to both hydration of a charged head group of phosphoric acid in DSPE and a packing effect of PEG chains into micellar structures. The pair-distance distribution functions, p(r), extracted from the GIFT analysis of SAXS intensities show that the DSPE-PEGs form spherical-like micelles in water having the maximum diameter of approximately 16, 22, and 31 nm, respectively, for M(PEG) = 2000, 5000, and 12,000 Da and nearly identical aggregation numbers of 72 (+/-10%). The DSPE-PEG micelles behave as charged colloids whose interparticle interaction potential can be approximated by the screened Coulomb potential model. The extracted pair correlation function g(r) demonstrates that both electrostatic repulsion induced by the charged head group and excluded volume effects of the fully hydrated PEG layer contribute to repulsive interactions among the PEG-lipid micelles. This should be a key factor for the function of PEG lipids as a stabilizer of liposomes.


A Replication-Defective Human Cytomegalovirus Vaccine Elicits Humoral Immune Responses Analogous to Those with Natural Infection.
Human cytomegalovirus (HCMV) can cause congenital infections, which are a leading cause of childhood disabilities. Since the rate of maternal-fetal transmission is much lower in naturally infected (HCMV-seropositive) women, we hypothesize that a vaccine candidate capable of eliciting immune responses analogous to those of HCMV-seropositive subjects may confer protection against congenital HCMV. We have previously described a replication-defective virus vaccine based on strain AD169 (D. Wang, D. C. Freed, X. He, F. Li, et al., Sci Transl Med 8:362ra145, 2016, https://doi.org/10.1126/scitranslmed.aaf9387). The vaccine, named V160, has been shown to be safe and immunogenic in HCMV-seronegative human subjects, eliciting both humoral and cellular immune responses (S. P. Adler, S. E. Starr, S. A. Plotkin, S. H. Hempfling, et al., J Infect Dis 220:411-419, 2019, https://doi.org/10.1093/infdis/171.1.26). Here, we further showed that sera from V160-immunized HCMV-seronegative subjects have attributes similar in quality to those from seropositive subjects, including high-avidity antibodies to viral antigens, coverage against a panel of genetically distinct clinical isolates, and protection against viral infection in diverse types of human cells in culture. More importantly, vaccination appeared efficient in priming the human immune system, inducing memory B cells in six V160 recipients at frequencies comparable to those of three HCMV-seropositive subjects. Our results demonstrate the ability of V160 to induce robust and durable humoral memory responses to HCMV, justifying further clinical evaluation of the vaccine against congenital HCMV.IMPORTANCEIn utero HCMV infection can lead to miscarriage or childhood disabilities, and an effective vaccine is urgently needed. Since children born to women who are seropositive prior to pregnancy are less likely to be affected by congenital HCMV infection, it has been hypothesized that a vaccine capable of inducing an immune response resembling the responses in HCMV-seropositive women may be effective. We previously described a replication-defective virus vaccine that has been demonstrated safe and immunogenic in HCMV-seronegative subjects. Here, we conducted additional analyses to show that the vaccine can induce antibodies with functional attributes similar to those from HCMV-seropositive subjects. Importantly, vaccination can induce long-lived memory B cells at frequencies comparable to those seen in HCMV-seropositive subjects. We conclude that this vaccine is a promising candidate that warrants further clinical evaluation for prevention of congenital HCMV.


The effects of frusemide, saralasin and hypotension on fetal plasma renin activity and on fetal renal function.
1. In eleven chronically catheterized fetal sheep aged 124-142 days, hypotension caused by infusion of sodium nitroprusside (1.6-3.3 mg/h) and competitive antagonism of angiotensin II by saralasin (3.3 mg/h) both caused a fall in fetal urine flow (P less than 0.02 and P less than 0.05, respectively), and in sodium excretion (P less than 0.05 and P less than 0.01) because they both caused a fall in glomerular filtration rate (G.F.R., P less than 0.02 and P less than 0.01). Neither hypotension nor saralasin had any significant effect on fractional sodium reabsorption. Saralasin only caused a significant fall in systolic pressure (P = 0.05) while infusion of sodium nitroprusside caused a fall in both systolic and diastolic pressure (P less than 0.005 and P less than 0.02). 2. Frusemide (6 mg I.V) caused a marked natriuresis and diuresis (F = 24.9, P less than 0.005 and F = 30.5, P less than 0.005). This effect was maximal within 30 min. There was no change in fetal G.F.R. and there was a significant decrease in the fraction of the filtered sodium load that was reabsorbed (F = 10.44, P less than 0.0025). Fetal mean plasma renin activity (p.r.a.) rose progressively throughout (F = 9.3, P less than 0.005). When frusemide was given to fetal sheep which were hypotensive because they were infused with sodium nitroprusside, it still caused a diuresis (F = 5.73, P less than 0.025) and the fraction of the filtered sodium load that was reabsorbed decreased (F = 4.06, P less than 0.05) to a similar extent to that seen in animals given frusemide alone. On the other hand, frusemide was ineffective as a diuretic i.e. it had no effect on fractional sodium reabsorption, when given to fetal sheep which were infused with saralasin. 3. Injection of frusemide was associated with a significant rise in the diastolic pressures of hypotensive fetuses (P less than 0.05). Furthermore, when the infusion of saralasin was terminated 1.5 h after frusemide injection, blood pressure rose significantly (F = 11.19, P less than 0.0005 for systolic pressure and F = 7.15, P less than 0.005 for diastolic pressure) and p.r.a. fell (F = 4.78, P less than 0.025). 4. It is concluded that the fetal renin-angiotensin system can play a significant role in regulation of fetal blood pressure.(ABSTRACT TRUNCATED AT 400 WORDS)


Erythritol is a pentose-phosphate pathway metabolite and associated with adiposity gain in young adults.
Metabolomic markers associated with incident central adiposity gain were investigated in young adults. In a 9-mo prospective study of university freshmen (n = 264). Blood samples and anthropometry measurements were collected in the first 3 d on campus and at the end of the year. Plasma from individuals was pooled by phenotype [incident central adiposity, stable adiposity, baseline hemoglobin A1c (HbA1c) > 5.05%, HbA1c < 4.92%] and assayed using GC-MS, chromatograms were analyzed using MetaboliteDetector software, and normalized metabolite levels were compared using Welch's t test. Assays were repeated using freshly prepared pools, and statistically significant metabolites were quantified in a targeted GC-MS approach. Isotope tracer studies were performed to determine if the potential marker was an endogenous human metabolite in men and in whole blood. Participants with incident central adiposity gain had statistically significantly higher blood erythritol [P < 0.001, false discovery rate (FDR) = 0.0435], and the targeted assay revealed 15-fold [95% confidence interval (CI): 13.27, 16.25] higher blood erythritol compared with participants with stable adiposity. Participants with baseline HbA1c > 5.05% had 21-fold (95% CI: 19.84, 21.41) higher blood erythritol compared with participants with lower HbA1c (P < 0.001, FDR = 0.00016). Erythritol was shown to be synthesized endogenously from glucose via the pentose-phosphate pathway (PPP) in stable isotope-assisted ex vivo blood incubation experiments and through in vivo conversion of erythritol to erythronate in stable isotope-assisted dried blood spot experiments. Therefore, endogenous production of erythritol from glucose may contribute to the association between erythritol and obesity observed in young adults.


'The positive feel': Unpacking the role of positive thinking in people with multiple sclerosis's thinking aloud about staying physically active.
People with multiple sclerosis experience barriers to physical activity. Thought processes are interwoven with garnering motivation to overcome these barriers. This study investigated in-depth the role of positive thinking in physical activity motivation of two women and two men with multiple sclerosis. Participants thought aloud while completing standardised measures of physical activity, stages of change and self-efficacy, and in response to planned and spontaneous questions. Four themes were formulated using inductive thematic analysis: thoughts about purpose, self-efficacy, the past and reinforcement through positive thinking. These findings have implications for physical activity theories and delivering appropriate physical activity interventions to the multiple sclerosis community.


Serotonin synthesis, release and reuptake in terminals: a mathematical model.
Serotonin is a neurotransmitter that has been linked to a wide variety of behaviors including feeding and body-weight regulation, social hierarchies, aggression and suicidality, obsessive compulsive disorder, alcoholism, anxiety, and affective disorders. Full understanding of serotonergic systems in the central nervous system involves genomics, neurochemistry, electrophysiology, and behavior. Though associations have been found between functions at these different levels, in most cases the causal mechanisms are unknown. The scientific issues are daunting but important for human health because of the use of selective serotonin reuptake inhibitors and other pharmacological agents to treat disorders in the serotonergic signaling system. We construct a mathematical model of serotonin synthesis, release, and reuptake in a single serotonergic neuron terminal. The model includes the effects of autoreceptors, the transport of tryptophan into the terminal, and the metabolism of serotonin, as well as the dependence of release on the firing rate. The model is based on real physiology determined experimentally and is compared to experimental data. We compare the variations in serotonin and dopamine synthesis due to meals and find that dopamine synthesis is insensitive to the availability of tyrosine but serotonin synthesis is sensitive to the availability of tryptophan. We conduct in silico experiments on the clearance of extracellular serotonin, normally and in the presence of fluoxetine, and compare to experimental data. We study the effects of various polymorphisms in the genes for the serotonin transporter and for tryptophan hydroxylase on synthesis, release, and reuptake. We find that, because of the homeostatic feedback mechanisms of the autoreceptors, the polymorphisms have smaller effects than one expects. We compute the expected steady concentrations of serotonin transporter knockout mice and compare to experimental data. Finally, we study how the properties of the the serotonin transporter and the autoreceptors give rise to the time courses of extracellular serotonin in various projection regions after a dose of fluoxetine. Serotonergic systems must respond robustly to important biological signals, while at the same time maintaining homeostasis in the face of normal biological fluctuations in inputs, expression levels, and firing rates. This is accomplished through the cooperative effect of many different homeostatic mechanisms including special properties of the serotonin transporters and the serotonin autoreceptors. Many difficult questions remain in order to fully understand how serotonin biochemistry affects serotonin electrophysiology and vice versa, and how both are changed in the presence of selective serotonin reuptake inhibitors. Mathematical models are useful tools for investigating some of these questions.


Implementing a transitional care program to reduce hospital readmissions among older adults.
This research examines the early implementation of an evidence-based intervention, adapted from the Coleman Care Transitions Intervention and community-based models, aimed at reducing preventable hospital readmissions among older adults. To better understand program implementation, we conducted and analyzed in-depth interviews on the basis of the Promoting Action on Research Implementation in Health Services conceptual framework. Contextual factors, evidence support for the intervention, and facilitation techniques should be taken into account when implementing transitional care programs.


Association of Plasma Neurofilament Light With Neurodegeneration in Patients With Alzheimer Disease.
Existing cerebrospinal fluid (CSF) or imaging (tau positron emission tomography) biomarkers for Alzheimer disease (AD) are invasive or expensive. Biomarkers based on standard blood test results would be useful in research, drug development, and clinical practice. Plasma neurofilament light (NFL) has recently been proposed as a blood-based biomarker for neurodegeneration in dementias. To test whether plasma NFL concentrations are increased in AD and associated with cognitive decline, other AD biomarkers, and imaging evidence of neurodegeneration. In this prospective case-control study, an ultrasensitive assay was used to measure plasma NFL concentration in 193 cognitively healthy controls, 197 patients with mild cognitive impairment (MCI), and 180 patients with AD dementia from the Alzheimer's Disease Neuroimaging Initiative. The study dates were September 7, 2005, to February 13, 2012. The plasma NFL analysis was performed in September 2016. Associations were tested between plasma NFL and diagnosis, Aβ pathologic features, CSF biomarkers of neuronal injury, cognition, brain structure, and metabolism. Among 193 cognitively healthy controls, 197 patients with mild cognitive impairment, and 180 patients with AD with dementia, plasma NFL correlated with CSF NFL (Spearman ρ = 0.59, P < .001). Plasma NFL was increased in patients with MCI (mean, 42.8 ng/L) and patients with AD dementia (mean, 51.0 ng/L) compared with controls (mean, 34.7 ng/L) (P < .001) and had high diagnostic accuracy for patients with AD with dementia vs controls (area under the receiver operating characteristic curve, 0.87, which is comparable to established CSF biomarkers). Plasma NFL was particularly high in patients with MCI and patients with AD dementia with Aβ pathologic features. High plasma NFL correlated with poor cognition and AD-related atrophy (at baseline and longitudinally) and with brain hypometabolism (longitudinally). Plasma NFL is associated with AD diagnosis and with cognitive, biochemical, and imaging hallmarks of the disease. This finding implies a potential usefulness for plasma NFL as a noninvasive biomarker in AD.


Disease manifestations and pathogenic mechanisms of Group A Streptococcus.
Streptococcus pyogenes, also known as group A Streptococcus (GAS), causes mild human infections such as pharyngitis and impetigo and serious infections such as necrotizing fasciitis and streptococcal toxic shock syndrome. Furthermore, repeated GAS infections may trigger autoimmune diseases, including acute poststreptococcal glomerulonephritis, acute rheumatic fever, and rheumatic heart disease. Combined, these diseases account for over half a million deaths per year globally. Genomic and molecular analyses have now characterized a large number of GAS virulence determinants, many of which exhibit overlap and redundancy in the processes of adhesion and colonization, innate immune resistance, and the capacity to facilitate tissue barrier degradation and spread within the human host. This improved understanding of the contribution of individual virulence determinants to the disease process has led to the formulation of models of GAS disease progression, which may lead to better treatment and intervention strategies. While GAS remains sensitive to all penicillins and cephalosporins, rising resistance to other antibiotics used in disease treatment is an increasing worldwide concern. Several GAS vaccine formulations that elicit protective immunity in animal models have shown promise in nonhuman primate and early-stage human trials. The development of a safe and efficacious commercial human vaccine for the prophylaxis of GAS disease remains a high priority.


Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer.
Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase. We randomly assigned patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, who had or did not have brain metastases, to receive either tucatinib or placebo, in combination with trastuzumab and capecitabine. The primary end point was progression-free survival among the first 480 patients who underwent randomization. Secondary end points, assessed in the total population (612 patients), included overall survival, progression-free survival among patients with brain metastases, confirmed objective response rate, and safety. Progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.42 to 0.71; P<0.001), and the median duration of progression-free survival was 7.8 months and 5.6 months, respectively. Overall survival at 2 years was 44.9% in the tucatinib-combination group and 26.6% in the placebo-combination group (hazard ratio for death, 0.66; 95% CI, 0.50 to 0.88; P = 0.005), and the median overall survival was 21.9 months and 17.4 months, respectively. Among the patients with brain metastases, progression-free survival at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group (hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P<0.001), and the median progression-free survival was 7.6 months and 5.4 months, respectively. Common adverse events in the tucatinib group included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. Diarrhea and elevated aminotransferase levels of grade 3 or higher were more common in the tucatinib-combination group than in the placebo-combination group. In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib. (Funded by Seattle Genetics; HER2CLIMB ClinicalTrials.gov number, NCT02614794.).