Variation patterns of cervical alignment in ankylosing spondylitis-related thoracolumbar kyphosis following pedicle subtraction osteotomy in the sitting position: an EOS-based investigation.
Both unchanged upper cervical lordosis combined with decreased lower cervical lordosis and decreased upper cervical lordosis combined with decreased lower cervical lordosis have been reported to occur after correction surgery for adult spinal deformity. However, variations in cervical alignment after correction surgery in patients with ankylosing spondylitis (AS) have not been investigated. The current study aimed to investigate the variations in cervical alignment following the correction surgery in AS patients with thoracolumbar kyphosis. Patients with AS who underwent pedicle subtraction osteotomy (PSO) for thoracolumbar kyphosis from June 2016 to June 2019 with a minimum of 1-year follow-up were reviewed. Patients were grouped according to the presence (ossified group) and absence (non-ossified group) of total ossification of the anterior longitudinal ligament (ALL) in the lower cervical spine. Radiographic parameters, including thoracolumbar, craniocervical, and global radiographic parameters, were measured on lateral sitting EOS images. Thirty-two patients (27 males and 5 females) with a mean follow-up of 1.5 years were identified. There were 21 patients in the non-ossified group and 11 patients in the ossified group. After PSO, both groups showed a decrease in the occiput-C7 angle (p < 0.001 for both). In the non-ossified group, the C2-7 angle decreased significantly (p < 0.001), while the occiput-C2 angle remained unchanged (p = 0.570). In the ossified group, the occiput-C2 angle decreased significantly (p < 0.001), while C2-7 angle remained unchanged (p = 0.311). In addition, the change in occiput-C2 was correlated with the osteotomy angle in the ossified group (R = 0.776, p = 0.005). The variation patterns of cervical alignment following correction surgery for AS-related thoracolumbar kyphosis were different based on patients with or without total ossification of ALL in the lower cervical spine. When planning PSO for patients in the ossified group, restoration of the physiological upper cervical lordosis angle could be achieved by adjusting the osteotomy angle.


Sweet-talk: role of host glycosylation in bacterial pathogenesis of the gastrointestinal tract.
Glycosylation is a key modification of proteins and lipids and is involved in most intermolecular and intercellular interactions. The gastrointestinal mucus gel is continuous and can be divided into two layers: a secreted loosely associated layer and a layer firmly attached to the mucosa. In addition, the membrane-bound glycosylated proteins and lipids create a glycocalyx, which remains adherent on each cell and is dynamic and responsive to the physiological state and environment of the cell. The secreted glycans form a mucus gel layer that serves as a physicochemical sensor and barrier network and is primarily composed of mucins and associated peptides. These glycans protect gut epithelial cells from chemical, biological and physical insults and are continuously renewed. Pathogens colonise and invade the host epithelial cells using protein-protein and glycan-lectin interactions. During the process of colonisation and infection, the glycosylation state of both host and pathogen change in response to the presence of the other. This complex modulation of glycan expression critically determines pathogenesis and the host response in terms of structural changes and immune response. In addition, by influencing host immunity and gut glycosylation, the microbiota can further effect protection against pathogens. In this review, the roles of host glycosylation in interactions with two prevalent bacterial pathogens, Campylobater jejuni and Helicobacter pylori, are discussed to illustrate important concepts in pathogenesis.


Mango (Mangifera indica L.) polyphenols reduce IL-8, GRO, and GM-SCF plasma levels and increase Lactobacillus species in a pilot study in patients with inflammatory bowel disease.
Inflammatory bowel disease (IBD) characterized by chronic intestinal inflammation and intestinal microbial dysbiosis present a major risk factor in the development of colorectal cancer. Previously, dietary polyphenols from mango (Mangifera indica L.) such as gallotannins and gallic acid have been shown to mitigate intestinal inflammation and carcinogenesis, as well as modulate intestinal microbial composition. To further translate findings from preclinical models, we hypothesized that mango polyphenols possess anti-inflammatory and microbiome-modulatory activities and may improve symptoms of IBD, reduce biomarkers for inflammation and modulate the intestinal microbiome when administered as an adjuvant treatment in combination with conventional medications in patients with mild to moderate IBD. In this study, ten participants received a daily dose of 200-400 g of mango pulp for 8 weeks (NCT02227602). Mango intake significantly improved the primary outcome Simple Clinical Colitis Activity Index (SCCAI) score and decreased the plasma levels of pro-inflammatory cytokines including interleukin-8 (IL-8), growth-regulated oncogene (GRO) and granulocyte macrophage colony-stimulating factor (GM-CSF) by 16.2% (P = .0475), 25.0% (P = .0375) and 28.6% (P = .0485), all factors related to neutrophil-induced inflammation, respectively. Mango intake beneficially altered fecal microbial composition by significantly increasing the abundance of Lactobacillus spp., Lactobacillus plantarum, Lactobacillus reuteri and Lactobacillus lactis, which was accompanied by increased fecal butyric acid production. Therefore, enriching diet with mango fruits or potentially other gallotannin-rich foods seems to be a promising adjuvant therapy combined with conventional medications in the management of IBD via reducing biomarkers of inflammation and modulating the intestinal microbiota.


New Zealand Drivers Study: a follow-up study of newly licensed drivers.
Despite significant improvement since graduated licensing was introduced, traffic-related injury remains the leading cause of death and hospitalisation among young New Zealanders. Most research to date has used routinely collected crash data but has been limited in that these databases do not, and realistically cannot, include the level of detail required to ensure that learner driver policy and programmes are based on sound scientific evidence applicable to young drivers in the current New Zealand context. To examine the driving-related experiences of newly licensed drivers to identify factors associated with increased or decreased risk of negative traffic outcomes. Multistage prospective cohort study. New Zealand. Newly licensed drivers. background demographic details, pre-licence driving, previous crashes, driving intentions, motivations for driving and licensing, sensation seeking, aggression, impulsivity, quality and quantity of driving experience, driving supervision, driving behaviour, alcohol and other drug use, compliance with New Zealand's graduated driver licensing scheme, driver training/education, cell phone use, and sleep. crash, conviction, infringements, risky driving. participants and their parents. Outcomes: participants and official records. BIAS: On the basis of a pilot study, participation and attrition bias are likely to be minimal. A comparison of baseline data for those followed and those not followed will be undertaken. Information bias will be minimised by standardised questionnaires. Information on potential confounders is to be collected and controlled for in analyses. STUDY SIZE: 5000 (including 1500 Māori). Survival analysis, logistic or Poisson regression, generalised estimating equations.


Adaptive tuning of cell sensory diversity without changes in gene expression.
In the face of uncertainty, cell populations tend to diversify to enhance survival and growth. Previous studies established that cells can optimize such bet hedging upon environmental change by modulating gene expression to adapt both the average and diversity of phenotypes. Here, we demonstrate that cells can tune phenotypic diversity also using posttranslational modifications. In the chemotaxis network of Escherichia coli, we find, for both major chemoreceptors Tar and Tsr, that cell-to-cell variation in response sensitivity is dynamically modulated depending on the presence or absence of their cognate chemoeffector ligands in the environment. Combining experiments with mathematical modeling, we show that this diversity tuning requires only the environment-dependent covalent modification of chemoreceptors and a standing cell-to-cell variation in their allosteric coupling. Thus, when environmental cues are unavailable, phenotypic diversity enhances the population's readiness for many signals. However, once a signal is perceived, the population focuses on tracking that signal.


2-Mercapto-Quinazolinones as Inhibitors of Type II NADH Dehydrogenase and Mycobacterium tuberculosis: Structure-Activity Relationships, Mechanism of Action and Absorption, Distribution, Metabolism, and Excretion Characterization.
Mycobacterium tuberculosis ( MTb) possesses two nonproton pumping type II NADH dehydrogenase (NDH-2) enzymes which are predicted to be jointly essential for respiratory metabolism. Furthermore, the structure of a closely related bacterial NDH-2 has been reported recently, allowing for the structure-based design of small-molecule inhibitors. Herein, we disclose MTb whole-cell structure-activity relationships (SARs) for a series of 2-mercapto-quinazolinones which target the ndh encoded NDH-2 with nanomolar potencies. The compounds were inactivated by glutathione-dependent adduct formation as well as quinazolinone oxidation in microsomes. Pharmacokinetic studies demonstrated modest bioavailability and compound exposures. Resistance to the compounds in MTb was conferred by promoter mutations in the alternative nonessential NDH-2 encoded by ndhA in MTb. Bioenergetic analyses revealed a decrease in oxygen consumption rates in response to inhibitor in cells in which membrane potential was uncoupled from ATP production, while inverted membrane vesicles showed mercapto-quinazolinone-dependent inhibition of ATP production when NADH was the electron donor to the respiratory chain. Enzyme kinetic studies further demonstrated noncompetitive inhibition, suggesting binding of this scaffold to an allosteric site. In summary, while the initial MTb SAR showed limited improvement in potency, these results, combined with structural information on the bacterial protein, will aid in the future discovery of new and improved NDH-2 inhibitors.


Diabetes-impaired wound healing is improved by matrix therapy with heparan sulfate glycosaminoglycan mimetic OTR4120 in rats.
Wound healing in diabetes is frequently impaired, and its treatment remains a challenge. We tested a therapeutic strategy of potentiating intrinsic tissue regeneration by restoring the wound cellular environment using a heparan sulfate glycosaminoglycan mimetic, OTR4120. The effect of OTR4120 on healing of diabetic ulcers was investigated. Experimental diabetes was induced by intraperitoneal injection of streptozotocin. Seven weeks after induction of diabetes, rats were ulcerated by clamping a pair of magnet disks on the dorsal skin for 16 h. After magnet removal, OTR4120 was administered via an intramuscular injection weekly for up to 4 weeks. To examine the effect of OTR4120 treatment on wound heal-ing, the degree of ulceration, inflammation, angiogenesis, and collagen synthesis were evaluated. We found that OTR4120 treatment significantly reduced the degree of ulceration and the time of healing. These effects were associated with reduced neutrophil infiltration and macrophage accumulation and enhanced angiogenesis. OTR4120 treatment also increased the collagen content with an increase of collagen type I biosynthesis and reduction of collagen type III biosynthesis. Moreover, restoration of the ulcer biomechanical strength was significantly enhanced after OTR4120 treatment. This study shows that matrix therapy with OTR4120 improves diabetes-impaired wound healing.


Role of lymphangiogenesis in epithelial ovarian cancer.
We investigated the significance of lymphatic count, vascular count and angiogenic growth factors using immunohistochemistry in 108 tumour specimens of epithelial ovarian cancer with antibodies to lymphatic vessel endothelial hyaluronan receptor (LYVE-1), platelet endothelial cell adhesion molecule CD31, vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP) in epithelial ovarian cancer to understand the pathogenesis of metastasis in ovarian cancer. The effect of prognostic variables on progression-free and overall survival was assessed. On multivariate analysis, bulky residual disease after surgery was the best prognostic indicator (P<0.001) for progression-free and overall survival (P<0.001). Lymphatic count was statistically significant as a prognostic factor for progression-free (P=0.05) and overall survival (P=0.04). However, lymphatic count did not impact on survival curves. No correlation was found between lymphatic count and age, histological subtype, FIGO stage or residual disease. Vascular count, VEGF or TP expressions were not significant in either analysis. Lymphatic spread may be significant in aiding metastases in ovarian cancer but requires other biological factors to act in conjunction, as it does not have clearcut prognostic significance. Dissemination of ovarian cancer does not occur primarily through vascular or lymphatic routes but may occur through direct intraperitoneal spread of disease.


Diagnosis and treatment of pediatric myelodysplastic syndromes: A survey of the North American Pediatric Aplastic Anemia Consortium.
Myelodysplastic syndromes (MDS) represent a group of clonal hematopoietic stem cell disorders that commonly progress to acute myeloid leukemia (AML). The diagnostics, prognostics, and treatment of adult MDS are established but do not directly translate to children and adolescents. Pediatric MDS is a rare disease, characterized by unique cytogenetics and histology compared with adult MDS, and often arises secondary to germline predisposition or cytotoxic exposures. Our objective was to highlight aspects of diagnosis/management that would benefit from further systematic review toward the development of clinical practice guidelines for pediatric MDS. The North American Pediatric Aplastic Anemia Consortium (NAPAAC) is composed of collaborative institutions with a strong interest in pediatric bone marrow failure syndromes and hematologic malignancies. The NAPAAC MDS working group developed a national survey distributed to 35 NAPAAC institutions to assess data on (1) clinical presentation of pediatric MDS, (2) diagnostic evaluation, (3) criteria for diagnosis, (4) supportive care and treatment decisions, and (5) role of hematopoietic stem cell transplantation (HSCT). Twenty-eight of 35 institutions returned the survey. Most centers agreed on a common diagnostic workup, though there was considerable variation regarding the criteria for diagnosis. Although there was consensus on supportive care, treatment strategies, including the role of cytoreduction and HSCT, varied across centers surveyed. There is lack of national consensus on diagnosis and treatment of pediatric MDS. This survey identified key aspects of MDS management that will warrant systematic review toward the goal of developing national clinical practice guidelines for pediatric MDS.


Epidemiology and management of chronic constipation in elderly patients.
Constipation is a common functional gastrointestinal disorder, with prevalence in the general population of approximately 20%. In the elderly population the incidence of constipation is higher compared to the younger population, with elderly females suffering more often from severe constipation. Treatment options for chronic constipation (CC) include stool softeners, fiber supplements, osmotic and stimulant laxatives, and the secretagogues lubiprostone and linaclotide. Understanding the underlying etiology of CC is necessary to determine the most appropriate therapeutic option. Therefore, it is important to distinguish from pelvic floor dysfunction (PFD), slow and normal transit constipation. Evaluation of a patient with CC includes basic blood work, rectal examination, and appropriate testing to evaluate for PFD and slow transit constipation when indicated. Pelvic floor rehabilitation or biofeedback is the treatment of choice for PFD, and its efficacy has been proven in clinical trials. Surgery is rarely indicated in CC and can only be considered in cases of slow transit constipation when PFD has been properly excluded. Other treatment options such as sacral nerve stimulation seem to be helpful in patients with urinary dysfunction. Botulinum toxin injection for PFD cannot be recommended at this time with the available evidence. CC in the elderly is common, and it has a significant impact on quality of life and the use of health care resources. In the elderly, it is imperative to identify the etiology of CC, and treatment should be based on the patient's overall clinical status and capabilities.


Clinical, surgical, and pathological findings in client-owned rabbits with histologically confirmed appendicitis: 19 cases (2015-2019).
To report clinical, surgical, and pathological findings in client-owned rabbits with histologically confirmed appendicitis. 19 rabbits. Medical records for client-owned rabbits that had a histologic diagnosis of appendicitis were reviewed. Median age of the rabbits at presentation was 24.0 months (range, 4 to 84 months). Seventeen cases occurred during the summer and fall seasons. Decreased appetite (17/19 rabbits), abnormal rectal temperature (hyperthermia, 9/16 rabbits; hypothermia, 4/16 rabbits), hypocalcemia (8/11 rabbits), and hypoglycemia (7/15 rabbits) were common signs. Abdominal ultrasonography and CT findings were suggestive of appendicitis in 6 of 8 rabbits and in 1 of 2 rabbits, respectively. Of the 6 rabbits that received medical treatment, 3 died at 48 hours, 1 died at 24 hours after hospitalization, and 1 died at 10 days after presentation; 1 rabbit was alive at 1,030 days after presentation. Of the 8 rabbits that underwent appendectomy, 3 died before discharge from the hospital and 1 died 113 days after surgery; 4 rabbits were alive at 315, 334, 1,433, and 1,473 days after presentation. The remaining 5 rabbits either died or were euthanized before treatment could be instituted. In each of the 19 rabbits, the appendix had evidence of severe inflammation with mucosal ulceration, heterophilic inflammation, and necrotic debris. For rabbits with decreased appetite and an apparently painful abdomen, hyperthermia, hypocalcemia, or hypoglycemia, appendicitis should be considered as a differential diagnosis. Further comparisons of medical and surgical treatments are required to establish treatment recommendations for rabbits with appendicitis.


A combined luciferase-expressing Leishmania imaging/RT-qPCR assay provides new insights into the sequential bilateral processes deployed in the ear pinna of C57BL/6 mice.
Leishmania/L. major was identified as the etiological agent of human localized cutaneous leishmaniasis. L. major metacyclic promastigotes/MP - the infectious form transmitted by sand flies - were enriched from axenically-derived cultures and inoculated into the dermis of mice (10(3) or 10(4) luciferase-expressing L. major MP inoculated into the C57BL/6 mouse ear pinna). Quantitative readout assays were then combined with imaging of this L. major-hosting skin site and established i) that a specific period of time - depending upon the L. major load used for the inoculation - is required for the L. major-hosting ear pinna to be continuously populated by a balanced population of functional regulatory and effector T lymphocytes, and that ii) this balance coincides with persisting low numbers of amastigotes in more or less rapidly healing skin. This approach also established that, whatever the MP inoculum load delivered to the primary site, the immune processes that reduce the L. major amastigote population also account for concomitant immunity, namely remodelling of the secondary site - where 10(4) MP were delivered - as a clinically silent niche hosting a small L. major population.


Treatment of severe malaria with artemisinin derivatives. A systematic review of randomised controlled trials.
This systematic review of randomised or pseudorandomised trials aimed at summarising the effectiveness and safety of artemisinin drugs for treating severe falciparum malaria in adults and children. Survival was better with artemisinin drugs in 1.265 patients compared with 1.183 treated with quinine (OR: 0.68; 95% CI: 0.55-0.84). However, the difference is barely significant when only studies with adequate concealment of allocation at enrolment are included in the analysis (OR: 0.77; 95% CI: 0.61-0.98). In 1784 patients with cerebral malaria, mortality was also lower with artemisinin drugs overall (OR: 0.70; 95% CI: 0.55-0.90), but not significantly better than quinine in studies reporting adequate concealment of allocation. No difference in neurological sequelae has been demonstrated. Artemisinin drugs clear parasites from the blood faster than quinine. Adverse effects are similarly common with artemisinin drugs and quinine, although reporting varies between trials. There is no evidence from this review that any one artemisinin derivative is better than the others, but comparative studies are few, small and heterogeneous.


Mixed matrix formulations with MOF molecular sieving for key energy-intensive separations.
Membrane-based separations can improve energy efficiency and reduce the environmental impacts associated with traditional approaches. Nevertheless, many challenges must be overcome to design membranes that can replace conventional gas separation processes. Here, we report on the incorporation of engineered submicrometre-sized metal-organic framework (MOF) crystals into polymers to form hybrid materials that successfully translate the excellent molecular sieving properties of face-centred cubic (fcu)-MOFs into the resultant membranes. We demonstrate, simultaneously, exceptionally enhanced separation performance in hybrid membranes for two challenging and economically important applications: the removal of CO2 and H2S from natural gas and the separation of butane isomers. Notably, the membrane molecular sieving properties demonstrate that the deliberately regulated and contracted MOF pore-aperture size can discriminate between molecular pairs. The improved performance results from precise control of the linkers delimiting the triangular window, which is the sole entrance to the fcu-MOF pore. This rational-design hybrid approach provides a general toolbox for enhancing the transport properties of advanced membranes bearing molecular sieve fillers with sub-nanometre-sized pore-apertures.


Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial.
Gastrointestinal stromal tumour is the most common sarcoma of the intestinal tract. Imatinib mesylate is a small molecule that inhibits activation of the KIT and platelet-derived growth factor receptor alpha proteins, and is effective in first-line treatment of metastatic gastrointestinal stromal tumour. We postulated that adjuvant treatment with imatinib would improve recurrence-free survival compared with placebo after resection of localised, primary gastrointestinal stromal tumour. We undertook a randomised phase III, double-blind, placebo-controlled, multicentre trial. Eligible patients had complete gross resection of a primary gastrointestinal stromal tumour at least 3 cm in size and positive for the KIT protein by immunohistochemistry. Patients were randomly assigned, by a stratified biased coin design, to imatinib 400 mg (n=359) or to placebo (n=354) daily for 1 year after surgical resection. Patients and investigators were blinded to the treatment group. Patients assigned to placebo were eligible to crossover to imatinib treatment in the event of tumour recurrence. The primary endpoint was recurrence-free survival, and analysis was by intention to treat. Accrual was stopped early because the trial results crossed the interim analysis efficacy boundary for recurrence-free survival. This study is registered with ClinicalTrials.gov, number NCT00041197. All randomised patients were included in the analysis. At median follow-up of 19.7 months (minimum-maximum 0-56.4), 30 (8%) patients in the imatinib group and 70 (20%) in the placebo group had had tumour recurrence or had died. Imatinib significantly improved recurrence-free survival compared with placebo (98% [95% CI 96-100] vs 83% [78-88] at 1 year; hazard ratio [HR] 0.35 [0.22-0.53]; one-sided p<0.0001). Adjuvant imatinib was well tolerated, with the most common serious events being dermatitis (11 [3%] vs 0), abdominal pain (12 [3%] vs six [1%]), and diarrhoea (ten [2%] vs five [1%]) in the imatinib group and hyperglycaemia (two [<1%] vs seven [2%]) in the placebo group. Adjuvant imatinib therapy is safe and seems to improve recurrence-free survival compared with placebo after the resection of primary gastrointestinal stromal tumour. US National Institutes of Health and Novartis Pharmaceuticals.


Identification and optimization of hydrazone-gallate derivatives as specific inhibitors of DNA methyltransferase 3A.
DNA methylation is the most studied epigenetic event. Since the methylation profile of the genome is widely modified in cancer cells, DNA methyltransferases are the target of new anticancer therapies. Nucleosidic inhibitors suffer from toxicity and chemical stability, while non-nucleosidic inhibitors lack potency. Here, we found a novel DNMT inhibitor scaffold by enzymatic screening and structure-activity relationship studies. The optimization studies led to an inhibitor containing three fragments: a gallate frame, a hydrazone linker and a benzothiazole moiety. Interestingly, the compound inhibits DNMT3A with micromolar potency (EC50 = 1.6 μM) and does not inhibit DNMT1; this DNMT3A selectivity is supported by a docking study. Finally, the compound reactivates a reporter gene in leukemia KG-1 cells.


Reduction of transpiration and altered nutrient allocation contribute to nutrient decline of crops grown in elevated CO(2) concentrations.
Plants grown in elevated [CO(2) ] have lower protein and mineral concentrations compared with plants grown in ambient [CO(2) ]. Dilution by enhanced production of carbohydrates is a likely cause, but it cannot explain all of the reductions. Two proposed, but untested, hypotheses are that (1) reduced canopy transpiration reduces mass flow of nutrients to the roots thus reducing nutrient uptake and (2) changes in metabolite or enzyme concentrations caused by physiological changes alter requirements for minerals as protein cofactors or in other organic complexes, shifting allocation between tissues and possibly altering uptake. Here, we use the meta-analysis of previous studies in crops to test these hypotheses. Nutrients acquired mostly by mass flow were decreased significantly more by elevated [CO(2) ] than nutrients acquired by diffusion to the roots through the soil, supporting the first hypothesis. Similarly, Mg showed large concentration declines in leaves and wheat stems, but smaller decreases in other tissues. Because chlorophyll requires a large fraction of total plant Mg, and chlorophyll concentration is reduced by growth in elevated [CO(2) ], this supports the second hypothesis. Understanding these mechanisms may guide efforts to improve nutrient content, and allow modeling of nutrient changes and health impacts under future climate change scenarios.


Treatability and fate of various phosphorus fractions in different wastewater treatment processes.
The increasingly more stringent phosphorus (P) discharge limits, which are below the concentrations reliably achievable with currently available technologies, demand for better understanding of phosphorus removal mechanisms. This study investigated the compositional fractions of phosphorus (P) in various effluents as well as the efficacy of different levels of treatment processes for removing different fractions of P in wastewater. The results showed that BNR can effectively remove most fractions of P, with relatively higher efficiencies (>93%) towards bioavailable forms of P including soluble reactive P (sRP), particulate reactive P (pRP) portion and particulate acid hydrolysable P (pAHP) and, it showed relatively lower efficiency (78%) towards organic P. Soluble acid hydrolysable P (sAHP) was not effectively removed (<40%). Chemical P removal process was more effective for elimination of sRP, sAHP and particulate organic P (pOP), but was not as effective for removing pAHP and, it exhibited nearly no removal of dissolved organic P (DOP). We found that chemical P removal process led to a significant increase in the concentration of pRP by up to 255%, indicating that these pRP (presumably as chemically bounded P) are likely formed through chemical precipitation/co-adsorption. Only 22% and 64% of the pRP was removed through tertiary clarifier and filtration, respectively. This implies that chemical addition converts sRP into particulate-associated P, mostly as pRP that was not easily removed by sedimentation and filtration, therefore, the efficacy of chemical P removal highly depends on the effectiveness of solid and liquid separation process. As more sRP and particulate P were removed through the series of treatment processes, the percentage contribution from organic P increases with the level of treatment due to its recalcitrant nature. Our results indicated that in order to achieve extremely low effluent P levels, technologies and processes that can enhance pRP and DOP removal will be required.


The 18-kDa Translocator Protein as a CNS Drug Target: Finding Our Way Through the Neuroinflammation Fog.
The 18-kDa translocator protein (TSPO) is located in the outer mitochondrial membrane where it is thought to co-regulate steroidogenesis, cellular bioenergetics as well as several other cellular processes. Originally discovered as a binding site for diazepam outside the CNS, notably in steroidogenic tissue and mononuclear phagocytes, the TSPO's historical designation was peripheral benzodiazepine receptor. Much of the recent interest in TSPO is due to the observation that its regulation in the brain is associated with microglial activation. Importantly, this activation can be visualized in vivo by positron emission tomography (PET) using TSPO ligands. TSPO levels in normal brain tissue are close to current detection limits, being restricted to blood vessels and possibly areas of natural cell turnover. However, any progressive tissue damage is associated with a marked increase in TSPO expression, most prominently in activated microglia. Therefore, the inducible TSPO expression can serve as an exquisitely responsive sensor in a range of active brain pathologies, which are often conflated under the term 'neuroinflammation'. However, what occurs histologically in 'neuroinflammation' is different from classical brain tissue inflammation in the vast majority of cases. The resulting conceptual confusion poses potentially significant risks for patients who receive misguided anti-inflammatory treatment. It also obscures the fact that microglia may have other important roles, notably at synapses. 'Neuroinflammation' is at the current level of our understanding primarily the observation of dynamic tissue changes in the brain, the relevance of which for disease progression or brain plasticity phenomena is likely to be context dependent and remains to be worked out in detail. Here, we discuss the potential of TSPO as a therapeutic drug target for CNS disorders. In this review, we focus on psychiatric and neurodegenerative disorders, elaborate the role of TSPO and the effects of TSPO ligands on common disease phenotypes reviewing evidence from both animal models and patient cohorts and discuss future directions. As a modulator of pivotal cell processes, TSPO may serve as a drug target in well defined translational applications.


Use of automated sequencing of polymerase chain reaction-generated amplicons to identify three types of cholera toxin subunit B in Vibrio cholerae O1 strains.
Cholera toxin is the principal factor causing the profuse intestinal fluid secretion that is characteristic of cholera. The DNA sequences of the cholera toxin subunit B structural genes from 45 Vibrio cholerae O1 strains isolated in 29 countries over a period of 70 years were determined by automated DNA sequencing of polymerase chain reaction-generated amplicons. Three types of cholera toxin B subunit gene (ctxB) were identified. Genotype 1 was found in strains of classical biotype worldwide and El Tor biotype strains associated with the U.S. Gulf Coast, genotype 2 was found in El Tor biotype strains from Australia, and genotype 3 was found in El Tor biotype strains from the seventh pandemic and the recent Latin American epidemic. All base changes correspond to an amino acid substitution in the B subunit of the cholera toxin. Heterogenicity in the B subunit could have implications for vaccine development and diagnostic tests for cholera toxin and antitoxin. We conclude that this technology provides timely and potentially useful epidemiological information.


Establishment of a local psychiatric service.
The Faroe Islands are a group of islands in the North Atlantic Ocean between Norway and Iceland inhabited by about 42,000 people. They are considered a nation with home rule within the Danish Kingdom. A Psychiatric Department was not established on the islands until 1969. Before this, psychiatric patients were referred to the local General Hospital and about half of the patients in each diagnostic group were sent on the Psychiatric Hospital in Nykøbing on Zealand, Denmark. Since the establishment of the department, admissions have increased in all diagnostic groups, especially in the group of senile psychoses. The total increase amounts to 2.4 times the admission rates of psychiatric cases to the General Hospital and 4.4 times the admission rates to the Psychiatric Hospital in Nykøbing in the last years prior to the start of the local service. The outpatient department has grown steadily, the patients attending are distributed in diagnostic groups similar to Danish outpatient departments.


Repeated irradiation with suberythemal ultraviolet B reduces the number of epidermal Langerhans cells.
The influence of repeated low-dose ultraviolet B (UVB) radiation, to which we are exposed in daily life, has not been fully clarified, although the damage caused by exposure to high-dose UVB radiation has been well-studied in recent years. To investigate skin damage caused by repeated low-dose exposure, we evaluated the extent of injury to the Langerhans cells which are known to be involved in the cutaneous immune system. The backs of hairless mice were exposed to the following doses of UVB radiation: 100 mJ/cm(2) once, 50 mJ/cm(2) twice, 25 mJ/cm(2) four times or 10 mJ/cm(2) ten times. Skin specimens were taken for histochemical and electron microscopic examination 24 h after the final irradiation. Epidermis exposed to UVB radiation demonstrated a decrease in the number of Langerhans cells which showed less dendricity. The population of these cells in specimens exposed to repeated suberythemal doses was reduced to 40%, whereas exposure to a single high dose of UVB with the same energy resulted in a reduction of only 33%. These results indicate that repeated suberythemal doses injure Langerhans cells more than a single high-dose exposure. Furthermore, Birbeck granules in Langerhans cells of UVB-irradiated epidermis were reduced and tended to show shortening of their rod portion. The present study suggested that repeated challenge with suberythemal UVB radiation, to which we are all exposed in daily life, can cause substantial damage to Langerhans cells.


Process-induced phase transformation of berberine chloride hydrates.
Berberine is a natural quaternary ammonium alkaloid used clinically in the chloride salt form for the treatment of diarrhea in many Asian countries. Although the hydrate formation of berberine chloride (BCl) is well documented, the associated mechanism and implications in pharmaceutical formulation have not been studied in detail. In this study, pure BCl dihydrate and BCl tetrahydrate were recrystallized from water and their phase transformation behaviors under defined conditions were investigated. Additionally, pharmacopoeial grade BCl material consisting predominantly of the dihydrate form was examined for potential phase changes when being subjected to a conventional wet granulation procedure for tablet production. Results from solubility measurements, thermal analysis, variable temperature-powder X-ray diffraction (VT-PXRD), and variable temperature-Fourier transform infrared spectroscopy (VT-FTIR) confirmed the solid-state interconversions between the tetrahydrate and dihydrate at 30-49 degrees C and between the dihydrate and anhydrate at 70-87 degrees C. Consistent with the observed phase changes of the two pure hydrates, wet massing of the pharmacopoeial grade BCl sample led to a thermodynamics-driven transition to the tetrahydrate form at room temperature while subsequent tray drying at 50 degrees C caused a reversion back to the dihydrate form. The rate and extent of such hydrate conversion depended largely on the water activity of the granulated powder matrix, which in turn was governed by the particular excipients employed. The present findings have important implications in the regulation of the hydrate forms of BCl in the finished products using specific excipients.


TREX is a conserved complex coupling transcription with messenger RNA export.
The essential yeast proteins Yra1 and Sub2 are messenger RNA export factors that have conserved counterparts in metazoans, designated Aly and UAP56, respectively. These factors couple the machineries that function in splicing and export of mRNA. Here we show that both Yra1 and Sub2 are stoichiometrically associated with the heterotetrameric THO complex, which functions in transcription in yeast. We also show that Sub2 and Yra1 interact genetically with all four components of the THO complex (Tho2, Hpr1, Mft1 and Thp2). Moreover, these components operate in the export of bulk poly(A)(+) RNA as well as of mRNA derived from intronless genes. Both Aly and UAP56 associate with human counterparts of the THO complex. Together, these data define a conserved complex, designated the TREX ('transcription/export') complex. The TREX complex is specifically recruited to activated genes during transcription and travels the entire length of the gene with RNA polymerase II. Our data indicate that the TREX complex has a conserved role in coupling transcription to mRNA export.


Distinguishing a Majorana zero mode using spin-resolved measurements.
One-dimensional topological superconductors host Majorana zero modes (MZMs), the nonlocal property of which could be exploited for quantum computing applications. We use spin-polarized scanning tunneling microscopy to show that MZMs realized in self-assembled Fe chains on the surface of Pb have a spin polarization that exceeds that stemming from the magnetism of these chains. This feature, captured by our model calculations, is a direct consequence of the nonlocality of the Hilbert space of MZMs emerging from a topological band structure. Our study establishes spin-polarization measurements as a diagnostic tool to distinguish topological MZMs from trivial in-gap states of a superconductor.


Tobacco Dependence Treatment Grants: A Collaborative Approach to the Implementation of WHO Tobacco Control Initiatives.
The number of global tobacco-related deaths is projected to increase from about 6 million to 8 million annually by 2030, with more than 80% of these occurring in low- and middle-income countries (LMICs). The World Health Organization Framework Convention on Tobacco Control (FCTC) came into force in 2005 and Article 14 relates specifically to the treatment of tobacco dependence. However, LMICs, in particular, face several barriers to implementing tobacco dependence treatment. This paper is a descriptive evaluation of a novel grant funding mechanism that was initiated in 2014 to address these barriers. Global Bridges. Healthcare Alliance for Tobacco Dependence Treatment aims to create and mobilize a global network of healthcare professionals and organizations dedicated to advancing evidence-based tobacco dependence treatment and advocating for effective tobacco control policy. A 2014 request for proposals (RFP) focused on these goals, particularly in LMICs, where funding for this work had been previously unavailable. 19 grants were awarded by Global Bridges to organizations in low- and middle-income countries across all six WHO regions. Virtually all focused on developing a tobacco dependence treatment curriculum for healthcare providers, while also influencing the political environment for Article 14 implementation. As a direct result of these projects, close to 9,000 healthcare providers have been trained in tobacco dependence treatment and an estimated 150,000 patients have been offered treatment. Because most of these projects are designed with a "train-the-trainer" component, two years of grant funding has been a tremendous catalyst for accelerating change in tobacco dependence treatment practices throughout the world. In order to foster such exponential growth and continue to maintain the impact of these projects, ongoing financial, educational, and professional commitments are required.


Cardiorespiratory fitness relates more strongly than physical activity to cardiovascular disease risk factors in healthy children and adolescents: the European Youth Heart Study.
Physical activity and cardiorespiratory fitness are closely related to health variables in adults, especially those considered to be among risk factors for cardiovascular diseases. The possible tracking of cardiovascular disease risk factors from childhood to adulthood makes it important to increase our understanding of the complex relationships between physical activity, cardiorespiratory fitness and cardiovascular risk factors early in life. A cross-sectional, school-based study on healthy children and adolescents, aged 9-10 years (295 girls, 295 boys) and 15-16 years (302 girls, 233 boys) was performed during a school year in Sweden and Estonia, as part of the European Youth Heart Study. Total physical activity, and minutes spent in inactivity and activity of moderate or higher intensity were measured by accelerometry. A maximal ergometer bike test was used for estimation of cardiorespiratory fitness. The risk factors included blood pressure and fasting blood levels of insulin, glucose, triglycerides, total cholesterol and high-density lipoprotein cholesterol. Canonical correlations between physical activity and cardiorespiratory fitness versus cardiovascular disease risk factors showed significant associations in both age and sex groups (rc=0.46-0.61, P<0.0001). The cardiorespiratory fitness was found to be the strongest contributor to these relationships. In girls high values of the physical activity variables were also associated with a favourable cardiovascular profile. Cardiorespiratory fitness relates more strongly to cardiovascular risk factors than components of objectively measured physical activity in children and adolescents. Physical activity becomes more important in the 15-year-old adolescents, indicating that these modifiable lifestyle factors increase in importance with age.


Densities of Agrilus auroguttatus and Other Borers in California and Arizona Oaks.
We investigated within-tree population density of a new invasive species in southern California, the goldspotted oak borer, Agrilus auroguttatus Schaeffer (Coleoptera: Buprestidae), with respect to host species and the community of other borers present. We measured emergence hole densities of A. auroguttatus and other borers on the lower stem (bole) of naïve oaks at 18 sites in southern California and on co-evolved oaks at seven sites in southeastern Arizona. We sampled recently dead oaks in an effort to quantify the community of primary and secondary borers associated with mortality-species that were likely to interact with A. auroguttatus. Red oaks (Section Lobatae) produced greater densities of A. auroguttatus than white oaks (Section Quercus). On red oaks, A. auroguttatus significantly outnumbered native borers in California (mean ± SE of 9.6 ± 0.7 versus 4.5 ± 0.6 emergence holes per 0.09 m² of bark surface), yet this was not the case in Arizona (0.9 ± 0.2 versus 1.1 ± 0.2 emergence holes per 0.09 m²). In California, a species that is taxonomically intermediate between red and white oaks, Quercus chrysolepis (Section Protobalanus), exhibited similar A. auroguttatus emergence densities compared with a co-occurring red oak, Q. kelloggii. As an invasive species in California, A. auroguttatus may affect the community of native borers (mainly Buprestidae and Cerambycidae) that feed on the lower boles of oaks, although it remains unclear whether its impact will be positive or negative.


Path integration in place cells of developing rats.
Place cells in the hippocampus and grid cells in the medial entorhinal cortex rely on self-motion information and path integration for spatially confined firing. Place cells can be observed in young rats as soon as they leave their nest at around 2.5 wk of postnatal life. In contrast, the regularly spaced firing of grid cells develops only after weaning, during the fourth week. In the present study, we sought to determine whether place cells are able to integrate self-motion information before maturation of the grid-cell system. Place cells were recorded on a 200-cm linear track while preweaning, postweaning, and adult rats ran on successive trials from a start wall to a box at the end of a linear track. The position of the start wall was altered in the middle of the trial sequence. When recordings were made in complete darkness, place cells maintained fields at a fixed distance from the start wall regardless of the age of the animal. When lights were on, place fields were determined primarily by external landmarks, except at the very beginning of the track. This shift was observed in both young and adult animals. The results suggest that preweaning rats are able to calculate distances based on information from self-motion before the grid-cell system has matured to its full extent.


Effects of attentional focus on motor learning in children with autism spectrum disorder.
Inability to acquire a new motor skill is a common motor difficulty in children with autism spectrum disorder. The purpose of this study is to examine whether the motor learning benefits of an external focus of attention for typically developing children and children with intellectual disabilities could also be applied to children with autism spectrum disorder. Children ( N = 65; mean age = 10.01 years) diagnosed with high-functioning autism spectrum disorder were randomly assigned into one of the three groups: external focus ( n = 22), internal focus ( n = 22), and control ( n = 21). They were required to throw beanbags at a static target for 50 acquisition trials, 10 retention trials, and 10 transfer trials. While all three groups learnt the skills in a similar manner during the acquisition phase, the internal focus group demonstrated more robust motor performance than the external focus group and the control group in both retention and transfer tests, while there was no difference between the external focus group and the control group in both retention and transfer tests. The findings provide evidence that internal focus of attention may be more effective for facilitating motor learning in children with autism spectrum disorder. However, further study is needed to determine the factors contributing to this finding.


Phosphorylation of Rad55 on serines 2, 8, and 14 is required for efficient homologous recombination in the recovery of stalled replication forks.
DNA damage checkpoints coordinate the cellular response to genotoxic stress and arrest the cell cycle in response to DNA damage and replication fork stalling. Homologous recombination is a ubiquitous pathway for the repair of DNA double-stranded breaks and other checkpoint-inducing lesions. Moreover, homologous recombination is involved in postreplicative tolerance of DNA damage and the recovery of DNA replication after replication fork stalling. Here, we show that the phosphorylation on serines 2, 8, and 14 (S2,8,14) of the Rad55 protein is specifically required for survival as well as for normal growth under genome-wide genotoxic stress. Rad55 is a Rad51 paralog in Saccharomyces cerevisiae and functions in the assembly of the Rad51 filament, a central intermediate in recombinational DNA repair. Phosphorylation-defective rad55-S2,8,14A mutants display a very slow traversal of S phase under DNA-damaging conditions, which is likely due to the slower recovery of stalled replication forks or the slower repair of replication-associated DNA damage. These results suggest that Rad55-S2,8,14 phosphorylation activates recombinational repair, allowing for faster recovery after genotoxic stress.


Narcissism and romantic relationships: The differential impact of narcissistic admiration and rivalry.
Narcissism is known to be related to romantic success in short-term contexts (dating, early stage relationships) but also to problems in long-term committed relationships. We propose that these diverging romantic outcomes of narcissism can be explained by differential associations with agentic versus antagonistic dimensions of grandiose narcissism: Narcissistic Admiration and Rivalry. Both dimensions serve the central narcissistic goal of gaining and maintaining a grandiose self-view, but do so by different processes: Admiration is characterized by the tendency to promote the positivity of one's self-view by seeking social admiration (assertive self-enhancement). Rivalry is characterized by the tendency to protect oneself from a negative self-view by derogating others (antagonistic self-protection). Across 7 studies (total N = 3,560) using diverse measures and methodological approaches (self-, peer, and partner reports, as well as interpersonal perception measures in video-based studies, face-to-face laboratory encounters, and online surveys), we show that the short-term romantic appeal associated with narcissism is primarily attributable to the dimension of Admiration, whereas the long-term romantic problems associated with narcissism are primarily attributable to the dimension of Rivalry. These results highlight the utility of a 2-dimensional reconceptualization of grandiose narcissism for explaining its heterogeneous romantic outcomes. The findings further underscore the idea that different facets of personality traits might impact different aspects of romantic relationship quality, depending on the stage of the relationship. Such a more nuanced view increases the predictive validity of personality traits in social relationship research. (PsycINFO Database Record


CE: Understanding the Nurse's Role in Managing Gaucher Disease.
: Lysosomal storage disorders (LSDs) are a group of inherited metabolic conditions, the overall incidence of which is estimated to range from one in 5,000 to one in 7,000 live births. Gaucher disease, the most common LSD, is of autosomal recessive inheritance. It results from a deficiency of acid β-glucocerebrosidase and can affect the spleen, liver, bone, bone marrow, and central nervous system. Gaucher disease is clinically classified into one of three phenotypes, depending on the absence or presence of neurodegenerative disease and the rate of disease progression. Although there is no cure for Gaucher disease, it may be treated with enzyme replacement and substrate reduction therapy. With the development of enzyme testing through dried blood spots, Gaucher disease may now be detected at birth through newborn screening. The purpose of this article is to review the epidemiology and pathophysiology of Gaucher disease, update nurses on advances in newborn screening, diagnosis, and management of this genetic disorder, and highlight the role of nurses in the diagnosis and care of patients with Gaucher disease.


End-of-life transitions among nursing home residents with cognitive issues.
Health care transitions in the last months of life can be burdensome and potentially of limited clinical benefit for patients with advanced cognitive and functional impairment. To examine health care transitions among Medicare decedents with advanced cognitive and functional impairment who were nursing home residents 120 days before death, we linked nationwide data from the Medicare Minimum Data Set and claims files from 2000 through 2007. We defined patterns of transition as burdensome if they occurred in the last 3 days of life, if there was a lack of continuity in nursing homes after hospitalization in the last 90 days of life, or if there were multiple hospitalizations in the last 90 days of life. We also considered various factors explaining variation in these rates of burdensome transition. We examined whether there was an association between regional rates of burdensome transition and the likelihood of feeding-tube insertion, hospitalization in an intensive care unit (ICU) in the last month of life, the presence of a stage IV decubitus ulcer, and hospice enrollment in the last 3 days of life. Among 474,829 nursing home decedents, 19.0% had at least one burdensome transition (range, 2.1% in Alaska to 37.5% in Louisiana). In adjusted analyses, blacks, Hispanics, and those without an advance directive were at increased risk. Nursing home residents in regions in the highest quintile of burdensome transitions (as compared with those in the lowest quintile) were significantly more likely to have a feeding tube (adjusted risk ratio, 3.38), have spent time in an ICU in the last month of life (adjusted risk ratio, 2.10), have a stage IV decubitus ulcer (adjusted risk ratio, 2.28), or have had a late enrollment in hospice (adjusted risk ratio, 1.17). Burdensome transitions are common, vary according to state, and are associated with markers of poor quality in end-of-life care.


Production and utilization of acellular lung scaffolds in tissue engineering.
Pulmonary disease is a worldwide public health problem that reduces the quality of life and increases the need for hospital admissions as well as the risk for premature death for those affected. For many patients, lung transplantation is the only chance for survival. Unfortunately, there is a significant shortage of lungs for transplantation and since the lung is the most likely organ to be damaged during procurement many lungs deemed unacceptable for transplantation are simply discarded. Rather than discarding these lungs they can be used to produce three-dimensional acellular (AC) natural lung scaffolds for the generation of engineered lung tissue. AC scaffolds are lungs whose original cells have been destroyed by exposure to detergents and physical methods of removing cells and cell debris. This creates a lung scaffold from the skeleton of the lungs themselves. The scaffolds are then used to support adult, stem or progenitor cells which can be grown into functional lung tissue. Recent studies show that engineered lung tissues are capable of surviving after in vivo transplantation and support limited gas exchange. In the future engineered lung tissue has the potential to be used in clinical applications to replace lung functions lost following injury or disease. This manuscript discusses recent advances in development and use of AC scaffolds to support engineering of lung tissues.


Death by 'ice': fatal methamphetamine intoxication of a body packer case detected by postmortem computed tomography (PMCT) and validated by autopsy.
Fatal acute methamphetamine (MA) poisoning in cases of internal drug trafficking is rarely described in the literature. This case study reports an MA 'body packer' who died from fatal methamphetamine intoxication due to leaking drug packages in the alimentary tract. The deceased was examined by postmortem computed tomography (PMCT), and the results were correlated to subsequent autopsy and toxicological findings. The deceased was arrested by the police when he was found disoriented in the city of Kuala Lumpur. He was transferred to the emergency department on suspicion of drug abuse. The initial drug screening was reactive for amphetamines. Shortly after admission to the hospital, he died despite rigorous resuscitation attempts. The postmortem plain chest and abdominal radiographs revealed multiple suspicious opacities in the gastrointestinal tract attributable to body packages. An unenhanced whole body PMCT revealed twenty-five drug packages, twenty-four in the stomach and one in the transverse colon. At least two were disintegrating, and therefore leaking. The autopsy findings were consistent with the PMCT results. Toxicology confirmed the diagnosis of fatal methamphetamine intoxication.


Is the relationship between increased knee muscle strength and improved physical function following exercise dependent on baseline physical function status?
Clinical guidelines recommend knee muscle strengthening exercises to improve physical function. However, the amount of knee muscle strength increase needed for clinically relevant improvements in physical function is unclear. Understanding how much increase in knee muscle strength is associated with improved physical function could assist clinicians in providing appropriate strength gain targets for their patients in order to optimise outcomes from exercise. The aim of this study was to investigate whether an increase in knee muscle strength is associated with improved self-reported physical function following exercise; and whether the relationship differs according to physical function status at baseline. Data from 100 participants with medial knee osteoarthritis enrolled in a 12-week randomised controlled trial comparing neuromuscular exercise to quadriceps strengthening exercise were pooled. Participants were categorised as having mild, moderate or severe physical dysfunction at baseline using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Associations between 12-week changes in physical function (dependent variable) and peak isometric knee extensor and flexor strength (independent variables) were evaluated with and without accounting for baseline physical function status and covariates using linear regression models. In covariate-adjusted models without accounting for baseline physical function, every 1-unit (Nm/kg) increase in knee extensor strength was associated with physical function improvement of 17 WOMAC units (95% confidence interval (CI) -29 to -5). When accounting for baseline severity of physical function, every 1-unit increase in knee extensor strength was associated with physical function improvement of 24 WOMAC units (95% CI -42 to -7) in participants with severe physical dysfunction. There were no associations between change in strength and change in physical function in participants with mild or moderate physical dysfunction at baseline. The association between change in knee flexor strength and change in physical function was not significant, irrespective of baseline function status. In patients with severe physical dysfunction, an increase in knee extensor strength and improved physical function were associated. ANZCTR 12610000660088 . Registered 12 August 2010.


Defining "success" in recruitment of underrepresented populations to cancer clinical trials: moving toward a more consistent approach.
Although medically underserved groups bear a heavy burden of cancer disease and governmental agencies have required inclusion of minorities and women in cancer clinical trials since 1993, many of these groups are underrepresented in cancer prevention or treatment clinical trials. To assess and enhance recruitment of underrepresented populations into cancer-related clinical trials, investigators and governmental agencies need consistent measurement approaches for recruitment that can be applied to diverse settings where trials are conducted. We conducted a systematic review to evaluate what measurement approaches were used to evaluate the success of recruitment of underrepresented groups into cancer prevention or treatment trials, and whether these recruitment goals were stated a priori. Only two articles reported an a priori recruitment goal. The recruitment measurement approaches varied considerably, with no consistent standard, especially for individual trials. By using the empiric evidence from this review in conjunction with the National Institutes of Health (NIH) guidelines, we constructed a framework for choosing consistent a priori recruitment goals for underrepresented groups based on the research question and study location. Using consistent measurement approaches for underrepresented groups will improve comparability of recruitment strategies across trials, improve equity in distribution of benefits and burdens of cancer-related clinical trials, and may improve applicability of trial results to multiple populations.


A controllable honeycomb-like amorphous cobalt sulfide architecture directly grown on the reduced graphene oxide-poly(3,4-ethylenedioxythiophene) composite through electrodeposition for non-enzyme glucose sensing.
A facile, controllable two-step electrodeposition synthesis route was developed, whereby a honeycomb-like amorphous cobalt sulfide architecture was obtained via direct growth on a glassy carbon electrode (GCE) functionalized by a reduced graphene oxide-poly(3,4-ethylenedioxythiophene) (rGO-PEDOT) composite film as an electrode for glucose detection. This electrodeposition method is binder-free, rapid, low-cost and preparation-controlled. The effects of the concentration ratio between CoCl2·6H2O and thiourea, deposition scanning rate and deposition cycles on glucose detection were investigated, and the optimum preparation conditions were determined. The characterization results indicated that the honeycomb-like cobalt sulfide architecture was formed by growing vertically amorphous CoxSy nanosheets with a thickness of about 20-50 nm on the rGO-PEDOT surface, and the morphology of cobalt sulfide could be controlled by regulating the deposition cycles. Under optimal conditions, the sensor exhibited a wide linear range from 0.2 to 1380 μM (R2 = 0.9976), a sensitivity of 113.46 μA mM-1 cm-2, a low detection limit of 0.079 μM and a response time of 3 s. This sensor also displayed good selectivity, reproducibility and repeatability for non-enzyme glucose sensing. More importantly, the sensor was successfully used to determine glucose in human blood serum samples, and the results were consistent with hospital test results.


A new training method for velopharyngeal dysfunction: Self-inhalation for hypernasality.
There are various methods to treat velopharyngeal dysfunction including surgery and rehabilitation therapy. Even if a rehabilitation program is effective, the evaluation of its efficacy remains subjective. In this paper, we propose a new method of rehabilitation training for velopharyngeal dysfunction focusing on the objective peak inspiratory flow (PIF) rate. Four patients, who were diagnosed with velopharyngeal dysfunction without cleft palate at ENT clinic of the National Hospital Organization, Tokyo Medical Center, participated in this study. All patients underwent our original rehabilitation program for velopharyngeal dysfunction, a method using the In-Check Dial, Turbohaler model. As a self-training rehabilitation program, we asked them to inhale forcefully 10 times daily at home using the In-Check Dial to increase the value of PIF rate for 3 months. We measured the patients' PIF rates with the In-Check Dial at the ENT clinic at the initial visit and after the 3-month training. The PIF rates of the four patients without nasal clips were higher than the rates with nasal clips at the initial visit. After the training, PIF rate without a nasal clip of all patients increased than the rate at the initial visit, which represented significant difference (P < 0.05). Also, after 3 months, PIF rate without a nasal clip was higher or equal than the rates with a nasal clip at the initial visit except one case. Naso-pharyngo-laryngeal fiberscopy did not detect salivary pooling around larynx and mirror fogging test did not show nasal escape in the three of four patients after 3 months of training. All reported improvement in dysphagia and dysarthria. This new method can be used not only to evaluate velopharyngeal function but also as an effective self-training treatment.


A National Examination Of Long-Term Care Setting, Outcomes, And Disparities Among Elderly Dual Eligibles.
The benefits of expanding funding for Medicaid long-term care home and community-based services (HCBS) relative to institutional care are often taken as self-evident. However, little is known about the outcomes of these services, especially for racial and ethnic minority groups, whose members tend to use the services more than whites do, and for people with dementia who may need high-intensity care. Using national Medicaid claims data on older adults enrolled in both Medicare and Medicaid, we found that overall hospitalization rates were similar for HCBS and nursing facility users, although nursing facility users were generally sicker as reflected in their claims history. Among HCBS users, blacks were more likely to be hospitalized than non-Hispanic whites were, and the gap widened among blacks and whites with dementia. Also, conditional on receiving HCBS, Medicaid HCBS spending was higher for whites than for nonwhites, and higher Medicare and Medicaid hospital spending for blacks and Hispanics did not offset this difference. Our findings suggest that home and community-based services need to be carefully targeted to avoid adverse outcomes and that the racial/ethnic disparities in access to high-quality institutional long-term care are also present in HCBS. Policy makers should consider the full costs and benefits of shifting care from nursing facilities to home and community settings and the potential implications for equity.


Zinc and Manduca sexta hemocyte functions.
Two metalloproteases have recently been linked to the immune response in Lepidoptera. In addition, zinc is highly important in many mammalian immune-related functions. Because of these, we investigated the effect of zinc and two zinc-protease inhibitors on Manduca sexta hemocyte behavior in vitro. Plasmatocytes were significantly more elongated in Grace's medium supplemented with 100 micro m zinc chloride than in the absence of zinc. To test whether zinc-dependent proteases were responsible for the increased length seen in the presence of zinc, we tested two zinc-protease inhibitors, phosphoramidon and bestatin. Each resulted in decreased plasmatocyte length compared to the control, but the distributions of lengths differed with each inhibitor. Each inhibitor also affected plasmatocyte network formation in vitro. This work suggests (1) that at least two different zinc proteases are involved in the cellular defense response of M. sexta, and (2) that zinc should be included in media used for in vitro studies of the immune response.


Early-Phase Studies of Biomarkers: What Target Sensitivity and Specificity Values Might Confer Clinical Utility?
Many cancer biomarker research studies seek to develop markers that can accurately detect or predict future onset of disease. To design and evaluate these studies, one must specify the levels of accuracy sought. However, justified target levels are rarely available. We describe a way to calculate target levels of sensitivity and specificity for a biomarker intended to be applied in a defined clinical context. The calculation requires knowledge of the prevalence or incidence of cases in the clinical population and the ratio of benefit associated with the clinical consequences of a positive biomarker test in cases (true positive) to cost associated with a positive biomarker test in controls (false positive). Guidance is offered on soliciting the cost/benefit ratio. The calculations are based on the longstanding decision theory concept of providing a net benefit on average in the population, and they rely on some assumptions about uniformity of costs and benefits to those tested. Calculations are illustrated with 3 applications: predicting colon cancer recurrence in stage 1 patients; predicting interval breast cancer (between mammography screenings); and screening for ovarian cancer. It is feasible to specify target levels of biomarker performance that enable evaluation of the potential clinical impact of biomarkers in early-phase studies. Nevertheless, biomarkers meeting the criteria should still be tested rigorously in studies that measure the actual impact on patient outcomes of using the biomarker to make clinical decisions.


Moving from theory to practice: experience of implementing a learning supporting model designed to increase patient involvement and autonomy in care.
In implementing new programs of care, such as person-centered care, there is a risk that the focus will be at an organizational level, instead of a level that describes what happens in the personal development among staff. The aim of this study was to describe experiences of the implementation process of a learning supporting model designed to increase patient involvement and autonomy in care. The project, which lasted 2 years, involved training sessions, supervision and reflective meetings. Over the period, the staff who participated focused on developing their dialogues with patients to make the patients aware of their own capabilities and to encourage them to be fully involved in the treatment. A reflective lifeworld approach was used. Data were collected through interviews, notes and written stories, and analyzed using hermeneutic analysis with a focus on meanings. At the beginning of the project, the participants perceived the model as abstract and difficult to understand but supervision and reflection sessions enabled understanding and changed the participants' approach to caring. The participants described the model as an approach used in challenging patients to become involved in their care and to take charge of their lives when living with a chronic life-threatening disease. The participants' experience of implementing the model has not been easy but has led to increased self-confidence and feelings of improved competence in dialogue with patients. Using the PARISH model when critically examining the results shows that in the implementation process there were some difficulties, e.g. the context was supportive and facilitating but there was no appointed facilitator. By making participation in improvement work voluntary, the impact of such work becomes less efficient, less cost-effective and probably less sustainable. Furthermore, implementation needs encouragement since changing approaches takes time and requires patience. Group supervision sessions seem an appropriate way to translate research into practice; systematic scheduled and mandatory group supervision sessions would, therefore, probably make implementation more robust and sustainable. In addition, a well-trained facilitator would be able to motivate staff to undertake daily reflection and participate in group supervision sessions. Reflection seems to be a key component in the personal learning necessary to change work routines and approaches.


Patient Centered Hazard Ratio Estimation Using Principal Stratification Weights: Application to the NORCCAP Randomized Trial of Colorectal Cancer Screening.
In randomized trials, the most commonly reported method of effect estimation is intention-to-treat (ITT), and to a lesser extent the per-protocol. The ITT is preferred because it is an unbiased estimator of the effect of treatment assignment. However, if there is any non-adherence the ITT is a biased estimate of the treatment effect, defined as the contrast between the potential outcome if treated versus the potential outcome if not treated. The treatment effect is most relevant to patients. Principal stratification is a framework for estimating treatment effects that combines potential outcomes and latent adherence strata. It yields an unbiased estimator of the complier average causal effect (CACE) for a difference in means or proportions, in the setting of all-or-nothing adherence. This paper addresses estimation of the causal hazard ratio for the compliers in a setting of right censoring of a time-to-event. We propose a novel approach to operationalizing principal stratification using weights. We report the results of simulations that vary the amount of adherence and selection bias that show the hazard ratio estimators we propose have minimal bias compared to the ITT, and per-protocol estimators. We demonstrate the approach using a population based randomized controlled trial of colorectal cancer screening subject to a high frequency of nonadherence in the screening arm.


Cranberry anthocyanin as an herbal medicine lowers plasma cholesterol by increasing excretion of fecal sterols.
Interest in using herbal medicines to treat the hypercholesterolemia is increasing. Cranberry extract could decrease plasma cholesterol, however, the active ingredients and the underlying mechanisms remain largely unknown. The present study was to test the hypothesis that cranberry anthocyanins (CrA) were at least one of the active ingredients responsible for the cholesterol-lowering activity of cranberry fruits via a mechanism of increasing fecal sterol excretion. Forty-four hamsters were randomly divided into five groups and fed one of the five diets, namely a non-cholesterol control diet (NCD), a high-cholesterol control diet (HCD), a HCD diet supplemented with a low dose of 1% CrA (CL), a HCD diet supplemented with a high dose of 2% CrA (CH), and a HCD diet supplemented with 0.5% cholestyramine as a positive control drug (P-CTL), respectively, for six weeks. Plasma lipoprotein cholesterol was quantified using the enzymatic kits, while the gene expressions of transporters, enzymes and receptors involved in cholesterol absorption and metabolism were quantified using the quantitative RT-PCR. Fecal sterols were quantified using gas chromatography (GC). Plasma total cholesterol and aorta atherosclerotic plaque decreased dose-dependently with the increasing amounts of CrA added into diets. This was accompanied by a dose-dependent increase in excretion of both neutral and acidic sterols. CrA had no effect on the mRNA levels of intestinal Niemann-Pick C1 like 1 protein (NPC1L1), acyl CoA:cholesterol acyltransferase2 (ACAT2), microsomal triacylglycerol transport protein (MTP), and ATP binding cassette transporter 5 (ABCG5) as well as hepatic cholesterol-7α-hydroxylase (CYP7A1), 3-Hydroxy-3-methylglutaryl reductase (HMG-CoA-R), sterol regulatory element binding protein 2 (SREBP2), LDL receptor (LDL-R), and Liver X receptor alpha (LXRα). CrA as an herbal medicine could favorably modify the lipoprotein profile in hamsters fed a high cholesterol diet by enhancing excretion of fecal neutral and acidic sterols, most likely not mediated by interaction with genes of transporters, enzymes and proteins involved in cholesterol absorption and metabolism.


Collection and Reporting of Indigenous Status Information in Cancer Registries Around the World.
Worldwide, Indigenous people often have disproportionally worse health and lower life expectancy than their non-Indigenous counterparts. Despite the impact of cancer on life expectancy, little is known about the burden of cancer for Indigenous people primarily because of the paucity of data. We investigated the collection and reporting of Indigenous status information among a global sample of population-based cancer registries (PBCRs). An online survey was e-mailed to eligible registries using set inclusion criteria. Respondents were asked questions on the collection, reporting, and quality assessment of Indigenous status in their registers. Eighty-three PBCRs from 25 countries were included. Of these, 66% reported that their registry collected Indigenous status data, although the quality of this variable had been assessed in less than half in terms of completeness (38%) and accuracy (47%). Two thirds of PBCRs who collected Indigenous status data (67%), from nine of 25 countries responded that cancer statistics for Indigenous people were reported using registry data. Key barriers to the collection of Indigenous status information included the lack of data collection at the point of care (79%), lack of transfer of Indigenous status to the cancer registry (46%), inadequate information systems (43%), and legislative limitations (32%). Important variations existed among world regions, although the lack of Indigenous status data collection at the point of care was commonly reported across all regions. High-quality data collection is lacking for Indigenous peoples in many countries. To ensure the design and implementation of cancer control activities required to reduce disparities for Indigenous populations, health information systems, including cancer registries, need to be strengthened, and this must be done in dialogue with Indigenous leaders.


Sunset Science. II. A useful diagram.
We present diagrams that show how layers in atmospheric thermal structure are related to the altitudes at which they are seen tangentially. These dip diagrams show that the inferior mirage greatly magnifies the apparent angular size of the lowest few centimeters of atmosphere. Conversely, inversion layers below eye level are compressed-even to zero apparent thickness, in ducts. The diagrams show that, even when distant objects are miraged, the ray crossings occur beyond the lowest point on each ray where the line of sight is tangent to a horizontal surface in the atmosphere. Therefore the apparent altitudes of these tangent points are a monotonic function of their actual heights in the atmosphere. This monotonicity explains an apparent paradox in low-Sun images.


Generalizing Deep Whole Brain Segmentation for Pediatric and Post- Contrast MRI with Augmented Transfer Learning.
Generalizability is an important problem in deep neural networks, especially in the context of the variability of data acquisition in clinical magnetic resonance imaging (MRI). Recently, the Spatially Localized Atlas Network Tiles (SLANT) approach has been shown to effectively segment whole brain non-contrast T1w MRI with 132 volumetric labels. Enhancing generalizability of SLANT would enable broader application of volumetric assessment in multi-site studies. Transfer learning (TL) is commonly to update neural network weights for local factors; yet, it is commonly recognized to risk degradation of performance on the original validation/test cohorts. Here, we explore TL by data augmentation to address these concerns in the context of adapting SLANT to anatomical variation (e.g., adults versus children) and scanning protocol (e.g., non-contrast research T1w MRI versus contrast-enhanced clinical T1w MRI). We consider two datasets: First, 30 T1w MRI of young children with manually corrected volumetric labels, and accuracy of automated segmentation defined relative to the manually provided truth. Second, 36 paired datasets of pre- and post-contrast clinically acquired T1w MRI, and accuracy of the post-contrast segmentations assessed relative to the pre-contrast automated assessment. For both studies, we augment the original TL step of SLANT with either only the new data or with both original and new data. Over baseline SLANT, both approaches yielded significantly improved performance (pediatric: 0.89 vs. 0.82 DSC, p<0.001; contrast: 0.80 vs 0.76, p<0.001). The performance on the original test set decreased with the new-data only transfer learning approach, so data augmentation was superior to strict transfer learning.


Cholera in children in Karachi from 1990 through 1995: a study of cases admitted to a tertiary care hospital.
Although cholera is an endemic disease in Bangladesh, India and other countries, it was never a significant cause of gastroenteritis in Pakistan before 1988. Since then, cases of cholera are identified each year, both in adults and children in Pakistan. In order to see the contribution of Vibrio cholerae as a cause of gastroenteritis in children, we reviewed the cases of cholera admitted in the pediatric ward of the Aga Khan University Hospital, Karachi, Pakistan. Of 4346 children hospitalized with gastroenteritis during 1990 through 1995, 348 children (8%) were confirmed to have cholera. The youngest child with cholera was seven days old. The mean age was 31 +/- 34 months. The cases of cholera were received from all over the city. Most cases were due to Vibrio cholerae Ogawa biotype ELTOR but the new strain, i.e., Vibrio cholerae 0139 was isolated in 14% cases in 1994. The sensitivity of Vibrio cholerae has also changed. In 1994, the organisms were resistant to commonly recommended antibiotics, i.e., tetracycline, ampicillin and erythrocin but sensitive to ceftrioxone, cefixime, ofloxacin and nalidixic acid. Adequate measures to improve hygiene and sanitation and supply of safe potable water is needed to prevent any future epidemic of cholera in the city.


Applications of microbial cytochrome P450 enzymes in biotechnology and synthetic biology.
Cytochrome P450 enzymes (P450s) are a superfamily of monooxygenase enzymes with enormous potential for synthetic biology applications. Across Nature, their substrate range is vast and exceeds that of other enzymes. The range of different chemical transformations performed by P450s is also substantial, and continues to expand through interrogation of the properties of novel P450s and by protein engineering studies. The ability of P450s to introduce oxygen atoms at specific positions on complex molecules makes these enzymes particularly valuable for applications in synthetic biology. This review focuses on the enzymatic properties and reaction mechanisms of P450 enzymes, and on recent studies that highlight their broad applications in the production of oxychemicals. For selected soluble bacterial P450s (notably the high-activity P450-cytochrome P450 reductase enzyme P450 BM3), variants with a multitude of diverse substrate selectivities have been generated both rationally and by random mutagenesis/directed evolution approaches. This highlights the robustness and malleability of the P450 fold, and the capacity of these biocatalysts to oxidise a wide range of chemical scaffolds. This article reviews recent research on the application of wild-type and engineered P450s in the production of important chemicals, including pharmaceuticals and drug metabolites, steroids and antibiotics. In addition, the properties of unusual members of the P450 superfamily that do not follow the canonical P450 catalytic pathway are described.


Individual cell-only bioink and photocurable supporting medium for 3D printing and generation of engineered tissues with complex geometries.
Scaffold-free engineering of three-dimensional (3D) tissue has focused on building sophisticated structures to achieve functional constructs. Although the development of advanced manufacturing techniques such as 3D printing has brought remarkable capabilities to the field of tissue engineering, technology to create and culture individual cell only-based high-resolution tissues, without an intervening biomaterial scaffold to maintain construct shape and architecture, has been unachievable to date. In this report, we introduce a cell printing platform which addresses the aforementioned challenge and permits 3D printing and long-term culture of a living cell-only bioink lacking a biomaterial carrier for functional tissue formation. A biodegradable and photocrosslinkable microgel supporting bath serves initially as a fluid, allowing free movement of the printing nozzle for high-resolution cell extrusion, while also presenting solid-like properties to sustain the structure of the printed constructs. The printed human stem cells, which are the only component of the bioink, couple together via transmembrane adhesion proteins and differentiate down tissue-specific lineages while being cultured in a further photocrosslinked supporting bath to form bone and cartilage tissue with precisely controlled structure. Collectively, this system, which is applicable to general 3D printing strategies, is a paradigm shift for printing of scaffold-free individual cells, cellular condensations and organoids, and may have far reaching impact in the fields of regenerative medicine, drug screening, and developmental biology.


The Symptom Intensity Scale, fibromyalgia, and the meaning of fibromyalgia-like symptoms.
To characterize a scale for the measurement of fibromyalgia (FM)-like symptoms; to investigate whether FM is a discrete disorder; to understand the significance of FM-like symptoms; and to investigate causal and noncausal factors in the development of such symptoms. We evaluated 25,417 patients with rheumatic disease using the Symptom Intensity (SI) Scale, a self-report scale that combines a count of pain in 19 nonarticular regions with a visual analog scale for fatigue. We studied this scale in relation to demographics, clinical symptoms, and serious outcomes, including serious medical illnesses, hospitalization, work disability, and death. Compared with other rheumatic disease assessments, the SI scale was the best identifier of symptoms associated with FM content, including an increase in general medical symptoms. SI scale elevations were associated with increases in cardiovascular disorders, hospitalization, work disability, and death. Persons with socioeconomic disadvantage by reason of sex, ethnicity, household income, marital status, smoking, and body mass had increased SI scores. For almost all clinical variables studied, the prevalence and/or severity of the variable increased linearly with SI scores. We identified a clinical marker for general symptom intensification that applies in all patients and is independent of a diagnosis of FM. We found no clinical basis by which FM may be identified as a separate entity. Higher scores on the SI scale were associated with more severe medical illness, greater mortality, and sociodemographic disadvantage, and these factors appear to play a role in the development of FM-like symptoms and symptom intensification.


Levels of expression of the genes for glutathione reductase, glutathione peroxidase, catalase and CuZn-superoxide dismutase in rat lens and liver.
Oxidative mechanisms are thought to play a major role in several biological phenomena, including cataract formation. In the following studies we determined the relative levels of expression of the genes for the mRNAs for glutathione peroxidase (GPx), glutathione reductase (GR), CuZn-superoxide dismutase (CuZn-SOD) and catalase, in both the rat lens and liver. Northern blot hybridization methods were used to determine the mRNA size. The RNase protection method was used to determine levels of expression for these mRNAs plus levels of expression for alpha A-crystallin and gamma-crystallin mRNAs in the lens, and gamma-actin mRNAs in both the lens and the liver; using [32P]-labeled specific cRNA probes transcribed from the various cDNA clones for the mRNAs being studied. The data was normalized relative to the level of expression of alpha A-crystallin and gamma-actin mRNAs in the lens, and to gamma-actin mRNA in the liver. We find the levels of the mRNAs in the lens fall in the following descending order: GPx > GR > CuZn-SOD > catalase, in the same order as has been reported for the activities of the enzymes in the lens. In the liver, levels of these mRNAs were as follows: GPx > CuZn-SOD > GR > catalase. In the liver, CuZn-SOD mRNA was expressed at about four times the level found in the lens, GPx at three times, catalase at three times and GR at about the same level.(ABSTRACT TRUNCATED AT 250 WORDS)


Amyloid-β misfolding as a plasma biomarker indicates risk for future clinical Alzheimer's disease in individuals with subjective cognitive decline.
We evaluated Aβ misfolding in combination with Aβ42/40 ratio as a prognostic tool for future clinical progression to mild cognitive impairment (MCI) or dementia due to Alzheimer's disease (AD) in individuals with subjective cognitive decline (SCD). Baseline plasma samples (n = 203) from SCD subjects in the SCIENCe project and Amsterdam Dementia Cohort (age 61 ± 9 years; 57% male, mean follow-up time 2.7 years) were analyzed using immuno-infrared-sensor technology. Within 6 years of follow-up, 22 (11%) individuals progressed to MCI or dementia due to AD. Sensor readout values > 1646 cm- 1 reflected normal Aβ folding; readouts at ≤ 1646 cm- 1 reflected low and at < 1644 cm- 1 high misfolding. We used Cox proportional hazard models to quantify Aβ misfolding as a prognostic biomarker for progression to MCI and dementia due to AD. The accuracy of the predicted development of MCI/AD was determined by time-dependent receiver operating characteristic (t-ROC) curve analyses that take individual follow-up and conversion times into account. Statistical models were adjusted for age, sex, and APOEε4 status. Additionally, plasma Aβ42/40 data measured by SIMOA were statistically analyzed and compared. All 22 patients who converted to MCI or AD-dementia within 6 years exhibited Aβ misfolding at baseline. Cox analyses revealed a hazard ratio (HR) of 19 (95% confidence interval [CI] 2.2-157.8) for future conversion of SCD subjects with high misfolding and of 11 (95% CI 1.0-110.1) for those with low misfolding. T-ROC curve analyses yielded an area under the curve (AUC) of 0.94 (95% CI 0.86-1.00; 6-year follow-up) for Aβ misfolding in an age, sex, and APOEε4 model. A similar model with plasma Aβ42/40 ratio yielded an AUC of 0.92 (95% CI, 0.82-1.00). The AUC increased to 0.99 (95% CI, 0.99-1.00) after inclusion of both Aβ misfolding and the Aβ42/40 ratio. A panel of structure- and concentration-based plasma amyloid biomarkers may predict conversion to clinical MCI and dementia due to AD in cognitively unimpaired subjects. These plasma biomarkers provide a noninvasive and cost-effective alternative for screening early AD pathological changes. Follow-up studies and external validation in larger cohorts are in progress for further validation of our findings.


3D fusion of intravascular ultrasound and coronary computed tomography for in-vivo wall shear stress analysis: a feasibility study.
Wall shear stress, the force per area acting on the lumen wall due to the blood flow, is an important biomechanical parameter in the localization and progression of atherosclerosis. To calculate shear stress and relate it to atherosclerosis, a 3D description of the lumen and vessel wall is required. We present a framework to obtain the 3D reconstruction of human coronary arteries by the fusion of intravascular ultrasound (IVUS) and coronary computed tomography angiography (CT). We imaged 23 patients with IVUS and CT. The images from both modalities were registered for 35 arteries, using bifurcations as landmarks. The IVUS images together with IVUS derived lumen and wall contours were positioned on the 3D centerline, which was derived from CT. The resulting 3D lumen and wall contours were transformed to a surface for calculation of shear stress and plaque thickness. We applied variations in selection of landmarks and investigated whether these variations influenced the relation between shear stress and plaque thickness. Fusion was successfully achieved in 31 of the 35 arteries. The average length of the fused segments was 36.4 ± 15.7 mm. The length in IVUS and CT of the fused parts correlated excellently (R (2) = 0.98). Both for a mildly diseased and a very diseased coronary artery, shear stress was calculated and related to plaque thickness. Variations in the selection of the landmarks for these two arteries did not affect the relationship between shear stress and plaque thickness. This new framework can therefore successfully be applied for shear stress analysis in human coronary arteries.


An inventory of European data sources for the long-term safety evaluation of methylphenidate.
To compile an inventory of European healthcare databases with potential to study long-term effects of methylphenidate (MPH) in patients with attention deficit hyperactivity disorder (ADHD). Potential databases were identified through expert opinion, the website of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance, and literature search. An online survey was conducted among database providers/coordinators to ascertain the databases' appropriateness for inclusion into the inventory. It included questions about database characteristics, sample size, availability of information on drug exposure, clinical data and accessibility. Forty-two databases from 11 countries were identified and their coordinators invited to participate; responses were obtained for 22 (52.4 %) databases of which 15 record ADHD diagnoses. Eleven had sufficient data on ADHD diagnosis, drug exposure, and at least one type of outcome information (symptoms/clinical events, weight, height, blood pressure, heart rate) to assess MPH safety. These were Aarhus University Prescription Database, Danish National Birth Cohort (Denmark); German Health Interview and Examination Survey for Children and Adolescents; Health Search Database Thales, Italian ADHD Register, Lombardy Region ADHD Database (Italy); Avon Longitudinal Study of Parents and Children, General Practice Research Database, The Health Improvement Network, QResearch (UK) and IMS Disease Analyzer (UK, Germany, France). Of the 20 databases with no responses, information on seven from publications and/or websites was obtained; Pedianet and the Integrated Primary Care Information database were considered suitable. Many European healthcare databases can be used for multinational long-term safety studies of MPH. Methodological research is underway to investigate the feasibility of their pooling and analysis.


Privacy-preserving Collaborative Training for Medical Image Analysis Based on Multi-Blockchain.
As artificial intelligence and big data analysis develop rapidly, data privacy, especially patient medical data privacy, is getting more and more attention. The study aims to strengthen the protection of private data while ensuring the model training process; this article introduces a multi-Blockchain-based decentralized collaborative machine learning training method for medical image analysis. In this way, researchers from different medical institutions are able to collaborate to train models without exchanging sensitive patient data. Partial parameter update method is applied to prevent indirect privacy leakage during model propagation. With the peer-to-peer communication in the multi-Blockchain system, a machine learning task can leverage auxiliary information from another similar task in another Blockchain. In addition, after the collaborative training process, personalized models of different medical institutions will be trained. The experimental results show that our method achieves similar performance with the centralized model-training method by collecting data sets of all participants and prevents private data leakage at the same time. Transferring auxiliary information from similar task on another Blockchain has also been proven to effectively accelerate model convergence and improve model accuracy, especially in the scenario of absence of data. Personalization training process further improves model performance. Our approach can effectively help researchers from different organizations to achieve collaborative training without disclosing their private data.


N-Heterocyclic carbenes and charge separation in heterometallic s-block silylamides.
Addition of the N-heterocyclic carbene (NHC), 1,3-bis(2,6-di-isopropylphenyl)imidazol-2-ylidene (IPr), to equimolar quantities of group 1 and group 2 bis(trimethylsilyl)amides results in the isolation of charge separated species, [M(IPr)(2)](+)[M'{N(SiMe(3))(2)}(3)](-) (M = Li, Na, K; M' = Mg, Ca, Sr, Ba). Although these systems were found to be prone to the separation of oily, most likely liquid clathrate, materials, either slow cooling or careful diffusion of the less polar solvent hexane into toluene solutions yielded nine crystalline heterobimetallic complexes in which the coordination sphere of the cationic group 1 center was found by X-ray diffraction analysis to be provided by two IPr ligands. These derivatives are the first examples of any compounds in which coordination at the central alkali metal cation is provided exclusively by NHC ligands and, for the cases where M = Na, are the first instances of any type in which an NHC ligand is bound to sodium. The anionic group 2-containing component of each compound was found to comprise three bis(trimethylsilyl)amido ligands coordinated in an approximately trigonal array about the divalent metal center. The bonding within the unusual cationic components of the compounds has been investigated by density functional theoretical (DFT) methods. Natural Bond Orbital (NBO) analyses have revealed that the coordination is provided by donation of the sp-hydridized IPr lone pair into the valence s-orbital of the alkali metal cation and are consistent with weaker binding, and consequently more labile solution behavior, as group 1 is descended.