A mixed-methods evaluation of the impact of a pharmacist-led feedback pilot intervention on insulin prescribing in a hospital setting.

AIMS: To explore the impact of a prescribing feedback intervention on insulin prescribing. METHODS: This was a mixed-methods study in a hospital setting. An insulin prescribing feedback intervention was delivered verbally and in writing to twelve doctors. Insulin prescribing error frequency was compared to ten doctors who had not received the feedback intervention. Insulin prescribing was audited over four weeks at the start and end of the intervention period. Semi-structured interviews were conducted with participating doctors who had received feedback, and qualitative data analysed thematically to explore the impact of the intervention on their prescribing practice. RESULTS: Prescribing data were collected on 370 insulin prescriptions with 241 errors identified. A significant reduction (χ2 = 22.6, p=<0.05) in insulin prescribing error frequency was observed in the intervention group, with a non-significant increase reported in the control group. Feedback was received positively and considered valuable by doctors, supporting development of their knowledge and skills and encouraging reflection on their prescribing performance. Doctors described enhanced confidence in insulin prescribing and a desire to improve as a prescriber and avoid harm, with feedback raising awareness of their development needs. Prescribers also described enhanced team work, with greater information and feedback seeking behavior to inform future prescribing decisions. CONCLUSIONS: Feedback has potential to improve insulin prescribing and is a valued and acceptable process intervention for doctors. The impact on insulin prescribing practice is varied and complex influencing the capability, opportunity and motivation of prescribers to adapt and evolve their behavior in response to ongoing feedback.

The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis.

Mitochondrial topoisomerase IB (TOP1MT) is a nuclear-encoded topoisomerase, exclusively localized to mitochondria, which resolves topological stress generated during mtDNA replication and transcription. Here, we report that TOP1MT is overexpressed in cancer tissues and demonstrate that TOP1MT deficiency attenuates tumor growth in human and mouse models of colon and liver cancer. Due to their mitochondrial dysfunction, TOP1MT-KO cells become addicted to glycolysis, which limits synthetic building blocks and energy supply required for the proliferation of cancer cells in a nutrient-deprived tumor microenvironment. Mechanistically, we show that TOP1MT associates with mitoribosomal subunits, ensuring optimal mitochondrial translation and assembly of oxidative phosphorylation complexes that are critical for sustaining tumor growth. The TOP1MT genomic signature profile, based on Top1mt-KO liver cancers, is correlated with enhanced survival of hepatocellular carcinoma patients. Our results highlight the importance of TOP1MT for tumor development, providing a potential rationale to develop TOP1MT-targeted drugs as anticancer therapies.

Artificial Manduca sexta forewings for flapping-wing micro aerial vehicles: how wing structure affects performance.

A novel approach to fabricating and testing artificial insect wings has been developed. Utilizing these new techniques, locally harvested hawk moth (Manduca sexta) forewings are compared to engineered forewings with varying wing structures. A number of small, flexible engineered forewings were fabricated with identical planform size and shape but with variations in camber, ribbing, thickness and composition. A series of static and dynamic assessments compares the forewings in terms of structure and performance. Data from these experiments show that the fabrication method can produce artificial forewings with similar properties to that of M. sexta. Flexural stiffness (EI) data shows a maximum percent difference of 41% between the left and right natural M. sexta forewings, whereas engineered forewings have a maximum percent difference of 18%. When deflection is induced from the ventral side of the forewing, EI values are at least 9.1% higher than when it is induced from the dorsal side. According to simulations, approximately 57% of this difference can be attributed to the camber of the forewings. Fabricated forewings produced comparable amounts of lift to natural M. sexta forewings (1.00 gF and 0.96 gF at 25 Hz flapping frequency respectively).

Policy Transfer Among Regional-Level Organizations: Insights from Source Water Protection in Ontario.

Organizations at the local and regional scales often face the challenge of developing policy mechanisms rapidly and concurrently, whether in response to expanding mandates, newly identified threats, or changes in the political environment. In the Canadian Province of Ontario, rapid, concurrent policy development was considered desirable by 19 regional organizations tasked with developing policies for protection of drinking water sources under very tight and highly prescribed mandates. An explicit policy transfer approach was used by these organizations. Policy transfer refers to using knowledge of policies, programs, and institutions in one context in the development of policies, programs, and institutions in another. This paper assesses three online mechanisms developed to facilitate policy transfer for source water protection in Ontario. Insights are based on a survey of policy planners from the 19 regional organizations who used the three policy transfer tools, supplemented by an analysis of three policies created and transferred among the 19 regional source water protection organizations. Policy planners in the study indicated they had used policy transfer to develop source protection policies for their regions-a finding confirmed by analysis of the text of policies. While the online policy transfer tools clearly facilitated systematic policy transfer, participants still preferred informal, direct exchanges with their peers in other regions over the use of the internet-based policy transfer mechanisms created on their behalf.

Prevalence and associated factors of sexual problems after early-stage breast cancer treatment: results of a French exploratory survey.

OBJECTIVE: The objective of this study was to assess the prevalence and associated factors of sexual activity, sexual problems or sexual satisfaction in French early-stage breast cancer survivors (BCS). METHODS: Eight hundred and fifty eligible, post-treatment (6 months-5 years) female patients, aged 18-70 years, randomly selected from a consultation list, were invited to fill in questionnaires exploring quality of life (EORTC QLQ-C30 and QLQ-BR23), body image scale, and sexuality (Sexual Activity Questionnaire-SAQ; Relationship and Sexuality Scale; French Sexual Behaviour Survey-CSF). RESULTS: Fifty-three percent of BCS agreed to participate. Participating women (n=378) were younger, more often premenopausal at diagnosis and with a more recent diagnosis than non-respondents. The prevalence of sexual problems was significantly higher in BCS compared with adjusted data from a French female representative sample (p<0.0001). In logistic regression, no sexual activity (R(2) =0.37) or sexual dissatisfaction (R(2) =0.28) were associated with the feeling of emotional separation in the couple or of partner's fear of sexual intercourse, lower emotional functioning, poorer body image, or co-morbidities. In sexually active women (71% of respondents), lower frequency of sexual activity (R(2) =0.26), lower sexual pleasure (R(2) =0.22), or higher sexual discomfort (R(2) =0.22) were associated with the feeling of emotional separation in the couple or of partner's fear of sexual intercourse, lower emotional functioning, age (>50 years), nausea, or insomnia (all Hosmer-Lemeshow tests: p=NS). CONCLUSIONS: Psychological factors including the perception of the couple relationship appeared prominent in BCS women's experience of sexual problems.

Inhibitory effects of omacetaxine on leukemic stem cells and BCR-ABL-induced chronic myeloid leukemia and acute lymphoblastic leukemia in mice.

Omacetaxine mepesuccinate (formerly homoharringtonine) is a molecule with a mechanism of action that is different from tyrosine kinase inhibitors, and its activity in chronic myeloid leukemia (CML) seems to be independent of the BCR-ABL mutation status. Using BCR-ABL-expressing myelogenous and lymphoid cell lines and mouse models of CML and B-cell acute lymphoblastic leukemia (B-ALL) induced by wild-type BCR-ABL or T315I mutant-BCR-ABL, we evaluated the inhibitory effects of omacetaxine on CML and B-ALL. We showed that more than 90% of the leukemic stem cells were killed after treatment with omacetaxine in vitro. In contrast, less than 9 or 25% of the leukemic stem cells were killed after treating with imatinib or dasatinib, respectively. After 4 days of treatment of CML mice with omacetaxine, Gr-1(+)myeloid leukemia cells decreased in the peripheral blood of the treated CML mice. In the omacetaxine-treated B-ALL mice, only 0.8% of the B220(+)leukemia cells were found in peripheral blood, compared with 34% of the B220(+)leukemia cells in the placebo group. Treatment with omacetaxine decreased the number of leukemia stem cells and prolonged the survival of mice with BCR-ABL-induced CML or B-ALL.

Surveillance for West Nile virus cases in Louisiana 2001-2004.

West Nile virus (WNV) was first detected in Louisiana during August of 2001. An outbreak of 204 human cases of neuro-invasive disease (NID) and 25 deaths occurred in 2002. In the 2 years following, lower numbers of human cases were identified (101 NID cases in 2003 and 84 in 2004) but intense localized foci were observed. The incidence of NID has been particularly high in the elderly (65 years and older). The distribution of West Nile cases has consisted of sporadic cases with a few very intense foci. Annually, human cases have occurred from June through December, with a peak number of new cases in August. As compared with other WNV serosurveys conducted in the United States, it appears that the WNV seroprevalence in Louisiana is not elevated.

Identification of a MADS-box gene, FLOWERING LOCUS M, that represses flowering.

The timing of flowering is important for the reproductive success of plants. Here we describe the identification and characterization of a new MADS-box gene, FLOWERING LOCUS M (FLM), which is involved in the transition from vegetative to reproductive development. FLM is similar in amino-acid sequence to FLC, another MADS-box gene involved in flowering-time control. flm mutants are early flowering in both inductive and non-inductive photoperiods, and flowering time is sensitive to FLM dosage. FLM overexpression produces late-flowering plants. Thus FLM acts as an inhibitor of flowering. FLM is expressed in areas of cell division such as root and shoot apical regions and leaf primordia.

Loss of FLOWERING LOCUS C activity eliminates the late-flowering phenotype of FRIGIDA and autonomous pathway mutations but not responsiveness to vernalization.

The MADS domain--containing transcription factor FLOWERING LOCUS C (FLC) acts as an inhibitor of flowering and is a convergence point for several pathways that regulate flowering time in Arabidopsis. In naturally occurring late-flowering ecotypes, the FRIGIDA (FRI) gene acts to increase FLC levels, whereas the autonomous floral promotion pathway and vernalization act to reduce FLC expression. Previous work has shown that the Landsberg erecta allele of FLC, which is not a null allele, is able to partially suppress the late-flowering phenotype of FRIGIDA and mutations in the autonomous pathway. In this study, using a null allele of FLC, we show that the late-flowering phenotype of FRIGIDA and autonomous pathway mutants are eliminated in the absence of FLC activity. In addition, we have found that the downregulation of SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 by FRI and autonomous pathway mutants also is mediated by FLC. Complete loss of FLC function, however, does not eliminate the effect of vernalization. Thus, FRI and the autonomous pathway may act solely to regulate FLC expression, whereas vernalization is able to promote flowering via FLC-dependent and FLC-independent mechanisms.

Effect of excisional therapy and highly active antiretroviral therapy on cervical intraepithelial neoplasia in women infected with human immunodeficiency virus.

OBJECTIVE: Our purpose was to determine the rates of recurrence, persistence, and progression of cervical intraepithelial neoplasia in women who were seropositive for human immunodeficiency virus after excisional therapy with and without highly active antiretroviral therapy. STUDY DESIGN: The records of 118 women with cervical intraepithelial neoplasia, 56 of whom were infected with human immunodeficiency virus and 62 of whom were not infected, were examined to compare outcomes. Demographic, behavioral, and clinical indices were analyzed. RESULTS: Of 54 women infected with human immunodeficiency virus, 31 (57.4%) had persistent or recurrent cervical intraepithelial neoplasia, in comparison with 10 (16.7%) of 60 noninfected women (P <.01). Progression occurred in 4 (16.7%) of 54 in the infected group and in 3 (5.0%) of 60 in the noninfected group (P <.05). In 21 (60.0%) of 35 infected women, in comparison with 8 (32%) of 25 noninfected women, disease persisted 6 months after diagnosis if treatment was not given (P <.05). Of 19 infected women, 10 (52.6%) had recurrent disease after treatment, compared with 2 (5.7%) of 35 noninfected women (P <.01). Risk factors for recurrence in women who were seropositive for human immunodeficiency virus included margin involvement of specimens obtained by loop electrosurgical excision (87.5% vs 20.0%l; P <.05). Exposure to highly active antiretroviral therapy, including therapy with protease inhibitors, was associated with a lower recurrence or persistence rate (17.6% vs. 70.3%; P <.05) and a lower progression rate (0% vs. 24%; P <.05). CONCLUSION: Women infected with human immunodeficiency virus had high rates of recurrent and persistent cervical intraepithelial neoplasia despite standard therapy. Low CD4(+) levels and margin involvement of specimens obtained by loop electrosurgical excision are risk factors for recurrence. The use of highly active antiretroviral therapy is associated with a lower risk of recurrence, persistence, and progression of cervical intraepithelial neoplasia.

Making collaborative watershed management work: the confluence of state and regional initiatives.

Initiatives in the Neponset, Ipswich, and Sudbury-Assabet-Concord watersheds highlight how watershed-scale innovation in engaging nongovernment participants is influenced, but not dominated, by the statewide program, the Massachusetts Watershed Initiative. The presence or absence of three elements--external support, process, and issue--and the order in which they occur, shape the viability of collaborative watershed-scale management initiatives. External support includes providing personnel or funding from outside an initiative. Process is the interaction among individuals undertaking watershed-wide policy development and/or implementation. An issue is an attention-requiring concern, vital to a watershed, that can most effectively be addressed by a coordinated strategy among different parties. A process generated by an issue is sustainable and amenable to enhancement through external support. The contribution of external support is most apparent when outside assistance is provided after an issue has crystallized into clear problem needs that can be addressed through specific research projects or implementation activities. Process is central in shaping issues, utilizing external support, and generating management results. The outcomes of voluntary processes in the three watershed initiatives highlight how the evolution of the Massachusetts Watershed Initiative leads to, and depends upon, the development of watershed-scale initiatives.

Molecular analysis of FRIGIDA, a major determinant of natural variation in Arabidopsis flowering time.

Vernalization, the acceleration of flowering by a long period of cold temperature, ensures that many plants overwinter vegetatively and flower in spring. In Arabidopsis, allelic variation at the FRIGIDA (FRI) locus is a major determinant of natural variation in flowering time. Dominant alleles of FRI confer late flowering, which is reversed to earliness by vernalization. We cloned FRI and analyzed the molecular basis of the allelic variation. Most of the early-flowering ecotypes analyzed carry FRI alleles containing one of two different deletions that disrupt the open reading frame. Loss-of-function mutations at FRI have thus provided the basis for the evolution of many early-flowering ecotypes.

Renal sarcoidosis with superimposed postinfectious glomerulonephritis presenting as acute renal failure.

We describe two patients with sarcoidosis with lesions of granulomatous interstitial nephritis (GIN) and postinfectious glomerulonephritis (GN). Both patients presented with heavy proteinuria, hematuria, and renal failure. Renal histology in both showed GIN and glomerular changes of proliferative GN with hump-like subepithelial deposits by electron microscopy of postinfectious GN. Antecedent history of pneumonia was present in one, and ASO titer was elevated in the other. The proteinuria and azotemia improved in both with steroid therapy. Reports of "postinfectious" or diffuse proliferative GN in patients with sarcoidosis are rare. The authors are unaware of reports of concomitant sarcoid GIN and postinfectious GN. Although acute renal insufficiency or failure can occur with GIN or other more common renal lesions primary glomerular disease should be considered in patients with sarcoidosis who present with renal dysfunction. This is a US government work. There are no restrictions on its use.

Nineteen eating disorder scales: Comparison by focus, ease, response format, and readability.

Eating scales vary enormously in focus, ease, response format, and readability. As part of a larger study related to ethnicity and eating scales, we examined differences in eating scales to determine whether some scales may be more global and culture free in application than others. Ease of readability is related to the educational and cultural background of those to whom the scales are administered. Thus, 30 years of psychological literature (1968-1997) was reviewed; 40 eating disorder scales were found and requested from their authors. Using those who responded, 19 major scales were compared by focus, response format, validity, length, structure, reading level, and reading complexity. As expected, scales vary enormously in focus, length, content, and response format. Readability (as grade level) ranged from a high of 10.6 to a low of 1.1; 70% of the rated scales were rated as "highly readable."

Natural allelic variation identifies new genes in the Arabidopsis circadian system.

We have analysed the circadian rhythm of Arabidopsis thaliana leaf movements in the accession Cvi from the Cape Verde Islands, and in the commonly used laboratory strains Columbia (Col) and Landsberg (erecta) (Ler), which originated in Northern Europe. The parental lines have similar rhythmic periods, but the progeny of crosses among them reveal extensive variation for this trait. An analysis of 48 Ler/Cvi recombinant inbred lines (RILs) and a further 30 Ler/Col RILs allowed us to locate four putative quantitative trait loci (QTLs) that control the period of the circadian clock. Near-isogenic lines (NILs) that contain a QTL in a small, defined chromo- somal region allowed us to confirm the phenotypic effect and to map the positions of three period QTLs, designated ESPRESSO, NON TROPPO and RALENTANDO. Quantitative trait loci at the locations of RALENTANDO and of a fourth QTL, ANDANTE, were identified in both Ler/Cvi and Ler/Col RIL populations. Some QTLs for circadian period are closely linked to loci that control flowering time, including FLC. We show that flc mutations shorten the circadian period such that the known allelic variation in the MADS-box gene FLC can account for the ANDANTE QTL. The QTLs ESPRESSO and RALENTANDO identify new genes that regulate the Arabidopsis circadian system in nature, one of which may be the flowering-time gene GIGANTEA.

The gibberellic acid biosynthesis mutant ga1-3 of Arabidopsis thaliana is responsive to vernalization.

The Arabidopsis mutant ga1-3 contains a deletion in an enzyme that catalyzes an early step in the synthesis of gibberellic acid. It has been shown that ga1-3 mutant plants cannot flower under 8-h short-day (SD) conditions, even after vernalization. In this article, we present data demonstrating that the ga1-3 mutation does not block the response to vernalization in intermediate photoperiods or in long-day conditions in a late-flowering, vernalization-responsive background. Thus, GA may not have a direct role in the vernalization response in Arabidopsis, but it may be required for an alternate pathway that promotes flowering in noninductive photoperiods.

FLOWERING LOCUS C encodes a novel MADS domain protein that acts as a repressor of flowering.

Winter-annual ecotypes of Arabidopsis are relatively late flowering, unless the flowering of these ecotypes is promoted by exposure to cold (vernalization). This vernalization-suppressible, late-flowering phenotype results from the presence of dominant, late-flowering alleles at two loci, FRIGIDA (FRI) and FLOWERING LOCUS C (FLC). In this study, we report that flc null mutations result in early flowering, demonstrating that the role of active FLC alleles is to repress flowering. FLC was isolated by positional cloning and found to encode a novel MADS domain protein. The levels of FLC mRNA are regulated positively by FRI and negatively by LUMINIDEPENDENS. FLC is also negatively regulated by vernalization. Overexpression of FLC from a heterologous promoter is sufficient to delay flowering in the absence of an active FRI allele. We propose that the level of FLC activity acts through a rheostat-like mechanism to control flowering time in Arabidopsis and that modulation of FLC expression is a component of the vernalization response.