Optimizing insulin pump therapy: the potential advantages of using a structured diabetes management program

Use of continuous subcutaneous insulin infusion (CSII) therapy improves glycemic control, reduces hypoglycemia and increases treatment satisfaction in individuals with diabetes. As a number of patient- and clinician-related factors can hinder the effectiveness and optimal usage of CSII therapy, new approaches are needed to address these obstacles.

Ceriello and colleagues recently proposed a model of care that incorporates the collaborative use of structured SMBG into a formal approach to personalized diabetes management within all diabetes populations. We adapted this model for use in CSII-treated patients in order to enable the implementation of a workflow structure that enhances patient–physician communication and supports patients’ diabetes self-management skills.

We recognize that time constraints and current reimbursement policies pose significant challenges to healthcare providers integrating the Personalised Diabetes Management (PDM) process into clinical practice. We believe, however, that the time invested in modifying practice workflow and learning to apply the various steps of the PDM process will be offset by improved workflow and more effective patient consultations. This article describes how to implement PDM into clinical practice as a systematic, standardized process that can optimize CSII therapy.     

Susceptibility of Treatment-Naive Hepatitis C Virus (HCV) Clinical Isolates to HCV Protease Inhibitors

In order to assess the natural variation in susceptibility to hepatitis C virus (HCV) NS3 protease inhibitors (PIs) among untreated HCV patient samples, the susceptibilities of 39 baseline clinical isolates were determined using a transient-replication assay on a panel of HCV PIs, including two α-ketoamides (VX-950 and SCH-503034) and three macrocyclic inhibitors (MK-7009, ITMN-191, and TMC-435350). Some natural variation in susceptibility to all HCV PIs tested was observed among the baseline clinical isolates. The susceptibility to VX-950 correlated strongly with the susceptibility to SCH-503034. A moderate correlation was observed between the susceptibilities to ITMN-191 and MK-7009. In contrast, the phenotypic correlations between the α-ketoamides and macrocyclic inhibitors were significantly lower. This difference is partly attributable to reduced susceptibility of the HCV variants containing the NS3 polymorphism Q80K (existing in 47% of genotype 1a isolates) to the macrocyclic compounds but no change in the sensitivity of the same variants to the α-ketoamides tested. Our results suggest that the natural variation in baseline susceptibility may contribute to different degrees of antiviral response among patients in vivo, particularly at lower doses.Hepatitis C virus (HCV) is characterized by a high degree of genetic diversity because of its rapid replication rate and turnover, combined with the poor fidelity of the HCV RNA-dependent RNA polymerase (RdRp) (3, 5, 32). The nucleotide sequences among the six different genotypes (GTs) differ at 30 to 35% of nucleotide sites (25, 26). Each of the six major GTs of HCV contains a series of closely related subtypes whose nucleotide sequences typically differ from each other by 20 to 25%. Furthermore, 5 to 8% sequence divergence is present between individual strains (variants) of HCV within a given subtype. A comprehensive analysis of HCV NS3 sequences from a larger number of GT-1 isolates found that amino acid polymorphisms were detected all along the protease sequence, including residues associated either with resistance to HCV protease inhibitors (PIs) (V36, I170, and D168) or with compensatory mutations (I72, T72, Q86, and I153) (1, 2, 30). However, many questions remain, including whether natural variation in the NS3 protease sequence impacts the susceptibility of HCV to PIs currently in development and whether there are any relationships among the chemotypes of the PIs and their baseline susceptibilities.Hepatitis C virus NS3/4A serine PIs have demonstrated potent antiviral activity in subjects infected with HCV GT-1 by specifically blocking NS3/4A protease-dependent HCV polyproprotein processing. Among these PIs, VX-950 (telaprevir) and SCH-503034 (boceprevir), the two most clinically advanced NS3/4A serine PIs, are both α-ketoamide compounds that covalently bind to the active-site serine of the protease (6, 9, 10, 14, 16, 22). These drugs also have similar resistance profiles. Mutations V36A/M, T54A, R155K, and A156S in the NS3 protease gene, conferring a low level of resistance to VX-950, were identified in HCV GT-1-infected patients treated with VX-950 monotherapy or in combination with alpha interferon (IFN-α) and ribavirin (11, 21). In addition, the single mutant A156T or A156V or the double mutant at positions 36/155 or 36/156, all conferring high-level resistance, were observed in some VX-950-treated patients. Similarly, samples from SCH-503034-treated patients revealed the emergence of the low- to moderate-level resistance mutations T54A, V170A, and A156S and, less commonly, the high-level resistance mutant A156T (27, 28).More recently, other HCV PIs, including ITMN-191, TMC-435350, and MK-7009, have progressed to the early stages of clinical evaluation (12, 15, 19, 20, 23, 29). These compounds are structurally related macrocyclic inhibitors that are chemically distinct from VX-950 and SCH-503034. The mutations that display a reduced susceptibility to ITMN-191 include D168A/E/V, A156S/V, F43S, Q41R, and S138T in the NS3 protease; S489L in the NS3 helicase; and V23A in NS4A (24). S489L in the helicase domain buttresses the P2 pocket, and the substitution V23A is at a site in the NS4A peptide cofactor that borders the P1′ pocket (24). The F43S, Q41R, R155K, A156T, and D168Y mutations in NS3 also displayed low- to high-level reduced sensitivity to MK-7009 (12). Since these PIs had some overlapping and some nonoverlapping resistance profiles, it would be of interest to compare their potencies against the natural HCV variants derived from treatment-naïve patient isolates.Standard replicon assays limit the assessment of the inhibitory activities of anti-HCV compounds to a few laboratory-optimized strains. These assays may not reflect the range of activities of a compound against the heterogeneous viral population that exists in HCV-infected patients. Previously, we have reported the development of a replicon-based shuttle vector to allow rapid phenotypic analysis of the NS3 protease domain from samples of a large number of HCV-infected patients (18). We demonstrated a high success rate and reproducibility of the novel replicon-based phenotypic assay. However, the assay sensitivity for detection of mutants in a mixed population may be reduced for resistance mutations that are less fit or with lower levels of resistance or samples containing only a small proportion of a mutant in a population (18). For example, reduced susceptibility to BILN-2061 was observed for mutant/wild-type mixtures of 5%/95% for the D168V mutation but was observed for only 50%/50% mixtures for the A156T resistance mutation. Using this phenotypic-analysis assay, the susceptibilities of a panel of HCV treatment-naïve clinical isolates to VX-950 (telaprevir), SCH-503034 (boceprevir), ITMN-191, MK-7009, and TMC-435350, as well as GS-9132 (also known as ACH-806, an NS4A antagonist [31]), were evaluated in the present study. GS-9132 was included in the study, as mutations that conferred resistance mapped in the NS4A-binding region of NS3, although the precise mechanism of action of GS-9132 has not been fully elucidated. Overall, the baseline clinical isolate susceptibilities were compared among this panel of drugs. Finally, the effects of natural substitutions in the HCV protease gene on drug susceptibilities were investigated.     

Associations among attachment characteristics,patients’ assessment of therapeutic factors,and treatment outcome following inpatient psychodynamic group psychotherapy

Abstract

Within a multisite study, including 289 inpatients from six different hospitals who underwent interpersonal-psychodynamic group psychotherapy, associations among attachment characteristics, therapeutic factors, and treatment outcome were investigated. Attachment characteristics were assessed with an interview-based measure (Adult Attachment Prototype Rating [AAPR]) as well as an attachment self-report (Bielefeld Questionnaire of Client Expectations [BQCE]). Therapeutic factors were measured retrospectively with the Düsseldorf Therapeutic Factors Questionnaire and treated as an individual- as well as a hospital-specific characteristic. On an individual level, only the group climate factor independently predicted treatment outcome (i.e., Symptom Checklist-90-R Global Severity Index and Inventory of Interpersonal Problems mean). If simultaneously but separately included into a path model, analyses revealed independent significant effects of AAPR-Security and BQCE-Security on group climate. If modeled as a latent variable (common attachment security), a substantially higher proportion of group climate variance could be explained. Further analyses revealed interactions between particular therapeutic factors and attachment characteristics, indicating a particular importance of these therapeutic factors for different attachment categories.     

The Structure of Autism Spectrum Disorder Symptoms in the General Population at 18 Months

It is unclear whether symptoms of autism spectrum disorder (ASD) in young children in the population fit the three-factor structure of ASD as described in the DSM-IV, and cluster together in individual subjects. This study analysed questionnaire data on ASD symptoms filled in by mothers of 11,332 18-month-old children that was collected in the context of the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health. Confirmatory Factor Analyses showed that the three-factor model had a significantly better fit then the two- and one-factor model of ASD symptoms. Latent class analysis revealed four homogeneous groups of children (classes) with different scores for Social Interaction and Communication at one hand and Stereotypies/Rigidity at the other hand.     

Vaccination and Antibody Testing in Cats

Vaccines protect cats from serious diseases by inducing antibodies and cellular immune responses. Primary vaccinations and boosters are given according to vaccination guidelines provided by industry and veterinary organizations, based on minimal duration of immunity (DOI). For certain diseases, particularly feline panleukopenia, antibody titres correlate with protection. For feline calicivirus and feline herpesvirus, a similar correlation is absent, or less clear. In this review, the European Advisory Board on Cat Diseases (ABCD) presents current knowledge and expert opinion on the use of antibody testing in different situations. Antibody testing can be performed either in diagnostic laboratories, or in veterinary practice using point of care (POC) tests, and can be applied for several purposes, such as to provide evidence that a successful immune response was induced following vaccination. In adult cats, antibody test results can inform the appropriate re-vaccination interval. In shelters, antibody testing can support the control of FPV outbreaks by identifying potentially unprotected cats. Antibody testing has also been proposed to support decisions on optimal vaccination schedules for the individual kitten. However, such testing is still expensive and it is considered impractical to monitor the decline of maternally derived antibodies.     

Prognostic implications of microRNA-21 overexpression in pancreatic ductal adenocarcinoma: an international multicenter study of 686 patients

Despite progress in genomic characterization, no single prognostic marker that can be evaluated using an easy-to-perform and relatively inexpensive method is available for pancreatic ductal adenocarcinoma (PDAC). MicroRNAs, which are stable, tumor- and tissue-specific molecules, are potentially ideal biomarkers, and we established an inter-laboratory validated method to investigate miR-21 as a prognostic biomarker in PDAC. The study samples of PDAC patients were recruited from a test cohort of Glasgow (n = 189) and three validation cohorts of Pisa (n = 69), Sydney (n = 249), and International Cancer Genome Consortium (ICGC) (n = 249). Tissue microarrays were used for miR-21 staining by chromogenic in situ hybridization (CISH). The patients were subdivided into no/low and high miR-21 staining groups using a specific histoscore. Furthermore, miR-21 staining was evaluated against clinicopathological variables and follow-up data by Fisher/log-rank test and Cox proportional models. The prognostic variables found to be significant in univariate analysis (P value < 0.10) were included in multivariate analysis in a backward-stepwise fashion. MiR-21 expression was cytoplasmic, with more consistent staining in the malignant ductal epithelium than in the stroma. The expression of miR-21 was significantly associated with tumor size and lymph node metastasis, whereas no association was observed with other clinicopathological variables. High miR-21 staining (histoscore ≥ 45 [median score]) was an independent predictor of survival in the Glasgow test cohort (HR 2.37, 95% CI: 1.42-3.96, P < 0.0001) and three validation cohorts (Pisa, HR 2.03, 95% CI: 1.21-3.39, P = 0.007; Sydney, HR 2.58, 95% CI (1.21-3.39), P < 0.0001; and ICGC, HR 3.34, 95% CI: 2.07-5.84, P = 0.002) when adjusted for clinical variables in a multivariate model. In comparison to the patients with low miR-21, the patients with high miR-21 expression had significant increase in OS as they benefit from gemcitabine-based adjuvant chemotherapy (Glasgow 16.5 months [with chemotherapy] vs 10.5 months [without chemotherapy]); Sydney 25.0 vs 10.6; ICGC 25.2 vs 11.9. These results indicated that miR-21 is a predictor of survival, prompting prospective trials. Evaluation of miR-21 offers new opportunities for the stratification of patients with PDAC and might facilitate the implementation of clinical management and therapeutic interventions for this devastating disease.