Psychosocial and behavioural prognostic factors for diabetic foot ulcer development and healing: a systematic review.

AIM: To investigate whether ulceration, amputation and healing of foot ulcers in people living with diabetes are associated with psychosocial and behavioural factors. METHODS: We searched MEDLINE, Embase, PsychINFO, CINAHL and The Cochrane Library to March 2019 for longitudinal studies with multivariable analyses investigating independent associations. Two reviewers extracted data and assessed risk of bias. RESULTS: We identified 15 eligible studies involving over 12 000 participants. Clinical and methodological heterogeneity precluded meta-analysis, so we summarize narratively. Risk of bias was moderate or high. For ulceration, we found significantly different results for people with and without an ulcer history. For those with no ulcer history, moderate quality evidence suggests depression increases ulcer risk [three studies; e.g. hazard ratio (HR) 1.68 (1.20, 2.35) per Hospital Anxiety and Depression Scale (HADS) standard unit]. Better foot self-care behaviour reduces ulcer risk [HR 0.61 (0.40, 0.93) per Summary of Diabetes Self-Care Activities scale standard unit; one study]. For people with diabetes and previous ulcers, low- or very low-quality evidence suggests little discernible association between ulcer recurrence and depression [e.g. HR 0.88 (0.61, 1.27) per HADS standard unit], foot self-care, footwear adherence or exercise. Low-quality evidence suggests incomplete clinic attendance is strongly associated with amputation [odds ratio (OR) 3.84 (1.54, 9.52); one study]. Evidence for the effects of other psychosocial or behavioural factors on ulcer healing and amputation is very low quality and inconclusive. CONCLUSIONS: Psychosocial and behavioural factors may influence the development of first ulcers. More high quality research is needed on ulcer recurrence and healing. (Open Science Framework Registration: https://osf.io/ej689).

Effectiveness of psychosocial interventions for the prevention and treatment of foot ulcers in people with diabetes: a systematic review.

AIM: To identify and synthesize the evidence for the effectiveness of psychosocial interventions to promote the healing, and/or reduce the occurrence of, foot ulceration in people with diabetes. METHODS: In March 2019 we searched CENTRAL, Medline, Embase and PsycInfo for randomized controlled trials of interventions with psychosocial components for people with diabetes. The primary outcomes of this review were foot ulceration and healing. We assessed studies using the Cochrane risk-of-bias tool, the TIDieR checklist and GRADE. We conducted narrative synthesis and random-effects meta-analysis. RESULTS: We included 31 randomized controlled trials (4511 participants), of which most (24 randomized controlled trials, 4093 participants) were prevention studies. Most interventions were educational with a modest psychosocial component. Ulceration and healing were not reported in most studies; secondary outcomes varied. Evidence was of low or very low quality because of high risks of bias and imprecision, and few studies reported adherence or fidelity. In groups where participants had prior ulceration, educational interventions had no clear effect on new ulceration (low-quality evidence). Two treatment studies, assessing continuous pharmacist support and an intervention to promote understanding of well-being, reported healing but their evidence was also of very low quality. CONCLUSION: Most psychosocial intervention randomized controlled trials assessing foot ulcer outcomes in people with diabetes were prevention studies, and most interventions were primarily educational. Ulcer healing and development were not well reported. There is a need for better understanding of psychological and behavioural influences on ulcer incidence, healing and recurrence in people with diabetes. Randomized controlled trials of theoretically informed interventions, which assess clinical outcomes, are urgently required. (PROSPERO registration: CRD42016052960).

Development of quality indicators for hip and knee arthroplasty rehabilitation.

OBJECTIVE: To develop quality indicators (QIs) reflecting the minimum acceptable standard of rehabilitation care before and after elective total hip arthroplasty (THA) and total knee arthroplasty (TKA) for osteoarthritis (OA). METHODS: Informed by high quality evidence and using a modified RAND-UCLA Delphi approach, an 18-member Canadian panel of clinicians, researchers and patients considered 81 proposed QIs (40 for THA, 42 for TKA) addressing rehabilitation before and after elective THA and TKA. Panelists rated QIs for their importance and validity on a 9-point Likert scale through two rounds of online rating interspersed with a moderated and anonymous online discussion forum. Those QIs with median ratings of ≥7 for importance and validity with no disagreement based on the inter-percentile range adjusted for symmetry were included in the final sets. RESULTS: Fifteen panelists from seven provinces and varied practice settings completed the Delphi process. Of the 81 plus one additional QIs (total of 82), 67 (82%) were rated as both important and valid (31 for THA, 36 for TKA). For THA, 14 pre-op, six acute and eight post-acute QIs were accepted. For TKA, 16 pre-op, 10 acute and eight post-acute indicators were accepted. Two of three 'across-continuum' QIs were rated appropriate for both procedures. CONCLUSION: This work represents the first QIs with which to measure, report and benchmark quality of care in patients receiving rehabilitation before and after THA/TKA surgery. The QIs will be further tested for reliability and feasibility before being widely disseminated in clinical settings and used to assess care gaps.

Highly prevalent Russian HIV-1 V3-loop sequence variants are susceptible to maraviroc.

INTRODUCTION: Maraviroc inhibits CCR5-tropic HIV-1 across different subtypes in vitro and has demonstrated efficacy in clinical trials. V3-loop amino acid variants observed in individual maraviroc-resistant viruses have not been found to be predictive of reduced susceptibility. Sequence-database searches have demonstrated that approximately 7.3% of viruses naturally encode these variants, raising concerns regarding potential pre-existing resistance. A study from Russia reported that combinations of these same amino acids are present in the V3 loops of the Russian variant subtype A (IDU-A, now A6) with a much greater prevalence (range: 74.4%-92.3%) depending on the combination. However, these studies and database searches did not include phenotypic evaluation. METHODS: Sixteen Russian HIV-1 isolates (including sub-subtype A6 viruses) were assessed for V3 loop sequence and phenotypic susceptibility to maraviroc. RESULTS: All 12 of the A6 viruses and 2/4 subtype B isolates encoded V3-loop variants that have previously been identified in individual virus isolates with reduced susceptibility to maraviroc. However, despite the prevalence of these V3-loop amino acid variants among the tested viruses, phenotypic sensitivity to maraviroc was observed in all instances. Similarly, reduced susceptibility to maraviroc was not found in virus from participants who experienced virologic failure in a clinical study of maraviroc in Russia (A4001101, [NCT01275625]). DISCUSSION: Altogether, these data confirm that the presence of individual or combinations of V3-loop amino acid residues in sub-subtype A6 viruses alone does not predict natural resistance to maraviroc and that V3-loop genotype analysis of R5 virus prior to treatment is not helpful in predicting clinical outcome.

V3-Loop genotypes do not predict maraviroc susceptibility of CCR5-tropic virus or clinical response through week 48 in HIV-1-infected, treatment-experienced persons receiving optimized background regimens.

Viruses from 15 of 35 maraviroc-treated participants with virologic failure and CCR5-tropic (R5) virus in the MOTIVATE studies at Week 24 had reduced maraviroc susceptibility. On-treatment amino acid changes were observed in the viral envelope glycoprotein 120 third variable (V3)-loop stems and tips and differed between viruses. No amino acid change reliably predicted reduced susceptibility, indicating that resistance was genetic context-dependent. Through Week 24, poor adherence was associated with maraviroc-susceptible virologic failure, whereas reduced maraviroc susceptibility was associated with suboptimal background regimen activity, highlighting the importance of overall regimen activity and good adherence. Predictive values of pretreatment V3-loop sequences containing these Week 24 mutations or other variants present at >3% in pretreatment viruses of participants with virologic failure at Week 48 were retrospectively assessed. Week 48 clinical outcomes were evaluated for correlates with pretreatment V3-loop CCR5-tropic sequences from 704 participants (366 responders; 338 virologic failures [83 with R5 virus with maraviroc susceptibility assessment]). Seventy-five amino acid variants with >3% prevalence were identified among 23 V3-loop residues. Previously identified variants associated with resistance in individual isolates were represented, but none were associated reliably with virologic failure alone or in combination. Univariate analysis showed virologic-failure associations with variants 4L, 11R, and 19S (P < 0.05). However, 11R is a marker for CXCR4 tropism, whereas neither 4L nor 19S was reliably associated with reduced maraviroc susceptibility in R5 failure. These findings from a large study of V3-loop sequences confirm lack of correlation between V3-loop genotype and clinical outcome in participants treated with maraviroc.Clinical trial registration numbers (ClinicalTrials.gov): NCT00098306 and NCT00098722.

The conserved carboxy terminal region of HIV-1 gp120 is recognized by seronegative HIV-exposed people.

OBJECTIVE: To screen HIV-positive, long-term exposed seronegative and low-risk individuals for the presence of antibodies against regions of HIV-1 gp120 that share some degree of homology with HLA. METHODS: Sera were obtained from 63 HIV-1-infected subjects [52 Centers for Disease Control and Prevention (CDC) stage 2 and 11 stages 3/4], 32 HIV-exposed uninfected (HEU) subjects and from 24 low-risk HIV-1 seronegative individuals. They were tested by a peptide-based enzyme-linked immunosorbent assay (ELISA) for reactivity against peptides derived from the HIV-1 gp120 C-terminal region that contain regions of MHC sequence/structural similarity. Ten randomly selected sera from each group were also screened for anti-class I antibodies. RESULTS: Thirty per cent of the long-term HIV-1-exposed seronegative individuals had antibodies against the conserved C-terminal region (C5) of HIV-1 gp120. However, sera from HEU individuals showed no reactivity against other peptides derived from the C2 region of gp120, also an HLA homologous region. Anti-C terminal gp120 antibodies were mainly of IgM subclass, although IgG-specific antibodies were also present. In addition, 70% of HEU individuals had antibodies to HLA class I molecules compared with 15% of HIV-positive patients (restricted to only those HIV-positive patients with anti C-terminal antibodies). CONCLUSION: Our results suggest that antibody responses against the C-terminal region of HIV gp120 and HLA class I may represent markers of apparent natural protection against HIV-1 infection.

Recombinant proricin binds galactose but does not depurinate 28 S ribosomal RNA.

Preproricin transcripts microinjected into Xenopus oocytes were expressed and the product was segregated by the oocyte endoplasmic reticulum and core glycosylated. Recombinant proricin was soluble, stabilised by intramolecular disulfide bonds and biologically active in that it could bind to immobilized lactose (selectin 2) or immobilized asialofetuin. Affinity-purified proricin did not catalyse the depurination of 28 S ribosomal RNA unless it was reduced, when slight but significant activity was observed. Gel filtration of the reduced proricin fraction showed that this depurination activity was not associated with proricin. The activity was apparently due to ricin A chain released by reduction from mature ricin which was, in turn, generated from proricin, presumably via endogenous oocyte endoprotease activity.

Optimisation of a peptide-based indirect ELISA for the detection of antibody in the serum of HIV-1 seropositive patients.

A modified peptide-based indirect ELISA technique for the detection of HIV-1 specific antibodies in the sera of HIV-1 seropositive individuals is described. We found that the reduction of non-specific binding of HIV-1 seropositive sera to the ELISA plate was essential for the reliable detection of serum antibodies in the peptide based indirect ELISA. Optimal results were obtained using Immulon microtitre plates, different concentrations of denatured. purified grade of casein in the blocking (1%) and washing (0.25%) solutions and by diluting HIV-1 seropositive sera 1 in 1600. These conditions reduced non-specific binding and improved assay sensitivity. We show that the inclusion of a control peptide is essential to reducing the incidence of false positive and false negative results. Taken together, the modifications described in this report improve reliability of the peptide-based indirect ELISA without compromising its sensitivity and have particular relevance for those wishing to apply the peptide-based indirect ELISA technique to serum samples which exhibit high levels of non-specific binding. To illustrate this, levels of antibody in the sera of HIV-1 seropositive and seronegative donors that are specific for peptides derived from a conserved region of HIV-1 gp120 sharing homology with the FAS apoptosis antigen were analysed using this technique.

The role of HIV gp120 in the disruption of the immune system.

The existence of HIV positive individuals who do not appear to progress to disease, or do so only very slowly (LTNPs), strongly suggest that factors other than virus pathogenicity determine disease. The occurence of HIV infected chimpanzees that remain disease free and other African SIV infected primates where disease is apparently species specific underscores the importance of host factors [1,2]. We have examined the immune response of LTNP patients using a variety of techniques including intracellular cytokine FACscan, anchor PCR analysis of the T cell receptor and HLA typing of class II genes by DNA sequencing. Our results to date confirm that the development of disease is consistent with activation of a susceptible immune system, and that this could be due to the fact that HLA-like sequences of HIV may 'allo' activate the host immune response. In order to test this hypothesis further we have examined whether gp120 itself can bind and present specific peptides which may be capable of eliciting 'allo' activation responses in particular hosts.

Repertoire breadth of human CD4+ T cells specific for HIV gp120 and p66 (primary antigens) or for PPD and tetanus toxoid (secondary antigens)

Antigen derived peptides bound on MHC class II molecules on presenting cells stimulate specific CD4 lymphocytes that are in a naive state if antigen is given for the first time, or in a memory state if antigen has been previously encountered. In order to compare clonal heterogeneity of the human CD4+ T helper repertoire in primary vs. recall responses, we have generated T cell lines in vitro by repeated stimulation of peripheral lymphocytes with primary or with recall antigens. Clonal heterogeneity was broad in the case of recall response to tetanus toxoid or PPD, with a high frequency of specific precursors (> 100 cells/10(6) lymphocytes). In contrast, T cell lines responsive to primary antigens (HIV gp120 or HIV p66) were oligoclonal as defined by TCR V beta gene usage and by spectratyping, and the precursor frequency was low (< 2 cells/10(6) lymphocytes). Primary T cell lines generated from blood samples drawn at different times from the same donor showed that clones with identical TCR CDR3 region coding sequences were expanded, suggesting that in these individuals a large progeny derived from one single precursor is present, even though a previous encounter with the antigen was not documented. Assuming an even in vivo distribution of such cells, the presence of one precursor every 10(6) CD4 lymphocytes (within the CD4 T repertoire that comprises roughly 10(11) CD4 T cells) indicates that approximately 10(5) identical T cells from the same clonal precursor account for the primary response against the model antigens we have studied.

HIV gp120 plus specific peptides are recognized in a similar manner to specific HLA plus peptide by HLA-restricted antigen-specific T-cell lines.

HIV induces disease only following chronic activation of the immune system. Other retroviruses such as the mouse mammary tumour virus (MMTV) activate a large percentage of T cells by encoding a superantigen (SAg). To date there is no evidence that HIV encodes a SAg. An alternative way to induce pan-activation of the immune system is by allogeneic stimulation, which occurs following transplantation. Here we extend previous work which demonstrated that HIVpg120 could bind peptides in a similar manner to HLA, by demonstrating that human antigen presenting cells (APCs) expressing gp120 (but not DR1) can present a DR1-restricted peptide to induce proliferation of a DR1-restricted peptide-specific T-cell line in a similar manner to the same peptide presented by a DR1 expressing APC. Our data provide strong support for the hypothesis that the HLA-like regions of gp120 encode functional properties shared with HLA, and could explain the extraordinary clinical and immunological similarities between AIDS and chronic graft versus host disease.

Fusion/entry inhibitors as therapies for HIV.

A combination of three or more antiretroviral drugs, commonly termed 'highly active antiretroviral therapy' (HAART), has become the standard-of-care treatment for HIV-related disease in the developed world. Since its initiation in the mid 1990s, HAART has led to substantial reductions in both mortality and morbidity. There are, however, significant problems associated with existing therapies including high pill burdens and serious side effects in many patients, as well as the emergence and transmission of drug-resistant HIV variants. There is, therefore, a need for new medicines to treat HIV infections, both from the existing drug classes and, perhaps more importantly, a need for medicines that act against the virus in entirely new ways. In recent years, much has been learned about how HIV enters its target cells and this work has led to the identification of compounds that potently inhibit the individual steps of viral entry. The status of current research focussed on preventing HIV entry is described below.

Anticholinergic agents for chronic asthma in adults.

BACKGROUND: Anticholinergic agents such as ipratropium bromide are sometimes used in the treatment of chronic asthma. They effect bronchodilation and have also been used in combination with beta2-agonists in the management of chronic asthma. OBJECTIVES: To examine the effectiveness of anticholinergic agents versus placebo and in comparison with beta2-agonists or as adjunctive therapy to beta2-agonists. SEARCH STRATEGY: The Cochrane Airways Group asthma and wheeze database was searched with a pre-defined search strategy. Searches were current as of August 2003. Reference lists of articles were also examined. SELECTION CRITERIA: Randomised trials or quasi-randomised trials were considered for inclusion. Studies assessing an anticholinergic agent versus placebo or in combination/comparison with beta2-agonists were included. In practice, all beta2-agonists were short acting. Short-term (less than 24 hours duration) and longer-term studies were separated; the latter are reported in this review and the former in the review, "Anticholinergic agents for chronic asthma in adults short term". DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed abstracts for retrieval of full text articles. Papers were then assessed for suitability for inclusion in the review. Data from included studies were extracted by two reviewers and entered into the software package (RevMan 4.2). We contacted authors for missing data and some responded. Adverse effect data were analysed if reported in the included studies. MAIN RESULTS: The studies analysed were in two groups: those comparing anticholinergics with placebo and those comparing the combination of anticholinergics with short acting beta2-agonists versus short acting beta2-agonists alone. The former group had 13 studies involving 205 participants included in this review, and the latter 9 studies involving 440 patients. Generally methodological quality was poorly reported, and there were some reservations with respect to the quality of the studies. Despite the limited number of studies that could be combined, anticholinergic agents in comparison with placebo resulted in more favourable symptom scores particularly in respect of daytime dyspnoea (WMD -0.09 (95%CI -0.14, -0.04, 3 studies, 59 patients). Daily peak flow measurements also showed a statistically significant improvement for the anticholinergic (e.g. morning PEF: WMD =14.38 litres/min (95%CI 7.69, 21.08; 3 studies, 59 patients). However the clinical significance is small and in terms of peak flow measurements equates to approximately a 7% increase over placebo. The more clinically relevant comparison of a combination of anticholinergic plus short acting beta2-agonist versus short acting beta2-agonist alone gave no evidence in respect of symptom scores or peak flow rates of any significant differences between the two regimes. Again there are reservations with respect to the quality of the information from which these conclusions are drawn. REVIEWERS' CONCLUSIONS: Overall this review provides no justification for routinely introducing anticholinergics as part of add-on treatment for patients whose asthma is not well controlled on standard therapies. This does not exclude the possibility that there may be a sub-group of patients who derive some benefit and a trial of treatment in individual patients may still be justified. The role of long term anticholinergics such as tiotropium bromide has yet to be established in patients with asthma and any future trials might draw on the messages derived from this review.

Frontal lobe deficits in domestic violence offenders.

Functional frontal lobe deficits were examined in 38 men who committed domestic violence and 38 control participants. Dependent measures that examine frontal lobe deficits, including the Wisconsin Card Sorting Test (D. A. Grant & E. A. Berg, 1948), the Stroop Color-Word Test (J. R. Stroop, 1935), and Trails B (R. M. Reitan & L. A. Davidson, 1974), were used. The prediction that men who commit domestic violence would perform more poorly on neuropsychological measures related to frontal lobe deficits was only partially supported. A discriminate analysis was significant (p < .05), explaining approximately 7% of the variance; Trails B was the only contributor to that equation. The men who committed battery took significantly longer to complete Trails B than the control participants, suggesting that the men who committed battery may not have been as good as the control participants at inhibiting the competing response and therefore took longer to complete the task. The groups did not significantly differ on the other neuropsychological measures.

A survey of physiotherapists' experience using outcome measures in total hip and knee arthroplasty.

PURPOSE: To identify physiotherapists' familiarity with and experience using outcome measures (OMs) along the care continuum for patients undergoing total joint arthroplasty (TJA) of the hip and knee. Views on future use and barriers were also captured. METHODS: A stratified random sample of physiotherapists in one Canadian province completed a questionnaire about 19 standardized and clinically feasible OMs. Analyses included descriptive statistics and chi-square and McNemar tests to compare use of OMs for clinical decision making and program evaluation. RESULTS: Of 694 physiotherapists surveyed, 298 (43%) responded. Of these, 172 (58%) treated TJA clients and completed the full questionnaire. A majority worked in public practice settings and >1 care phase (e.g., pre-op, acute, rehab). All physiotherapists reported using ≥1 OM and having greater experience using performance-based measures than patient-reported OMs. OMs were used more often for clinical decision making than for program evaluation. Dissatisfaction with available tools was evident from respondents' comments. Several barriers to using OMs were identified in varied clinical settings and care phases. CONCLUSIONS: While physiotherapists use a variety of OMs along the TJA continuum, there remain challenges to routine use across clinical settings, care phases, and patient sub-groups.

Objectif : Déterminer dans quelle mesure les physiothérapeutes savent bien utiliser les mesures des résultats (MR) sur le continuum des soins chez les patients qui subissent une arthroplastie totale (AT) de la hanche et du genou, ainsi que leur expérience en la matière. On a saisi aussi leur opinion sur l'utilisation future et les obstacles. Méthodes : Un échantillon aléatoire stratifié de physiothérapeutes d'une province du Canada a répondu à un questionnaire sur 19 MR normalisées et faisables sur le plan clinique. Les analyses ont inclus des statistiques descriptives et des tests du chi-carré et de McNemar afin de comparer l'utilisation des MR pour la prise de décisions cliniques et l'évaluation de programmes. Résultats : Sur 694 physiothérapeutes sondés, 298 (43%) ont répondu, dont 172 (58%) ont traité des clients qui ont subi une AT et répondu au questionnaire au complet. Une majorité d'entre eux travaillait en pratique publique et dans >1 phase de soins (p. ex., préopératoires, actifs, réadaptation). Tous les physiothérapeutes ont déclaré utiliser ≥1 MR et avoir plus d'expérience des mesures fondées sur le rendement que des MR déclarées par les patients. Les MR étaient utilisées plus souvent dans la prise de décisions cliniques que dans l'évaluation de programmes. Les commentaires des répondants ont révélé leur insatisfaction face aux outils disponibles. On a défini un certain nombre d'obstacles à l'utilisation des MR dans divers contextes cliniques et phases de soins. Conclusions : Les physiothérapeutes utilisent un éventail de MR sur tout le continuum de l'AT, mais il reste des défis à relever sur le plan de l'utilisation de routine entre les contextes cliniques, les phases de soins et les sous-groupes de patients.

Economic modelling of diagnostic and treatment pathways in National Institute for Health and Care Excellence clinical guidelines: the Modelling Algorithm Pathways in Guidelines (MAPGuide) project.

BACKGROUND: National Institute for Health and Care Excellence (NICE) clinical guidelines (CGs) make recommendations across large, complex care pathways for broad groups of patients. They rely on cost-effectiveness evidence from the literature and from new analyses for selected high-priority topics. An alternative approach would be to build a model of the full care pathway and to use this as a platform to evaluate the cost-effectiveness of multiple topics across the guideline recommendations. OBJECTIVES: In this project we aimed to test the feasibility of building full guideline models for NICE guidelines and to assess if, and how, such models can be used as a basis for cost-effectiveness analysis (CEA). DATA SOURCES: A 'best evidence' approach was used to inform the model parameters. Data were drawn from the guideline documentation, advice from clinical experts and rapid literature reviews on selected topics. Where possible we relied on good-quality, recent UK systematic reviews and meta-analyses. REVIEW METHODS: Two published NICE guidelines were used as case studies: prostate cancer and atrial fibrillation (AF). Discrete event simulation (DES) was used to model the recommended care pathways and to estimate consequent costs and outcomes. For each guideline, researchers not involved in model development collated a shortlist of topics suggested for updating. The modelling teams then attempted to evaluate options related to these topics. Cost-effectiveness results were compared with opinions about the importance of the topics elicited in a survey of stakeholders. RESULTS: The modelling teams developed simulations of the guideline pathways and disease processes. Development took longer and required more analytical time than anticipated. Estimates of cost-effectiveness were produced for six of the nine prostate cancer topics considered, and for five of eight AF topics. The other topics were not evaluated owing to lack of data or time constraints. The modelled results suggested 'economic priorities' for an update that differed from priorities expressed in the stakeholder survey. LIMITATIONS: We did not conduct systematic reviews to inform the model parameters, and so the results might not reflect all current evidence. Data limitations and time constraints restricted the number of analyses that we could conduct. We were also unable to obtain feedback from guideline stakeholders about the usefulness of the models within project time scales. CONCLUSIONS: Discrete event simulation can be used to model full guideline pathways for CEA, although this requires a substantial investment of clinical and analytic time and expertise. For some topics lack of data may limit the potential for modelling. There are also uncertainties over the accessibility and adaptability of full guideline models. However, full guideline modelling offers the potential to strengthen and extend the analytical basis of NICE's CGs. Further work is needed to extend the analysis of our case study models to estimate population-level budget and health impacts. The practical usefulness of our models to guideline developers and users should also be investigated, as should the feasibility and usefulness of whole guideline modelling alongside development of a new CG. FUNDING: This project was funded by the Medical Research Council and the National Institute for Health Research through the Methodology Research Programme [grant number G0901504] and will be published in full in Health Technology Assessment; Vol. 17, No. 58. See the NIHR Journals Library website for further project information.

The innate immune response, clinical outcomes, and ex vivo HCV antiviral efficacy of a TLR7 agonist (PF-4878691).

Hepatitis C virus (HCV) infection is an issue of global concern, and studies are ongoing to identify new therapies that are both effective and safe. PF-4878691 is a Toll-like receptor 7 (TLR7) agonist modeled so as to dissociate its antiviral activities from its inflammatory activities. In a proof-of-mechanism study in healthy volunteers who received doses of 3, 6, and 9 mg of PF-4878691 twice a week for 2 weeks, PF-4878691 induced biomarkers of the immune and interferon (IFN) responses in a dose-dependent and dose-frequency-related manner. A novel finding was induction of TLR7 expression in vivo in response to PF-4878691, leading to an amplified biomarker response. A nonresponder at the 9-mg dose had a polymorphism in the IFN-α receptor 1 subunit (Val168Leu). Two subjects who had received 9-mg doses experienced serious adverse events (SAEs), characterized by flu-like symptoms, hypotension, and lymphopenia, leading to early termination of the study. TLR7 stimulation results in a pharmacologic response at levels commensurate with predicted antiviral efficacy, but these doses are associated with SAEs, raising concerns about the therapeutic window of this class of compounds for the treatment of HCV infection.

Anatomical and functional changes in the lower urinary tract after radical hysterectomy with lymph node dissection as studied by dynamic urethrocystography and simultaneous urethrocystometry.

Seventeen urologically healthy women undergoing standardized radical hysterectomy with lymph node dissection for stage I carcinoma of the cervix were evaluated urodynamically before, immediately after, and 1 year after surgery, by dynamic videourethrocystography and simultaneous urethrocystometry. The surgical technique had been developed in order to preserve as much of the nerve and blood supply to the bladder and urethra as possible. Major dysfunction was found in the early postoperative state, but the lower urinary tract almost always regained its preoperative functional status in the course of approximately 1 year. There were no long-lasting functional changes which interfered with daily life, although small static and dynamic changes were observed. The changes occurred chiefly above the urogenital diaphragm. The results of the two urodynamic examinations, each giving different information, corresponded well. Used together they gave a more complete picture than used separately. Dynamic videourethrocystography offered information about the function of the bladder and urethra which could not be obtained by urethrocystometry alone.

Dynamic urethrocystography in women.

A technique for video urethrocystography in women is described and evaluated from the results of examinations on 76 subjects. The patients were examined seated in the lateral position and investigations were carried out at rest, and during straining and coughing, micturition and holding-back maneuvers. Special attention was paid to the overall morphology and the position of the bladder base, the bladder neck and the urethra. Apart from the contour of the symphysis, which in some patients was difficult to identify, the various structures were easily displayed. Also the dynamics of the function of the bladder base, the bladder neck and the urethra were visualized. Almost all patients were able to carry out all parts of the examination including micturition without difficulty. TLD dosimeters in the vagina and uterus showed a low radiation dose to the ovaries.