Development of an online, patient-centred decision aid for patients with oropharyngeal cancer in the transoral robotic surgery era.

BACKGROUND: Radiotherapy (rt) has been the standard treatment for early oropharyngeal cancer, achieving excellent outcomes, but with significant toxicities. Transoral robotic surgery (tors) has emerged as a promising alternative. A decision aid (da) can help to establish patient treatment preferences. METHODS: A da was developed and piloted in 40 healthy adult volunteers. Assuming equal oncologic outcomes of the treatments, participants indicated their preference. The treatment trade-off point was then established, and participant perceptions were elicited. RESULTS: More than 80% of participants initially selected tors for treatment, regardless of facilitator background. For all participants, the treatment trade-off point changed after an average 15% cure benefit. Treatment toxicities, duration, novelty, and perceptions all influenced treatment selection. All subjects valued the da. CONCLUSIONS: A da developed for early oropharyngeal cancer treatment holds promise in the era of shared decision-making. Assuming equal cure rates, tors was preferred over rt by healthy volunteers.

Securing an OTL-HNS residency: how competitive is it? Comparing medical student perceptions to actual Canadian statistics.

BACKGROUND: The residency match is an important event in an aspiring physician's career. Otolaryngology - Head and Neck Surgery (OTL-HNS) is a surgical specialty that has enjoyed high numbers of applicants to its residency programs. However, recent trends in Canada show a decline in first-choice applicants to several surgical fields. Factors thought to influence a medical student's choice include role models, career opportunities and work-life balance. The notion of perceived competitiveness is a factor that has not yet been explored. This study sought to compare competitiveness of OTL-HNS, as perceived by Canadian medical students to residency match statistics published yearly by CaRMS (Canadian Residency Matching Service), with the hope of informing future decisions of surgical residency programs. METHODS: An electronic survey was created and distributed to all medical students enrolled in the 17 Canadian medical schools. After gathering demographic information, students were asked to rank what they perceived to be the five most competitive disciplines offered by CaRMS. They were also asked to rank surgical specialties from most to least competitive. Publically available data from CaRMS was then collected and analyzed to determine actual competitiveness of admissions to Canadian OTL-HNS residency programs. RESULTS: 1194 students, from first to fourth year of medical school, completed the survey. CaRMS statistics over the period from 2008 to 2014 demonstrated that the five most competitive specialties were Plastic Surgery, Dermatology, Ophthalmology, Emergency Medicine and OTL-HNS. Among surgical disciplines, OTL-HNS was third most competitive, where on average 72% of students match to their first-choice discipline. When students were questioned, 35% ranked OTL-HNS amongst the top five most competitive. On the other hand 72%, 74% and 80% recognized Opthalmology, Dermatology and Plastic Surgery as being among the five most competitive, respectively. We found that fourth-year medical students were significantly more knowledgeable about the competitiveness of both OTL-HNS and Plastic Surgery compared to first-year students (p < 0.01). CONCLUSION: Overall, Canadian medical students may underestimate the competitiveness of OTL-HNS. Furthermore, competitiveness would appear to be a concept that resonates with medical students during the match process.

Clinical aspects of cytomegalovirus antiviral resistance in solid organ transplant recipients.

Despite advances in the prophylaxis and acute treatment of cytomegalovirus (CMV), it remains an important pathogen affecting the short- and long-term clinical outcome of solid organ transplant. The emergence of CMV resistance in a patient reduces the clinical efficacy of antiviral therapy, complicates therapeutic and clinical management decisions, and in some cases results in loss of the allograft and/or death of the patient. There is increasing use of antiviral prophylaxis after transplant with little expansion in the range of antiviral agents effective in treatment of CMV. Further understanding is needed of the risk factors for development of CMV antiviral resistance and of therapeutic strategies for treating patients infected with resistant viruses. We review the current status of CMV resistance in solid organ transplant recipients, and provide diagnostic and therapeutic suggestions for the clinician in managing antiviral resistance.

Viral factors influencing the outcome of human cytomegalovirus infection in liver transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) remains the leading viral cause of disease following orthotopic liver transplantation (OLT) despite the availability of antiviral agents for prophylaxis and therapy. OBJECTIVE: Examine the viral factors that influence the outcome of CMV infection following valganciclovir prophylaxis or laboratory-guided preemptive therapy in OLT recipients. STUDY DESIGN: The value of valganciclovir prophylaxis and laboratory-guided preemptive therapy for the prevention of CMV infection and disease was observed in 64 OLT recipients. Prophylaxis was given to all CMV seronegative recipients receiving a liver from a seropositive donor (D+R-; n=15), and all other recipients were randomised to receive either prophylaxis (n=24) or laboratory-guided preemptive therapy (n=25). Recipients were monitored for CMV DNAemia, viral load, emergence of antiviral resistant strains and co-infections. RESULTS: CMV end-organ disease and antiviral resistant strains only occurred in D+R- recipients despite the use of prophylaxis in these patients. The D+R- recipients commencing prophylaxis immediately following transplantation had better outcomes compared to those for whom prophylaxis was delayed due to renal impairment. Prophylaxis reduced the incidence of CMV DNAemia, persistent infection, and high viral loads for CMV seropositive (D-R+and D+R+) recipients, but laboratory-guided preemptive therapy effectively controlled CMV infection and prevented disease in these OLT recipients. CONCLUSION: Delaying the commencement of valganciclovir prophylaxis may be associated with worse outcomes for high-risk OLT recipients. Laboratory-guided pre-emptive therapy remains an alternative approach for seropositive recipients at lower risk of CMV disease.

Diversity of antiviral-resistant human cytomegalovirus in heart and lung transplant recipients.

Immunocompromised transplant recipients are at high risk for human cytomegalovirus (CMV)-related infection and disease. Antiviral prophylaxis and treatment have reduced CMV morbidity and mortality, but at times promote development of antiviral-resistant CMV strains that can significantly contribute to adverse clinical outcomes in transplant recipients. We have investigated CMV genotypes in transplant recipients (bone marrow, stem cell, kidney, heart, lung, and liver) receiving antiviral prophylaxis or preemptive therapy or treatment, to determine the viral characteristics and clinical impact of antiviral-resistant CMV in these different groups. Antiviral-resistant CMV strains were detected by polymerase chain reaction sequencing of the CMV protein kinase (UL97) and viral DNA polymerase (UL54) genes from clinical specimens. A trend toward more frequent detection of multidrug resistance and co-circulation of multiple resistant strains was seen in heart and lung transplant recipients compared with other transplantation types. A greater diversity and number of UL97 and UL54 mutations were observed in heart and lung transplant recipients; whereas antiviral-resistant CMV infections in other transplant recipients were predominantly the result of a single mutant genotype. Furthermore, 43% (6/14) of CMV-positive heart and lung transplant recipients were infected with CMV strains containing UL54 mutations conferring multidrug resistance compared with only 6% (1/18) of CMV-positive recipients of other transplanted organs or stem cells. Emergence of CMV strains containing previously unrecognized UL54 mutations (F412S and D485N) also occurred in 1 lung and 1 heart transplant recipient. The development of these mutations under antiviral selective pressure, and clinical outcome of infection suggests these mutations are likely to confer antiviral resistance. Emergence of CMV antiviral resistance remains a significant issue in immunocompromised patients treated with antiviral agents, and emphasizes the relevance of regular antiviral resistance testing when designing optimal patient-management strategies.

Interpretation of Mycobacterium tuberculosis antigen-specific IFN-gamma release assays (T-SPOT.TB) and factors that may modulate test results.

BACKGROUND: Data about T cell antigen-specific (ESAT-6 and CFP-10) IFN-gamma release assays (IGRAs) during and after completion of anti-tuberculous (TB) treatment are limited and highly discordant. Thus, the utility of IGRAs as a surrogate marker of mycobacterial burden remain unclear. METHODS: To investigate factors that modulate IGRA responses during anti-TB treatment we used a standardised assay (T-SPOT.TB) in 33 patients with culture positive tuberculosis. RESULTS: Significantly more patients in the early (< or = 4 months of anti-TB treatment) rather than the late phase (> 4 months or completed anti-TB treatment) had positive IGRA responses [10/12 (83%) vs 4/21 (19%); p < or = 0.01]. Thus, 17/21 (81%) in the late phase or who had completed treatment (mean duration of treatment = 8.7 months) were IGRA negative, despite having robust antigen-specific recall proliferative responses. In these 17 patients prolonged incubation (5 days vs overnight), use of different antigen preparations (protein vs peptide) and addition of endotoxin, failed to elicit positive responses. CONCLUSIONS: In treated TB patients the discordant IGRA data remain unexplained by variation in laboratory protocols and are more likely due to host or environmental factors. In a low burden setting IGRAs may be a promising surrogate marker of mycobacterial disease burden.

Discrepancy between self-reported and observed hand hygiene behaviour in healthcare professionals.

Hand hygiene behaviour in 71 healthcare professionals was observed on hospital wards for a total of 132 h, encompassing 1284 hand hygiene opportunities. Questionnaires completed by the participants were used to compare actual behaviours with self-reported behaviours, as well as intentions and attitudes towards hand hygiene. Observed practice showed very poor rates of adherence to guidelines and indicated that staff failed to take account of risk, even with patients colonized with meticillin-resistant Staphylococcus aureus. Observed practice was unrelated to carers' intentions and self-reported behaviour. The results suggest that hand hygiene interventions that target changes in attitudes, intentions or self-reported practice are likely to fail in terms of changing behaviour, and consideration is given to how this could be remedied.

Correlates of placental infection with cytomegalovirus, parvovirus B19 or human herpes virus 7.

Vertical transmission of viruses is an important cause of morbidity in the fetus and neonate. Placental viral infection indicates risk of vertical transmission, but not always transmission to, or disease of the fetus. Specimens from mothers and babies from three groups-two prospective and one retrospective cohort-were tested for pathogens of teratogenic potential using multiplex PCR. Placental infection was present in 13% of the 105 samples collected. Assessment of the prospective cohorts showed cytomegalovirus (CMV) detected in 4% of placentae from unselected women, parvovirus B19 in 1% and Ureaplasma parvum in 1% of placentae. In a retrospective cohort of women at high risk of transmitting congenital infection due to seroconversion during pregnancy, miscarriage or stillbirth, CMV was detected in 64% and human herpes virus type 7 in 9% of placentae. Of 14 PCR-positive placentae, two were associated with the birth of a living symptomatic infant, two with stillbirth, one with miscarriage, and two with elective terminations of pregnancy. Directed laboratory assessment of women at high risk of transmitting congenital infection, on the basis of clinical or laboratory markers, is important for accurate diagnosis of adverse outcomes of pregnancy. However, routine screening for viruses in the placentae from women with a low-risk serological profile for transmitting congenital infection is unlikely to result in significant numbers of additional diagnoses and is confounded by inadequacy of current diagnostic methods. The major pathogen detected in all cases of placental infection associated with fetal death was human CMV.

Development of multiplex PCRs for detection of common viral pathogens and agents of congenital infections.

Potential causes of congenital infection include Toxoplasma gondii and viruses such as cytomegalovirus (CMV), enterovirus, hepatitis C virus, herpes simplex virus types 1 and 2 (HSV-1 and -2), human herpesvirus types 6, 7, and 8, lymphocytic choriomeningitis virus, parvovirus, rubella virus, and varicella-zoster virus. Testing for each of these agents using nucleic acid tests is time consuming and the availability of clinical samples such as amniotic fluid or neonatal blood is often limited. The aim of this study was to develop multiplex PCRs (mPCRs) for detection of DNA and RNA agents in the investigation of congenital infection and an mPCR for the viruses most commonly requested in a diagnostic virology laboratory (CMV, Epstein-Barr virus, enterovirus, HSV-1, HSV-2, and varicella-zoster virus). The assays were assessed using known pathogen-positive tissues (cultures, placentae, plasma, and amniotic fluid) and limits of detection were determined for all the agents studied using serial dilutions of plasmid targets. Nested PCR was performed as the most sensitive assay currently available, and detection of the amplicons using hybridization to labeled probes and enzyme-linked immunosorbent assay detection was incorporated into three of the four assays. This allowed detection of 10 to 10(2) copies of each agent in the samples processed. In several patients, an unexpected infection was diagnosed, including a case of encephalitis where HSV was the initial clinical suspicion but CMV was detected. In the majority of these cases the alternative agent could be confirmed using reference culture, serology, or fluorescence methods and was of relevance to clinical care of the patient. The methods described here provide useful techniques for diagnosing congenital infections and a paradigm for assessment of new multiplex PCRs for use in the diagnostic laboratory.

Murine cytomegalovirus resistant to antivirals has genetic correlates with human cytomegalovirus.

Human cytomegalovirus (HCMV) resistance to antivirals is a significant clinical problem. Murine cytomegalovirus (MCMV) infection of mice is a well-described animal model for in vivo studies of CMV pathogenesis, although the mechanisms of MCMV antiviral susceptibility need elucidation. Mutants resistant to nucleoside analogues aciclovir, adefovir, cidofovir, ganciclovir, penciclovir and valaciclovir, and the pyrophosphate analogue foscarnet were generated by in vitro passage of MCMV (Smith) in increasing concentrations of antiviral. All MCMV antiviral resistant mutants contained DNA polymerase mutations identical or similar to HCMV DNA polymerase mutations known to confer antiviral resistance. Mapping of the mutations onto an MCMV DNA polymerase three-dimensional model generated using the Thermococcus gorgonarius Tgo polymerase crystal structure showed that the DNA polymerase mutations potentially confer resistance through changes in regions surrounding a catalytic aspartate triad. The ganciclovir-, penciclovir- and valaciclovir-resistant isolates also contained mutations within MCMV M97 identical or similar to recognized GCV-resistant mutations of HCMV UL97 protein kinase, and demonstrated cross-resistance to antivirals of the same class. This strongly suggests that MCMV M97 has a similar role to HCMV UL97 in the phosphorylation of nucleoside analogue antivirals. All MCMV mutants demonstrated replication-impaired phenotypes, with the lowest titre and plaque size observed for isolates containing mutations in both DNA polymerase and M97. These findings indicate DNA polymerase and protein kinase regions of potential importance for antiviral susceptibility and replication. The similarities between MCMV and HCMV mutations that arise under antiviral selective pressure increase the utility of MCMV as a model for in vivo studies of CMV antiviral resistance.

Hand hygiene posters: motivators or mixed messages?

Poster campaigns regarding hand hygiene are commonly used by infection control teams to improve practice, yet little is known of the extent to which they are based on established theory or research. This study reports on the content analysis of hand hygiene posters (N=69) and their messages (N=75) using message-framing theory. The results showed that posters seldom drew on knowledge about effective ways to frame messages. Frequently, they simply conveyed information 'telling' rather than 'selling' and some of this was confusing. Most posters were not designed to motivate, and some conveyed mixed messages. Few used fear appeals. Hand hygiene posters could have a greater impact if principles of message framing were utilized in their design. Suggestions for gain-framed messages are offered, but these need to be tested empirically.

Hand hygiene posters: selling the message.

This literature review was undertaken to determine the established theory and research that might be utilized to inform the construction of persuasive messages on hand hygiene posters. It discusses the principles of message framing and the use of fear appeals. Current theory suggests that the most effective messages for health promotion behaviours should be framed in terms of gains rather than losses for the individual. However, as clinical hand hygiene is largely for the benefit of others (i.e. patients), messages should also invoke a sense of personal responsibility and appeal to altruistic behaviour. The use of repeated minimal fear appeals have their place. Posters that simply convey training messages are not effective persuaders.

Cytomegalovirus antiviral resistance associated with treatment induced UL97 (protein kinase) and UL54 (DNA polymerase) mutations.

HCMV-related illness due to infections with antiviral resistant virus was verified by phenotypic and genotypic assays in 17% (8/47) of high-risk immunocompromised Australian patients. Selective PCR-sequencing of UL97 (protein kinase; PK) and UL54 (DNA polymerase; DNApol) regions important for antiviral sensitivity, identified the majority (6/8) of resistant strains through detection of mutations known to confer antiviral resistance. Additionally, eight UL54 (DNApol) mutations (N408K, T691S, A692V, S695T, L737M, A834P, V955I, and A972V) of unknown phenotype were identified in six specimens from patients with clinical evidence of antiviral resistant infections. One isolate was resistant to ganciclovir (GCV) and another resistant to PFA on phenotypic testing where mutations in UL97 (PK) or UL54 (DNApol) were not detected, suggesting a loss of correlation between phenotype and genotype. Selective PCR-sequencing of UL97 (PK) and UL54 (DNApol) provided rapid and comprehensive results, but missed some resistance detected by phenotypic assays. A combination of phenotypic and genotypic assays is recommended for complete analysis of CMV antiviral resistance, as well as further definition of the clinical relationship between novel UL54 (DNApol) mutations and antiviral resistance.

The epidemiology of glycopeptide-resistant enterococci on a haematology unit--analysis by pulsed-field gel electrophoresis.

As part of an interventional study to determine glycopeptide-resistant enterococci (GRE) acquisition on a three-ward haematology unit, rectal swabs were taken weekly from 293 patients recruited to the study between June 1995 and December 1996. The GRE isolates obtained from the first positive rectal swab from 120 colonized patients, the isolates from 7 patients with clinical infection and 43 isolates obtained from the ward environment were compared by pulsed-field gel electrophoresis (PFGE). Sixty-three of 120 patients were colonized by one of strains A-H, while 49 were colonized by unique strains. The first 18 weeks were associated with the highest prevalence of GRE by rectal swab, with a single strain A responsible for 52% of acquisitions on ward 2, 22% on ward 3 and 36% on ward 4. Other smaller ward associated clusters were evident. Environmental sampling of ward 2 during this time showed that all but 2 of 30 isolates were indistinguishable from strain A. As the GRE prevalence fell, rectal swab and environmental isolates became more heterogeneous, and strain A disappeared after week 55. GRE prevalence rose again in the final 15 weeks of the study, and a new predominant strain B emerged on ward 2 responsible for 50% of new acquisitions. In the seven patients with clinical infection with GRE, the clinical isolates were compared with the contemporaneous rectal swab isolate, and were found to be the same in only two cases. An analysis of five long-term carriers colonized for a median of 19 weeks (range 11-34) showed colonization with at least two and in one case six distinct strains, raising the question of how many strains may be colonizing a patient at any one time, and suggesting that multiple colonies should be analysed. These data suggest that cross-infection was an important factor in the spread of GRE when the colonization rate was high.

Human cytomegalovirus strains associated with congenital and perinatal infections.

The genotypes of human cytomegalovirus (HCMV) isolates from pediatric patients differs from those of infected adults in Australia. Genotypes were determined by PCR amplification of glycoprotein B (gB) sequences, with subsequent analysis by restriction fragment length polymorphism, single-stranded conformation polymorphism, heteroduplex mobility analysis and direct DNA sequencing. Restriction fragment length polymorphism analysis of gB showed genotypes gB1 (39%) and gB3 (30%) were more prevalent in infected children and two new genotypes (gB6 and gB7) were found. Single-stranded conformation polymorphism was used to group isolates into 22 further subtypes and suggested longitudinal co-infection or viral mutation was occurring over time. Heteroduplex mobility analysis was found to be the most accurate and concise of the four methods used for genotyping HCMV isolates. DNA sequencing was used to confirm the results obtained from heteroduplex mobility analysis, and identified two isolates that were incorrectly genotyped by restriction fragment length polymorphism analysis. Heteroduplex mobility analysis efficiently genotyped all samples and allowed estimation of sequence variation between isolates. These data suggest certain gB genotypes are associated more commonly with childhood infections, and these differ from strains associated with invasive disease in HIV patients.

Type 2 cytokine gene activation and its relationship to extent of disease in patients with tuberculosis.

The extent of type 2 cytokine gene expression in patients with pulmonary tuberculosis (TB) was studied by use of quantitative nested reverse-transcription polymerase chain reaction on freshly isolated peripheral blood mononuclear cells. Interleukin (IL)-4 and IL-13 mRNA expression was significantly greater in patients-median mRNA copy numbers were 1.7 and 1.1 log10 higher, respectively-than in matched tuberculin-positive control subjects. Significant correlations with radiologic extent of disease and serum IgE levels supported the biologic significance of these results. Interferon-gamma mRNA copy numbers exceeded those of type 2 cytokines but were only marginally lower in patients than in control subjects. Gene expression of an IL-4 splice variant (IL-4delta2) was bimodally distributed in both patient and control groups. Patients with greater IL-4delta2 expression also expressed more IL-4 mRNA and had more extensive disease. Type 2 cytokines are associated with immunopathologic changes in TB patients but could be a cause or consequence of disease.

Is the detection of Mycobacterium tuberculosis DNA by ligase chain reaction worth the cost: experiences from an inner London teaching hospital.

AIMS: To evaluate the clinical usefulness and the costs of using a rapid, commercial ligase chain reaction test (LCx) to detect Mycobacterium tuberculosis directly from clinical samples. METHODS: A prospective study of 2120 routine clinical specimens from 1161 patients over a 13 month period. Investigations for mycobacterial disease by microscopy, culture, and the Abbott LCx assay were performed. Sequential LCx assays were monitored in a cohort of patients undergoing treatment. The costs of the assay were calculated using the WELCAN system. Sensitivity, specificity, and positive and negative predictive values of the LCx assay were compared with conventional tests. The performance of the assay in patients undergoing treatment and cost in terms of WELCAN units converted to pounds/annum was studied. RESULTS: The assay was 85%/88% sensitive and 98%/100% specific in culture confirmed/clinically confirmed cases of tuberculosis, respectively. The assay was not useful for the measurement of treatment outcomes. The test cost approximately 42,500 Pounds/annum. CONCLUSIONS: The assay is a rapid, sensitive, and specific adjunct to clinical diagnosis, especially in differentiating non-tuberculous mycobacteria. However, it does not differentiate old and treated tuberculosis from reactivated disease, it is not useful to monitor adherence to treatment, and it is expensive.

Improving permissive infection of human cytomegalovirus in cell culture.

Changes in human cytomegalovirus (HCMV) titre occurring under different conditions were studied using plaque assay. No significant change in titre was found using primary embryonic fibroblasts or primary foreskin fibroblasts, or with the addition of dexamethasone to the medium. Significant increases in titre were found when standard cultures were pre-incubated in medium containing DEAE-dextran and/or calcium chloride. However, DEAE-dextran and/or calcium chloride had no significant effect on HCMV detection using the shell vial assay, possibly because enhancement affects permissive infection, but not surface expression of viral antigens. DEAE-dextran and calcium chloride can be included in the medium of standard cultures as a means of obtaining higher titres of HCMV, and are particularly useful for isolates that are difficult to culture.