Analysis of cytomegalovirus DNA polymerase (UL54) mutations in solid organ transplant patients receiving valganciclovir or ganciclovir prophylaxis

We previously reported the absence of CMV UL97 (kinase) gene resistance mutations up to 12 months post-transplant following 100 days of valganciclovir prophylaxis, and a low incidence of resistance mutations following 100 days of oral ganciclovir prophylaxis in a prospective multicenter study in solid organ transplant recipients excluding lung transplants. Herein, we report UL54 (DNA polymerase) gene sequencing results for all patients with previous UL97 PCR-positive samples (n = 99) in our study. One UL54 resistance mutation (L545S known to confer ganciclovir and cidofovir resistance) was detected in a routine day-100 sample from an asymptomatic patient who received oral ganciclovir. Notably, this CMV UL54 mutation occurred in the absence of a UL97 mutation. Additionally, new UL54 variants were observed. Thus, emergence of CMV UL54 mutations in the absence of UL97 mutations is a rare but possible event that is not necessarily associated with detrimental clinical outcome in solid organ transplant recipients.     

Incidence and characterization of cytomegalovirus resistance mutations among pediatric solid organ transplant patients who received valganciclovir prophylaxis

BackgroundDrug-resistant cytomegalovirus (CMV) infections can cause significant morbidity among high-risk transplant recipients.ObjectivesThe aims of this study were to determine the incidence and clinical consequences of CMV mutations conferring ganciclovir resistance in pediatric solid organ transplant (SOT) patients who received valganciclovir oral solution or tablets for prophylaxis of CMV disease. Recombinant CMV mutants were also generated to assess the role of two UL97 mutations of unknown significance.Study designGenotypic resistance mutations and CMV viral load were sought in blood samples from pediatric SOT recipients who received valganciclovir prophylaxis for 100 days. Recombinant viruses containing novel CMV UL97 mutations were generated using a bacterial artificial chromosome containing the CMV genome to assess ganciclovir susceptibility.ResultsOverall, four known resistance UL97 mutations were observed in blood samples from 2 of 46 patients during the study with no development of CMV disease. Two UL97 changes (M615V and V466G) of unknown significance and one UL97 mutation (C603R) associated with ganciclovir resistance, but not yet confirmed by marker transfer, were also detected. Recombinant viruses containing these novel mutations were generated to assess ganciclovir susceptibility. The M615V recombinant virus was susceptible to ganciclovir while the V466G and C603R mutant viruses displayed 3.5-fold and 3.6-fold decreases in susceptibility, respectively.ConclusionsThe low incidence of ganciclovir resistance-associated mutations and the absence of clinical consequences associated with drug-resistant viruses observed in this pilot study should encourage the design of larger clinical trials aimed at evaluating the efficacy of valganciclovir prophylaxis and treatment in the pediatric setting.     

Successful valganciclovir treatment of post‐transplant cytomegalovirus infection in the presence of UL97 mutation N597D

Mutations in the human cytomegalovirus (CMV) UL97 protein kinase are the most common mechanism of ganciclovir (GCV) resistance in the clinical setting. A CMV strain with a previously unrecognized UL97 mutation N597D was identified in the blood of a heart transplant recipient who experienced a persistent CMV infection with high viral loads accompanying pain and fever while receiving valganciclovir (valGCV) therapy. The N597D mutation was transferred by mutagenesis to an antiviral sensitive CMV strain for analysis of antiviral susceptibility by standardized phenotypic assay. Recombinant phenotyping showed N597D conferred a less than twofold increase in GCV IC₅₀ compared to the sensitive control strain. Despite the presence of this mutation, valGCV eventually resolved the infection after 6 weeks of therapy. A subsequent CMV reactivation was also responsive to valganciclovir. This case illustrates the diversity of UL97 mutations in the codon segment 590–607 usually associated with GCV resistance, with some mutations producing minimal levels of resistance that do not preclude a therapeutic response to the drug. Accurate interpretation of genotypic test results ultimately requires experimental determination of the level of resistance conferred by newly discovered UL97 mutations. J. Med. Virol. 81:507–510, 2009. © 2009 Wiley‐Liss, Inc.     

The prevention and treatment of complicated grief: a meta-analysis

Background

Bereaved individuals are at increased risk of mental and physical disorders, and prevention and treatment of complicated grief is indicated. Earlier quantitative reviews have not focused on the effect of bereavement interventions on (complicated) grief. Therefore the main objective of this meta-analysis was to determine the short-term and long-term effect of both preventive and treatment interventions on complicated grief.

Methods

Randomized controlled trials for prevention or treatment of complicated grief were identified through a systematic literature search. Electronic databases and reference lists of earlier review articles served as data sources. Data were analyzed with REVMAN 5.0.14.

Results

Fourteen randomized controlled trials met the inclusion criteria. Study quality differed among the trials. Contrary to preventive interventions, treatment interventions yielded significant pooled standardized mean differences in favor of the (specific) grief intervention at post-test and follow-up. During the follow-up period, the positive effect of treatment interventions for complicated grief even increased.

Conclusions

Treatment interventions can effectively diminish complicated grief symptoms. Preventive interventions, on the other hand, do not appear to be effective. Limitations of the meta-analysis and future research options are discussed.     

White matter hyperintensities and cognition: Testing the reserve hypothesis

Objective

White matter hyperintensities (WMH), visualized on T2-weighted MRI, are thought to reflect small-vessel vascular disease. Much like other markers of brain disease, the association between WMH and cognition is imperfect. The concept of reserve may account for this imperfect relationship. The purpose of this study was to test the reserve hypothesis in the association between WMH severity and cognition. We hypothesized that individuals with higher amounts of reserve would be able to tolerate greater amounts of pathology than those with lower reserve.

Methods

Neurologically healthy older adults (n = 717) from a community-based study received structural MRI, neuropsychological assessment, and evaluation of reserve. WMH volume was quantified algorithmically. We derived latent constructs representing four neuropsychological domains, a measure of cognitive reserve, and a measure of brain reserve. Measures of cognitive and brain reserve consisted of psychosocial (e.g., education) and anthropometric (e.g., craniometry) variables, respectively.

Results

Increased WMH volume was associated with poorer cognition and higher cognitive and brain reserve were associated with better cognition. Controlling for speed/executive function or for language function, those with higher estimates of cognitive reserve had significantly greater degrees of WMH volume, particularly among women. Controlling for cognitive functioning across all domains, individuals with higher estimates of brain reserve had significantly greater WMH volume.

Conclusions

For any given level of cognitive function, those with higher reserve had more pathology in the form of WMH, suggesting that they are better able to cope with pathology than those with lower reserve. Both brain reserve and cognitive reserve appear to mitigate the impact of pathology on cognition.     

Development of new cytomegalovirus UL97 and DNA polymerase mutations conferring drug resistance after valganciclovir therapy in allogeneic stem cell recipients.

BACKGROUND: We report on two allogeneic stem cell transplant recipients who developed cytomegalovirus disease associated with new viral mutations that conferred antiviral drug resistance. METHODS: Blood specimens obtained during symptomatic disease were analyzed for mutations in the CMV UL97 and DNA polymerase genes and new mutations were assessed by recombinant phenotyping. RESULTS: Rising cytomegalovirus (CMV) antigenemia occurred after 4-5 months of preemptive valganciclovir therapy, followed by symptomatic CMV disease including fatal pneumonia in one case. In one case, a new viral UL97 mutation (deletion of codons 601-603) was found which conferred 15-fold increased ganciclovir resistance. In the other case, a known UL97 resistance mutation M460V and a new DNA polymerase (pol) mutation D413A were found. D413A conferred ganciclovir and cidofovir resistance. CONCLUSIONS: Known and newly discovered drug resistance mutations arising during preemptive therapy may complicate post-transplant CMV disease in stem cell recipients. Improved recombinant phenotyping methods enable the rapid quantitation of the resistance conferred by newly identified UL97 and pol mutations.     

Relationship of insulin resistance to psychobehavioral characteristics of overweight and obese African American children

Objectives

The objective of this study was to evaluate the relationships of insulin resistance to positive as well as negative dimensions of the child's emotions, behavior and personality (hereafter referred to as “psychobehavioral characteristics”) in a convenience sample of inner-city, overweight and obese, African American children.

Methods

A secondary analysis was performed on a sample of 127 children ages 9-12 yr old who were participating in a community-based, Type 2 diabetes prevention program. Psychobehavioral characteristics of children were assessed using both child and parent ratings derived from the Behavioral Assessment for Children, 2nd edition (BASC-2). Body fatness was evaluated using anthropometric techniques, and insulin resistance (HOMA-IR) was calculated from fasting glucose and insulin concentrations. Hierarchical multiple linear regression models were employed with BASC scales as dependent variables and HOMA-IR as the independent variable of interest.

Results

After adjusting for child age, pubertal stage, gender, family socioeconomic index, and intervention group assignment, child HOMA-IR was related at p < 0.05 to less favorable scores for parent-report of behavioral symptoms and externalizing problems composites, and to content scales for bullying and negative emotionality. Additionally, child HOMA-IR was related at p < 0.01 to less favorable scores for child-report inattention/hyperactivity composite. Body fatness suppressed the unfavorable relationship between HOMA-IR and these and other psychobehavioral characteristics as the degree of significance was higher following adjustment for body fatness in this cohort.

Conclusion

More than one psychobehavioral characteristic were associated with body fatness and insulin resistance in the overweight children of this study. Whether the associations are due to several, or only one, of these psychobehavioral characteristics could not be determined. A much larger and future study will be needed to determine which, if any, of these psychobehavioral characteristics are independently associated with insulin resistance in overweight children.     

Goal difficulty and goal commitment affect adoption of a lower glycemic index diet in adults with type 2 diabetes

Objective

Few studies have examined the effect of goal difficulty on behavioral change even though goal setting is widely used in diabetes education. The effect of a goal to consume either 6 or 8 servings/day of low glycemic index (LGI) foods was evaluated in this study.

Methods

Adults 40-65 years old with type 2 diabetes were randomly assigned to the 6 or 8 serving/day treatment group following a 5-week GI intervention. Perceived goal difficulty, commitment, satisfaction, and self-efficacy were evaluated, and four day food records assessed dietary intake.

Results

Both groups increased consumption of LGI foods (P < 0.001); there were no significant differences in the change in consumption between groups. Participants who were more committed to the goal perceived the goal to be less difficult (P < 0.01). Those with greater efficacy beliefs were more committed to their goal, perceived the goal to be less difficult, and were more satisfied with their performance (all P < 0.05).

Conclusion

A specific goal regarding LGI foods can facilitate the adoption of a lower GI diet. Future research is needed to determine if goal commitment or goal difficulty mediate the process.

Practice implications

Clinicians should help clients set specific goals regarding dietary change.     

Promoting decision aid use in primary care using a staff member for delivery

Objective

To determine the feasibility and effectiveness of in-clinic decision aid distribution using a care assistant.

Methods

We identified potentially eligible patients scheduled for upcoming appointments in our General Internal Medicine Clinic (n = 1229). Patients were deemed eligible for two decision aids: prostate cancer screening and/or weight loss surgery. Patients were approached to view the decision aid in-clinic. Our primary measures were the proportion of decision aids distributed to eligible patients, and the proportion of decision aids viewed.

Results

Among 913 patients who attended their scheduled appointments, 58% (n = 525) were approached and eligibility was assessed by the staff member. Among the 471 who remained eligible, 57% (n = 268) viewed at least a portion of the target decision aid. The mean viewing time for patients who watched less than the complete decision aid was 13 min.

Conclusions

In clinic viewing of decision aids may be a feasible and effective distribution method in primary care.

Practice implications

In clinic distribution requires an electronic health information system to identify potentially eligible patients, and a staff member dedicated to DA distribution. Brief decision aids (less than 10 min) are needed so patients can complete their use prior to the visit to facilitate patient-physician decision making.     

A course for nurses to handle difficult communication situations. A randomized controlled trial of impact on self-efficacy and performance

Objective

To evaluate the impact of a communication skills course for nurses on how to handle difficult communication situations in their daily work.

Methods

A 7-h course was developed using a construct of “Awareness, Feelings, Listen, Solve” (AFLS). A pedagogy of experiential, learner-centered learning was adopted. The course evaluation used a randomized controlled design with pre- and post-measures of self-efficacy and performance.

Results

Forty-one nurses volunteered and thirty-three nurses completed all assigned parts of the study. On self-assessment, there was significant improvement for self-efficacy (F = 24.43, p < 0.001), but not for emotional awareness. On performance, there was no significant improvement between intervention and control groups (F = 3.46, p = 0.073).

Conclusion

A short course for nurses on handling difficult communication situations achieved significant improvements in self-efficacy but not in performance.

Practice implications

Teaching communication skills in community-based settings is important for the safety and effectiveness of patient care. Sponsoring organizations should weigh trade-offs between feasibility and achievement of measurable improvements in performance. One possible approach is to focus on specific communication skills rather than a full suite of skills.     

Tele-health: lessons and strategies from specialists in poison information

Objective

The use of the telephone for providing healthcare is growing. The aim of this exploratory study was to describe tele-health lessons and strategies as discussed by specialists who provide information and recommendations on poison control hotlines.

Methods

Three focus groups of 25 participants who work as specialists in poison information in poison control centers were conducted. Group discussions were analyzed using qualitative content analysis.

Results

Themes that emerged from the data on strategies for telephone communication include: taking control of the call, developing a therapeutic relationship, tailoring communication to fit each caller, preventing information overload, confirming caller understanding, and hands-on training for the development of telephone communication skills.

Conclusion

Specialists in poison information identified challenges specific to communicating with patients over the telephone and reported several types of strategies they used to manage them.

Practice implications

Telephone communication training may be needed to assist health care providers in improving their communication skills.     

Automatic detection of epileptic seizures on the intra-cranial electroencephalogram of rats using reservoir computing

Introduction

In this paper we propose a technique based on reservoir computing (RC) to mark epileptic seizures on the intra-cranial electroencephalogram (EEG) of rats. RC is a recurrent neural networks training technique which has been shown to possess good generalization properties with limited training.

Materials

The system is evaluated on data containing two different seizure types: absence seizures from genetic absence epilepsy rats from Strasbourg (GAERS) and tonic-clonic seizures from kainate-induced temporal-lobe epilepsy rats. The dataset consists of 452 hours from 23 GAERS and 982 hours from 15 kainate-induced temporal-lobe epilepsy rats.

Methods

During the preprocessing stage, several features are extracted from the EEG. A feature selection algorithm selects the best features, which are then presented as input to the RC-based classification algorithm. To classify the output of this algorithm a two-threshold technique is used. This technique is compared with other state-of-the-art techniques.

Results

A balanced error rate (BER) of 3.7% and 3.5% was achieved on the data from GAERS and kainate rats, respectively. This resulted in a sensitivity of 96% and 94% and a specificity of 96% and 99% respectively. The state-of-the-art technique for GAERS achieved a BER of 4%, whereas the best technique to detect tonic-clonic seizures achieved a BER of 16%.

Conclusion

Our method outperforms up-to-date techniques and only a few parameters need to be optimized on a limited training set. It is therefore suited as an automatic aid for epilepsy researchers and is able to eliminate the tedious manual review and annotation of EEG.     

Bayesian tracking of intracranial pressure signal morphology

Background

The waveform morphology of intracranial pressure (ICP) pulses holds essential informations about intracranial and cerebrovascular pathophysiological variations. Most of current ICP pulse analysis frameworks process each pulse independently and therefore do not exploit the temporal dependency existing between successive pulses. We propose a probabilistic framework that exploits this temporal dependency to track ICP waveform morphology in terms of its three peaks.

Material

ICP and electrocardiogram (ECG) signals were recorded from a total of 128 patients treated for various intracranial pressure related conditions.

Methods

The tracking is posed as inference in a graphical model that associates a random variable to the position of each peak. A key contribution is to exploit a nonparametric Bayesian inference algorithm that offers robustness and real time performance. A simple, yet effective learning procedure estimates the statistical, nonlinear, dependencies between the peaks in a nonparametric way using evidence collected from manually annotated pulses.

Results

Experiments demonstrate the effectiveness of the tracking framework on real ICP pulses and its robustness to occlusion and missing peaks. On artificialy distorted ICP sequences, the average error in latency in comparision with MOCAIP detector was reduced as follows: 11.88-8.09 ms, 11.80-6.90 ms, and 11.76-7.46 ms for the first, second, and third peak, respectively.

Conclusion

The proposed tracking algorithm sucessfuly increases the temporal resolution of detecting ICP pulse morphological changes from the minute-level to the beat-level.     

Can wireless text messaging improve adherence to preventive activities? Results of a randomised controlled trial

Objective

To determine the effectiveness of cell phone wireless text messaging for improving adherence to a healthy behaviour.

Design

A randomised, unblinded, controlled trial was conducted with 102 subjects, 18 years or older, each having a cell phone and willing to take 1 vitamin C pill per day for 1 month for preventive reasons. Intervention group participants received text messaging reminders and were asked to acknowledge receiving their messages after taking the vitamins, whereas control group subjects had no text messaging activity.

Measurements

Self-reported adherence and the number of participant text messages acknowledging vitamins taken.

Results

Both groups reported an increased adherence after the trial: by 246% for the intervention group and by 131% for the control group. There was a non-significant difference between the two groups at endpoint: an average difference of 0.8 between the number of pills missed in the last week of the trial (2.5 out of 7 in the intervention and 3.3 out of 7 in the control group) with a power of 0.54. The study revealed a significant correlation (coefficient = −0.352, sig. = 0.01) between the average number of text messaging acknowledgements sent by the intervention group participants and the number of pills they reported missed during the last week of the trial.

Conclusion

This was a small randomised controlled trial with inconclusive but encouraging results. It suggests a new approach in addressing insufficient adherence in outpatient conditions and shows that the use of information technology tools for compliance warrants further research.     

Doctors in a Southeast Asian country communicate sub-optimally regardless of patients' educational background

Objective

To explore the relationship between the style of doctor-patient communication and patients’ educational background in a Southeast Asian teaching hospital setting using the Roter Interaction Analysis System (RIAS).

Methods

We analyzed a total of 245 audio-taped consultations involving 30 internal medicine residents with 7-10 patients each in the internal medicine outpatient clinics. The patients were categorized into a group with a high and a group with a low educational level. We ranked the data into 41 RIAS utterances and RIAS-based composite categories in order of observed frequency during consultations.

Results

The residents invariantly used a paternalistic style irrespective of patients’ educational background. The RIAS utterances and the composite categories show no significant relationship between communication style and patients’ educational level.

Conclusion

Doctors in a Southeast Asian country use a paternalistic communication style during consultations, regardless of patients’ educational background.

Practice implication

To approach a more partnership doctor-patient communication, culture and clinical environment concern of Southeast Asian should be further investigated.     

Health outcome prioritization to elicit preferences of older persons with multiple health conditions

Objective

To develop and test a simple tool to elicit the preferences of older persons based on prioritization of universal health outcomes.

Methods

Persons age ≥65 participating in a larger study were asked to rank 4 outcomes on a visual analogue scale: (1) maintaining independence, (2) staying alive, (3) reducing/eliminating pain, (4) reducing/eliminating other symptoms.

Results

Interviewers rated 73% of the 81 participants as having good to excellent understanding, and cognitive interviews demonstrated the tool captured how participants thought about trade-offs. Test-retest reliability was fair to poor for ranking most of the outcomes as either most or least important (kappa .28-1.0). Patient characteristics associated with ranking “keeping you alive” as most important have been shown to be associated with a preference for life-sustaining treatment, a related construct. There was substantial variability in the outcome ranked as most important.

Conclusions

The task of ranking 4 universal health outcomes was well understood, captured what was important when considering trade-offs, and demonstrated content validity. However, test-retest reliability was fair to poor.     

Teaching and evaluating breaking bad news: a pre-post evaluation study of a teaching intervention for medical students and a comparative analysis of different measurement instruments and raters

Objective

To investigate changes of different domains of breaking bad news (bbn) competences after a teaching module for medical students, and to collage the results generated by different approaches of evaluation.

Methods

Rating of medical student-SP interactions by means of a global rating scale and a detailed checklist used by SPs and independent raters.

Results

Students improved their breaking bad news competency. However, the changes vary between the different domains of bbn competency. In addition, results generated by different evaluation instruments differ.

Conclusion

This study serves as a stimulus for further research on the training of specific elements of bbn and different approaches of evaluating bbn competency.

Practice implications

In light of the different facets of bbn competency, it is important to set priorities regarding the teaching aims and to provide a consistent approach.     

Patients’ reaction to the disclosure of rare dreaded adverse events

Background

Physicians must frequently inform their patients of the risks of rare, but serious, adverse events (AEs).

Objective

To examine how patients react to the disclosure of rare AEs.

Methods

Outpatients viewed a video of a physician describing a medication associated with a rare AE. Subjects then rated their worry, perceived chance of developing the AE, and willingness to take the medication.

Results

Non-White men were more likely to perceive a greater chance of developing the AE compared to White men [Adjusted odds ratio (95% CI) = 3.37 (1.09-10.45)]; White women were more likely to be worried [2.00 (0.95-4.24)] and to perceive a greater chance of developing the [6.22 (2.50-15.50)], perceive a greater chance of developing the AE [6.27 (2.43-16.15)], and be less willing to take the medication [0.23 (0.09-0.59)], compared to White men.

Conclusions

Gender and ethnicity influence how patients react to disclosure of rare, but serious, AEs.

Practice implications

An improved understanding of patients’ risk perceptions is required to inform the development of best practices to improve risk communication.