Non-comparative evaluation of the safety of aerosolized amphotericin B lipid complex in patients undergoing allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplant (HSCT) recipients are at increased risk for invasive fungal infections (IFIs) over prolonged periods of time. Aerosolized amphotericin B lipid complex (ABLC) has shown promise in lung transplant recipients as a convenient means of delivering protective drug to the upper airways avoiding systemic toxicities. The safety and tolerability of aerosolized ABLC in 40 subjects undergoing allogeneic HSCT was prospectively investigated in an open-labeled, non-comparative study. Subjects received aerosolized ABLC treatment once daily for 4 days, then once weekly for 13 weeks; fluconazole was administered daily as standard of care through post-transplant day 100. Pulmonary mechanics were measured before and after each dose of inhaled ABLC; adverse events (AEs) and the development of IFI were also monitored. Cough, nausea, taste disturbance, or vomiting followed 2.2% of 458 total inhaled ABLC administrations; 5.2% of inhaled ABLC administrations were associated with >or=20% decrease in pulmonary function measurements (forced expiratory volume in 1 second or forced vital capacity) and none required treatment with bronchodilators or withdrawal from study. Four mild AEs were considered possibly or probably related to study treatment; no deaths or withdrawals from treatment were attributed to study drug. Of 3 proven IFIs occurring during the study period, only 1, a catheter-related case of disseminated fusariosis, occurred while the subject was receiving study medication. Aerosolized ABLC was well tolerated in allogeneic HSCT recipients. With only 1 of 40 subjects developing IFI while receiving treatment, the combination of fluconazole and inhaled ABLC warrants further study as antifungal prophylaxis following allogeneic HSCT.     

Genetic resistance to experimental infection with Mycobacterium bovis in red deer (Cervus elaphus)

Tuberculosis (Tb) caused by Mycobacterium bovis is a worldwide threat to livestock and humans. One control strategy is to breed livestock that are more resistant to Mycobacterium bovis. In a 3-year heritability study 6 farmed red deer stags were selected from 39 on the basis of their differing responses to experimental challenge via the tonsillar sac with approximately 500 CFU of M. bovis. Two stags remained uninfected, two were moderately affected, and two developed serious spreading Tb. Seventy offspring, bred from these six stags by artificial insemination using stored semen, were similarly challenged with M. bovis. The offspring showed patterns of response to M. bovis challenge similar to those of their sires, providing evidence for a strong genetic basis to resistance to Tb, with an estimated heritability of 0.48 (standard error, 0.096; P < 0. 01). This is the first time the heritability of Tb resistance in domestic livestock has been measured. The breeding of selection lines of resistant and susceptible deer will provide an ideal model to study the mechanisms of Tb resistance in a ruminant and could provide an additional strategy for reducing the number and severity of outbreaks of Tb in farmed deer herds. Laboratory studies to identify genetic and immunological markers for resistance to Tb are under way. Preliminary studies showed no associations between NRAMP or DRB genes and resistance to Tb in deer. Patterns of immune responses seen in resistant animals suggest that both innate and acquired pathways of immunity are necessary to produce the resistant phenotype.     

Development and Validation of Patient-Reported Outcome Measures for Sleep Disturbance and Sleep-Related Impairments

Study Objectives:

To develop an archive of self-report questions assessing sleep disturbance and sleep-related impairments (SRI), to develop item banks from this archive, and to validate and calibrate the item banks using classic validation techniques and item response theory analyses in a sample of clinical and community participants.

Design:

Cross-sectional self-report study.

Setting:

Academic medical center and participant homes.

Participants:

One thousand nine hundred ninety-three adults recruited from an Internet polling sample and 259 adults recruited from medical, psychiatric, and sleep clinics.

Interventions:

None.

Measurements and Results:

This study was part of PROMIS (Patient-Reported Outcomes Information System), a National Institutes of Health Roadmap initiative. Self-report item banks were developed through an iterative process of literature searches, collecting and sorting items, expert content review, qualitative patient research, and pilot testing. Internal consistency, convergent validity, and exploratory and confirmatory factor analysis were examined in the resulting item banks. Factor analyses identified 2 preliminary item banks, sleep disturbance and SRI. Item response theory analyses and expert content review narrowed the item banks to 27 and 16 items, respectively. Validity of the item banks was supported by moderate to high correlations with existing scales and by significant differences in sleep disturbance and SRI scores between participants with and without sleep disorders.

Conclusions:

The PROMIS sleep disturbance and SRI item banks have excellent measurement properties and may prove to be useful for assessing general aspects of sleep and SRI with various groups of patients and interventions.

Citation:

Buysse DJ; Yu L; Moul DE; Germain A; Stover A; Dodds NE; Johnston KL; Shablesky-Cade MA; Pilkonis PA. Development and validation of patient-reported outcome measures for sleep disturbance and sleep-related impairments. SLEEP 2010;33(6):781-792.     

Blockade of endothelinergic receptors prevents development of proliferative vitreoretinopathy in mice

Proliferative vitreoretinopathy (PVR) is characterized by severe glial remodeling. Glial activation and proliferation that occur in brain diseases are modulated by endothelin-1 (ET-1) and its receptor B (ETR-B). Because retinal astrocytes contain ET-1 and express ETR-B, we studied the changes of these molecules in an experimental mouse model of PVR and in human PVR. Both ET-1 and ETR-B immunoreactivities increased in mouse retina after induction of PVR with dispase. Epi- and subretinal outgrowths also displayed these immunoreactivities in both human and experimental PVR. Additionally, myofibroblasts and other membranous cell types showed both ET-1 and ETR-B immunoreactivities. In early stages of experimentally induced PVR, prepro-ET-1 and ETR-B mRNA levels increased in the retina. These mRNA levels also increased after retinal detachment (RD) produced by subretinal injection. Treatment of mice with tezosentan, an antagonist of endothelinergic receptors, reduced the histopathological hallmarks of dispase-induced PVR: retinal folding, epiretinal outgrowth, and gliosis. Our findings in human and in dispase-induced PVR support the involvement of endothelinergic pathways in retinal glial activation and the phenotypic transformations that underlie the growth of membranes in this pathology. Elucidating these pathways further will help to develop pharmacological treatments to prevent PVR. In addition, the presence of ET-1 and ETR-B in human fibrous membranes suggests that similar treatments could be helpful after PVR has been established.     

Clinically significant symptom change in children with attention‐deficit/hyperactivity disorder: does it correspond with reliable improvement in functioning?

This study examined the relation between clinically significant (CS) change in symptoms of attention‐deficit/hyperactivity disorder (ADHD) and of oppositional defiant disorder (ODD), and reliable change in multiple domains of functioning in children who participated in the Multimodal Treatment Study of Children with ADHD. Children with CS change in symptoms were significantly more likely than children without CS change to have reliable change across five domains of functioning. Interestingly, however, depending on the measure of functioning, 14 to 52% of children who did not achieve CS change in symptoms showed reliable improvement in functional domains. The results have implications for the definition and measurement of CS change in child treatment‐outcome studies. © 2008 Wiley Periodicals, Inc. J Clin Psychol 65:1–18, 2009.     

Relation between stillbirth and specific chlorination by-products in public water supplies

During water treatment, chlorine reacts with naturally occurring organic matter in surface water to produce a number of by-products. Of the by-products formed, trihalomethanes (THMs) are among the highest in concentration. We conducted a retrospective cohort study to evaluate the relationship between the level of total THM and specific THMs in public water supplies and risk for stillbirth. The cohort was assembled from a population-based perinatal database in the Canadian province of Nova Scotia and consisted of almost 50,000 singleton deliveries between 1988 and 1995. Individual exposures were assigned by linking mother's residence at the time of delivery to the levels of specific THMs monitored in public water supplies. Analysis was conducted for all stillbirths and for cause-of-death categories based on the physiologic process responsible for the fetal death. Total THMs and the specific THMs were each associated with increased stillbirth risk. The strongest association was observed for bromodichloromethane exposure, where risk doubled for those exposed to a level of [greater and equal to] 20 microg/L compared to those exposed to a level < 5 microg/L (relative risk = 1. 98, 95% confidence interval, 1.23-3.49). Relative risk estimates associated with THM exposures were larger for asphyxia-related deaths than for unexplained deaths or for stillbirths overall. These findings suggest a need to consider specific chlorination by-products in relation to stillbirth risk, in particular bromodichloromethane and other by-product correlates. The finding of a stronger effect for asphyxia deaths requires confirmation and research into possible mechanisms.     

Information exchange and the robustness of organizational networks

The dynamics of information exchange is an important but understudied aspect of collective communication, coordination, and problem solving in a wide range of distributed systems, both physical (e.g., the Internet) and social (e.g., business firms). In this paper, we introduce a model of organizational networks according to which links are added incrementally to a hierarchical backbone and test the resulting networks under variable conditions of information exchange. Our main result is the identification of a class of multiscale networks that reduce, over a wide range of environments, the likelihood that individual nodes will suffer congestion-related failure and that the network as a whole will disintegrate when failures do occur. We call this dual robustness property of multiscale networks "ultrarobustness." Furthermore, we find that multiscale networks attain most of their robustness with surprisingly few link additions, suggesting that ultrarobust organizational networks can be generated in an efficient and scalable manner. Our results are directly relevant to the relief of congestion in communication networks and also more broadly to activities, like distributed problem solving, that require individuals to exchange information in an unpredictable manner.     

Adductor myositis as a cause of childhood hip pain

Two cases of bacterial adductor myositis that presented as painful hips in boys aged 4 and 9 years are reported. Clinically, there was severe pain and a high pyrexia, a raised C-reactive protein and positive blood cultures but a negative hip ultrasound. Urgent magnetic resonance imaging demonstrated changes throughout the adductor muscles in keeping with bacterial myositis. Both boys settled with intravenous antibiotic therapy. We propose that magnetic resonance imaging is a valuable tool in the assessment of infection around the hip and should be indicated when other investigations have excluded a septic arthritis but the child remains unwell.     

Perinatal brachial plexus palsy

Perinatal brachial plexus palsy (PBPP) has been traditionally classified into three types: upper plexus palsy (Erb's) affecting the C5, C6, and +/- C7 nerve roots, lower plexus palsy (Klumpke's) affecting the C8 and T1 nerve roots, and total plexus palsy. Although most cases will resolve spontaneously, the natural history of the remaining cases is influenced by contractures of uninvolved muscle groups and subluxation or dislocation of the shoulder and elbow. Microsurgical nerve repair has demonstrated to provide improved outcomes compared to conservative treatment, while advancements in secondary reconstruction have offered significant improvements in the performance of activities of daily living for older children with unresolved plexus palsy.