Patient-reported fatigue and its impact on patients with systemic lupus erythematosus.

Fatigue is a hallmark symptom of systemic lupus erythematosus (SLE), often associated with flares, side effects of treatment, and extensive organ damage and may have a significant impact on health-related quality of life (HrQoL). To date, the experience of fatigue in patients with SLE is underexplored. This study explored the experience of fatigue in patients with SLE and its impact on their lives through qualitative interviews. This cross-sectional qualitative study was conducted with 22 adult patients with SLE, recruited from two clinical sites in the United States. In-person semi-structured interviews were conducted and thematic analysis was performed focusing on the experience of fatigue in SLE. Results indicated that 21 out of 22 patients experienced fatigue due to SLE. Patients reported that fatigue was variable in nature in terms of both severity and frequency. Fatigue was described as having an impact on multiple aspects of a patient's life: emotions, cognition, work, activities of daily living, leisure activities, social activities, and family activities. Understanding how patients with SLE describe the symptom of fatigue and how it impacts their lives is the key to better understanding how to measure fatigue in clinical studies evaluating new treatments for SLE.

In-band OSNR monitoring using a pair of Michelson fiber interferometers.

Two polarization-independent Michelson fiber interferometers with different optical delays were used to measure the in-band OSNR of an optical signal from 5 to 30 dB within an accuracy of 0.5 dB. Using an expansion of the amplitude autocorrelation function of the signal around zero delay, it was possible to perform measurements without any prior knowledge of the signal. The system is shown to be immune to the effects of modulation frequency (up to 10G), partially and fully polarized noise, chromatic dispersion and poorly biased modulators.

Considerations for development of an evidence dossier to support the use of mobile sensor technology for clinical outcome assessments in clinical trials.

BACKGROUND: Mobile sensors offer enormous potential for the collection of informative clinical endpoints in clinical trials to support regulatory decision making and product labelling. There are currently no specific guidelines on the information needed to enable regulators to review and accept proposed endpoints derived from mobile sensors for use in drug development trials. OBJECTIVE: The purpose of this working group report is to recommend the structure and content of an evidence dossier intended to support whether a clinical endpoint derived from mobile sensor data is fit-for-purpose for use in regulatory submissions for drug approvals. EVIDENCE DOSSIER: The structure and content of a dossier to provide evidence supporting the use of a sensor-derived clinical endpoint is described. Sections include clinical endpoint definition and positioning, the concept of interest, the context of use, clinical validation and interpretation, study implementation, and analytical validity with sensor performance verification in support of the selected sensor. CONCLUSIONS: In the absence of definitive regulatory guidance, this report provides a considered approach to compiling a comprehensive body of evidence to justify acceptance of mobile sensors for support of new drug applications.

Psychometric evaluation of a patient-reported symptom assessment tool for adults with haemophilia (the HAEMO-SYM).

In patients with haemophilia, repeated bleeding events result in significant comorbid conditions that can degrade health-related quality of life. Clinician-reported symptom measures are available for use in patients with haemophilia A or B; however, there has not been a validated patient-reported symptom evaluation instrument available for haemophilia to date. The objective of this study was to develop and evaluate a self-report instrument, the HAEMO-SYM, for measuring symptom severity in patients with haemophilia. Eighty-four haemophilic subjects from Canada and the USA were enrolled and completed the HAEMO-SYM, SF-36, and Health Assessment Questionnaire-Functional Disability Index (HAQ-FDI). Four-week reproducibility was evaluated in 72 stable subjects. Construct validity was assessed by correlating subscale scores with the SF-36, HAQ-FDI, a coping questionnaire and clinical scores. The final 17-item HAEMO-SYM has two subscales: pain and bleeds. Internal consistency reliability was good (Cronbach's alphas, 0.86-0.94) and test-retest reliability was good (Intraclass Correlation Coefficients, 0.75-0.94). HAEMO-SYM subscale scores were significantly correlated with SF-36 scores (P < 0.05 for all except HAEMO-SYM Pain and SF-36 Mental Health), HAQ-FDI scores (P < 0.05 for all but HAEMO-SYM Bleeds with HAQ-FDI Hygiene and Reach), Gilbert scale (P < 0.01), coping (P < 0.05) and global pain (P < 0.001). Mean HAEMO-SYM scores varied significantly in groups defined by severity, HIV status and treatment regimen. Greater symptom severity was associated with more severe disease, HIV-positive status and prophylaxis treatment. The results of this study suggest that the HAEMO-SYM, a haemophilia-specific symptom severity instrument, has good reliability and provides evidence that supports construct validity in patients with haemophilia.

Polarization dependence of a GaAs-based two-photon absorption microcavity photodetector.

In this paper, the polarization response of a GaAs based two-photon absorption microcavity photodetector has been studied. The deviation in the dependence of the detector response from that of bulk GaAs is shown to be due to the birefringence of the cavity. A theoretical model based on the convolution of the cavity birefringence and the polarization dependence of two-photon absorption in GaAs is described and shown to match the measured polarization dependence of the microcavity detector very well.

Cross-cultural development and psychometric evaluation of a patient-reported health-related quality of life questionnaire for adults with haemophilia.

Co-morbidities of haemophilia, such as arthropathy and blood-borne infections, can adversely affect the quality of life of adult patients with haemophilia. The purpose of this study was to develop and validate a haemophilia-specific health-related quality of life questionnaire for adults (HAEMO-QoL-A). Subjects with varying severities of haemophilia completed the HAEMO-QoL-A at baseline and 4 weeks. Other assessments included the SF-36 and Health Assessment Questionnaire - Functional Disability Index (HAQ-FDI). Two-hundred and twenty-one participants completed the 41-item HAEMO-QoL-A covering six domains (Physical Functioning, Role Functioning, Worry, Consequences of Bleeding, Emotional Impact and Treatment Concerns) and four independent items. Internal consistency was good-to-excellent (Cronbach's alpha-range: 0.75-0.95). Test-retest reproducibility was good, with intraclass correlation coefficients >0.80 except for the Emotional Impact domain (0.79). Concurrent validity between the HAEMO-QoL-A total and subscale scores and all SF-36 subscale scores were generally good (correlations range: 0.13-0.87). Significant correlations between the HAEMO-QoL-A and the HAQ-FDI ranged from -0.14 to -0.69. There were non-significant correlations with the Treatment Concerns subscale and with the Worry subscale. The HAEMO-QoL-A discriminated significantly between adults with haemophilia by severity and HIV status. The Physical Functioning subscale discriminated between patients receiving prophylactic or on-demand therapy. The HAEMO-QoL-A is a valid and reliable instrument for assessing quality of life in haemophilia patients.

A universal biosensing platform based on optical micro-ring resonators.

The use of optical micro-ring resonators as a platform for quantitative and qualitative biosensing applications was explored. Vertically coupled, high refractive index micro-ring resonators, used as sensing elements, were fabricated on silicon chips by photolithographic techniques. An optical reader system consisting of a near-infrared broad band light source and an optical spectrum analyzer were employed for data acquisition. Micro-ring resonator surfaces were modified with specific target receptors, including antibodies and single-stranded DNA oligonucleotides. The system was successfully used for label-free, specific, and rapid detection of whole bacterial cells, proteins and nucleic acids.

Development of a stable liquid formulation of live attenuated influenza vaccine.

Vaccination is the most effective means of preventing influenza. However, the cost of producing annual seasonal influenza vaccines puts them out of reach for most developing countries. While live attenuated influenza vaccines are among the most efficacious and can be manufactured at low cost, they may require lyophilization to be stable enough for developing-country use, which adds a significant cost burden. The development of a liquid live attenuated seasonal influenza vaccine that is stable for around a year-the duration of an annual influenza season-would significantly improve not only the production output but also the use and accessibility of influenza vaccines in low-resource settings. In this study, potential stabilizing excipients were screened and optimized using the least stable influenza vaccine strain presently known, H1N1 (A/California/07/2009), as a model. The stability-conferring properties of the lead formulations were also tested with a Type B strain of influenza virus (B/Brisbane/60/2008). Stability was also evaluated with higher titers of influenza virus and exposure to agitation and freeze-thaw stresses to further confirm the stability of the lead formulations. Through this process, we identified a liquid formulation consisting of sucrose phosphate glutamate buffer with 1% arginine and 0.5% recombinant human serum albumin that provided storage stability of one year at 2-8°C for the influenza A and B strains tested.

Amphotericin biosynthesis in Streptomyces nodosus: deductions from analysis of polyketide synthase and late genes.

BACKGROUND: The polyene macrolide amphotericin B is produced by Streptomyces nodosus ATCC14899. Amphotericin B is a potent antifungal antibiotic and has activity against some viruses, protozoans and prions. Treatment of systemic fungal infections with amphotericin B is complicated by its low water-solubility and side effects which include severe nephrotoxicity. Analogues with improved properties could be generated by manipulating amphotericin biosynthetic genes in S. nodosus. RESULTS: A large polyketide synthase gene cluster was cloned from total cellular DNA of S. nodosus. Nucleotide sequence analysis of 113193 bp of this region revealed six large polyketide synthase genes as well as genes for two cytochrome P450 enzymes, two ABC transporter proteins, and genes involved in biosynthesis and attachment of mycosamine. Phage KC515-mediated gene disruption was used to show that this region is involved in amphotericin production. CONCLUSIONS: The availability of these genes and the development of a method for gene disruption and replacement in S. nodosus should allow production of novel amphotericins. A panel of analogues could lead to identification of derivatives with increased solubility, improved biological activity and reduced toxicity.

Culturing primary and transformed neuronal cells for studying pseudorabies virus infection.

This chapter discusses the culture of primary sympathetic neurons (superior cervical ganglia) from rat embryos and PC12 cells differentiated into neurons for use in viral infection experiments. Methods are described for the use of a neurotropic herpesvirus, pseudorabies virus (PRV), to analyze the assembly, egress, and transport of viral antigens in neurons.

SNPCEQer: detecting SNPs in sequences generated by the Beckman CEQ2000 DNA Analysis System.

SNPCEQer identifies and reports SNPs in sequences obtained from the Beckman CEQ2000 DNA Analysis System. SNPCEQer aligns sequences obtained using CEQ2000 heterozygote detection analysis and reports discrepancies between individual sequences and the consensus sequence it generates from this set as SNPs when the individual base calls have high-quality values. SNPCEQer reported comparable numbers of SNPs to the UNIX-based PolyPhred (148 vs. 165, respectively) in regions amplified from eight genes. A total of 21 different SNPs was discovered. Each gene region was analyzed in 96-306 samples. SNPCEQer was designed to operate from Windows NT, making SNP detection more accessible to users without UNIX systems. SNPCEQer is available free of charge at http://innovation.swmed.edu.

Dose equivalent, absorbed dose and charge spectrum investigation in low Earth orbit.

Particle intensity, dose equivalent and absorbed dose have been measured on board the space shuttle Endeavour during STS-108 in December 2001 by Dublin Institute for Advanced Studies (DIAS). The dose estimates are based on very accurate measurements of recoils produced in CR-39 by cosmic ray primary and secondary protons and heavier nuclei and by secondary neutrons. The corresponding LET spectra were used to determine dose equivalent and absorbed dose values. Estimates of the total flux of Z > or = 2 nuclei have been undertaken and a preliminary charge spectrum was measured. Some comparisons are made with preliminary data obtained on STS-105 (ISS Expedition) and other missions using CR-39 detectors.

Cosmic ray measurements at aircraft altitudes and comparison with predictions of computer codes.

Extensive measurements of dose exposure of aircrew have been carried out in recent years using passive detectors on subsonic and supersonic air routes by DIAS (Dublin Institute for Advanced Studies). Studies were based on measurement of LET spectra using nuclear recoils produced in CR-39 nuclear track detectors by high energy neutrons and protons. The detectors were calibrated using energetic heavy ions. Data obtained were compared with the predictions of the EPCARD and CARI-6 codes. Good agreement has been found between the experimental and theoretical values.

Investigation of cosmic rays and their secondaries at aircraft altitudes.

A very extensive study of the radiation field at aircraft altitudes has been carried out over the last few years. These investigations formed part of a European wide collaboration involving several laboratories with extensive experience in cosmic ray research and/or dosimetry. Among the main topics investigated were the charge spectra, LET spectra, anisotropy and dose values. The measurements were performed on subsonic and supersonic flights covering a wide range of altitudes and latitudes. Several active and passive instruments were employed in these studies and some results obtained with nuclear track detectors are described here. Comparisons are made with the results of other experiments and theoretical estimates using computer codes.

Cosmic rays and dosimetry at aviation altitudes.

Recent concerns regarding the effects of the cosmic radiation field at aircraft altitudes on aircrew have resulted in a renewed interest in detailed measurements of the neutral and charged particle components in the atmosphere. CR-39 nuclear track detectors have been employed on a number of subsonic and supersonic aircraft to measure charge spectra and LET spectra at aircraft altitudes. These detectors are ideal for long term exposures required for these studies and their passive nature makes them suitable for an environment where interference with flight instrumentation could be a problem. We report here on measurements and analysis of short range tracks which were produced by high LET particles generated mainly by neutron interactions at aviation altitudes. In order to test the overall validity of the technique measurements were also carried out at the CERN-CEC field which simulates the radiation field at aviation altitudes and good agreement was found with dose values obtained using mainly heavy ion calibration.

Galactosemia: clinical features, diagnosis and management. A case report.

The case report and discussion presented here were prepared in response to legislation in Louisiana which requires that the Dept of Health and Hospitals establish a program to inform physicians and hospitals of the current medical standards for the diagnosis, clinical management, and recognition of galactosemia. Classical galactosemia is an inborn error of galactose metabolism caused by a deficiency of galactose-1-phosphate uridryl transferase. It is inherited as an autosomal recessive trait and its estimated occurrence is 1/60,000. The presenting symptoms which include vomiting, diarrhea, jaundice, and failure to thrive result from the ingestion of foods containing galactose--breast milk and formulas containing cow's milk. Although some states routinely screen all newborns for galactosemia, the results of the newborn screening are often not available before the infant presents with symptoms. Early recognition and immediate withdrawal of galactose from the diet can prevent serious morbidity and mortality. There is significant clinical variability and not all infants present with typical acute manifestations of the disease.

Patient preferences among third agent HIV medications: a US and German perspective.

The objective is to assess patient preferences for attributes associated with third agent HIV medications, including fosamprenavir/ritonavir (FPVr), fosamprenavir (FPV), lopinavir/ritonavir (LPVr), atazanavir (ATZ), and efavirenz (EFV). Subjects with HIV were recruited in the US and Germany to complete a computerized adaptive conjoint survey that assessed 13 attributes, including moderate to severe side effects, regimen convenience, drug resistance and efficacy. Literature on the target third-agent HIV drugs was used to identify percentage risk and severity level descriptions for each attribute. The derived preference (utility) weights for each attribute level informed the calculation of relative importance estimates for each attribute and the desirability of combinations of attributes matching the respective target third agents. The analysis included 288 HIV-positive participants (US: 132; Germany: 156), 205 of whom were treatment-experienced and 83 of whom were treatment-naïve. Of the 13 medication attributes evaluated, developing drug resistance, the risk of lipodystrophy, the risk of gastronitestinal side effects (diarrhoea, nausea and vomiting) and regimen convenience had the greatest impact on preferences. The profile based on FPVr was most preferred. Differences in the risk of developing drug resistance, risk of lipodystrophy, risk of gastrointestinal side effects and regimen convenience would likely be most influential in the perceived relative value of a third-agent medication. Physicians may wish to consider these features, especially when discussing HIV treatment options with their patients.

Heterogeneity of a fluorescent tegument component in single pseudorabies virus virions and enveloped axonal assemblies.

The molecular mechanisms responsible for long-distance, directional spread of alphaherpesvirus infections via axons of infected neurons are poorly understood. We describe the use of red and green fluorescent protein (GFP) fusions to capsid and tegument components, respectively, to visualize purified, single extracellular virions and axonal assemblies after pseudorabies virus (PRV) infection of cultured neurons. We observed heterogeneity in GFP fluorescence when GFP was fused to the tegument component VP22 in both single extracellular virions and discrete puncta in infected axons. This heterogeneity was observed in the presence or absence of a capsid structure detected by a fusion of monomeric red fluorescent protein to VP26. The similarity of the heterogeneous distribution of these fluorescent protein fusions in both purified virions and in axons suggested that tegument-capsid assembly and axonal targeting of viral components are linked. One possibility was that the assembly of extracellular and axonal particles containing the dually fluorescent fusion proteins occurred by the same process in the cell body. We tested this hypothesis by treating infected cultured neurons with brefeldin A, a potent inhibitor of herpesvirus maturation and secretion. Brefeldin A treatment disrupted the neuronal secretory pathway, affected fluorescent capsid and tegument transport in the cell body, and blocked subsequent entry into axons of capsid and tegument proteins. Electron microscopy demonstrated that in the absence of brefeldin A treatment, enveloped capsids entered axons, but in the presence of the inhibitor, unenveloped capsids accumulated in the cell body. These results support an assembly process in which PRV capsids acquire a membrane in the cell body prior to axonal entry and subsequent transport.

Caffeine citrate in the NICU.

Administering caffeine citrate is a safe, noninvasive way to treat premature infants with persistent apnea. This drug decreases the frequency of apneic episodes, thus reducing the need for mechanical ventilation. It is given once a day, either orally or intravenously. Ideally, caffeine citrate can treat apnea of prematurity and prevent insults to the premature infant's neurological status.