Conjunctivitis in dupilumab clinical trials.

BACKGROUND: Dupilumab blocks the shared receptor component for interleukin (IL)-4 and IL-13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate-to-severe atopic dermatitis (AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate-to-severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate-to-severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for dupilumab vs. placebo. OBJECTIVES: To characterize further the occurrence and risk factors of conjunctivitis in dupilumab clinical trials. METHODS: We evaluated randomized placebo-controlled trials of dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47). RESULTS: In most AD trials, dupilumab-treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis. CONCLUSIONS: Conjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab-treated patients require further study. What's already known about this topic? Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD). In most dupilumab AD trials, dupilumab-treated patients had higher conjunctivitis incidence than those receiving placebo. Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare. Conjunctivitis incidence was very low and similar for dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis. What does this study add? This analysis confirms and extends the results of the individual clinical trials. Baseline disease-related factors, including AD severity, prior conjunctivitis history and certain biomarkers (thymus and activation-regulated chemokine, IgE, eosinophils), were associated with increased incidence of conjunctivitis. Patients who responded well to dupilumab had reduced incidence of conjunctivitis. Further study is needed to elucidate the aetiology and treatment of conjunctivitis in dupilumab-treated patients with AD.

Dynamic contrast-enhanced perfusion processing for neuroradiologists: model-dependent analysis may not be necessary for determining recurrent high-grade glioma versus treatment effect.

BACKGROUND AND PURPOSE: Dynamic contrast-enhanced perfusion MR imaging has proved useful in determining whether a contrast-enhancing lesion is secondary to recurrent glial tumor or is treatment-related. In this article, we explore the best method for dynamic contrast-enhanced data analysis. MATERIALS AND METHODS: We retrospectively reviewed 24 patients who met the following conditions: 1) had at least an initial treatment of a glioma, 2) underwent a half-dose contrast agent (0.05-mmol/kg) diagnostic-quality dynamic contrast-enhanced perfusion study for an enhancing lesion, and 3) had a diagnosis by pathology within 30 days of imaging. The dynamic contrast-enhanced data were processed by using model-dependent analysis (nordicICE) using a 2-compartment model and model-independent signal intensity with time. Multiple methods of determining the vascular input function and numerous perfusion parameters were tested in comparison with a pathologic diagnosis. RESULTS: The best accuracy (88%) with good correlation compared with pathology (P = .005) was obtained by using a novel, model-independent signal-intensity measurement derived from a brief integration beginning after the initial washout and by using the vascular input function from the superior sagittal sinus for normalization. Modeled parameters, such as mean endothelial transfer constant > 0.05 minutes(-1), correlated (P = .002) but did not reach a diagnostic accuracy equivalent to the model-independent parameter. CONCLUSIONS: A novel model-independent dynamic contrast-enhanced analysis method showed diagnostic equivalency to more complex model-dependent methods. Having a brief integration after the first pass of contrast may diminish the effects of partial volume macroscopic vessels and slow progressive enhancement characteristic of necrosis. The simple modeling is technique- and observer-dependent but is less time-consuming.

CT imaging correlates of genomic expression for oral cavity squamous cell carcinoma.

BACKGROUND AND PURPOSE: Imaging correlates of genetic expression have been found for prognostic and predictive biomarkers of some malignant diseases, including breast and brain tumors. This study tests the hypothesis that imaging findings correlate with relevant genomic biomarkers in oral cavity squamous cell carcinoma. MATERIALS AND METHODS: Surplus frozen tissue from 27 untreated patients with oral cavity squamous cell carcinoma who underwent preoperative CT imaging was analyzed for gene expression. A team of neuroradiologists blinded to the genomic analysis results reviewed an extensive list of CT findings. The imaging correlated with genomic expression for cyclin D1, angiogenesis-related genes (vascular endothelial growth factor receptors and ligands), which relate to enhancement on the basis of other tumor types; and epidermal growth factor receptor, which may relate to proliferation and mass effect. RESULTS: Expression of vascular endothelial growth factor receptors 1 and 2 correlated with the enhancement of the primary tumor (P = .018 and P = .025, respectively), whereas the epidermal growth factor receptor correlated with mass effect (P = .03). Other exploratory correlations included epidermal growth factor receptor to perineural invasion (P = .05), and certain vascular endothelial growth factor receptors and ligands to mass effect (P = .03) and increased (P = .01) or decreased (P = .02) primary tumor size. CONCLUSIONS: We report that CT imaging correlates with gene expression in untreated oral cavity squamous cell carcinoma. Enhancement of the primary tumor and degree of mass effect correlate with relevant genomic biomarkers, which are also potential drug targets. Eventually, treatment decisions may be aided by combining imaging findings into meaningful phenotypes that relate directly to genomic biomarkers.

Improving imaging diagnosis of persistent nodal metastases after definitive therapy for oropharyngeal carcinoma: specific signs for CT and best performance of combined criteria.

BACKGROUND AND PURPOSE: Criteria for detection of persistent nodal metastases in treated oropharyngeal tumors are sensitive but nonspecific, leading to unnecessary nodal dissections. Developing specific imaging criteria for persistent nodal metastases could improve diagnosis while decreasing patient morbidity. MATERIALS AND METHODS: Patients with oropharyngeal squamous cell carcinoma with nodal metastases treated by definitive radiation therapy and subsequent nodal dissection were retrospectively evaluated. One hundred thirty-eight patients had pre- and posttherapy contrast-enhanced CTs evaluated by radiologists blinded to the status of pathologically proved hemineck persistent nodal metastases. Composite scoring criteria for CT, combined from individual parameters, were compared with radiologists' opinions, previous multiparameter criteria, and outcome data. RESULTS: New low-attenuation areas and a lack of size change (<20% cross sectional area) were both highly specific for persistent nodal metastases (99%; P = .0004). Extranodal disease on pretherapy imaging was moderately specific (86%; P = .001). The CSC correctly placed 29 patients in a low-risk category compared with 14 by previously reported criteria and radiologist reports. With good second-rater reliability, the CSC cutoff values stratified patients at highest risk of persistent nodal metastases, thereby improving specificity while maintaining sensitivity. CONCLUSIONS: Comparing pre- and posttherapy examinations improves specificity by discriminating focal findings and size change compared with a single time point. The CSC can categorize the risk of persistent nodal metastases more accurately than previous CT methods. This finding has the potential to improve resource use and reduce surgical morbidity.

Imaging of carotid canal sympathetic plexus schwannoma.

One case report of a schwannoma involving the sympathetic plexus in the carotid canal has been reported previously. This article presents 2 additional cases of this rare entity with associated clinical and unique radiographic findings. All patients presented with diplopia among other symptoms, and they had enhancing masses that smoothly expanded the carotid canal on cross-sectional imaging. Comparison with the index case and differential diagnosis of more common pathologies in this area are discussed.

Gross synovial fluid analysis in the differential diagnosis of joint effusion.

AIMS: To develop an objective and easy to complete standardised questionnaire for documentation of synovial fluid (SF) gross appearance and use it in the assessment of patients presenting to the rheumatology service with a joint effusion. METHODS: A standardised questionnaire to record the gross appearance of SF was developed. Interobserver error in recorded observations and direct gross analysis of synovial fluid between four observers was calculated in a pilot study. In a prospective study over 8 months, SF gross analysis and cell count were documented in all patients presenting with a joint effusion. Fusch Rosenthal manual counting chamber was used for calculating SF cell counts. RESULTS: There was good interobserver agreement on direct gross analysis and between questionnaire assessors (mean kappa 0.889). 80 SF samples were collected. Gross analysis was performed in all samples and cell count in 72. Of the specimens thought to be inflammatory on gross analysis, 31% were found to be non-inflammatory based on cell count; however, 12 of these patients had an established inflammatory arthritis. Gross analysis had a sensitivity of 94% and specificity of 58% when used to determine whether SF is inflammatory or non-inflammatory. The positive and negative predictive values were 0.69 and 0.91 respectively. CONCLUSIONS: SF cell count did not add any information when SF gross analysis suggested a non-inflammatory process. Gross analysis was better than cell count to determine a potentially septic joint fluid. Further work needs to be done on the value of SF cell counts if gross analysis suggests the fluid to be inflammatory.

HIV-associated morbidity, mortality and diagnostic testing opportunities among inpatients at a referral hospital in northern Tanzania.

Hospitalized patients with HIV infection are among the most likely to benefit from the expanding availability of anti-retroviral therapy in sub-Saharan Africa. Between 1990 and 2000, 3667 people known to be HIV-infected were admitted to Kilimanjaro Christian Medical Centre (KCMC) in Moshi, northen Tanzania. The level of inpatient mortality among these patients varied from 15%-21%, and the proportion of the HIV-infected patients admitted who were female increased significantly, from 45% at the start of the study period to 52% at the end (P <0.001). When the medical records for 1683 of the HIV-infected patients who had been admitted between 1996 and 2001 were reviewed, the most prevalent diagnoses on admission were found to be pulmonary tuberculosis (21%), malaria (14%) and gastro-enteritis/diarrhoea (12%) among the adults, and non-tubercular pulmonary infection (21%), pulmonary tuberculosis (19%) and gastro-enteritis/diarrhoea (12%) among the children. The crude odds ratios (OR) for inpatient death were greatest for adults presenting with meningitis [OR=3.7; 95% confidence interval (CI)=2.1-6.7], septicaemia (OR=2.9; CI=1.2-7.3) or renal disease (OR=2.6; CI=1.2-5.7), and mortality was higher for men than for women (OR=1.4; CI=1.1-1.8). A single-day, point-prevalence survey in September 2001, among the KCMC's inpatients, identified HIV infection in 21% of those surveyed, many (44%) of the patients found positive being previously unaware of their infection. HIV infection remains a major cause of hospitalization and mortality in Moshi. A policy of routine testing would increase the number of HIV infections detected, allowing improvements in case management and in the prevention of infection.

Modified weighting method for forward-looking ring-annular arrays.

Side-looking Intravascular Ultrasound Systems (IVUS) systems provide high resolution cross-sectional images of vascular structure. However, blood velocity estimation is hampered by the orthogonality of the primary blood flow direction to the imaging plane, and do not image in front of the catheter. A forward-looking aperture would improve the ability to guide interventions and allow Doppler processing for improved blood speed estimates; however, catheter-based systems delivered over a guide wire limit forward-looking array geometry to annular variations. Unfortunately, the imaging characteristics of annular arrays are inferior to a full aperture disk. A modified weighting method for a practical synthetic phased, ring-annular array is presented that achieves a transmit-receive aperture and on-axis performance comparable to a full aperture disk array.

Factors predictive of subsequent deterioration in rheumatoid cervical myelopathy.

OBJECTIVE: To identify the features of rheumatoid cervical spine disease associated with deterioration resulting in the need for surgical intervention or death. PATIENTS AND METHODS: Patients with rheumatoid cervical myelopathy who underwent cervical spine magnetic resonance imaging (MRI) between 1991 and 1996 were identified. Patients requiring immediate surgical intervention were excluded. The remainder were divided into two groups. Deterioration group: patients requiring surgical intervention during the follow-up period and deaths resulting from cervical myelopathy. Conservative group: all other patients. Relevant clinical features and radiology reports were extracted retrospectively from the casesheet. RESULTS: The deterioration group comprised 11 patients (12%), median time to deterioration 15 months (range 4-84 months). The conservative group included 82 patients. Initial clinical features did not differ significantly between the two groups. Sixty per cent of those patients with compression or impingement at the atlanto-axial level on first MRI deteriorated over a median of 12 months (range 4-36 months). CONCLUSION: Deterioration is likely if there is evidence of cord compromise at the atlanto-axial level on MRI regardless of initial clinical and plain X-ray features.

Role of clinical microbiology laboratories in the management and control of infectious diseases and the delivery of health care.

Modern medicine has led to dramatic changes in infectious diseases practice. Vaccination and antibiotic therapy have benefited millions of persons. However, constrained resources now threaten our ability to adequately manage threats of infectious diseases by placing clinical microbiology services and expertise distant from the patient and their infectious diseases physician. Continuing in such a direction threatens quality of laboratory results, timeliness of diagnosis, appropriateness of treatment, effective communication, reduction of health care-associated infections, advances in infectious diseases practice, and training of future practitioners. Microbiology laboratories are the first lines of defense for detection of new antibiotic resistance, outbreaks of foodborne infection, and a possible bioterrorism event. Maintaining high-quality clinical microbiology laboratories on the site of the institution that they serve is the current best approach for managing today's problems of emerging infectious diseases and antimicrobial agent resistance by providing good patient care outcomes that actually save money.

Lifestyle influences on outcome in rheumatoid arthritis.

Functional status in rheumatoid arthritis (RA) as assessed by the HAQ is poorer in the West of Scotland than the USA or elsewhere. There is a possible link with social deprivation, which is common within the Greater Glasgow Healthboard area. Our aim was to determine if differences in lifestyle could contribute to the poorer functional outcome found in socially deprived patients.

Enhanced green fluorescent protein as a marker for localizing murine cytomegalovirus in acute and latent infection.

A recombinant murine cytomegalovirus (mCMV) that expresses enhanced green fluorescent protein (EGFP) under control of the native immediate-early 1/3 promoter was constructed to detect directly sites of viral activity in latent and reactivated infections. The recombinant virus had acute and latent infection characteristics similar to those of wild-type mCMV. Rare green-fluorescing foci were observed in paraffin sections from lungs and spleens infected latently. Positive immunoperoxidase staining for EGFP in sections of the same lung tissues suggests that these cells may be sites of restricted viral gene expression. EGFP was detected easily in tissue explants reactivating from latent infection in vitro. Morphology and adhesion characteristics of fluorescing cells suggest that viral reactivation occurs in tissue macrophages in explant cultures. The observations presented in this study demonstrate the usefulness of EGFP-expressing recombinants as tools for direct tracking of mCMV activity in vivo and in vitro.

Improved medical and surgical management of cervical spine disease in patients with rheumatoid arthritis over 10 years.

OBJECTIVES: (1) To compare clinical outcome and symptomatology of rheumatoid cervical myelopathy between patients managed conservatively and surgically. (2) To determine if surgical outcome has improved since the series published from this unit in 1987. (3) To examine the role of magnetic resonance imaging (MRI) in the diagnosis of cervical myelopathy. METHODS: Patients undergoing MRI of the cervical spine between 1991 and 1996 were identified. Case records were reviewed retrospectively. RESULTS: 111 patients with RA underwent 124 MRI scans. The median age at onset of cervical spine symptoms was 58 years (range 16-87) with median disease duration of 16 years (range 1-59). 18 (16%) required surgery immediately after MRI. 93 (84%) were managed conservatively, 9 of whom (10%) later required surgery. 2/7 deaths in the conservative group were directly related to cervical myelopathy. Patients requiring surgery were more likely to report paraesthesia, weakness, unsteadiness and to exhibit extensor plantar reflexes, gait disturbance, and reduced power. MRI findings did not correlate with clinical features. When compared with the 1974-82 cohort, fewer patients had severe myelopathy (Ranawat grade IIIB) before surgery (34% versus 7%). Early postoperative mortality improved from 9% to 0% and surgical complication rate fell from 50% to 22%. 89% of patients in the 1991-96 cohort reported subjective improvement in overall function. CONCLUSION: In this series surgical outcome has improved. The major factor in this more favourable outcome is probably that patients presenting with rheumatoid cervical myelopathy are now referred for surgery at an earlier stage of disease. Clinical findings correlate poorly with MRI findings, therefore clinical history should remain the key to determining the need for MRI.

The Quality of Australian Health Care Study: implications for education of failure in quality and safety of health care.

Medical and health professional education needs to renew regularly the perspective from which it defines curriculum. The theme of this paper is that the study of health service in action will identify educational priorities for any country with the particular aim of improving the quality of health care and the effectiveness of clinicians within the system of health care. The Quality of Australian Health Care Study is the largest study of its kind to date. It is a study of adverse outcomes in health care resulting from error. From a study of causes, circumstance and strategies for prevention an educational agenda emerges, dealing both with clinical aspects of care and the less well-documented role of system errors. Studies of system errors in industry and other high risk occupations and systems are now lending insight to issues of error and safety in health care. A new agenda for health professional curriculum is the study of health services in action-the anatomy, physiology and pathology of health systems. Eight educational priorities were recommended to the National Task Force to improve patient safety and quality of care. These are discussed together with a broad strategy for curriculum implementation. The need for a health system that supports and informs practitioners involved in clinical and system errors, the extension of training to incorporate health system managers, and the extension of the consideration of safety to public awareness are discussed.

High frequency optoacoustic arrays using etalon detection.

Two-dimensional phased arrays for high frequency (>30 MHz) ultrasonic imaging are difficult to construct using conventional piezoelectric technology. A promising alternative involves optical detection of ultrasound, where the array element size is defined by the focal spot of a laser beam. Element size and spacing on the order of a few microns are easily achieved, suitable for imaging at frequencies exceeding 100 MHz. We have previously shown images made from a receive-only, two-dimensional optoacoustic array operating at 10 to 50 MHz. The main drawback of optical detection has been poor sensitivity when compared with piezoelectric detection. In this paper, we explore a different form of optical detection demonstrating improved sensitivity and offering a potentially simple method for constructing two-dimensional arrays. Results from a simple experiment using an etalon sensor confirm that the sensitivity of etalon detection is comparable with piezoelectric detection. This paper concludes with a proposal for a high frequency optoacoustic array system using an etalon.