Non-Invasive Gene Expression Testing to Rule Out Melanoma.

The Pigmented Lesion Assay (PLA) is a gene expression test that helps rule out melanoma and has the potential to reduce the need for surgical biopsies of atypical pigmented skin lesions. Utilizing a new technological platform for the non-invasive profiling of skin, the assay analyzes samples collected from adhesive patches for expression of two key genes (PRAME and LINC00518) known to be overexpressed in melanoma. The test result is binary (positive/negative) based on the detection of one or both genes. PLA positive cases are generally biopsied to establish the histopathologic diagosis, while PLA negative cases are considered for ongoing monitoring. The combination of visual inspection with histopathology, the current gold standard for melanoma diagnosis, has a relatively low negative predictive value (NPV) of approximately 83%, meaning that 17% of melanomas will be interpreted as benign lesions. In contrast, the PLA has a very high NPV (>99%). Further, with its high specificity (69-91%), use of the PLA can reduce the number of false positive samples subjected to histopathology review. By adding the PLA to the current care pathway, the number of surgical biopsies needed to find a melanoma (number needed to biopsy) is markedly reduced from 20-25 biopsies for dermatologists and 39 biopsies for physician assistants, to an average of 2.7. To date, unnecessary surgical procedures of benign lesions have been reduced by 88% based on a sample of more than 20,000 analyzed cases. This has resulted in fewer missed melanomas and significant cost savings to health care systems.

Short-read whole genome sequencing for determination of antimicrobial resistance mechanisms and capsular serotypes of current invasive Streptococcus agalactiae recovered in the USA.

OBJECTIVES: Our objective was to evaluate and exploit a whole genome sequence (WGS) bioinformatics pipeline for predicting antimicrobial resistance and capsular serotypes from invasive group B streptococci (iGBS). METHODS: For 1975 iGBS recovered during 2015 from CDC's Active Bacterial Core surveillance, we compared pipeline predictions with broth dilution testing. Fifty-six isolates from earlier surveillance were included for testing ß-lactams. Conventional serotyping was compared to WGS-based assignments for 302 isolates. RESULTS: All 28 isolates with reduced susceptibility to ß-lactam antibiotics harboured one of 19 rare PBP2x types. Resistances to erythromycin/clindamycin (808/1975 isolates, 41.0%), erythromycin (235/1975, 11.9%) and lincosamide/streptogramin A/pleuromutilins (56/1975, 2.8%) were predicted by the presence of erm-methylase, mef and lsa determinants, respectively (41 of 56 lsa gene-positive isolates also contained lnu, erm and/or mef genes). Presence of both erm and lsa determinants (25 isolates) predicted non-susceptibility to quinupristin/dalfopristin. Most isolates (1680/1975, 85.1%) were tet gene-positive, although 41/1565 (2.6%) tetM-positive isolates were tetracycline-susceptible. All 53 fluoroquinolone-resistant isolates contained ParC and/or GyrA substitutions. Resistances to rifampin (eight isolates), trimethoprim, chloramphenicol and vancomycin (two isolates each) were predicted by the pipeline. Resistance to macrolides/lincosamides without pipeline prediction was rare and correlated to divergent resistance genes or rRNA A2062G substitution. A selection of 267 isolates assigned WGS-based serotypes were also conventionally serotyped. Of these, 246 (92.1%) were in agreement, with the remaining 21 (7.8%) conventionally non-serotypeable. For 32 of 1975 isolates (1.6%), WGS-based serotypes could not be assigned. CONCLUSION: The WGS-based assignment of iGBS resistance features and serotypes is an accurate substitute for phenotypic testing.

Actikerall™ (5-Fluorouracil 0.5% and Salicylic Acid 10%) Topical Solution for Patient-directed Treatment of Actinic Keratoses.

Actinic keratosis (AK), a common cutaneous lesion with the potential to transform into squamous cell carcinoma, has traditionally been treated with ablative and/or surgical procedures. Recently, a topical formulation combining 0.5% 5-fluorouracil with 10% salicylic acid (5-FU-SA) was introduced in Europe under the trade name Actikerall™ for the treatment of grade I/II AKs. In a single randomized phase III trial, 5-FU-SA was shown to be superior to diclofenac 3% gel in hyaluronic acid, as measured by the histological clearance of one defined lesion (72% vs. 59.1%) and by complete clinical clearance (55.4% vs. 32.0%). 5-FU-SA should be applied once daily to a total area of up to 25 cm(2), which may include the lesion(s) and a small area of surrounding skin (rim of healthy skin should not exceed 0.5 cm), for up to 12 weeks. The most common side effects are local inflammation and pruritus at the application site, and no serious adverse effects have been reported to date. Now commercially available in Canada, 5-FU-SA represents a patientapplied therapeutic option for the treatment of both overt and subclinical AKs.

Evaluation of coronary angiographic projections to balance the clinical yield with the radiation risk.

OBJECTIVE: Radiation safety principles dictate that imaging procedures should minimise the radiation risks involved, without compromising diagnostic performance. This study aims to define a core set of views that maximises clinical information yield for minimum radiation risk. Angiographers would supplement these views as clinically indicated. METHODS: An algorithm was developed to combine published data detailing the quality of information derived for the major coronary artery segments through the use of a common set of views in angiography with data relating to the dose-area product and scatter radiation associated with these views. RESULTS: The optimum view set for the left coronary system comprised four views: left anterior oblique (LAO) with cranial (Cr) tilt, shallow right anterior oblique (AP-RAO) with caudal (Ca) tilt, RAO with Ca tilt and AP-RAO with Cr tilt. For the right coronary system three views were identified: LAO with Cr tilt, RAO and AP-RAO with Cr tilt. An alternative left coronary view set including a left lateral achieved minimally superior efficiency (<5%), but with an ~8% higher radiation dose to the patient and 40% higher cardiologist dose. CONCLUSION: This algorithm identifies a core set of angiographic views that optimises the information yield and minimises radiation risk. This basic data set would be supplemented by additional clinically determined views selected by the angiographer for each case. The decision to use additional views for diagnostic angiography and interventions would be assisted by referencing a table of relative radiation doses for the views being considered.

Thresholds in forest bird occurrence as a function of the amount of early-seral broadleaf forest at landscape scales.

Recent declines in broadleaf-dominated, early-seral forest globally as a function of intensive forest management and/or fire suppression have raised concern about the viability of populations dependent on such forest types. However, quantitative information about the strength and direction of species associations with broadleaf cover at landscape scales are rare. Uncovering such habitat relationships is essential for understanding the demography of species and in developing sound conservation strategies. It is particularly important to detect points in habitat reduction where rates of population decline may accelerate or the likelihood of species occurrence drops rapidly (i.e., thresholds). Here, we use a large avian point-count data set (N = 4375) from southwestern and northwestern Oregon along with segmented logistic regression to test for thresholds in forest bird occurrence as a function of broadleaf forest and early-seral broadleaf forest at local (150-m radius) and landscape (500-2000-m radius) scales. All 12 bird species examined showed positive responses to either broadleaf forest in general, and/or early-seral broadleaf forest. However, regional variation in species response to these conditions was high. We found considerable evidence for landscape thresholds in bird species occurrence as a function of broadleaf cover; threshold models received substantially greater support than linear models for eight of 12 species. Landscape thresholds in broadleaf forest ranged broadly from 1.35% to 24.55% mean canopy cover. Early-seral broadleaf thresholds tended to be much lower (0.22-1.87%). We found a strong negative relationship between the strength of species association with early-seral broadleaf forest and 42-year bird population trends; species most associated with this forest type have declined at the greatest rates. Taken together, these results provide the first support for the hypothesis that reductions in broadleaf-dominated early-seral forest due to succession and intensive forest management have led to population declines of constituent species in the Pacific northwestern United States. Forest management treatments that maintain or restore even small amounts of broadleaf vegetation could mitigate further declines.

The role of cosmeceuticals in antiaging therapy.

As baby boomers get older, they have shown an increasing interest in maintaining a youthful appearance. As a result, there has been a corresponding increase in topical antiaging formulations, which are commonly referred to as cosmeceuticals. These products come with a seemingly limitless number of key active ingredients and claims of reducing the signs of aging and/or maintaining a youthful appearance. This paper reviews the more common cosmeceutical ingredients.

Imiquimod 5% cream for the treatment of actinic keratoses.

Actinic keratoses (AKs) are premalignant inflammatory skin lesions with the potential to transform into squamous cell carcinoma (SCC). There are several treatment options available for patients presenting with multiple AKs. Imiquimod is believed to stimulate and enhance host immune responses locally against skin tumors and viral infections. Five clinical studies to date have demonstrated its safety and efficacy in the treatment of actinic keratoses. Long-term follow-up studies examining recurrence rates are limited.

Topical 3% diclofenac in 2.5% hyaluronan gel for the treatment of actinic keratoses.

Actinic Keratoses (AKs) are epidermal skin lesions that have the potential to develop into squamous cell carcinoma. Many of the treatment options available can cause discomfort, pain or skin irritation. Topical 3% diclofenac in 2.5% hyaluronan gel (Solaraze, Bioglan Pharma) is a relatively new treatment that has been shown to be effective and well tolerated for the treatment of AKs.

The use of male or female voices in warnings systems: a question of acoustics.

Speech warnings and communication systems are increasingly used in noisy, high workload environments. An important decision in the development of such systems is the choice of a male or a female speaker. There is little objective evidence to support this decision, although there are many misconceptions and misunderstandings on this topic. This paper suggests that both acoustic and non-acoustic differences (such as social attributions towards speakers of different sexes) between male and female speakers is negligible, therefore the choice of speaker should depend on the overlap of noise and speech spectra. Female voices do however appear to have an advantage in that they can portray a greater range of urgencies because of their usually higher pitch and pitch range. An experiment is reported showing that knowledge about the sex of a speaker has no effect on judgements of perceived urgency, with acoustic variables accounting for such differences.

Topical treatment of actinic keratoses with 3.0% diclofenac in 2.5% hyaluronan gel.

BACKGROUND: Actinic keratoses (AKs) are premalignant skin lesions, which, if left untreated, can develop into squamous cell carcinoma. Current treatments for AKs are destructive and are often associated with significant adverse events. The development of an effective and well-tolerated topical treatment for AK is desirable. OBJECTIVES: To evaluate the efficacy and safety of 3.0% diclofenac in 2.5% hyaluronan gel as a treatment for AK. METHODS: This was a multicentre, double-blind, placebo-controlled study in which 195 patients with at least five AKs in up to three designated treatment blocks were randomized to four treatment groups. Patients randomized into the active treatment groups A30 (n = 49) and A60 (n = 48) received topical treatment with 3.0% diclofenac in 2.5% hyaluronan gel 0.5 g twice daily for 30 or 60 days, respectively. Patients in the placebo (vehicle gel) groups V30 (n = 49) and V60 (n = 49) received topical treatment with 2.5% hyaluronan gel 0.5 g twice daily for 30 or 60 days, respectively. Treatment efficacy was assessed by target and cumulative lesion number scores (TLNS and CLNS, respectively) and lesion total thickness score (TTS). Investigator and patient global improvement indices (IGII and PGII) were also used to rate overall improvement. RESULTS: Compared with placebo, significantly more patients given active treatment for 60 days had TLNS = 0 (33% vs. 10%, P < 0.05; an improvement of 64% compared with 34% with placebo), CLNS = 0 (31% vs. 8%, P < 0.05; an improvement of 54% compared with 23% with placebo) and TTS = 0 (25% vs. 6%, P < 0.05; an improvement of 59% compared with 31% with placebo). The IGII and PGII scores were also significantly better when active treatment was compared with placebo (P < 0.05). Both treatments were generally well tolerated and the incidence of the most common adverse events was similar between groups. CONCLUSIONS: Treatment with 3.0% diclofenac in 2.5% hyaluronan gel was effective when used for 60 days and was well tolerated in patients with AK.

Accumulation of somatic mutations in proliferating T cell clones from children treated for leukemia.

There is continued controversy as to the sequential steps and mechanism(s) responsible for the in vivo acquisition of multiple mutations during neoplastic transformation. We investigated the in vivo clonality and mutational spectra of hypoxanthine-guanine phosphoribosyltransferase (HPRT) mutations in T cells from children with acute lymphocytic leukemia (ALL) to gain insight into the mutagenic mechanisms associated with leukemogenesis. We observed several instances of multiple, independent HPRT mutations accumulating in vivo in T cell receptor (TCR) gene defined clones that had undergone extensive pre- and/or post-thymic expansion following chemotherapy. In addition, we also detected the accumulation of multiple unique single mutations within distinct expanding post-thymic T cell clones. This pattern of clonally restricted hypermutability is compatible with extensive cell proliferation and selection alone without postulating genomic instability. These observations provide a paradigm for a continuum of cellular events that eventually results in the clonal accumulation of mutations in selected populations of cells in vivo and may provide insight into the primary genetic events associated with leukemogenesis, as well as the development of second malignancies and drug resistance following chemotherapy.

Predictors of sunburn among Canadian adults.

BACKGROUND: Data from the 1996 National Survey on Sun Exposure & Protective Behaviors (4,023 respondents) were analyzed to identify independent predictors of sunburn among adult Canadians. METHODS: Multivariate models predicting sunburn odds were developed using unconditional logistic regression. Backward elimination model selection was used to identify independent predictors of sunburn. RESULTS: Nonbehavioral characteristics found to predict sunburn were younger age, male sex, light skin color, nonblack hair color, and birthplace in North America or Europe. Behavioral predictors of sunburn included high awareness of the UV Index, working outdoors in the summer, longer leisure time in the sun, forgetfulness about protecting oneself from the sun, and seeking a tan. Sun avoidance between 11 AM and 4 PM was associated with lower odds of sunburn, while seeking shade when outside and use of protective clothing showed nonsignificant associations with lower sunburn odds. Sunscreen use was found to have a nonsignificant positive association with sunburn. CONCLUSIONS: These findings highlight risk factors to be considered in the targeting of sunburn reduction strategies to high-risk groups and suggest that sun avoidance, seeking shade, and use of protective clothing may be effective in preventing sunburn.

Dural melanoma associated with ocular melanosis and multiple blue nevi.

BACKGROUND: Primary meningeal melanomas of the central nervous system (CNS) are a rare malignant process with the majority originating from the leptomeninges. Primary dural melanomas have been reported to occur in isolation or in conjunction with Nevus of Ota. The association of primary dural melanoma with multiple cutaneous blue nevi has not been reported previously. OBJECTIVE: To describe a case of a 41-year-old Asian woman patient with a primary dural melanoma that arose in association with ocular melanosis and multiple cutaneous blue nevi. The patient is alive almost more than 8 years after subtotal and subsequent total resection of her primary tumor. Primary dural melanomas, Nevus of Ota, and blue nevi are discussed in relation to their coexistence and potential for intracranial melanoma. CONCLUSION: CNS melanoma is regarded as an extremely aggressive disease with poor prognosis. This case and previous reports of dural melanomas occurring in isolation or with Nevus of Ota have demonstrated relatively prolonged survival after surgical intervention. We conclude that dural melanomas are less aggressive tumors requiring surgical extirpation only.

Varicella zoster virus. Recent advances in management.

OBJECTIVE: To provide an update on strategies for managing varicella zoster virus (VZV) and for preventing and treating established postherpetic neuralgia (PHN). QUALITY OF EVIDENCE: Treatment guidelines are based on randomized clinical trials. Recommendations concerning other aspects of VZV management (e.g., vaccination) are based mainly on expert opinion. MAIN MESSAGE: Varicella and herpes zoster caused by VZV can give rise to serious morbidity and mortality and should be treated. For preventing chickenpox, safe and effective immunization is widely recommended. Treating varicella-exposed seronegative pregnant women requires special attention because the virus can harm expectant mothers, fetuses, and newborns. The antiviral drugs, acyclovir, valacyclovir, and famciclovir, have been approved for treating herpes zoster and have a role in reducing the duration of PHN. Established PHN can be managed with analgesics, tricyclic antidepressants, and other agents. CONCLUSION: Vaccination and antiviral and other systemic agents can substantially reduce the morbidity associated with VZV infection.