Development and validation of the Physician's Global Assessment of Fingernail Psoriasis.

BACKGROUND: Several clinician-rated scoring systems are available to assess nail psoriasis severity, but only one has been partially validated. OBJECTIVE: To develop and validate the Physician's Global Assessment of Fingernail Psoriasis (PGA-F), a new clinician-rated severity scale. METHODS: A literature review, concept elicitation, pilot cognitive debriefing and clinical expert consultations informed the development of the PGA-F. A multistage mixed-methods analysis consisted of practising dermatologist cognitive interviews (n = 10) for instrument clarity, relevance and comprehensiveness. Inter-rater reliability (IRR) of ratings from dermatologists (n = 22) and clinical trial investigators (n = 8) was tested using many-facet Rasch analysis. Concurrent validity between the PGA-F and modified Nail Psoriasis Severity Index (mNAPSI) at screening and baseline was assessed along with the degree of discrimination. Intraclass correlation coefficient (ICC) for single raters at multiple assessments determined IRR. RESULTS: The PGA-F synthesizes severity ratings across multiple disease features that classify individuals into 1 of 5 levels (clear to severe). Cognitive interviews confirmed content validity: all (n = 10, 100%) participants who agreed clinical criteria were consistent with nail psoriasis; no mismatched severity levels; and training photographs were realistic representations. All PGA-F items were locally independent and targeted patients along the severity continuum with complementary precision (item fit statistics: < the 1.5 acceptability threshold; exact agreements among the dermatologists [44%] and trial investigators [61.5%] exceeded 40% of acceptability threshold). Clinician reliability exceeded the threshold of acceptability for dermatologists and clinical trial investigators: 0.85 and 0.73, respectively. There was adequate correlation (>0.30) between mNAPSI and PGA-F at baseline and Week 26 with significant discrimination of severity and monotonic increases in the mNAPSI for each level of categorical severity on the PGA-F. ICC results for each type of IRR indicate that clinicians were consistent in individual patient ratings. CONCLUSION: The PGA-F is a rapid, valid and reliable clinician-rated severity scale for use in clinical practice and research.

Baseline patient-reported outcomes from UNITE: an observational, international, multicentre registry to evaluate hidradenitis suppurativa in clinical practice.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, inflammatory, skin condition associated with many comorbidities and often has a substantial impact on patients' lives. OBJECTIVES: To evaluate symptom burden and health-related quality of life (HRQoL) at baseline in patients with HS in an observational, real-world, clinical setting using several tools including a validated HS-specific instrument. METHODS: This study evaluated HRQoL data from the international UNITE HS disease registry. Administration of patient-reported outcome (PRO) instruments and collection of data were executed per local regulations. All data were assessed using descriptive statistical methods. RESULTS: PRO data from 529 adults and 65 adolescents were evaluated. Most adults (64.5%) and adolescents (73.8%) were classified as Hurley Stage II with substantial disease burden at baseline. HS had a large effect (mean DLQI = 12.6) and moderate effect (mean CDLQI = 6.9) on the lives of adults and adolescents, respectively. Approximately 58% of adults and 41% of adolescents had anxiety scores beyond the normal range; 30% of adults and 16% of adolescents exhibited symptoms of depression. Based on HSSA and HSIA scores, approximately 30% of adults reported a substantial burden of multiple HS clinical symptoms and more than 45% reported a significant emotional impact of HS that adversely affected their intimate relationships. Only 60% of adults were employed and of those, 64% reported at least some degree of impairment while working because of HS. CONCLUSIONS: Based on PROs collected from patients enrolled in the UNITE registry, a real-world, clinical setting, HS has a significant negative impact on the everyday lives of patients affected by this disease.

Reliability of the hidradenitis suppurativa clinical response in the assessment of patients with hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa clinical response (HiSCR) is a validated clinical end point for measuring response to treatment in patients with hidradenitis suppurativa (HS). Previous studies have reported on the validity, responsiveness and meaningfulness of the HiSCR. OBJECTIVE: To evaluate the HiSCR for inter- and intrarater reliability characteristics. METHODS: A stand-alone, two-site, prospective, non-interventional observational study consisted of 22 patients, with self-reported severity between mild, moderate and severe HS. The Patient Global Impression of Change (PGI-C) scale was completed by patients at Timepoint 2. Descriptive statistics of Hurley Stage, total abscesses, total draining fistulas, total inflammatory nodules and total AN count (sum of inflammatory nodules and lesions) were reported at two timepoints. Inter-rater reliability and intrarater reliability for the HS lesion count tool were evaluated at two timepoints (baseline and Day 7) using the HS lesion count tool. Intraclass correlation (ICC) coefficients of lesion counts were calculated to evaluate inter- and intrarater reliability of lesion counts between pairs of dermatologists. RESULTS: The majority of patients demonstrated either no change or minimally worse PGI-C in HS scores. Descriptive statistics were similar between rater groups and timepoints assessed. Inter-rater ICC coefficients for abscess count at Timepoints 1 and 2 were 0.38 and 0.67. The ICC coefficients for draining fistula and AN count were ≥0.61 at both timepoints. In an exploratory model, ICC coefficients were ≥0.68 for all evaluated lesion counts. The test-retest reliability using ICC coefficients was ≥0.70 for total abscess, draining fistula, inflammatory nodule and AN count. CONCLUSION: The HS lesion count tool had an acceptable inter- and intrarater reliability, indicating that HiSCR has a strong degree of reproducibility and consistency in the evaluation of patients with HS.

Anxiety, depression and quality of life in family caregivers of palliative cancer patients during home care and after the patient's death.

We examined psychological parameters in family caregivers of palliative cancer patients before and after the death of the patients. Caregivers' data about depression and anxiety (Hospital Anxiety and Depression Scale), quality-of-life (Short Form-8 Health Survey), and social support (Oslo Social Support Scale) were collected at the beginning of home care (t1) and 2 months after the patient had died (t2). Regression models were employed to examine factors related to depression and anxiety in the bereaved caregivers. We interviewed 72 relatives, who were the primary caregiver of a patient. One-third (31.9%) of caregivers had high anxiety levels and 29.2% had high depression levels (t1, cut-off = 10). At t2, anxiety and depression had decreased significantly. There were no changes in quality-of-life over time. At both points of assessments, quality-of-life was lower than in the general population. Relevant factors for higher anxiety and depression in the bereaved caregivers were high levels of distress at t1, insufficient social support and low physical function. Bereaved caregivers were particularly depressed when they had been the spouse of the patient. Healthcare professionals should consider social isolation of caring relatives both during homecare and afterwards. Thus, it seems to be important to routinely offer support to spouses.

An evidence-based review of systemic treatments for itch.

BACKGROUND AND OBJECTIVE: Many treatment modalities are used for itch treatment in daily medical practices without adequate evidence of their efficacy. The purpose of this study was to provide an evidence-based review of the literature as to the clinical benefits of systemic anti-itch treatments. DATABASES AND DATA TREATMENT: We performed a systematic review and, when appropriate, meta-analysis from available placebo-controlled randomized controlled trails (RCTs). A systematic search of the literature was performed using Pub Med, Cochrane Library and EMBASE. The primary outcome was the change in the itch score comparing the intervention group and placebo group. The meta-analysis method was used to calculate the pooled outcome of each treatment modality. RESULTS: Twenty-six eligible RCTs were included. We found evidence for the effectiveness of: naltrexone (in cholestatic itch and atopic eczema), nalfurafine (in uraemic itch), gabapentin (in uraemic itch) and ursodeoxycholic acid (in intrahepatic cholestasis of pregnancy). The results of two RCTs with naltrexone in uremic itch are conflicting. On the other hand, we did not find any benefit from ondansetron (in cholestatic and uraemic itch), ergocalciferol (in uraemic itch), colesevelam (in cholestatic itch) or gabapentin (in cholestatic itch). The possible effectiveness of sertraline, paroxetine, cromolyn sodium, zinc sulphate, omega-3 fatty acid, montelukast, doxepin and rifampin need to be confirmed from future large studies, because the available evidence is insufficient. CONCLUSIONS: The findings from this study suggest the effective therapeutic approaches for itch. The major limitations are that there are small numbers of available RCTs and methodological differences across studies.

Elevated first trimester PAPP--a is associated with increased risk of placenta accreta.

OBJECTIVES: The objective of this article is to determine whether there were differences in first trimester serum analytes between cases of placenta previa with and without accreta. METHODS: Cases of placenta previa in which the patient had first trimester aneuploidy screening were identified. Pregnancy-associated plasma protein A (PAPP-A) and free beta human chorionic gonadotropin (fbhCG) MoMs were compared with those with an accreta. Accreta cases were also compared with published distributions to determine significance and to develop likelihood ratios based on MoM values. RESULTS: Eighty-two cases of previa were identified, including 16 with a histological diagnosis of placenta accreta. The median PAPP-A MoM of 1.68 in accreta was significantly greater than that of 0.98 in non-accreta (P = 0.002). For fbhCG, the median MoM was 1.00 and 1.01 in accreta and non-accreta, respectively. Of the 16 patients with accreta, 14 (87.5%, 95% confidence interval: [61.6%, 98.4%]) had PAPP-A MoM above 1.0. Six of 16 (37.5%) accreta cases were above the 90th percentile of the unaffected distribution. The likelihood ratios for accreta were 0.5, 2.0, and 3.0. PAPP-A MoMs were 0.19, 2.11, and 4.27, respectively. CONCLUSIONS: First trimester PAPP-A levels may be useful in identifying pregnancies at high risk for placenta accreta. Larger studies could incorporate both clinical and biochemical data into a risk algorithm.

In vitro antifungal activity of naftifine hydrochloride against dermatophytes.

The incidence of superficial dermatophytoses is high in developed countries, and there remains a need for effective topical antifungals. In this study, we evaluated the in vitro antifungal activity of naftifine hydrochloride, the active ingredient in naftifine hydrochloride cream and gel 1% and 2%, against dermatophytes. The MICs and minimum fungicidal concentrations (MFCs) of naftifine hydrochloride against 350 clinical strains, including Trichophyton rubrum, T. mentagrophytes, T. tonsurans, Epidermophyton floccosum, and Microsporum canis, were determined using the CLSI methodology. Subsets from this test panel were subsequently tested in a time-kill assay at 0.125×, 0.25×, 0.5×, and 1× the MFC for each isolate. CFU counts were performed over a period of 48 h of incubation. Additionally, in order to determine the potential for resistance development, six strains were subjected to 15 serial passages in concentrations higher than the MIC for each strain. MICs were determined following each passage. The MIC range against the dermatophyte isolates tested was 0.015 to 1.0 µg/ml, with naftifine hydrochloride being fungicidal against 85% of the Trichophyton species. The time-kill assay showed dose-dependent activity, with the greatest reduction in the numbers of CFU corresponding to the highest drug concentration. There was no increase in MIC for any strains following repeated exposure to naftifine hydrochloride. Naftifine hydrochloride demonstrated potent activity against all dermatophytes tested, and none of the isolates within this test panel demonstrated the potential for the development of resistance. Thus, future clinical studies of naftifine hydrochloride against dermatophytes may be warranted for the treatment of superficial dermatophytoses.

Generation of mouse and human induced pluripotent stem cells (iPSC) from primary somatic cells.

Cellular reprogramming consists of the conversion of differentiated cells into pluripotent cells; the so-called induced Pluripotent Stem Cells. iPSC are amenable to in vitro manipulation and, in theory, direct production of any differentiated cell type. Furthermore, iPSC can be obtained from sick individuals and subsequently used for disease modeling, drug discovery and regenerative treatments. iPSC production was first achieved by transducing, with the use of retroviral vectors, four specific transcription factors: Oct4, Klf4, Sox2 and c-Myc (OKSM), into primary cells in culture Takahashi and Yamanaka, (Cell 126(4):663-676, 2006). Many alternative protocols have since been proposed: repeated transfections of expression plasmids containing the four pluripotency-associated genes Okita et al. (Science 322(5903):949-953, 2008), lentiviral delivery of the four factors Sommer et al. (Stem Cells 27(3):543-549, 2009), Sendai virus delivery Fusaki et al. (Proceedings of the Japan Academy. Series B, Physical and Biological Sciences 85(8):348-362, 2009), removal of the reprogramming vectors by 'piggyBac' transposition Woltjen et al. (Nature 458(7239):766-770, 2009); Kaji et al. (Nature 458(7239):771-775, 2009), Cre-recombinase excisable viruses Soldner et al. (Cell 136(5):964-977, 2009), episomal vectors Yu et al. (Science 324(5928):797-801, 2009), cell-penetrating reprogramming proteins Zhou et al. (Stem Cells 4(5):381-384, 2009), mammalian artificial chromosomes Hiratsuka et al. (PLoS One 6(10):e25961, 2011) synthetically modified mRNAs Warren et al. (Scientific Reports 2:657, 2012), miRNA Anokye-Danso et al. (Cell Stem Cell 8(4):376-388, 2009); however, although some of these methods are commercially available, in general they still need to attain the reproducibility and reprogramming efficiency required for routine applications Mochiduki and Okita (Biotechnol Journal 7(6):789-797, 2012). Herein we explain, in four detailed protocols, the isolation of mouse and human somatic cells and their reprogramming into iPSC. All-encompassing instructions, not previously published in a single document, are provided for mouse and human iPSC colony isolation and derivation. Although mouse and human iPSC share similarities in the cellular reprogramming process and culture, both cell types need to be handled differently.

Probing angular correlations in sequential double ionization.

We study electron correlation in sequential double ionization of noble gas atoms and HCl in intense, femtosecond laser pulses. We measure the photoelectron angular distributions of Ne+ relative to the first electron in a pump-probe experiment with 8 fs, 800 nm, circularly polarized laser pulses at a peak intensity of a few 10(15) W/cm2. Using a linear-linear pump-probe setup, we further study He, Ar, and HCl. We find a clear angular correlation between the two ionization steps in the sequential double ionization intensity regime.

[Preoperative and postoperative imaging in patients with transposition of the great arteries]. / Prä- und Postoperative Bildgebung bei Patienten mit Transposition der großen Gefäße.

Transposition of the great arteries (TGA) is a rare disease representing not more than 3-5% of all congenital heart diseases. TGA is a cardiac anomaly in which the aorta arises entirely or largely from the morphological right ventricle and the pulmonary artery from the morphological left ventricle. This is called a ventriculo-arterial discordant connection and when accompanied by an atrio-ventricular concordant connection it is called a complete or D-transposition (D-TGA). The terms congenitally corrected TGA (ccTGA) or L-TGA describe an atrio-ventricular discordant connection. In D-TGA survival can only be achieved if additional shunting is simultaneously present, which possibly has to be created post-natal by the so-called Rashkind maneuver.Nowadays, an early anatomic correction using the arterial switch operation is the treatment of choice. Up to the 1980s, an atrial switch operation according to Senning/Mustard was performed. Apart from echocardiography the imaging modality of choice is usually MRI to assess the complex postoperative anatomy, viability of the myocardium and to perform a volumetric and functional assessment, including MR flow measurements. Multidetector computed tomography (MDCT) is used if there are contraindications to MRI or if an assessment of cardiac and especially coronary anatomy is the main interest.

A high-throughput screening for mammalian cell death effectors identifies the mitochondrial phosphate carrier as a regulator of cytochrome c release.

Functional annotation of complex genomes requires the development of novel experimental platforms with increased capacity. Here, we describe a high-throughput system designed to identify cDNAs whose overexpression induces morphologically distinct cell death modalities. The methodology incorporates two robotized steps, and relies on coexpression of library clones with GFP to reveal the morphological features presented by the dying cells. By using this system we screened 135 000 cDNA clones and obtained 90 independent molecules. Interestingly, three death categories were identified, namely; apoptotic, vacuolated and autophagic. Among the pro-apoptotic clones, we found four members of the mitochondrial carrier family: the phosphate and adenine nucleotide (type 3) transporters, and the mitochondrial carrier homologs (MTCHs) 1 and 2. Expression of these molecules induced cytochrome c release and caspase-9-dependent death. One of them, the phosphate carrier, was able to interact with members of the permeability transition pore complex ANT1 and VDAC1, and its binding to ANT1 was stabilized in the presence of apoptotic activators. Depletion of this carrier by siRNA delayed cytochrome c mobilization and apoptosis. These results attribute a previously undescribed apoptotic function to the phosphate carrier and, more generally, suggest that a common property of various mitochondrial transporters was exploited during evolution to regulate apoptosis.

Diagnosed skin diseases among migrant farmworkers in North Carolina: prevalence and risk factors.

Skin diseases are common among farmworkers, yet little research documents their prevalence and risk factors. This analysis documents the prevalence of skin diseases among farmworkers in North Carolina, examines variation in the prevalence across the agricultural season, and delineates factors associated with skin disease. Data are from a longitudinal surveillance study with assessments at approximately three-week intervals from May through October 2005. The sample included 304 farmworkers from 45 camps with 1048 data points. Data collection included a structured interview and a standard set often digital photographs. A board-certified dermatologist reviewed the photographs and made specific diagnoses in five categories: inflammatory disease, infection, pigmentary disorder, tumor, and trauma. The prevalences of the five skin disease categories and specific diagnoses are described with counts and frequencies for the entire season and for six time periods. The inflammatory disease and infectious disease categories are modeled with an extension of logistic regression that accounts for repeated measures and clustering of farmworkers within camps. Farmworkers experience high levels of inflammatory skin disease (57.2%) including acne, folliculitis, and contact dermatitis; infectious skin disease (73.8%) including tinea pedis, onychomycosis, and warts; pigmentary disorders (19.1%); and trauma (34.5%). The odds of inflammatory skin disease decreased with age, while those for infectious skin disease increased with age. The odds of inflammatory skin disease increased with pesticide exposure and decreasing housing quality. Skin diseases are highly prevalent among farmworkers. Research is needed to delineate specific factors causing high levels of infection and inflammation in this population.

A topical azithromycin preparation for the treatment of acne vulgaris and rosacea.

BACKGROUND: Erythromycin is a common therapy for acne and rosacea. A newer macrolide, azithromycin, offers superior tissue distribution and cellular concentration and is an effective oral anti-acne agent. Topical formulations such as erythromycin have been a major clinical therapy for acne. To date, no topical solution of azithromycin is available for the treatment of acne. OBJECTIVE: To prepare a stable topical 2% azithromycin formulation that could be used in an acne clinical trial to determine the efficacy of topical azithromycin in treating subjects with acne vulgaris and acne rosacea. METHODS: The study was divided into two phases. In phase I, azithromycin was prepared over a range of ethanol/water concentrations to determine solubility. The stability of a 2% azithromycin in 60% ethanol/water preparation was assessed by high-pressure liquid chromatography. The temperature, light, and pH dependence of the stability was also assessed. In phase II, a single center, randomized, double-blind, treatment-controlled study compared once-nightly application of topical 2% azithromycin versus 2% erythromycin. A total of 20 subjects with moderate inflammatory acne and 20 with rosacea were examined clinically at 0, 2, 4, 8, and 12 weeks for a 12-week period. Efficacy was evaluated with the Physician's Visual Analog Scale evaluation (PVAS), the papulopustule count, and acne severity rating (in subjects with acne). RESULTS: In phase I, azithromycin was soluble in 60% ethanol/water. A 2% azithromycin in 60% ethanol/water solution maintained stability at room temperature for up to 26 weeks but at 37 degrees C there was some decay (16%) at 26 weeks. The stability was greatest at pH 6.8 and was unaffected by ambient light exposure. In phase II, the number of inflammatory lesions decreased in both acne and rosacea subjects treated with 2% erythromycin (7.56, p=0.03 and 4.4, p=0.01, respectively). Azithromycin was not as effective for the treatment of rosacea. Both azithromycin (p=0.01) and erythromycin (p=0.03) treatment significantly reduced the inflammatory lesion count in acne vulgaris. No significant adverse events were identified in the acne group. In patients with rosacea, transient irritation occurred in five patients. CONCLUSIONS: A 2% azithromycin in 60% ethanol/water solution can be prepared and is stable for at least 6 months at room temperature. The methodology and power of the study were adequate to identify improvement in acne vulgaris and rosacea. Though it appears the formulation of topical azithromycin was at least comparable with topical erythromycin, larger studies would be needed to determine whether topical azithromycin has any significant advantage over topical erythromycin.

Anger and acne: implications for quality of life, patient satisfaction and clinical care.

BACKGROUND: Acne is a common skin disorder with a significant psychological and social impact for some people. Little is known about how personality and emotional traits affect acne and its impact on quality of life and treatment. Trait anger (TA), which is related to heart disease and other morbidities, may also affect acne and patients' adjustment to it. OBJECTIVES: To evaluate the relationship between TA and acne severity, skin-related quality of life, satisfaction with treatment, and adherence to treatment. PARTICIPANTS AND METHODS: A sample of 479 individuals with acne completed a survey instrument to assess acne severity, skin care practices, skin-related quality of life, satisfaction with treatment, adherence, TA and demographic variables. Respondents who reported high TA were compared with individuals with low TA on outcome variables. Regression analyses adjusted for covariates and identified the significant predictors of quality of life, satisfaction and adherence. RESULTS: High TA was unrelated to acne severity (P = 0.2) or frequency of face washing (P = 0.9). Anger was significantly related to both global quality of life (P < 0.001) and skin-related quality of life (P = 0.002) as well as to satisfaction with treatment (P = 0.001) and adherence to treatment advice (P = 0.05) in bivariate analyses. Regression analyses revealed that high TA remained a significant predictor of global (P < 0.001) and skin-related quality of life (P = 0.003) and satisfaction with treatment (P = 0.04), but not adherence to treatment advice (P = 0.8) after controlling for covariates. CONCLUSIONS: Anger is associated with the quality of patients' lives and with their satisfaction with treatment. Care of acne patients should include attention to anger and other chronic emotional states, quality of life, as well as to clinical severity. Simple guidelines are suggested for how clinicians might approach this important aspect of care.

Over-the-counter topical antipruritic agents are commonly recommended by office-based physicians: an analysis of US practice patterns.

BACKGROUND: Pruritus is one of the most common complaints among patients who visit physicians. Over-the-counter topical antipruritic medications are widely recommended by physicians and are self-administered by patients for the treatment of pruritus. However, there are few scientific controlled studies evaluating the effect of these drugs on pruritus. OBJECTIVES: To assess the role of physician-recommended over-the-counter medications for the treatment of pruritus. METHODS: Records were analyzed for office-based physician visits in which over-the-counter antipruritic topical medications were recommended in the National Ambulatory Medical Care Survey between the years 1995 and 2000. RESULTS: The largest proportion of over-the-counter antipruritic agent recommendations were during visits to dermatologists, accounting for 41% of all such recommendations. Other physicians that recommended such agents included family physicians and pediatricians, accounting respectively for 26% and 21% of the recommendations. The most commonly recommended over-the-counter medications included hydrocortisone preparations (72%) and diphenhydramine (15%). Over-the-counter medications were more frequently recommended in the pediatric age group. CONCLUSION: This study demonstrates that over-the-counter medications are frequently recommended for the treatment of pruritus.

Treatment of pityriasis versicolor in the United States.

BACKGROUND: Pityriasis versicolor is a common chronic superficial fungal infection of the skin. OBJECTIVE: The purpose of this study is to determine the frequency of visits for pityriasis versicolor and to assess how it is currently being treated. METHODS: Data from the National Ambulatory Medical Care survey were used from the years 1990-1999. RESULTS: There were 2.9 million visits per year in which pityriasis (tinea) versicolor was listed as a diagnosis; this corresponds to a visit rate of 110 visits per 100,000 persons per year. Visit rates varied among racial and ethnic groups, with the highest visit rates for black people and American Indians/Eskimos. A total of 76% of the medications listed at visits for pityriasis versicolor are FDA approved for the condition; however, many treatments that were prescribed were not. CONCLUSIONS: Given that as many as one-quarter of treatments prescribed for this easily treatable condition are inappropriate, continued education of medical practitioners concerning appropriate treatment options is needed.

Pruritus in adult dermatomyositis.

Dermatomyositis has a significant clinical component of pruritus that has not yet been studied. Pruritus can significantly affect the life of patients. The aim of the present work was to study the degree of pruritus experienced by patients. A four-question survey was sent to patients with documented dermatomyositis. The survey used a 100-mm Visual Analogue Scale (VAS) to describe current, worst and daily pruritus, and the effect this has on daily activities. Twenty-six subjects returned completed questionnaires: four had no pruritus; the majority had a significant amount with means above 50 on the VAS. A mean of 44.6 was found for the effect on daily life. Further studies should be performed to examine the prevalence and severity of pruritus in this population and it's effect on their quality of life. Clinicians must be aware of the significant pruritus and provide adequate therapy to improve quality of life.