Incidence and profile of skin cancers in patients following ultraviolet phototherapy without psoralens: A retrospective cohort study.

BACKGROUND: Psoralen + ultraviolet-A (PUVA) is associated with photocarcinogenesis. However, carcinogenic risk with other ultraviolet phototherapies remains unclear. OBJECTIVE: Evaluate whether phototherapy without psoralens increases skin cancer risk. METHODS: Retrospective cohort study of patients treated at a teaching-hospital phototherapy center (1977-2018). Skin cancer records were validated against pathology reports. Age-standardized incidence rates (ASIRs) of skin cancer were evaluated for gender, skin phototype, diagnosis, ultraviolet modality, anatomical site; and compared to provincial population incidence rates (2003). RESULTS: In total, 3506 patients treated with broadband-ultraviolet-B, narrowband-UVB and/or combined UVAB were assessed with a mean follow-up of 7.3 years. Majority of patients had psoriasis (60.9%) or eczema (26.4%). Median number of treatments was 43 (1-3598). Overall, 170 skin cancers (17 melanoma, 33 squamous cell carcinoma and 120 basal cell carcinoma) occurred in 79 patients. Patient-based and tumor-based ASIR of skin cancer was 149 (95% CI: 112-187)/100,000 and 264 (219-309)/100,000 person-years, respectively. There was no significant difference between tumor-based ASIRs for melanoma, squamous cell carcinoma, and basal cell carcinoma compared to the general population; or in phototherapy patients with-psoriasis or eczema; or immunosuppressants. No cumulative dose-response correlation between UVB and skin cancer was seen. LIMITATIONS: Treatment and follow-up duration. CONCLUSION: No increased risk of melanoma and keratinocyte cancer was found with phototherapy.

Oligomeric assembly regulating mitochondrial HtrA2 function as examined by methyl-TROSY NMR.

Human High temperature requirement A2 (HtrA2) is a mitochondrial protease chaperone that plays an important role in cellular proteostasis and in regulating cell-signaling events, with aberrant HtrA2 function leading to neurodegeneration and parkinsonian phenotypes. Structural studies of the enzyme have established a trimeric architecture, comprising three identical protomers in which the active sites of each protease domain are sequestered to form a catalytically inactive complex. The mechanism by which enzyme function is regulated is not well understood. Using methyl transverse relaxation optimized spectroscopy (TROSY)-based solution NMR in concert with biochemical assays, a functional HtrA2 oligomerization/binding cycle has been established. In the absence of substrates, HtrA2 exchanges between a heretofore unobserved hexameric conformation and the canonical trimeric structure, with the hexamer showing much weaker affinity toward substrates. Both structures are substrate inaccessible, explaining their low basal activity in the absence of the binding of activator peptide. The binding of the activator peptide to each of the protomers of the trimer occurs with positive cooperativity and induces intrasubunit domain reorientations to expose the catalytic center, leading to increased proteolytic activity. Our data paint a picture of HtrA2 as a finely tuned, stress-protective enzyme whose activity can be modulated both by oligomerization and domain reorientation, with basal levels of catalysis kept low to avoid proteolysis of nontarget proteins.

Micro-relief characterization of benign and malignant skin lesions by polarization speckle analysis in vivo.

BACKGROUND/PURPOSE: A recent direction in skin disease classification is to develop quantitative diagnostic techniques. Skin relief, colloquially known as roughness, is an important clinical feature. The aim of this study is to demonstrate a novel polarization speckle technique to quantitatively measure roughness on skin lesions in vivo. We then calculate the average roughness of different types of skin lesions to determine the extent to which polarization speckle roughness measurements can be used to identify skin cancer. METHODS: The experimental conditions were set to target the fine relief structure on the order of ten microns within a small field of view of 3 mm. The device was tested in a clinical study on patients with malignant and benign skin lesions that resemble cancer. The cancer group includes 37 malignant melanomas (MM), 43 basal cell carcinomas (BCC), and 26 squamous cell carcinomas (SCC), all categories confirmed by gold standard biopsy. The benign group includes 109 seborrheic keratoses (SK), 79 nevi, and 11 actinic keratoses (AK). Normal skin roughness was obtained for the same patients (301 different body sites proximal to the lesion). RESULTS: The average root mean squared (rms) roughness ± standard error of the mean for MM and nevus was equal to 19 ± 5 µm and 21 ± 3 µm, respectively. Normal skin has rms roughness of 31 ± 3 µm, other lesions have roughness of 35 ± 10 µm (AK), 35 ± 7 µm (SCC), 31 ± 4 µm (SK), and 30 ± 5 µm (BCC). CONCLUSION: An independent-samples Kruskal-Wallis test indicates that MM and nevus can be separated from each of the tested types of lesions, except each other. These results quantify clinical knowledge of lesion roughness and could be useful for optical cancer detection.

Full Stokes polarimetry using a monolithic off-axis polarizing interferometer and a 2D array sensor.

This paper describes a full Stokes polarimeter employing a monolithic off-axis polarizing interferometric module and a 2D array sensor. The proposed passive polarimeter provides a dynamic full Stokes vector measurement capability of around 30 Hz. As the proposed polarimeter employs no active devices and is operated by employing an imaging sensor, it has significant potential to become a highly compact polarization sensor for smartphone applications. To show the feasibility of the proposed passive dynamic polarimeter scheme, the full Stokes parameters of a quarter-wave plate are extracted and displayed on a Poincare sphere by varying the polarization state of the measured beam.

Defining Risk and Risk Factors for Unplanned ICU Admission of Trauma Patients.

BACKGROUND: Unplanned ICU admissions (up-ICUad) are associated with poor outcomes. It is difficult to identify who is at risk for up-ICUad in trauma patients. This study aimed to identify injury patterns and comorbidities associated with up-ICUad and develop a predictive tool for who is at risk. METHODS: A retrospective study compared trauma patients admitted to the floor who experienced an up-ICUad to similar patients without an up-ICUad. Univariate analysis and multivariate logistic regression identified independent risk factors associated with up-ICUad. Based on those factors, a Risk Score (RS) was created and compared between the two groups. RESULTS: 2.15% of the 7206 patients experienced an up-ICUad. The up-ICUad group was older, experienced longer length of stay, and had higher mortality. Age, congestive heart failure, COPD, peptic ulcer disease, mild liver disease, CKD, and significant injuries to the thorax, spine, and lower extremities were independently associated with up-ICUad. A RS equation was created and was used for each patient. CONCLUSIONS: Trauma patients are at increased risk for up-ICUad based on specific factors. These factors can be used to calculate a RS to determine who is at greatest risk for an up-ICUad which may be helpful for preventing up-ICUad.

A novel automated approach to rapid and precise in vivo measurement of hair morphometrics using a smartphone.

BACKGROUND: Although many hair disorders can be readily diagnosed based on their clinical appearance, their progression and response to treatment are often difficult to monitor, particularly in quantitative terms. We introduce an innovative technique utilizing a smartphone and computerized image analysis to expeditiously and automatically measure and compute hair density and diameter in patients in real time. METHODS: A smartphone equipped with a dermatoscope lens wirelessly transmits trichoscopy images to a computer for image processing. A black-and-white binary mask image representing hair and skin is produced, and the hairs are thinned into single-pixel-thick fiber skeletons. Further analysis based on these fibers allows morphometric characteristics such as hair shaft number and diameters to be computed rapidly. The hair-bearing scalps of fifty participants were imaged to assess the precision of our automated smartphone-based device in comparison with a specialized trichometry device for hair shaft density and diameter measurement. The precision and operation time of our technique relative to manual trichometry, which is commonly used by hair disorder specialists, is determined. RESULTS: An equivalence test, based on two 1-sided t tests, demonstrates statistical equivalence in hair density and diameter values between this automated technique and manual trichometry within a 20% margin. On average, this technique actively required 24 seconds of the clinician's time whereas manual trichometry necessitated 9.2 minutes. CONCLUSION: Automated smartphone-based trichometry is a rapid, precise, and clinically feasible technique which can significantly facilitate the assessment and monitoring of hair loss. Its use could be easily integrated into clinical practice to improve standard trichoscopy.

Frontline Perspectives on Physician Burnout and Strategies to Improve Well-Being: Interviews with Physicians and Health System Leaders.

BACKGROUND: Nationally over 50% of physicians report symptoms of burnout. OBJECTIVE: To understand the perspectives of health system leaders and frontline physicians on contributors to physician burnout and strategies to improve well-being. DESIGN: We conducted in-depth interviews with health system leaders and frontline physicians at a large, predominantly fee-for-service, multispecialty group practice with approximately 1300 physicians. PARTICIPANTS: The 17 participants included 15 physicians, (12 Internal Medicine and Family Medicine physicians and 3 from other specialties), 11 individuals in leadership roles, and 11 women. APPROACH: Interviews included a review of factors associated with burnout at the organization, asking participants which factors they believed contributed to burnout, questions about experiences of burnout, and what specific changes would improve well-being. KEY RESULTS: All 17 participants agreed that organizational factors were key contributors to burnout, while only 9 mentioned the salience of individual factors: "It does not matter how resilient or positive you are, the work environment, especially in primary care will eventually be a problem." An increasing workload associated with the electronic health record (EHR) and a culture focused on productivity were cited as contributing to burnout, especially among physicians in Internal Medicine and Family Medicine (primary care) departments. Physicians in primary care, women, and leaders described multiple barriers to well-being. Participants described responding to increased workloads by reducing clinical work hours. Participants suggested reducing and compensating EHR work, expanding care teams/support staff, reducing use of metrics, providing more support to leaders, changing the business model, and increasing positivity and collegiality, as essential to improving well-being. CONCLUSION: Interviews reveal a variety of interacting factors contributing to physician burnout. Reducing clinical work hours has become a coping strategy. Changes recommended to improve physician well-being include increasing support staff, reducing EHR workload, changing revenue generation and compensation approaches, and shifting organizational culture to place more value on physician wellness.

Junctophilin-2 is a target of matrix metalloproteinase-2 in myocardial ischemia-reperfusion injury.

Junctophilin-2 is a structural membrane protein that tethers T-tubules to the sarcoplasmic reticulum to allow for coordinated calcium-induced calcium release in cardiomyocytes. Defective excitation-contraction coupling in myocardial ischemia-reperfusion (IR) injury is associated with junctophilin-2 proteolysis. However, it remains unclear whether preventing junctophilin-2 proteolysis improves the recovery of cardiac contractile dysfunction in IR injury. Matrix metalloproteinase-2 (MMP-2) is a zinc and calcium-dependent protease that is activated by oxidative stress in myocardial IR injury and cleaves both intracellular and extracellular substrates. To determine whether junctophilin-2 is targeted by MMP-2, isolated rat hearts were perfused in working mode aerobically or subjected to IR injury with the selective MMP inhibitor ARP-100. IR injury impaired the recovery of cardiac contractile function which was associated with increased degradation of junctophilin-2 and damaged cardiac dyads. In IR hearts, ARP-100 improved the recovery of cardiac contractile function, attenuated junctophilin-2 proteolysis, and prevented ultrastructural damage to the dyad. MMP-2 was co-localized with junctophilin-2 in aerobic and IR hearts by immunoprecipitation and immunohistochemistry. In situ zymography showed that MMP activity was localized to the Z-disc and sarcomere in aerobic hearts and accumulated at sites where the striated JPH-2 staining was disrupted in IR hearts. In vitro proteolysis assays determined that junctophilin-2 is susceptible to proteolysis by MMP-2 and in silico analysis predicted multiple MMP-2 cleavage sites between the membrane occupation and recognition nexus repeats and within the divergent region of junctophilin-2. Degradation of junctophilin-2 by MMP-2 is an early consequence of myocardial IR injury which may initiate a cascade of sequelae leading to impaired contractile function.

Development of polarization speckle based on random polarization phasor sum.

The random-walk approach has been extended and applied to study the development of polarization speckle by taking the vector nature into account for stochastic electric fields. Based on the random polarization phasor sum, the first and second moments of the Stokes parameters of the resultant polarization speckle have been examined. Under certain assumptions about the statistics of the component polarization phasors that make up the sum, we present some of the details of the spatial derivation that lead to the expressions for the degree of polarization and the newly proposed Stokes contrast that are suitable for describing the polarization speckle development. This vectorial extension of the random walk will provide an intuitive explanation for the development of the polarization speckle.

Quantifying the visual appearance of sunscreens applied to the skin using indirect computer image colorimetry.

BACKGROUND: There is no accepted method to objectively assess the visual appearance of sunscreens on the skin. METHODS: We present a method for sunscreen application, digital photography, and computer analysis to quantify the appearance of the skin after sunscreen application. Four sunscreen lotions were applied randomly at densities of 0.5, 1.0, 1.5, and 2.0 mg/cm2 to areas of the back of 29 subjects. Each application site had a matched contralateral control area. High-resolution standardized photographs including a color card were taken after sunscreen application. After color balance correction, CIE L*a*b* color values were extracted from paired sites. Differences in skin appearance attributed to sunscreen were represented by ΔE, which in turn was calculated from the linear Euclidean distance within the L*a*b* color space between the paired sites. RESULTS: Sunscreen visibility as measured by median ΔE varied across different products and application densities and ranged between 1.2 and 12.1. The visibility of sunscreens varied according to product SPF, composition (organic vs inorganic), presence of tint, and baseline b* of skin (P < .05 for all). CONCLUSION: Standardized sunscreen application followed by digital photography and indirect computer-based colorimetry represents a potential method to objectively quantify visibility of sunscreen on the skin.

A Computer-Aided Decision Support System for Detection and Localization of Cutaneous Vasculature in Dermoscopy Images Via Deep Feature Learning.

Vascular structures of skin are important biomarkers in diagnosis and assessment of cutaneous conditions. Presence and distribution of lesional vessels are associated with specific abnormalities. Therefore, detection and localization of cutaneous vessels provide critical information towards diagnosis and stage status of diseases. However, cutaneous vessels are highly variable in shape, size, color and architecture, which complicate the detection task. Considering the large variability of these structures, conventional vessel detection techniques lack the generalizability to detect different vessel types and require separate algorithms to be designed for each type. Furthermore, such techniques are highly dependent on precise hand-crafted features which are time-consuming and computationally inefficient. As a solution, we propose a data-driven feature learning framework based on stacked sparse auto-encoders (SSAE) for comprehensive detection of cutaneous vessels. Each training image is divided into small patches of either containing or non-containing vasculature. A multilayer SSAE is designed to learn hidden features of the data in hierarchical layers in an unsupervised manner. The high-level learned features are subsequently fed into a classifier which categorizes each patch into absence or presence of vasculature and localizes vessels within the lesion. Over a test set of 3095 patches derived from 200 images, the proposed framework demonstrated superior performance of 95.4% detection accuracy over a variety of vessel patterns; outperforming other techniques by achieving the highest positive predictive value of 94.7%. The proposed Computer-Aided Diagnosis (CAD) framework can serve as a decision support system assisting dermatologists for more accurate diagnosis, especially in teledermatology applications in remote areas.

Predictors of 25-Hydroxyvitamin D Concentration Measured at Multiple Time Points in a Multiethnic Population.

The evidence for a relationship between serum vitamin D levels and nonskeletal health outcomes is inconsistent. The validity of single or predicted measurements of 25-hydroxyvitamin D (25(OH)D) concentration is unknown, as levels of this biomarker are highly seasonally variable. We compared models of 25(OH)D measured at baseline, at multiple time points throughout the year, and averaged over the year among 309 persons in Toronto, Ontario, Canada (43°N latitude) during 2009-2013. Information and blood samples were collected every 2 months. Baseline and average 25(OH)D concentrations were correlated (r = 0.88). Major factors associated with 25(OH)D level were similar across models and included race/ethnicity (concentrations in non-European groups were lower than those in Europeans), vitamin D supplement use of ≥1,000 IU/day (18.9 nmol/L (95% confidence interval (CI): 16.1, 21.8) vs. no supplement use in a full data set with all factors), and the presence of the group-specific component/vitamin D binding protein gene (GC/DBP) rs4588 functional polymorphism (AA vs. CC: -16.7 nmol/L (95% CI: -26.2, -7.1); CA vs. CC: -10.7 nmol/L (95% CI: -14.9, -6.5)). Most factors had similar associations in Europeans and non-Europeans. Genetic factors may play a greater role in average 25(OH)D concentrations. Prediction models for 25(OH)D are challenging and population-specific, but use of genetic factors along with a few common population-relevant, quantifiable nongenetic factors with strong associations may be the most feasible approach to vitamin D assessment over time.

Melanoma Epidemiology and Prevention.

The epidemiology of melanoma is complex, and individual risk depends on sun exposure, host factors, and genetic factors, and in their interactions as well. Sun exposure can be classified as intermittent, chronic, or cumulative (overall) exposure, and each appears to have a different effect on type of melanoma. Other environmental factors, such as chemical exposures-either through occupation, atmosphere, or food-may increase risk for melanoma, and this area warrants further study. Host factors that are well known to be important are the numbers and types of nevi and the skin phenotype. Genetic factors are classified as high-penetrant genes, moderate-risk genes, or low-risk genetic polymorphisms. Subtypes of tumors, such as BRAF-mutated tumors, have different risk factors as well as different therapies. Prevention of melanoma has been attempted using various strategies in specific subpopulations, but to date optimal interventions to reduce incidence have not emerged.

The prevalence of anxiety and depression in patients with or without hyperhidrosis (HH).

BACKGROUND: There are conflicting data about the correlation between hyperhidrosis (HH) and anxiety and depression. OBJECTIVE: We sought to determine the prevalence of anxiety and depression in patients with or without HH. METHODS: We examined 2017 consecutive dermatology outpatients from Vancouver, British Columbia, Canada, and Shanghai, China, using Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7 scales for anxiety and depression assessments. Multivariable logistic regression analysis was performed to evaluate if the impact of HH on anxiety and depression is dependent on demographic factors and diagnoses of the patients' presenting skin conditions. RESULTS: The prevalence of anxiety and depression was 21.3% and 27.2% in patients with HH, respectively, and 7.5% and 9.7% in patients without HH, respectively (P value <.001 for both). There were positive correlations between HH severity and the prevalence of anxiety and depression. Multivariable analysis showed that HH-associated increase in anxiety and depression prevalence is independent of demographic factors and presenting skin conditions. LIMITATION: The data from the questionnaires relied on the accuracy of patients' self-reports. CONCLUSION: Both single variant and multivariable analyses showed a significant association between HH and the prevalence of anxiety and depression in a HH severity-dependent manner.

Neuraminidase inhibitors for the treatment of influenza infection in people with cystic fibrosis.

BACKGROUND: Cystic fibrosis is the most common, life-threatening, recessively inherited disease of Caucasian populations. It is a multisystem disorder caused by a mutation in the gene encoding the cystic fibrosis transmembrane conductance regulator protein which is important in producing sweat, digestive juices and mucus.The impaired or absent function of this protein results in the production of viscous mucus within the lungs and an environment that is susceptible to chronic airway obstruction and pulmonary colonization by a range of pathogenic bacteria. Morbidity and mortality of cystic fibrosis is related to chronic pulmonary sepsis and its complications by these bacteria.Influenza can worsen the course of the disease in cystic fibrosis by increasing the risk of pneumonia and secondary respiratory complications. Antiviral agents form an important part of influenza management and include the neuraminidase inhibitors zanamivir and oseltamivir. These inhibitors can limit the infection and prevent the spread of the virus. OBJECTIVES: To assess the effects of neuraminidase inhibitors for the treatment of influenza infection in people with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Most recent search: 02 November 2015. SELECTION CRITERIA: Randomised controlled trials and quasi-randomised controlled trials comparing neuraminidase inhibitors with placebo or other antiviral drugs. DATA COLLECTION AND ANALYSIS: Two review authors had planned to independently screen studies, extract data and assess risk of bias using standard Cochrane methodologies. No studies were identified for inclusion. MAIN RESULTS: No relevant studies were retrieved after a comprehensive search of the literature. AUTHORS' CONCLUSIONS: We were unable to identify any randomised controlled studies or quasi-randomised controlled studies on the efficacy of neuraminidase inhibitors for the treatment of influenza infection in people with cystic fibrosis. The absence of high level evidence for the effectiveness of these interventions emphasises the need for well-designed, adequately powered, randomised controlled clinical studies.

Topical cystic fibrosis transmembrane conductance regulator gene replacement for cystic fibrosis-related lung disease.

BACKGROUND: Cystic fibrosis is caused by a defective gene encoding a protein called the cystic fibrosis transmembrane conductance regulator (CFTR), and is characterised by chronic lung infection resulting in inflammation and progressive lung damage that results in a reduced life expectancy. OBJECTIVES: To determine whether topical CFTR gene replacement therapy to the lungs in people with cystic fibrosis is associated with improvements in clinical outcomes, and to assess any adverse effects. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings.Date of most recent search: 05 May 2016.An additional search of the National Institutes for Health (NIH) Genetic Modification Clinical Research Information System (GeMCRIS) was also performed for the years 1992 to 2015.Date of most recent search: 20 April 2016. SELECTION CRITERIA: Randomised controlled studies comparing topical CFTR gene delivery to the lung, using either viral or non-viral delivery systems, with placebo or an alternative delivery system in people with confirmed cystic fibrosis. DATA COLLECTION AND ANALYSIS: The authors independently extracted data and assessed study quality. Authors of included studies were contacted and asked for any available additional data. Meta-analysis was limited due to differing study designs. MAIN RESULTS: Four randomised controlled studies met the inclusion criteria for this review, involving a total of 302 participants lasting from 29 days to 13 months; 14 studies were excluded. The included studies differed in terms of CFTR gene replacement agent and study design, which limited the meta-analysis. One study only enrolled adult males, the remaining studies included both males and females aged 12 years and over.Risk of bias in the studies was moderate. Random sequence generation and allocation concealment was only described in the more recent study; the remaining three studies were judged to have an unclear risk of bias. All four studies documented double-blinding to the intervention, but there is some uncertainty with regards to participant blinding in one study. Some outcome data were missing from all four studies.There were no differences in either the number of respiratory exacerbations or the number of participants with an exacerbation between replacement therapy or placebo groups at any time point. Meta-analysis of most respiratory function tests showed no difference between treatment and placebo groups, but the smallest study (n = 16) reported forced vital capacity (litres) increased more in the placebo group at up to 24 hours. A further study reported a significant improvement in forced expiratory volume at one second (litres) at 30 days after participants had received their first dose of favouring the gene therapy agent, but this finding was not confirmed when combined with at second study in the meta-analysis. The more recent study (n = 140) demonstrated a small improvement in forced vital capacity (per cent predicted) at two and three months and again at 11 and 12 months for participants receiving CFTR gene replacement therapy compared to those receiving placebo. The same study reported a significant difference in the relative change in forced expiratory volume at one second (per cent predicted) at two months, three months and 12 months.One small study reported significant concerns with "influenza-like" symptoms in participants treated with CFTR gene replacement therapy; this was not reported on repeated use of the same agent in a larger recent study.There was no other evidence of positive impact on outcomes, in particular improved quality of life or reduced treatment burden.Two studies measured ion transport in the lower airways; one (n = 16) demonstrated significant changes toward normal values in the participants who received gene transfer agents (P < 0.0001), mean difference 6.86 (95% confidence interval 3.77 to 9.95). The second study (n = 140) also reported significant changes toward normal values (P = 0.032); however, aggregate data were not available for analysis. In the most recent study, there was also evidence of increased salt transport in cells obtained by brushing the lower airway. These outcomes, whilst important, are not of direct clinical relevance. AUTHORS' CONCLUSIONS: One study of liposome-based CFTR gene transfer therapy demonstrated some improvements in respiratory function in people with CF, but this limited evidence of efficacy does not support this treatment as a routine therapy at present. There was no evidence of efficacy for viral-mediated gene delivery.Future studies need to investigate clinically important outcome measures.