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Metal-oxide semiconductors (MOS) are widely utilized for catalytic and photocatalytic applications in which the dynamics of charged carriers (e.g., electrons, holes) play important roles. Under operation conditions, photoinduced surface oxygen vacancies (PI-SOV) can greatly impact the dynamics of charge carriers. However, current knowledge regarding the effect of PI-SOV on the dynamics of hole migration in MOS films, such as titanium dioxide, is solely based upon volume-averaged measurements and/or vacuum conditions. This limits the basic understanding of hole-vacancy interactions, as they are not capable of revealing time-resolved variations during operation. Here, we measured the effect of PI-SOV on the dynamics of hole migration using time-resolved atomic force microscopy. Our findings demonstrate that the time constant associated with hole migration is strongly affected by PI-SOV, in a reversible manner. These results will nucleate an insightful understanding of the physics of hole dynamics and thus enable emerging technologies, facilitated by engineering hole-vacancy interactions.

Indirect calorimetry (IC)-guided nutrition might positively affect the clinical outcome of critically ill patients. In this systematic review and meta-analysis, our objective was to assess the benefit of isocaloric nutrition guided by IC, compared to hypocaloric nutrition, for critically ill patients admitted to the intensive care unit (ICU). We performed a systematic review of all randomized controlled trials published through January 2021, assessing the benefit of isocaloric nutrition guided by IC. The primary outcome was 28-day all-cause mortality. Secondary outcomes were ICU and 90-day all-cause mortality, rate of nosocomial infections, and adverse events. Four trials evaluating 1052 patients were included. Patients treated with isocaloric nutrition had a lower 28-day mortality rate (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.63–0.99, P = 0.04). No between-group difference was found in ICU and 90-day mortality (RR 0.92, 95% CI 0.68–1.23, P = 0.56 and RR 0.88, 95% CI 0.72–1.07; P = 0.2, respectively) and in the rate of nosocomial infections (RR 1.15, 95% CI 0.77–1.72, P = 0.51). A pooled analysis of studies that evaluated the benefit of isocaloric nutrition guided by IC, for critically ill patients in the ICU, has shown reduced 28-day mortality. However, there was no difference in 90-day mortality and nosocomial infection rate.

The use of high flow nasal cannula (HFNC) oxygen therapy is common in patients with respiratory distress to prevent intubation or ensure successful extubation. However, these critical patients also need medical nutritional support and practitioners are often reluctant to prescribe oral or enteral feeding, leading to a decrease in energy and protein intake. Vomiting and aspiration are the major concerns. A new technology detecting the presence and duration of gastro-esophageal reflux and preventing aspiration in real-time has been developed and our case shows how HFNC oxygen therapy exposes patients to significantly more reflux events as compared to mechanical ventilation. This is the first description of this technique observed in critical care.

Background: Treatment of advanced BRAF-mutant melanoma has changed dramatically in the past 3 years thanks to the approval of new immunotherapy and targeted therapy agents. Objectives: The goal of our survey was to investigate when immunotherapy and targeted therapy are used in the management of advanced melanoma patients and whether differences exist between the types of setting. Methods: Oncologists from academic centers, community-based centers, and private clinics were invited to participate in an online survey. Survey questions addressed the proportion of BRAF-mutant patients per treatment line, proportion of patients on targeted therapy and immunotherapy available in the United States, and reasons for prescribing each drug class. Results: A total of 101 physicians completed the survey, of which 47 worked in a private clinic, 33 in an academic center, and 21 in a community-based center. Academic center participants tended to see more severe patients ( P < .001) and had more patients in second-line treatment than participants from other setting types. In addition, academic center physicians had more patients in clinical trials ( P < .001), and they prescribed the ipilimumab and nivolumab combination more frequently. In terms of sequencing, all participants used targeted therapy for severe or rapidly progressing patients and immunotherapy for those who were less severe or slowly progressing. Conclusions: The findings illustrate the differences in treatment approach per type of setting, with patients in academic centers more likely to receive recently approved products or to be enrolled in clinical trials than those in community-based settings.

Metal oxide semiconductors (MOS) are extensively used for a wide range of industrial applications [1] – [3] , where defects states in MOS can strongly affect their overall performance, even at very low concentrations [4] , [5] . The functionality of MOS has been reported to be significantly altered through the addition of defects, whereby the materials can become more/less chemically active or the electronic properties are altered. Surface defects, in particular, are often one of the most reactive sites on the surface, greatly influencing MOS photocatalytic activity. Under UV irradiation conditions, interactions with photo- induced charge carriers can generate temporary oxygen vacancies, VO, defect states on the surface of MOS [6] , affecting the material properties during the defects’ lifetime.

The 300th Faraday discussion on hot electron processes in plasmonics and catalysis brought together a wide spectrum of delegates from across the globe. Scientists from across multiple disciplines, with a broad spectrum of experience and expertise, joined together in hope of identifying and answering the latest problems within the ever growing hot electron science community. In this paper we present a brief overview of the themes and topics presented at this meeting, highlighting the major findings of each presentation.

Even in ultralow quantities, oxygen vacancies (VO) drastically impact key properties of metal oxide semiconductors, such as charge transport, surface adsorption, and reactivity, playing central roles in functional materials performance. Current methods used to investigate VO often rely on specialized instrumentation under far from ideal reaction conditions. Hence, the influence of VO generated in situ during catalytic processes has yet to be probed. In this work, we assess in situ extrinsic surface VO formation and lifetime under photocatalytic conditions which we compare to photocatalytic performance. We show for the first time that lifetimes of in situ generated atomic VO play more significant roles in catalysis than their concentration, with strong correlations between longer-lived VO and higher photocatalytic activity. Our results indicate that enhanced photocatalytic efficiency correlates with goldilocks VO concentrations, where VO densities must be just right to encourage carrier transport while avoiding charge carrier trapping.

Indirect calorimetry (IC)-guided nutrition might positively affect the clinical outcome of critically ill patients. In this systematic review and meta-analysis, our objective was to assess the benefit of isocaloric nutrition guided by IC, compared to hypocaloric nutrition, for critically ill patients admitted to the intensive care unit (ICU). We performed a systematic review of all randomized controlled trials published through January 2021, assessing the benefit of isocaloric nutrition guided by IC. The primary outcome was 28-day all-cause mortality. Secondary outcomes were ICU and 90-day all-cause mortality, rate of nosocomial infections, and adverse events. Four trials evaluating 1052 patients were included. Patients treated with isocaloric nutrition had a lower 28-day mortality rate (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.63-0.99, P = 0.04). No between-group difference was found in ICU and 90-day mortality (RR 0.92, 95% CI 0.68-1.23, P = 0.56 and RR 0.88, 95% CI 0.72-1.07; P = 0.2, respectively) and in the rate of nosocomial infections (RR 1.15, 95% CI 0.77-1.72, P = 0.51). A pooled analysis of studies that evaluated the benefit of isocaloric nutrition guided by IC, for critically ill patients in the ICU, has shown reduced 28-day mortality. However, there was no difference in 90-day mortality and nosocomial infection rate.

INTRODUCTION Alternation in traditional vital signs can only be observed during advanced stages of hypovolemia and shortly before the hemodynamic collapse. However, even minimal blood loss induces a decrease in the cardiac preload which translates to a decrease in stroke volume, but these indices are not readily monitored. We aimed to determine whether minor hemodynamic alternations induced by controlled and standardized hypovolemia can be detected by a whole-body bio-impedance technology. METHODS This was a non-randomized controlled trial that enrolled healthy blood donors. Vital signs, as well as shock index and stroke volume (SV), were recorded using noninvasive cardiac system, a noninvasive whole-body impedance-based hemodynamic analysis system, during phlebotomy. RESULTS Sixty subjects were included in the study group and 20 in the control group. Blood loss of 450 mL resulted in a significant decrease in systolic blood pressure (5 mm Hg; 95% CI 3, 6) and SV (5.07 mL; 95% CI 3.21, 6.92), and increase in shock index (0.03 bpm/mm Hg; 95% CI 0.01, 0.05). Clinically detectable changes (≥10%) in blood pressure and shock index were detectable in 15% and 5%, respectively. SV decreased by more than 10% in 40% of blood donors. No significant changes occurred in the control group. CONCLUSION Continuous noninvasive monitoring of SV may be superior to conventional indices (e.g., heart rate, blood pressure, or shock index) for early identification of acute blood loss. As an operator-independent and point-of-care technology, the SV whole body bio-impedance measurement may assist in accurate monitoring of potentially bleeding patients and early identification of hemorrhage.

Purpose of review Instead of comparing iso versus low energy or high versus low protein intake, the proportions between nutrients and the effects of specific amino or fatty acids may yield promising benefits for the nutritional therapy of critically ill patients. Recent findings Larger proportion of carbohydrates than lipids is usual in most of the commercial products. However, patients suffering from sepsis and from acute kidney injury preferentially utilize lipids. Parenteral omega-3-fatty acids, in particular, may be beneficial. Protein source and amount are important factors to achieve the best absorption and an improved nitrogen balance. Hydrolyzed whey protein reaches the highest amino acid plasma level if administered in large doses (35% of the measured energy expenditure). Muscle mass preservation may be achievable with large protein intake. β-Hydroxy-β-methylbutyrate has been shown to improve muscle strength in a large meta-analysis. Summary The nutritional therapy should take into account the fact that lipids are more oxidized. Intravenous lipid emulsions containing olive and fish oil are preferred, improving morbidity significantly in a recent meta-analysis. Enteral protein should be selected carefully according to protein source, origin and amount. Hydrolyzed whey protein improves nitrogen balance. The ultimate goal is to preserve muscle mass and muscle function. β-Hydroxy-β-methylbutyrate may improve muscle strength.

Hybrid metal-semiconductor systems are promising substrates for field Raman analysis due to their ability to use both electromagnetic and chemical enhancement pathways for surface enhanced Raman spectroscopy (SERS). Photo-induced Raman spectroscopy (PIERS) has previously been shown to be a promising method utilizing an additional enhancement route through photo-inducing atomic surface oxygen vacancies in photocatalytic metal-oxide semiconductors. The photoinduced vacancies can form vibronic coupling resonances, known as charge transfers, with analyte molecules, enhancing the signal beyond conventional SERS enhancements. However, conventional UV sources most often used for excitation of the PIERS substrate are impractical in combination with portable Raman systems for field analysis. In this work we show how a small UVC LED, centered at 255 nm, can replicate the same results previously reported with the benefit of allowing greater in-situ real time measurements under constant UV exposure. The UV LED source can be controlled more easily and safely, making it a practical UV source for field PIERS analysis.

This paper examines aspects of violent, traumatic terrorist video propaganda produced by the Islamic State of Iraq and Syria (ISIS) within the theoretical confines of abjection and the use ...

Surface oxygen vacancy defects are some of the most reactive sites but are notoriously difficult to detect, often healing upon exposure to air. In article number https://doi.org/10.1002/advs.201901841, Ivan P. Parkin, Stefan A. Maier, and co‐workers show how photo‐induced enhanced Raman spectroscopy (PIERS) can be used to indirectly track vacancy formation and healing of photo‐induced vacancies under ambient conditions on metal oxide semiconductors.

Enhanced Raman relies heavily on finding ideal hot-spot regions which enable significant enhancement factors. In addition, the termed “chemical enhancement” aspect of SERS is often neglected due to its relatively low enhancement factors, in comparison to those of electromagnetic (EM) nature. Using a metal-semiconductor hybrid system, with the addition of induced surface oxygen vacancy defects, both EM and chemical enhancement pathways can be utilized on cheap reusable surfaces. Two metal-oxide semiconductor thin films, WO3 and TiO2, were used as a platform for investigating size dependent effects of Au nanoparticles (NPs) for SERS (surface enhanced Raman spectroscopy) and PIERS (photo-induced enhanced Raman spectroscopy – UV pre-irradiation for additional chemical enhancement) detection applications. A set concentration of spherical Au NPs (5, 50, 100 and 150 nm in diameter) was drop-cast on preirradiated metal-oxide substrates. Using 4-mercaptobenzoic acid (MBA) as a Raman reporter molecule, a significant dependence on the size of nanoparticle was found. The greatest surface coverage and ideal distribution of AuNPs was found for the 50 nm particles during SERS tests, resulting in a high probability of finding an ideal hot-spot region. However, more significantly a strong dependence on nanoparticle size was also found for PIERS measurements – completely independent of AuNP distribution and orientation affects – where 50 nm particles were also found to generate the largest PIERS enhancement. The position of the analyte molecule with respect to the metal-semiconductor interface and position of generated oxygen vacancies within the hot-spot regions was presented as an explanation for this result.

International audience; (600:[600]600) Sylwester Gawinkowski opened a general discussion of the paper by Jorge Salmon-Gamboa: Why you are using SiO 2 nanoparticles? Do they have any function or are they only the substrate to attach other active nano-particles to? You have shown that only gold nanoparticles attached to silica nanoparticles do not inuence the rate of reaction signicantly. You have also demonstrated that adding platinum decorations on the gold nanoparticles causes a strong increase in the reaction rate. The signicance of the gold nanoparticles would be more clearly shown with a simple experiment in which you have no gold nanoparticles but still have platinum decorations. Jorge Salmon-Gamboa replied: Silica nanoparticles were chosen as a nano-sized inert substrate for Au nanoparticles. This choice of substrate provides a larger surface area covered with the active Au-Pt nanoparticles, in contrast to the situation when the active particles are placed directly onto a at substrate. Aiming for applications, the SiO 2-Au-Pt nanoparticles can then in turn be attached onto a at surface, forming a solid device that can be submerged into water, avoiding the problem of water contamination by nanoparticles. The role of the Au nano-particles was investigated. Under illumination in the LSP spectral band (556-566 nm), SiO 2-Pt did not enhance the reaction rate. In contrast, under the same conditions, SiO 2-Au-Pt showed a considerably enhanced rate, proving that hot carriers were generated in Au (see Fig. 1 below). (601:[601]601) Yuri Diaz Fernandez continued the discussion: I have two questions: (1) Can you comment on the dispersity of the size distribution of metal and SiO 2 particles and how well controlled are these in your system?

New therapies for advanced melanoma have led to major advances, which, for the first time, showed improved survival for patients with this very challenging neoplasm. These new treatments are based on gene-targeted therapies or stimulation of immune responses. However, these treatments are not without challenges in terms of resistance and toxicity. Physicians should be aware of these side effects as prompt treatment may save lives. Melanoma genetics is also unravelling new genetic risk factors involving telomere genes as well as new gene pathways at the somatic level which may soon become therapeutic targets. It is also shedding new light onto the pathology of this tumour with links to neural diseases and longevity.

The rectal trumpet (RT) is a nasopharyngeal airway device that is inserted into the rectum for management of fecal incontinence. No published data exist on adverse events caused by the use of an RT. The purpose of this quality improvement project was to determine the rate of RT-associated hemorrhage among patients treated with an RT in our transplant intensive care unit (TICU). This quality improvement initiative and retrospective medical record review included all patients (N = 3933) cared for in a single specialty intensive care unit at a tertiary academic medical center between January 1, 2014, and May 31, 2016. We estimate that approximately 400 patients were treated with an RT. We found 3 possible and 9 probable cases of RT-associated hemorrhage, resulting in an estimated incident rate of 3% among RT-treated patients. All of these patients underwent invasive procedures for hemostasis. They received a mean of 4.9 units of packed red blood cell transfusions, and 9 experienced hypotension. Eight out of the 9 probable RT-associated hemorrhage patients experienced hemorrhage only after greater than 7 days of treatment with an RT. Following this initiative, RT use was banned in our TICU. The use of RTs can cause hemorrhage with clinically significant consequences.

Céline Audibert,1 Anna Perlaky,2 Mark Stuntz,2 Daniel Glass2 1Deerfield Institute, Epalinges, Switzerland; 2Deerfield Institute, New York, NY, USA Background: Advanced ovarian cancer patients have a poor prognosis, mainly because the disease is diagnosed at a late stage. A number of therapeutic approaches, such as neoadjuvant and maintenance therapies, have been developed to try to improve treatment outcome. In parallel, the targeted therapies bevacizumab and olaparib have recently been approved for ovarian cancer treatment. The goal of our survey was to provide a comprehensive, global depiction of advanced ovarian cancer treatments across different regions.Patients and methods: Oncologists from France, Italy, Germany, the UK, and the USA were invited to participate in an online survey. Participants were eligible if they personally managed at least 15 ovarian cancer patients. Quantitative questions addressed the proportion of patients in neoadjuvant, treatment, and maintenance settings; proportion of BRCA-positive patients; and the type of treatment prescribed per setting and per line of therapy, depending on the patient’s BRCA status.Results: A total of 138 respondents completed our survey in Europe and 132 in the USA. The proportions of patients in treatment, maintenance, and remission were identical across each country and line of treatment at 60%, 20%, and 20%, respectively. The proportion of BRCA-tested patients ranged from 45% in Italy to 73% in the USA, with 10% (UK)–21% (Italy) of tested patients having a positive status. Levels of bevacizumab and olaparib prescriptions differed based on the country, line of treatment, and setting, with a significant share of patients receiving both drugs outside of their approved indications for ovarian cancer treatment.Conclusion: This survey provides real-world data on how advanced ovarian cancer patients are currently treated: 1) BRCA testing was not performed systematically, which raises concerns regarding access to treatment and 2) absence of consensus regarding which chemotherapeutic regimens or targeted therapy to use in different stages of the disease. Keywords: advanced ovarian cancer, BRCA mutation, maintenance, treatment, targeted therapies&nbsp

Acute pulmonary embolism (PE) is usually a complication secondary to migration of a deep venous clot or thrombi to lungs, but other significant etiologies include air, amniotic fluid, fat, and bone marrow. Regardless of the underlying etiology, little progress has been made in finding an effective pharmacologic intervention for this serious complication. Among the wide spectrum of PE, massive PE is associated with considerable morbidity and mortality, primarily due to severely elevated pulmonary vascular resistance leading to right ventricular failure, hypoxemia, and cardiogenic shock. We currently have limited therapeutic options at our disposal. Inhaled nitric oxide (iNO) has been proposed as a potential therapeutic agent in cases of acute PE in which hemodynamic compromise secondary to increased pulmonary vascular resistance is present, based on iNO's selective dilation of the pulmonary vasculature and antiplatelet activity. A systematic search of studies using the PubMed database was undertaken in order to assess the available literature. Although there are currently no published randomized controlled trials on the subject, except a recently publish phase I trial involving eight patients, several case reports and case series describe and document the use of iNO in acute PE. The majority of published reports have documented improvements in oxygenation and hemodynamic variables, often within minutes of administration of iNO. These reports, when taken together, raise the possibility that iNO may be a potential therapeutic agent in acute PE. However, based on the current literature, it is not possible to conclude definitively whether iNO is safe and effective. These case reports underscore the need for randomized controlled trials to establish the safety and efficacy of iNO in the treatment of massive acute PE. The purpose of this article is to review the current literature in the use of iNO in the setting of PE given how acute PE causes acute onset of pulmonary hypertension.

In the International Visible Trait Genetics (VisiGen) Consortium, we investigated the genetics of human skin color by combining a series of genome-wide association studies (GWAS) in a total of 17,262 Europeans with functional follow-up of discovered loci. Our GWAS provide the first genome-wide significant evidence for chromosome 20q11.22 harboring the ASIP gene being explicitly associated with skin color in Europeans. In addition, genomic loci at 5p13.2 (SLC45A2), 6p25.3 (IRF4), 15q13.1 (HERC2/OCA2), and 16q24.3 (MC1R) were confirmed to be involved in skin coloration in Europeans. In follow-up gene expression and regulation studies of 22 genes in 20q11.22, we highlighted two novel genes EIF2S2 and GSS, serving as competing functional candidates in this region and providing future research lines. A genetically inferred skin color score obtained from the 9 top-associated SNPs from 9 genes in 940 worldwide samples (HGDP-CEPH) showed a clear gradual pattern in Western Eurasians similar to the distribution of physical skin color, suggesting the used 9 SNPs as suitable markers for DNA prediction of skin color in Europeans and neighboring populations, relevant in future forensic and anthropological investigations. Electronic supplementary material The online version of this article (doi:10.1007/s00439-015-1559-0) contains supplementary material, which is available to authorized users.

Lower vitamin D serum levels are linked to increasedmelanoma risk and poorer survival. Naevus counts areassociated with both melanoma risk and survival andto leucocyte telomere length. Vitamin D is also linkedto telomere biology with higher levels of vitamin D inindividuals with longer leucocyte telomere length despiteadjusting for age. Using the TwinsUK data, weexplored the association between naevus count, leucocytetelomere length and vitamin D serum levels.Increasing vitamin D levels were associated with increasingnaevus count: serum levels were 73.3 nmol/lin individuals with less than 50 naevi compared to78.8 nmol/l in individuals with more than 50 naevi(p= 0.002). In the final regression model, using naevuscount as a continuous variable, vitamin D remainedassociated with higher naevus counts despite adjustmentfor age, weight, height, season of samplingand twin relatedness (p=0.02). Further adjustmentfor leucocyte telomere length, decreased the magnitudeof the association but it remained significant soleucocyte telomere length is not the sole driver of thisassociation. Having large numbers of naevi is associatedwith higher vitamin D serum levels.

Background Management of melanoma during pregnancy can be extremely challenging. The reported incidence of melanoma in pregnancy ranges from 2.8 to 5.0 per 100 000 pregnancies. There are no guidelines for the management of melanoma during pregnancy. Methods The survey was designed to investigate the opinions of melanoma physicians on decision making in relation to pregnancy and melanoma. A clinical scenario-based survey on management of pregnancy in melanoma was distributed all over Europe via the membership of the EORTC and other European melanoma societies. Results A total of 290 questionnaires were returned with a larger participation from southern Europe. A large heterogeneity was found for the answers given in the different clinical scenarios with 50% of the answers showing discordance, especially regarding sentinel lymph node biopsy during pregnancy. Discordant answers were also found for the counselling of women about a potential delay in getting pregnant after a high-risk melanoma (35% for a 2 year wait minimum vs. 57% no waiting needed), while for thin melanomas, as expected, there was more concordance with 70% of the physicians recommending no delay. Fifteen per cent of physicians recommended an abortion in stage II melanoma during the third month of pregnancy. Twenty per cent of the responders advised against hormonal replacement therapy in melanoma patients. Conclusions The management of melanoma during pregnancy varies widely in Europe. At present, there is a lack of consensus in Europe, which may lead to very important decisions in women with melanoma, and guidelines are needed.

High nevus count is the strongest risk factor for melanoma, and although gene variants have been discovered for both traits, epigenetic variation is unexplored. We investigated 322 healthy human skin DNA methylomes associated with total body nevi count, incorporating genetic and transcriptomic variation. DNA methylation changes were identified at genes involved in melanocyte biology, such as RAF1 ( P = 1.2 × 10 −6 ) and CTC1 (region: P = 6.3 × 10 −4 ), and other genes including ARRDC1 ( P = 3.1 × 10 −7 ). A subset exhibited coordinated methylation and transcription changes within the same biopsy. The total analysis was also enriched for melanoma-associated DNA methylation variation ( P = 6.33 × 10 −6 ). In addition, we show that skin DNA methylation is associated in cis with known genome-wide association study single nucleotide polymorphisms for nevus count, at PLA2G6 ( P = 1.7 × 10 −49 ) and NID1 ( P = 6.4 × 10 −14 ), as well as melanoma risk, including in or near MC1R , MX2, and TERT / CLPTM1L ( P 1 × 10 −10 ) . Our analysis using a uniquely large dataset comprising healthy skin DNA methylomes identified known and additional regulatory loci and pathways in nevi and melanoma biology. This integrative study improves our understanding of predisposition to nevi and their potential contribution to melanoma pathogenesis.

Susan Polanco-Briceno,1 Daniel Glass,1 Cindy Plunkett2 1Deerfield Institute, New York, NY, USA; 2Department of Internal Medicine, Metabolism Endocrinology & Diabetes (MEND), University of Michigan, Ann Arbor, MI, USA Purpose: This study was designed to assess the awareness and utilization of resources to improve patients’ treatment experiences among endocrinologists who currently treat patients with acromegaly. Methods: A total of 4,280 US endocrinologists were randomly selected from the CMS National Plan and Provider Enumeration System and were invited by mail to participate in a 20-minute online survey. In order to qualify, respondents had to be the primary physician making treatment decisions for at least one patient for their acromegaly. Results: Results are based on responses from 126 physicians from primarily urban and suburban practices, with a median of five acromegaly patients. A total of 70% of patients are currently receiving drug therapy; among these, 91% are on octreotide (51%), lanreotide (29%), or pasireotide (11%), alone or in combination with another therapy. Nearly half of the respondents thought that the impact of patient adherence on therapy outcome for acromegaly was either not very (40%) or not at all (7%) significant. Respondents who believe patient adherence significantly impacts treatment outcome were significantly more likely to discuss automated adherence reminders (50% vs 26%; P=0.015), mobile administration programs (57% vs 35%; P=0.029), and symptom tracking (72% vs 42%; P=0.002). Overall, 44% of respondents routinely recommend education/emotional support programs, and 25% routinely recommend financial assistance programs. Respondents who believe patient adherence significantly impacts treatment outcome generally were more familiar with individual education and emotional support programs compared to those who do not, although they were not more likely to routinely refer patients to any of these resources. Conclusion: There are unmet needs with respect to increasing awareness among physicians of the importance of patient adherence to therapy, resources available to patients, and how collaboration among patients, nurses, and physicians can improve adherence and overall treatment experiences. Keywords: financial support programs, emotional support programs, referrals

Surface‐enhanced Raman spectroscopy (SERS) is a powerful analytical technique commonly used in the detection of traces of organic molecules. The mechanism of SERS is of a dual nature, with Raman scattering enhancements due to a combination of electromagnetic (EM) and chemical contributions. In conventional SERS, the EM component is largely responsible for the enhancement, with the chemical contribution playing a less significant role. An alternative technique, called photo‐induced enhanced Raman spectroscopy (PIERS) has been recently developed, using a photo‐activated semiconductor substrate to give additional chemical enhancement of Raman bands over traditional SERS. This enhancement is assigned to surface oxygen vacancies (V o) formed upon pre‐irradiation of the substrate. In this work, the exceptional chemical contribution in PIERS allows for the evaluation of atomic V o dynamics in metal oxide surfaces. This technique is applied to study the formation and healing rates of surface‐active V o in archetypical metal‐oxide semiconductors, namely, TiO2, WO3, and ZnO. Contrary to conventional analytical tools, PIERS provides intuitive and valuable information about surface stability of atomic defects at ambient pressure and under operando conditions, which has important implications in a wide range of applications including catalysis and energy storage materials., Oxygen vacancy defects play significant roles in altering the overall reactivity and functionality of metal oxides affecting both bulk and surface properties, even at very low concentrations. Surface vacancies have only previously been studied under far from operando conditions. Through photo‐induced enhanced Raman spectroscopy, a method to indirectly track the dynamics of photo‐induced surface oxygen vacancies is presented.

Epigenetic modifications such as DNA methylation play a key role in gene regulation and disease susceptibility. However, little is known about the genome-wide frequency, localization, and function of methylation variation and how it is regulated by genetic and environmental factors.We utilized the Multiple Tissue Human Expression Resource (MuTHER) and generated Illumina 450K adipose methylome data from 648 twins.We found that individual CpGs had low variance and that variability was suppressed in promoters.We noted that DNA methylation variation was highly heritable (2median = 0.34) and that shared environmental effects correlated with metabolic phenotype-associated CpGs. Analysis of methylation quantitative-trait loci (metQTL) revealed that 28% of CpGs were associated with nearby SNPs, and when overlapping them with adipose expression quantitative-trait loci (eQTL) from the same individuals, we found that 6% of the loci played a role in regulating both gene expression and DNA methylation. These associations were bidirectional, but there were pronounced negative associations for promoter CpGs. Integration of metQTL with adipose reference epigenomes and disease associations revealed significant enrichment of metQTL overlapping metabolic-trait or disease loci in enhancers (the strongesteffects were for high-density lipoprotein cholesterol and body mass index [BMI]). We followed up with the BMI SNP rs713586, a cg01884057 metQTL that overlaps an enhancer upstream of ADCY3, and used bisulphite sequencing to refine this region. Our results showed widespread population invariability yet sequence dependence on adipose DNA methylation but that incorporating maps of regulatory elements aid in linking CpG variation to gene regulation and disease risk in a tissue-dependent manner. © 2013 by The American Society of Human Genetics. All rights reserved.

Normal ageing is associated with diverse physiological changes in all organ systems but the rate and extent of these changes vary markedly among individuals. One aspect of ageing research focuses on the molecular profiling of the changes that occur with increasing age in humans. Such profiling has implications for disease prevention and treatment. New high-throughput 'omics' technologies (such as genomics, metabolomics, metagenomics and transcriptomics) are enabling detailed studies of these molecular changes and are thus revealing information about the biological pathways that change with age.

Summary The presence of a high nevus number is the strongest phenotypic predictor of melanoma risk. Here, we describe the results of a three-stage study directed at identifying risk variants for the high nevus phenotype. At the first stage, 263 melanoma cases from Barcelona were genotyped for 223 single-nucleotide polymorphisms (SNPs) in 39 candidate genes. Seven SNPs in the PAX3 gene were found to be significantly associated with nevus number under the additive model. Next, the associations for seven PAX3 variants were evaluated in 1217 melanoma cases and 475 controls from Leeds; and in 3054 healthy twins from TwinsUK. Associations with high nevus number were detected for rs6754024 (P values

Background.Sudden sensorineural hearing loss (SSHL) caused by opiate abuse or overuse has been well documented in the medical literature. Most documented case reports have involved either heroin or hydrocodone/acetaminophen. Recently, case reposts of methadone induced SSHL have been published.Case Report.We present the case of a 31-year-old man who developed SSHL after a methadone overdose induced stupor. He was subsequently restarted on methadone at his regular dose. On follow-up audiometry exams, he displayed persistent moderately severe sensorineural hearing loss bilaterally.Discussion.This case is notable because unlike all but one previously reported case, the patient—who was restated on methadone—did not make a complete recovery.Conclusion. Methadone overuse in rare cases causes SSHL.

available at http://www.ncbi.nlm.nih.gov/pubmed/26907743 Editorial Comment: This study examined the prevalence of Peyronie’s disease (PD) using a convenience sample of adult men participating in the Research Now general population panel. Respondents were categorized according to PD status (definitive, probable, no PD) and segmented by United States geographic region, and education and income levels. Of the 7,711 respondents 57 (0.7%) had definitive PD, while 850 (11.0%) had probable PD. It is believed that PD is under reported in the United States and may be related to patient age and geographic region. Allen D. Seftel, MD Suggested Reading Ziegelmann MJ, Viers BR, McAlvany KL et al: Restoration of penile function and patient satisfaction with intralesional collagenase clostridium histolyticum injection for Peyronie’s disease. J Urol 2016; 195: 1051. Nehra A, Alterowitz R, Culkin DJ et al: Peyronie’s disease: AUA guideline. J Urol 2015; 194: 745. Stewart CA, Yafi FA, Knoedler M et al: Intralesional injection of interferon-a2b improves penile curvature in men with Peyronie’s disease independent of plaque location. J Urol 2015; 194: 1704. Re: Outcomes of Surgical Management of Men with Peyronie’s Disease with Hourglass Deformity F. A. Yafi, G. Hatzichristodoulou, J. Wang, J. Anaissie, S. C. Sikka and W. J. Hellstrom Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana, and Department of Urology, Technical University of Munich, Munich, Germany Urology 2016; 91: 119e123. doi: 10.1016/j.urology.2016.01.032 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26876465available at http://www.ncbi.nlm.nih.gov/pubmed/26876465 Editorial Comment: The authors investigated the outcomes of 2 surgical interventions for Peyronie’s disease (PD) with hourglass deformity, ie partial excision and grafting (PEG, group 1) and inflatable penile prosthesis (IPP) implantation (group 2). A total of 50 patients with PD with hourglass deformity (26 with a history of PEG and 24 with IPP) were included in the study. All patients in both groups had significant (20% or greater) improvement in penile curvature, with mean changes of 68.1 degrees (12.7%) in the PEG group and 49.6 degrees (13.5%) in the IPP group (p

While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL), skin, and fat. The samples (156 LCL, 160 skin, 166 fat) were derived simultaneously from a subset of well-phenotyped healthy female twins of the MuTHER resource. We discover an abundance of cis-eQTLs in each tissue similar to previous estimates (858 or 4.7% of genes). In addition, we apply factor analysis (FA) to remove effects of latent variables, thus more than doubling the number of our discoveries (1,822 eQTL genes). The unique study design (Matched Co-Twin Analysis—MCTA) permits immediate replication of eQTLs using co-twins (93%–98%) and validation of the considerable gain in eQTL discovery after FA correction. We highlight the challenges of comparing eQTLs between tissues. After verifying previous significance threshold-based estimates of tissue-specificity, we show their limitations given their dependency on statistical power. We propose that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissue-specificity. Under this framework we demonstrate that 30% of eQTLs are shared among the three tissues studied, while another 29% appear exclusively tissue-specific. However, even among the shared eQTLs, a substantial proportion (10%–20%) have significant differences in the magnitude of fold change between genotypic classes across tissues. Our results underline the need to account for the complexity of eQTL tissue-specificity in an effort to assess consequences of such variants for complex traits., Author Summary Regulation of gene expression is a fundamental cellular process determining a large proportion of the phenotypic variance. Previous studies have identified genetic loci influencing gene expression levels (eQTLs), but the complexity of their tissue-specific properties has not yet been well-characterized. In this study, we perform cis-eQTL analysis in a unique matched co-twin design for three human tissues derived simultaneously from the same set of individuals. The study design allows validation of the substantial discoveries we make in each tissue. We explore in depth the tissue-dependent features of regulatory variants and estimate the proportions of shared and specific effects. We use continuous measures of eQTL sharing to circumvent the statistical power limitations of comparing direct overlap of eQTLs in multiple tissues. In this framework, we demonstrate that 30% of eQTLs are shared among tissues, while 29% are exclusively tissue-specific. Furthermore, we show that the fold change in expression between eQTL genotypic classes differs between tissues. Even among shared eQTLs, we report a substantial proportion (10%–20%) of significant tissue differences in magnitude of these effects. The complexities we highlight here are essential for understanding the impact of regulatory variants on complex traits.

Gene expression can provide biological mechanisms which underlie genetic associations with complex traits and diseases, but often the most relevant tissue for the trait is inaccessible and a proxy is the only alternative. Here, we investigate shared and tissue specific patterns of variability in expression in multiple tissues, to quantify the degree of sharing of causes (genetic or non-genetic) of variability in gene expression among tissues. Using gene expression in ~800 female twins from the TwinsUK cohort in skin, fat, whole blood and lymphoblastoid cell lines (LCLs), we identified 9166 significant cis-eQTLs in fat, 9551 in LCLs, 8731 in skin and 5313 in blood (1% FDR). We observed up to 80% of cis-eQTLs are shared in pairs of tissues. In addition, the cis genetic correlation between tissues is > 90% for 35% of the genes, indicating for these genes a largely tissue-shared component of cis regulation. However, variance components show that cis genetic signals explain only a small fraction of the variation in expression, with from 67–87% of the variance explained by environmental factors, and 53% of the genetic effects occurring in trans. We observe a trans genetic correlation of 0 for all genes except a few which show correlation between fat and skin expression. The environmental effects are also observed to be entirely tissue specific, despite related tissues largely sharing exposures. These results demonstrate that patterns of gene expression are largely tissue specific, strongly supporting the need to study higher order regulatory interactions in the appropriate tissue context with large samples sizes and diversity of environmental contexts.

Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10 -13) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10 -9), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10 -8). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis. © 2012 Nature America, Inc. All rights reserved.

Naevus count is the most predictable phenotypic risk factor for melanoma and is mainly influenced by genetic factors1,2,3. Melanoma disparities according to gender have been reported in many studies in term of body distribution, survival and to a lesser extent incidence1,2. It is well established that women are more likely to get melanoma on the lower limbs, whilst men are more prone to melanoma on the trunk. In this study, we explore the effects of gender on the distribution of naevi on the body in melanoma cases and controls from different latitudes and whether the odds ratios for melanoma associated with naevi at different body sites are affected by gender. Two case control studies are compared, one in the UK and the other in Australia using the same protocol for naevus counts and the same examiner1,2. This article is protected by copyright. All rights reserved.

Background Procedures that may optimize success in achieving live births from assisted reproductive technology (ART) continue to be examined. Not yet considered are the perspectives of fertility specialists regarding important developments in the fertility treatment field, current unmet needs, and anticipated future advances. In the current study, an 8-country survey of fertility specialists was conducted to provide a comprehensive, global depiction of fertility treatments across different regions. Methods Fertility specialists from France, Germany, Italy, Spain, the United Kingdom (UK), the United States (US), China, and Japan were invited to participate in an online survey. Participants were eligible if they personally managed ≥25 patients/month who were experiencing difficulty conceiving, and if they had performed ART fertility treatment with ≥1 patient in the previous month. Quantitative questions addressed the number of patients seen, main infertility causes, number of cycles performed, ART procedure type, and ART outcomes. Qualitative questions covered diagnostic trends, unmet needs, important advances, and expected future developments. Results The number of fertility specialists who completed the survey included 29 in France, 33 in Germany, 23 in Italy, 38 in Spain, 34 in the UK, 91 in the US, 50 in China, and 65 in Japan. Patient volume increased over the prior 2 years according to 67 % (242/363) of the fertility specialists. As expected, ART outcomes all declined with age in all countries. ART outcomes varied by country, with the highest implantation, pregnancy, and live birth rates reported by fertility specialists in the US and China and the lowest rates reported in France and Italy. The most frequently reported unmet needs in fertility treatment were financial coverage, improved implantation rate, and egg donation. Most frequently named future advancements expected to change the fertility treatment field included improved embryo selection through imaging and/or metabolomics, improved embryo implantation rate, and use of preimplantation genetic diagnosis. Conclusions This study, which follows a rigorous survey methodology, elucidates the current state of fertility specialists’ practices and perspectives on the global fertility treatment field, which highlights differences and similarities among countries. This research may inform further studies and procedural developments that might better improve and standardize ART.