Longitudinal profiling identifies co-occurring BRCA1/2 reversions, TP53BP1, RIF1 and PAXIP1 mutations in PARP inhibitor-resistant advanced breast cancer.

BACKGROUND: Resistance to therapies that target homologous recombination deficiency (HRD) in breast cancer limits their overall effectiveness. Multiple, preclinically validated, mechanisms of resistance have been proposed, but their existence and relative frequency in clinical disease are unclear, as is how to target resistance. PATIENTS AND METHODS: Longitudinal mutation and methylation profiling of circulating tumour (ct)DNA was carried out in 47 patients with metastatic BRCA1-, BRCA2- or PALB2-mutant breast cancer treated with HRD-targeted therapy who developed progressive disease-18 patients had primary resistance and 29 exhibited response followed by resistance. ctDNA isolated at multiple time points in the patient treatment course (before, on-treatment and at progression) was sequenced using a novel >750-gene intron/exon targeted sequencing panel. Where available, matched tumour biopsies were whole exome and RNA sequenced and also used to assess nuclear RAD51. RESULTS: BRCA1/2 reversion mutations were present in 60% of patients and were the most prevalent form of resistance. In 10 cases, reversions were detected in ctDNA before clinical progression. Two new reversion-based mechanisms were identified: (i) intragenic BRCA1/2 deletions with intronic breakpoints; and (ii) intragenic BRCA1/2 secondary mutations that formed novel splice acceptor sites, the latter being confirmed by in vitro minigene reporter assays. When seen before commencing subsequent treatment, reversions were associated with significantly shorter time to progression. Tumours with reversions retained HRD mutational signatures but had functional homologous recombination based on RAD51 status. Although less frequent than reversions, nonreversion mechanisms [loss-of-function (LoF) mutations in TP53BP1, RIF1 or PAXIP1] were evident in patients with acquired resistance and occasionally coexisted with reversions, challenging the notion that singular resistance mechanisms emerge in each patient. CONCLUSIONS: These observations map the prevalence of candidate drivers of resistance across time in a clinical setting, information with implications for clinical management and trial design in HRD breast cancers.

Obscure digestive bleeding.

A 50-year-old woman presented to the emergency department with several episodes of melena in the last week. The patient was not hemodynamically compromised and was conservatively managed. Urgent upper gastrointestinal endoscopy and colonoscopy showed no source of bleeding. Abdominal CT demonstrated three mural nodular lesions up to 2cm in the mid jejunum with hypervascular characteristics in arterial phase without active bleeding in venous phase. Angiography (Figure 1A) revealed three tumours with neo-angiogenesis and no active bleeding. Each lesion was stained with methylene blue and followed by embolization with coils. Exploratory laparotomy (Figure 1B) showed the three nodules marked by angiography. Intestinal resection of the affected segment was performed. Histopathological study proved the diagnosis of suspicion (Figure 2).

Postoperative complications and waiting time for surgical intervention after radiologically guided drainage of intra-abdominal abscess in patients with Crohn's disease.

BACKGROUND: In patients with active Crohn's disease (CD), treatment of intra-abdominal abscess usually comprises antibiotics and radiologically guided percutaneous drainage (PD) preceding surgery. The aim of this study was to investigate the risk of postoperative complications and identify the optimal time interval for surgical intervention after PD. METHODS: A multicentre, international, retrospective cohort study was carried out. Details of patients with diagnosis of CD who underwent ultrasonography- or CT-guided PD were retrieved from hospital records using international classification of disease (ICD-10) diagnosis code for CD combined with procedure code for PD. Clinical variables were retrieved and the following outcomes were measured: 30-day postoperative overall complications, intra-abdominal septic complications, unplanned intraoperative adverse events, surgical-site infections, sepsis and pathological postoperative ileus, in addition to abscess recurrence. Patients were categorized into three groups according to the length of the interval from PD to surgery (1-14 days, 15-30 days and more than 30 days) for comparison of outcomes. RESULTS: The cohort comprised 335 CD patients with PD followed by surgery. Median age was 33 (i.q.r. 24-44) years, 152 (45.4 per cent) were females, and median disease duration was 9 (i.q.r. 3.6-15) years. Overall, the 30-day postoperative complications rate was 32.2 per cent and the mortality rate was 1.5 per cent. After adjustment for co-variables, older age (odds ratio 1.03 (95 per cent c.i. 1.01 to 1.06), P < 0.012), residual abscess after PD (odds ratio 0.374 (95 per cent c.i. 0.19 to 0.74), P < 0.014), smoking (odds ratio 1.89 (95 per cent c.i. 1.01 to 3.53), P = 0.049) and low serum albumin concentration (odds ratio 0.921 (95 per cent c.i. 0.89 to 0.96), P < 0.001) were associated with higher rates of postoperative complications. A short waiting interval, less than 2 weeks after PD, was associated with a high incidence of abscess recurrence (odds ratio 0.59 (95 per cent c.i. 0.36 to 0.96), P = 0.042). CONCLUSION: Smoking, low serum albumin concentration and older age were significantly associated with postoperative complications. An interval of at least 2 weeks after successful PD correlated with reduced risk of abscess recurrence.

[Macrovipera lebetina obtusa Snake Venom as a Modulator of Antitumor Effect in S-180 Sarcoma Mouse Model].

Macrovipera lebetina obtusa (MLO) is a venomous snake endemic to Middle East. Here we describe the therapeutic potential of the MLO snake venom. In S-180 sarcoma-bearing mouse model, we showed that the MLO snake venom inhibits tumour growth by 50%. In human dermal microvascular endothelial cells (HMVEC-D), treatment with the MLO snake venom lead to an increase of expression levels of the vascular endothelial growth factor (VEGF), while the level of the expression of caspase 8 did not change. In HMVEC-D cells MLO snake venom induces necroptosis, rather than apoptosis. In the chick embryo chorioallantoic membrane (CAM) assay, exposure to MLO snake venom inhibited bFGF-induced angiogenesis by 22%. Taken together, these results indicate that the MLO snake venom has a potent cytotoxic activity. Regulated necroptic cell death pathway, which is engaged by MLO snake venom, may become a promising novel target for antitumor therapies.

Energetic trade-offs: Implications for selection between two bivalve prey species by a carnivorous muricid gastropod.

Active predators obtain energy and nutrients from prey through complex processes in which the energy gained must exceed the energy invested in finding and ingesting the prey. In addition, the amount of energy available will vary with the prey that are selected for consumption. The muricid gastropod Acanthina monodon inhabits rocky shores, where it routinely feeds on the mytilids Semimytilus algosus and Perumytilus purpuratus. In this study, S. algosus was highly preferred by the predator (over 90% were eaten) versus P. purpuratus (only 9% were eaten) when offered a mixed diet. The energetic cost of attacking one S. algosus individual was 91 J bivalve-1 while for P. purpuratus it was slightly higher: 95 J bivalve-1. Also, whereas A. monodon required on average 19 h to consume S. algosus, successful attacks on P. purpuratus required about 32% more time (25 h). In addition, a longer resting time was needed by the predator after preying on P. purpuratus before it initiated another attack. Moreover, the active metabolic costs associated with successfully attacking the prey increased 3.2 times over the basal metabolic costs when attacking S. algosus, but only by 2.5 times when attacking P. purpuratus. The calculations associated with preying on each species showed that the energetic gain per unit time likely accounts for the predator's preference for attacking S. algosus, even though predation on both species provided net energy gains for the predator. However, as S. algosus occurs seasonally at our study site, P. purpuratus would probably also be consumed due to its constant availability throughout the whole year.

Mediadores inflamatorios: su relación con el dolor crónico y problemas asociados. Revisión bibliográfica / Inflammatory mediators: its connection with chronic pain and associated problems. Review

Introducción: El dolor es una compleja interacción de sistemas, con un proceso que integra información sensorial, cognitiva y/o emocional proveniente de amenazas reales o potenciales. En el dolor crónico se ha observado una relación con otros síntomas somáticos y psicológicos como la depresión y la ansiedad, falta de sueño, fatiga y disminución de la capacidad cognitiva. Se ha demostrado que las citoquinas proinflamatorias y los síntomas asociados influyen en la probabilidad de padecer dolor crónico. El objetivo es analizar los niveles de los mediadores inflamatorios en patologías que cursan con dolor crónico y los trastornos relacionados para así comprender mejor el dolor de larga duración. Material y métodos: Para la realización de este trabajo se realizó una revisión de la literatura científica mediante una búsqueda sistematizada en enero de 2020 en las bases de datos Pubmed, CINHAL, Medline, Scopus y Web of Sciencie. Se aplicaron como criterios de inclusión: ser documentos publicados en los últimos 5 años y estar escritos en inglés o castellano. Como criterios de exclusión: estudios de revisión, artículos repetidos en otras bases o que trataran sobre otro tema. Resultados: 13 artículos fueron seleccionados tras aplicar los criterios de inclusión y exclusión. Todas las publicaciones son estudios observacionales. Se compararon los valores de citoquinas proinflamatorias en pacientes con dolor crónico, teniendo en cuenta el insomnio, la tolerancia al dolor, el catastrofismo, el género y el índice de masa corporal. Conclusión: El dolor crónico está condicionado por múltiples factores, por lo que se debe conocer la fisiopatología del mismo. De esta manera, la medición de la proteína C reactiva y de citoquinas proinflamatorias podría suponer un avance en la evaluación y seguimiento del paciente con dolor crónico.(AU)

Introduction: Pain is a complex interaction of systems, with a process that integrates sensory, cognitive and/or emotional information that comes from real or potential threats. It has been observed a connection in the chronic pain with other somatic and psychological symptoms, such as depression, anxiety, lack of sleep, fatigue and reduction of cognitive capacity. It has been demonstrated that proinflammatory cytokines and associated symptoms influence in the probability of suffering chronic pain. The objective is to analyze the levels of the inflammatory mediators in diseases with chronic pain and with related disorders, so that we can better understand long-term pain. Material and methods: To make this dissertation, a review of the scientific literature was carried out by a systematized search in the Pubmed, CINHAL, Medline, Scopus and Web of Science databases, in January 2020. The inclusion criteria were: to be documents written in English or Spanish and published in the last 5 years. The exclusion criteria were: review studies, and articles repeated in other databases or that addressed other topics. Results: 13 articles were selected after applying inclusion and exclusion criteria. All publications were observational studies. Proinflammatory cytokine values were compared in patients with chronic pain, taking into account insomnia, pain tolerance, catastrophism, gender and body mass index. Conclusion: Chronic pain is conditioned by multiple factors, so its physiopathology must be known. In this way, the measurement of the C-reactive protein and the proinflammatory cytokines could mean an advance in the evaluation and monitoring of the patient with chronic pain.(AU)

Genetics of facial telangiectasia in the Rotterdam Study: a genome-wide association study and candidate gene approach.

BACKGROUND: The severity of facial telangiectasia or red veins is associated with many lifestyle factors. However, the genetic predisposition remains unclear. OBJECTIVES: We performed a genome-wide association study (GWAS) on facial telangiectasia in the Rotterdam Study (RS) and tested for replication in two independent cohorts. Additionally, a candidate gene approach with known pigmentation genes was performed. METHODS: Facial telangiectasia were extracted from standardized facial photographs (collected from 2010-2013) of 2842 northwestern European participants (median age 66.9, 56.8% female) from the RS. Our GWAS top hits (P-value <10-6 ) were tested for replication in 460 elderly women of the SALIA cohort and in 576 additional men and women of the RS. Associations of top single nucleotide polymorphisms (SNPs) with expression quantitative trait loci (eQTL) in various tissues were reviewed (GTEx database) alongside phenotype associations in the UK biobank database. SNP-based associations between known pigmentation genes and facial telangiectasia were tested. Conditional analysis on skin colour was additionally performed. RESULTS: Our most significant GWAS signal was rs4417318 (P-value 5.38*10-7 ), an intergenic SNP on chromosome 12 mapping to the SLC16A7 gene. Other suggestive SNPs tagged genes ZNF211, ZSCAN4, ICOS and KCNN3; SNP eQTLs and phenotype associations tagged links to the vascular system. However, the top signals did not pass significance in the two replication cohorts. The pigmentation genes KIAA0930, SLCA45A2 and MC1R, were significantly associated with telangiectasia in a candidate gene approach but not independently of skin colour. CONCLUSION: In this GWAS on telangiectasia in a northwestern European population, no genome-wide significant SNPs were found, although suggestive signals indicate genes involved in the vascular system might be involved in telangiectasia. Significantly associated pigmentation genes underline the link between skin colour and telangiectasia.

Uso de sonda nasogástrica en pacientes sometidos a esofaguectomía: ¿Un gesto innecesario? / Nasogastric tube utilization after esophagectomy: an unnecessary gesture?

INTRODUCCIÓN: El empleo de una sonda descompresiva nasogástrica es aceptado como uno de los cuidados perioperatorios básicos tras una cirugía de resección esofágica. Sin embargo, con el desarrollo de los programas de rehabilitación multimodal en este campo y sin una evidencia clara que sustente su empleo, la indicación sistemática de dicha medida puede resultar controvertida. MATERIAL Y MÉTODOS: Estudio retrospectivo, descriptivo y comparativo de los casos intervenidos de esofaguectomía tipo Ivor-Lewis en nuestro centro desde enero de 2015 hasta diciembre de 2018 con colocación (Grupo S) o no de sonda (Grupo N) descompresiva en la plastia gástrica durante el postoperatorio. Se evaluaron variables epidemiológicas y diferencias entre los grupos en morbimortalidad postquirúrgica, estancia hospitalaria, inicio de la tolerancia oral y la necesidad de colocación de sonda nasogástrica. RESULTADOS: Un total de 43 pacientes fueron incluidos en este estudio con una mediana de edad de 61 años, siendo el 86% varones. El 46,5% eran hipertensos, el 25,5% presentaban enfermedad pulmonar y el 16,3% padecían diabetes mellitus. La mediana del tiempo de estancia hospitalaria fue de nueve días en el grupo S frente a 11,5 días del grupo N, sin diferencias en el inicio de la tolerancia oral. La tasa de dehiscencia anastomótica fue del 5% y del 0%, respectivamente. La mortalidad global fue del 2,3% en los primeros 90 días, sin diferencias entre los grupos y la necesidad de colocación de la sonda durante el postoperatorio se produjo únicamente en un paciente (4,3%) del grupo N. CONCLUSIONES: La no utilización de sonda nasogástrica durante el postoperatorio de una esofaguectomía tipo Ivor-Lewis es una medida segura y no está asociada a mayor número de complicaciones ni estancia hospitalaria, pudiendo mejorar la comodidad y la recuperación postoperatoria del paciente

INTRODUCTION: Nasogastric decompressive tube utilization has been accepted as one of the basic perioperative care measures after esophageal resection surgery. However, with the development of multimodal rehabilitation programs and without clear evidence to support their use, the systematic indication of this measure may be controversial. MATERIAL AND METHODS: Retrospective, descriptive and comparative study of patients who had undergone Ivor-Lewis esophagectomy in our center -from January 2015 to December 2018- with placement (Group S), or without placement (Group N) of a decompressive tube in gastroplasty during postoperative period. Epidemiological variables and differences between groups in post-surgical morbidity and mortality, hospital stay, onset of oral tolerance and the need for nasogastric tube placement were evaluated. RESULTS: A total of 43 patients were included in this study, with a median age of 61 years, being 86% male. 46.5% were hypertensive, 25.5% had lung disease and 16.3% had diabetes mellitus. The median length of hospital stay was 9 days in group S versus 11.5 days in group N, with no differences in the onset of oral tolerance. Anastomotic dehiscence rate was 5% and 0% respectively. The overall mortality was 2.3% in the first 90 days, without differences between the groups. Placement of nasogastric tube during postoperative period was required only in 1 patient (4.3%) of the group N. CONCLUSIONS: Non-use of nasogastric tube during postoperative period of an Ivor-Lewis esophagectomy is a safe measure, as it is not associated with a higher rate of complications or hospital stay. This fact may be able to improve patients' comfort and postoperative recovery

Nasogastric tube utilization after esophagectomy: an unnecessary gesture? / Uso de sonda nasogástrica en pacientes sometidos a esofaguectomía: ¿Un gesto innecesario?

INTRODUCTION: Nasogastric decompressive tube utilization has been accepted as one of the basic perioperative care measures after esophageal resection surgery. However, with the development of multimodal rehabilitation programs and without clear evidence to support their use, the systematic indication of this measure may be controversial. MATERIAL AND METHODS: Retrospective, descriptive and comparative study of patients who had undergone Ivor-Lewis esophagectomy in our center -from January 2015 to December 2018- with placement (Group S), or without placement (Group N) of a decompressive tube in gastroplasty during postoperative period. Epidemiological variables and differences between groups in post-surgical morbidity and mortality, hospital stay, onset of oral tolerance and the need for nasogastric tube placement were evaluated. RESULTS: A total of 43 patients were included in this study, with a median age of 61 years, being 86% male. 46.5% were hypertensive, 25.5% had lung disease and 16.3% had diabetes mellitus. The median length of hospital stay was 9 days in group S versus 11.5 days in group N, with no differences in the onset of oral tolerance. Anastomotic dehiscence rate was 5% and 0% respectively. The overall mortality was 2.3% in the first 90 days, without differences between the groups. Placement of nasogastric tube during postoperative period was required only in 1 patient (4.3%) of the group N. CONCLUSIONS: Non-use of nasogastric tube during postoperative period of an Ivor-Lewis esophagectomy is a safe measure, as it is not associated with a higher rate of complications or hospital stay. This fact may be able to improve patients' comfort and postoperative recovery.

Principal component analysis of seven skin-ageing features identifies three main types of skin ageing.

BACKGROUND: The underlying phenotypic correlations between wrinkles, pigmented spots (PS), telangiectasia and other related facial-ageing subphenotypes are not well understood. OBJECTIVES: To analyse the underlying phenotypic correlation structure between seven features for facial ageing: global wrinkling, perceived age (PA), Griffiths photodamage grading, PS, telangiectasia, actinic keratosis (AK) and keratinocyte cancer (KC). METHODS: This was a cross-sectional study. Facial photographs and a full-body skin examination were used. We used principal component analysis (PCA) to derive principal components (PCs) of common variation between the features. We performed multivariable linear regressions between age, sex, body mass index, smoking and ultraviolet radiation exposure and the PC scores derived from PCA. We also tested the association between the main PC scores and 140 single-nucleotide polymorphisms (SNPs) previously associated with skin-ageing phenotypes. RESULTS: We analysed data from 1790 individuals with complete data on seven features of skin ageing. Three main PCs explained 73% of the total variance of the ageing phenotypes: a hypertrophic/wrinkling component (PC1: global wrinkling, PA and Griffiths grading), an atrophic/skin colour component (PC2: PS and telangiectasia) and a cancerous component (PC3: AK and KC). The associations between lifestyle and host factors differed per PC. The strength of SNP associations also differed per component with the most SNP associations found with the atrophic component [e.g. the IRF4 SNP (rs12203592); P-value = 1·84 × 10-22 ]. CONCLUSIONS: Using a hypothesis-free approach, we identified three major underlying phenotypes associated with extrinsic ageing. Associations between determinants for skin ageing differed in magnitude and direction per component. What's already known about this topic? Facial ageing is a complex phenotype consisting of different features including wrinkles, pigmented changes, telangiectasia and cancerous-related growths; it is not clear how these phenotypes are related to each other and to other phenotypes. A few studies have described two main clinical phenotypes for photoageing, namely hypertrophic ageing and atrophic ageing, which have been based solely on the clinical assessment of photoageing characteristics. What does this study add? We are the first to use epidemiology data to identify three main components associated with photoageing, namely a hypertrophic component (global wrinkling; perceived age; Griffiths grading) and atrophic component (pigmented spots; telangiectasia) and a cancer component (actinic keratosis; keratinocyte cancer). Association analysis showed different effects and direction of environmental determinants and genetic associations with the three components, with the most significant gene variants associations found for the atrophic component.

Predicting keratinocyte carcinoma in patients with actinic keratosis: development and internal validation of a multivariable risk-prediction model.

BACKGROUND: Patients with actinic keratosis (AK) are at increased risk for developing keratinocyte carcinoma (KC) but predictive factors and their risk rates are unknown. OBJECTIVES: To develop and internally validate a prediction model to calculate the absolute risk of a first KC in patients with AK. METHODS: The risk-prediction model was based on the prospective population-based Rotterdam Study cohort. We hereto analysed the data of participants with at least one AK lesion at cohort baseline using a multivariable Cox proportional hazards model and included 13 a priori defined candidate predictor variables considering phenotypic, genetic and lifestyle risk factors. KCs were identified by linkage of the data with the Dutch Pathology Registry. RESULTS: Of the 1169 AK participants at baseline, 176 (15·1%) developed a KC after a median follow-up of 1·8 years. The final model with significant predictors was obtained after backward stepwise selection and comprised the presence of four to nine AKs [hazard ratio (HR) 1·68, 95% confidence interval (CI) 1·17-2·42], 10 or more AKs (HR 2·44, 95% CI 1·65-3·61), AK localization on the upper extremities (HR 0·75, 95% CI 0·52-1·08) or elsewhere except the head (HR 1·40, 95% CI 0·98-2·01) and coffee consumption (HR 0·92, 95% CI 0·84-1·01). Evaluation of the discriminative ability of the model showed a bootstrap validated concordance index (c-index) of 0·60. CONCLUSIONS: We showed that the risk of KC in patients with AK can be calculated with the use of four easily assessable predictor variables. Given the c-index, extension of the model with additional, currently unknown predictor variables is desirable. Linked Comment: Kim et al. Br J Dermatol 2020; 183:415-416.

Epidemiology and determinants of facial telangiectasia: a cross-sectional study.

BACKGROUND: Telangiectasia or red veins are one of the prominent features of facial skin ageing. To date, there are few studies investigating the determinants of telangiectasia. OBJECTIVES: We investigated lifestyle and physiological factors associated with facial telangiectasia in a large prospective Dutch cohort study. METHODS: Telangiectasia was quantified digitally from standardized facial photographs of 2842 North European participants (56.8% female, median age 66.9) from the Rotterdam Study, collected in 2010-2013. Effect estimates from multivariable linear regressions are presented as the percentage difference in the mean value of telangiectasia area per unit increase of a determinant (%Δ) with corresponding 95% CI. RESULTS: Significant determinants were older age [1.7%Δ per year (95% CI 1.4, 2.0)], female sex [18.3%Δ (95% CI 13.2, 23.6)], smoking [current versus never 38.4%Δ (95% CI 30.3, 47.0); former versus never 11.6%Δ (95% CI 6.6, 16.9)], a high susceptibility to sunburn [10.2%Δ (95% CI 5.4, 15.3)] and light skin colour [pale versus white-to-olive 31.4%Δ (95% CI 19.7, 44.1]; white vs. white-to-olive 9.2%Δ (95% CI 2.8, 16.0)]. CONCLUSIONS: In this large cohort study, we confirmed known and described new determinants of facial telangiectasia.

Tuning molecular dynamics by hydration and confinement: antiplasticizing effect of water in hydrated prilocaine nanoclusters.

In glass-forming substances, the addition of water tends to produce the effect of lowering the glass transition temperature, Tg. In a previous work by some of us (Ruiz et al., Sci. Rep., 2017, 7, 7470) we reported on a rare anti-plasticizing effect of water on the molecular dynamics of a simple molecular system, the pharmaceutically active prilocaine molecule, for which the addition of water leads to an increase of Tg. In the present work, we study pure and hydrated prilocaine confined in 0.5 nm and 1 nm pore size molecular sieves, and carry out a comparison with the bulk compounds in order to gain a better understanding of the microscopic mechanisms that result in this rare effect. We find that the Tg of the drug under nanometric confinement can be lower than the bulk value by as much as 17 K. Through the concurrent use of differential scanning calorimetry and broadband dielectric spectroscopy we are able to observe the antiplasticizing effect of water in prilocaine also under nanometric confinement, finding an increase of Tg of up to almost 6 K upon hydration. The extension of our analysis to nanoconfined systems provides a plausible explanation for the very uncommon antiplasticizing effect, based on the formation of water-prilocaine molecular complexes. Moreover, this study deepens the understanding of the behavior of drugs under confinement, which is of relevance not only from a fundamental point of view, but also for practical applications such as drug delivery.

Nasal and skin microbiomes are associated with disease severity in paediatric atopic dermatitis.

BACKGROUND: Alterations of the skin microbiome have been associated with atopic dermatitis (AD) and its severity. The nasal microbiome in relation to AD severity is less well studied. OBJECTIVES: We aimed to characterize the nasal and skin microbiomes in children with AD in relation to disease severity. In addition, we explored the differences and correlations between the nasal and skin communities. METHODS: We characterized the microbial composition of 90 nasal and 108 lesional skin samples cross-sectionally from patients with AD, using 16S-rRNA sequencing. In addition, a quantitative polymerase chain reaction was performed for Staphylococcus aureus and Staphylococcus epidermidis on the skin samples, and AD severity was estimated using the self-administered Eczema Area and Severity Index. RESULTS: We found an association between the microbial composition and AD severity in both the nose and skin samples (R2  = 2·6%; P = 0·017 and R2  = 7·0%; P = 0·004), strongly driven by staphylococci. However, other species also contributed, such as Moraxella in the nose. Skin lesions were positive for S. aureus in 50% of the children, and the presence and the load of S. aureus were not associated with AD severity. Although the nose and skin harbour distinct microbial communities (n = 48 paired samples; P < 0·001), we found that correlations exist between species in the nose and (other) species on the skin. CONCLUSIONS: Our results indicate that both the nasal and the skin microbiomes are associated with AD severity in children and that, next to staphylococci, other species contribute to this association.

Non-genetic and genetic predictors of a superficial first basal cell carcinoma.

BACKGROUND: Several observational studies have suggested differences in the risk factor profile between patients with superficial basal cell carcinomas (BCCs) and non-superficial BCCs. OBJECTIVE: To test the reproducibility of previous study findings and to find new genetic and non-genetic predictors for patients with a superficial first BCC. METHODS: A total of 14.628 participants of northwestern European descent aged 45 years or older from a prospective population-based cohort study (Rotterdam Study) were linked with the Dutch Pathology Registry (PALGA) of whom 1528 were identified as BCC patients. After exclusion, 948 eligible BCC patients remained for further non-genetic analyses and 1014 for genetic analyses. We included 11 phenotypic, environmental and tumour-specific characteristics, and 20 candidate single nucleotide polymorphisms (SNP) as potential predictors for patients with a superficial first BCC. We performed binary logistic multivariable regression analyses. RESULTS: We found that patients with a superficial first BCC were significantly younger, almost two times more often female and 12-18 times more likely to have their BCC on the trunk or extremities than patients with a non-superficial first BCC. One SNP (rs12203592), mapped to IRF4, looked promising (OR 1.83, 95% CI 1.13-2.97, P-value <0.05), but after adjustment for multiple testing, no significant differences in genetic make-up between superficial BCC and non-superficial BCC patients were found. CONCLUSION: We conclude that patients with a superficial BCC differ from non-superficial BCC patients with respect to environmental factors (tumour localization as a proxy for UVR exposure) and phenotypic characteristics (age and sex), but we found no difference in genotype. As superficial BCC patients develop their first BCCs at a younger age, they could be at higher lifetime risk for subsequent skin cancers and therefore be an important group for secondary prevention.

Reply to the 'Comment on "On the positional and orientational order of water and methanol around indole: a study on the microscopic origin of solubility" Phys. Chem. Chem. Phys., 2018, 20, DOI: '.

In his comment on a recent publication by us, G. Graziano claims that solubility differences of indole in methanol and water can be rationalized by the reversible work needed to create a cavity in the solvent of the size of the solute, in this case indole. This quantity, he argues, is closely related to the solvent accessible surface area, which is greater for methanol compared with water, thus making indole more soluble in the former solvent. G. Graziano asserts that it is this property which is responsible for the large difference between the solubilities of indole in methanol and water. Further, G. Graziano claims that the differences in excess entropies and in distance distribution functions of indole in methanol and water and in methanol and water as a cosolvent found in our original work (Henao, et al., Phys. Chem. Chem. Phys., 2016, 18, 23006) are too "small" to be able to account for the differences in solubility of the indole molecule. We show in this work that the differences found by us are not small, by displaying some selected distance distribution functions in an alternative way to that described in our original paper. In fact we conclude that the differences in these functions are quantitatively greater than those found by Graziano in his comment. Secondly, we show in this reply that although the increase of the solvent accessible surface area may rationalize the differences in the indole-methanol and indole-water binary systems, and thus the work required for cavity creation, it is insufficient to fully account for the increase of indole solubility in water by the addition of very small quantities of methanol in the ternary system indole-methanol-water. In other words, as stated in our original paper, methanol is actively changing the solvation shell and not just passively increasing the solvent accessible surface area around indole. As a result of these additional analyses, we conclude that our work on the solvation differences of indole in water and methanol successfully captures differences in the solvation shells of both solvents around indole in both binary and ternary systems. Finally, while we do agree that Graziano's calculations are able to capture the role of cavity creation to explain differences in solubility, we think that our results concerning the quantification of changes in molecular interaction should be added to the calculations suggested by him to lead to a full description of the solubility.

Prevalence and determinants of seborrhoeic dermatitis in a middle-aged and elderly population: the Rotterdam Study.

BACKGROUND: Seborrhoeic dermatitis is a chronic relapsing inflammatory skin disease with unclear pathophysiological mechanisms. OBJECTIVES: To establish which lifestyle and physiological determinants are associated with seborrhoeic dermatitis. METHODS: Seborrhoeic dermatitis was diagnosed by a trained physician during a full-body skin examination within the Rotterdam Study, a prospective population-based cohort study in middle-aged and elderly people. The current design is a comparative cross-sectional study embedded in the Rotterdam Study. Potential factors were identified from the literature and analysed in a multivariable logistic regression, including: age, sex, obesity, skin colour, stress, depression, education level, hypertension, climate, xerosis cutis, alcohol and tobacco use. RESULTS: Of the 5498 participants, 788 participants were diagnosed with seborrhoeic dermatitis (14·3%). We found associations between seborrhoeic dermatitis and male sex [adjusted odds ratio (OR) 2·09, 95% confidence interval (CI) 1·77-2·47], darker skin (adjusted OR 0·39, 95% CI 0·22-0·69), season (summer vs. winter: adjusted OR 0·63, 95% CI 0·48-0·82) and generalized xerosis cutis (adjusted OR 1·41, 95% CI 1·11-1·80). CONCLUSIONS: Seborrhoeic dermatitis is one of the most common inflammatory dermatoses in middle-aged and elderly individuals, especially during winter. Men, and people with a light and dry skin were most likely to have seborrhoeic dermatitis.

IgG response against Staphylococcus aureus is associated with severe atopic dermatitis in children.

BACKGROUND: An altered immune response against Staphylococcus aureus might contribute to inflammation and barrier damage in atopic dermatitis (AD). OBJECTIVES: To profile IgG antibodies against 55 S. aureus antigens in sera of children with mild-to-severe AD and to evaluate the association between IgG levels and disease severity. METHODS: In this cross-sectional study, we included children with AD from two interventional study cohorts, the Shared Medical Appointment (SMA) cohort (n = 131) and the older DAVOS cohort (n = 76). AD severity was assessed using the Self-Administered Eczema Area and Severity Index (SA-EASI) and levels of thymus and activation-regulated chemokine (TARC) in serum. IgG antibody levels against 55 S. aureus antigens were quantified simultaneously using a Luminex assay. Pair-wise correlations were calculated between the 55 IgG levels using the Spearman rank correlation test. Linear regression analysis was performed to test for associations between 55 IgG levels and SA-EASI and TARC, adjusting for age, sex and S. aureus colonization. RESULTS: In the SMA cohort, 16 antigens were associated with SA-EASI and 12 with TARC (10 overlapping antigens; P-values 0·001-0·044). The associated IgG antibodies targeted mainly secreted proteins with immunomodulatory functions. In the DAVOS study, IgG levels against only four and one S. aureus antigen(s) were associated with SA-EASI and TARC, respectively (no overlap). CONCLUSIONS: In young children, severity of AD is associated with an IgG response directed against S. aureus antigens with mainly immunomodulatory functions. These findings encourage further evaluation of the role of S. aureus in the pathogenesis of AD.

Incidence and relative survival of melanoma in children and adolescents in the Netherlands, 1989-2013.

BACKGROUND: Melanoma is rare in the first two decades of life. Trends in incidence differ across countries. OBJECTIVE: To describe incidence and relative survival of children and adolescents with melanoma in the Netherlands for children (0 through 11 years) and adolescents (12 through 19 years) separately. We hypothesized that adolescent melanoma increased in contrast to childhood melanoma, possibly due to a difference in cancer biology and sun exposure patterns. METHODS: Data on all patients of 0-19 years diagnosed between 1989 and 2013 with histologically confirmed cutaneous invasive melanoma were retrieved from the Netherlands Cancer Registry (NCR). Incidence trends were analysed with Joinpoint regression. Relative survival analysis was performed. RESULTS: Between 1989 and 2013, 80 children and 544 adolescents with melanoma were registered in the NCR. Median age at diagnosis was 17 years (IQR 15-18); the female-to-male ratio was 1.7 : 1 Statistically significant incidence trends were found in the older age group (12-19 years): an increasing incidence since 1991 [annual percentage change (APC) 3.2%, 95%CI 1.3-5.1] followed by a decrease from 2005 to 2013 (APC -4.9%, 95%CI -9.6-0.0). No incidence trends for childhood melanoma were observed (APC 0.3%, 95% CI -3.0-3.8). Relative survival at 1, 5 and 10 years was 98% (95% CI 97-99), 94% (95% CI 92-96) and 90% (95% CI 87-92), respectively. Survival was worse in males and higher Breslow thickness. CONCLUSIONS: Melanoma is very rare under the age of 12 with stable incidence rates. In comparison with childhood melanoma, melanomas in adolescents are more common with a decreasing trend in the past decade. Male sex and increasing Breslow thickness are associated with worse survival in paediatric melanoma patients.