Cholinergic signaling at the body wall neuromuscular junction distally inhibits feeding behavior in Caenorhabditis elegans.

Complex biological functions within organisms are frequently orchestrated by systemic communication between tissues. In the model organism Caenorhabditis elegans, the pharyngeal and body wall neuromuscular junctions are two discrete structures that control feeding and locomotion, respectively. Separate, the well-defined neuromuscular circuits control these distinct tissues. Nonetheless, the emergent behaviors, feeding and locomotion, are coordinated to guarantee the efficiency of food intake. Here, we show that pharmacological hyperactivation of cholinergic transmission at the body wall muscle reduces the rate of pumping behavior. This was evidenced by a systematic screening of the effect of the cholinesterase inhibitor aldicarb on the rate of pharyngeal pumping on food in mutant worms. The screening revealed that the key determinants of the inhibitory effect of aldicarb on pharyngeal pumping are located at the body wall neuromuscular junction. In fact, the selective stimulation of the body wall muscle receptors with the agonist levamisole inhibited pumping in a lev-1-dependent fashion. Interestingly, this response was independent of unc-38, an alpha subunit of the nicotinic receptor classically expressed with lev-1 at the body wall muscle. This implies an uncharacterized lev-1-containing receptor underpins this effect. Overall, our results reveal that body wall cholinergic transmission not only controls locomotion but simultaneously inhibits feeding behavior.

The utility of multiple genomic technologies for interpretation of modern next generation sequencing: A novel case of three FANCA gene variants resulting in autosomal recessive Fanconi anaemia.

Fanconi anaemia (FA) is a rare autosomal recessive condition resulting in changes in the FANC gene family. This report describes a case of Fanconi anaemia in a family with complex biallelic variants. The patient is a 32-year-old female diagnosed with FA on cascade testing during childhood with chromosome breakage studies. On examination she had a fixed deformity of the right thumb and the proximal interphalangeal joint was immobile. Her brother shared this radial abnormality and had FA, requiring a bone marrow transplant. She presented in adulthood seeking further BRCA advice and had next generation sequencing that showed three variants in the FANCA gene. One allele a known pathogenic change, the other had two sequence variants in tandem that have been reported as variants of uncertain significance. There is one other unrelated case of these two variants occurring together in cis, resulting in Fanconi anaemia. This case is an interesting example of three variants in the FANCA gene, one allele with a pathogenic deletion and the other with a single complex allele made up of two missense variants of uncertain significance, likely manifesting with FA. It highlights the utility of different genetic technologies in the interpretation of next generation sequencing.

An approach to recognising and identifying metabolic presentations in the paediatric Irish Traveller population.

The Irish Traveller population are an endogamous, traditionally nomadic, Irish population. Irish Travellers practice consanguinity in the majority of marriages, thus resulting in a higher rate of rare autosomal recessive conditions within the population due to homozygous variants. Herein, we outline the clinical phenotypes associated with metabolic conditions seen in this population presenting in the neonatal period, infancy and childhood. Although Irish Travellers are traditionally based in Ireland and the UK, there are populations also living in mainland Europe and the USA. While there is generally an understanding amongst Irish paediatricians of the recessive conditions seen with this population in Ireland, they may be less commonly encountered abroad. It is important to consider a non-genetic aetiology alongside any consideration for a metabolic disorder. CONCLUSION: This paper acts as a comprehensive review of the metabolic conditions seen and provides a guide for the investigation of an Irish Traveller child with a suspected metabolic condition. WHAT IS KNOWN: • The Irish Traveller population are an endogenous population. • There are higher rates of inherited metabolic conditions in this population compared to the general population in Ireland. WHAT IS NEW: • This paper is a comprehensive review of all known inherited metabolic conditions encountered in the Irish Traveller population.

Antimicrobial use and antimicrobial resistance monitoring in pig production in the United States of America.

Monitoring antimicrobial use (AMU) and antimicrobial resistance (AMR) on farms is recognised as an important component of antimicrobial stewardship, yet the process can be resource intensive. This paper describes a subset of findings from the first year of a collaboration across government, academia and a private sector veterinary practice focused on swine production in the Midwestern United States. The work is supported by participating farmers and the greater swine industry. Twice-annual collection of samples from pigs along with AMU monitoring occurred on 138 swine farms. Detection and resistance of Escherichia coli from pig tissues was assessed, and associations between AMU and AMR were evaluated. This paper describes the methods utilised and the first-year E. coli-related results from this project. Higher minimum inhibitory concentrations (MIC) for enrofloxacin and danofloxacin in E. coli from swine tissues were associated with the purchase of fluoroquinolones. There were no other significant associations between MIC and AMU combinations in E. coli isolated from pig tissues. This project represents one of the first attempts to monitor AMU as well as AMR in E. coli in a large-scale commercial swine system in the United States of America.

Alors même que la surveillance exercée sur l'utilisation des agents antimicrobiens (UAM) et sur la résistance aux agents antimicrobiens (RAM) dans les élevages est une composante majeure reconnue de la gestion des antimicrobiens, le processus en lui-même exige une mobilisation intensive de ressources. Les auteurs décrivent un sous-ensemble de résultats obtenus au cours de la première année d'une collaboration entre les pouvoirs publics, les universités et une clinique vétérinaire privée, axée sur la production porcine dans le Midwest des états-Unis d'Amérique. Ce travail est soutenu par les éleveurs participants et par le secteur porcin au sens large. Une collecte d'échantillons porcins a été effectuée deux fois par an, parallèlement à la surveillance de l'UAM dans 138 élevages. Il a été procédé à une recherche des Escherichia coli présents dans les tissus porcins prélevés puis à la détermination de la résistance aux antimicrobiens chez les microorganismes détectés ; les corrélations éventuelles entre l'UAM et la RAM ont ensuite été évaluées. Les auteurs décrivent les méthodes utilisées dans la cadre de ce projet ainsi que les résultats en lien avec les E. coli obtenus au cours de la première année. Une corrélation a été constatée entre l'augmentation des concentrations minimales inhibitrices (CMI) recueillies pour l'enrofloxacine et la danofloxacine vis-à-vis d'E. coli dans les tissus porcins analysés, d'une part, et l'achat de fluoroquinolones, d'autre part. Aucune autre corrélation significative n'a été décelée entre les CMI recueillies et les profils d'UAM concernant les E. coli isolés à partir des tissus porcins. Ce projet représente l'une des premières tentatives conduites aux états-Unis d'Amérique pour surveiller parallèlement l'UAM et la RAM chez les E. coli dans un système commercial de production porcine à grande échelle.

Aunque se tiene por sabido que la vigilancia en las explotaciones del uso de agentes antimicrobianos (UAM) y de la resistencia a los antimicrobianos (RAM) es un importante componente de la gestión de estos fármacos, no es menos cierto que el proceso puede consumir cuantiosos recursos. Los autores exponen un ubconjunto de observaciones realizadas durante el primer año de un proyecto de colaboración entre la administración pública, el mundo universitario y una clínica veterinaria privada que tenía por objeto de estudio la producción porcina en la zona del medio oeste de los Estados Unidos de América. Respaldaban el proyecto los productores que participaban en él y el sector de la industria porcina en general. Dos veces al año se obtuvieron muestras en 138 explotaciones porcinas, en las que también se seguía de cerca el UAM. Tras realizar pruebas de detección de Escherichia coli en tejidos porcinos y analizar la resistencia de esos microorganismos a antimicrobianos, se buscaron correlaciones entre el uso de estos fármacos y la presencia de eventuales resistencias. Los autores describen los métodos empleados y los resultados obtenidos el primer año del proyecto en relación con E. coli. Se observó una correlación entre la compra de fluoroquinolonas y el aumento de la concentración inhibitoria mínima (MIC) de enrofloxacina y de danofloxacina en los E. coli analizados. No se constató ninguna otra asociación significativa entre las MIC y el uso de diferentes antimicrobianos en los E. coli aislados a partir de tejido porcino. Este proyecto constituye una de las primeras tentativas de hacer seguimiento y balance del uso de agentes antimicrobianos y de la resistencia de E. coli a estos fármacos en el sistema de producción porcina industrial de los Estados Unidos de América.

Stabilized Radiation Pressure Acceleration and Neutron Generation in Ultrathin Deuterated Foils.

Premature relativistic transparency of ultrathin, laser-irradiated targets is recognized as an obstacle to achieving a stable radiation pressure acceleration in the "light sail" (LS) mode. Experimental data, corroborated by 2D PIC simulations, show that a few-nm thick overcoat surface layer of high Z material significantly improves ion bunching at high energies during the acceleration. This is diagnosed by simultaneous ion and neutron spectroscopy following irradiation of deuterated plastic targets. In particular, copious and directional neutron production (significantly larger than for other in-target schemes) arises, under optimal parameters, as a signature of plasma layer integrity during the acceleration.

Diet quality is associated with primary melanoma thickness.

BACKGROUND: Patients' diets can influence the outcome of several common cancers, but the effect on melanoma prognosis is unknown. OBJECTIVE: To assess the association between quality of melanoma patients' prediagnosis diets and primary tumour thickness, the main prognostic indicator for melanoma. METHODS: We used baseline data from patients newly diagnosed with tumour stage Ib to IV cutaneous melanoma, with completed questionnaires about food intake in the past year and other factors. Diet quality was measured by the Healthy Eating Index (HEI) and melanoma thickness was extracted from histopathology reports. We estimated prevalence ratios (PRadj ) and 95% confidence intervals (CIs) adjusted for confounding factors using Poisson regression models to assess associations between HEI scores and melanoma thickness. RESULTS: Of 634 study patients, 238 (38%) had melanomas >2 mm thick at diagnosis. Patients with the highest HEI scores were significantly less likely to be diagnosed with thick melanoma than patients with lowest HEI scores (PRadj 0.93, 95% CI 0.86-0.99) (Ptrend = 0.03). There was no evidence of effect modification by age, sex, previous melanoma or comorbidities. CONCLUSIONS: Melanoma thickness at diagnosis is significantly associated with quality of patients' diets before diagnosis.

Polygenic risk score as a determinant of risk of keratinocyte cancer in an Australian population-based cohort.

BACKGROUND: Keratinocyte cancer (KC) risk is determined by genetic and environmental factors. Genetic risk can be quantified by polygenic risk scores (PRS), which sum the combined effects of single nucleotide polymorphisms (SNPs). OBJECTIVES: Our objective here was to evaluate the contribution of the summed genetic score to predict the KC risk in the phenotypically well-characterized Nambour population. METHODS: We used PLINK v1.90 to calculate PRS for 432 cases, 566 controls, using 78 genome-wide independent SNPs that are associated with KC risk. We assessed the association between PRS and KC using logistic regression, stratifying the cohort into three risk groups (high 20%, intermediate 60%, low 20%). RESULTS: The fully adjusted model including traditional risk factors (phenotypic and sun exposure-related), showed a significant 50% increase in odds of KC per standard deviation of PRS (odds ratio (OR) = 1.51; 95% confidence interval (CI) = 1.30-1.76, P = 5.75 × 10-8 ). Those in the top 20% PRS had over three times the risk of KC of those in the lowest 20% (OR = 3.45; 95% CI = 2.18-5.50, P = 1.5 × 10-7 ) and higher absolute risk of KC per 100 person-years of 2.96 compared with 1.34. Area under the ROC curve increased from 0.72 to 0.74 on adding PRS to the fully adjusted model. CONCLUSIONS: These results show that PRS can enhance the prediction of KC above traditional risk factors.

Patterns of biomarker expression in patients treated with primary endocrine therapy - a unique insight using core needle biopsy tissue microarray.

PURPOSE: Prediction of response to primary endocrine therapy (PET) in older women is based on measurement of oestrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor (HER)-2. This study uses a unique method for construction of core needle biopsy (CNB) tissue microarray (TMA), to correlate expression of a panel of 17 biomarkers with clinical outcome, in patients receiving PET. METHODS: Over 37 years (1973-2010), 1758 older (≥ 70 years) women with operable primary breast cancer were managed in a single institution. Of these, 693 had sufficient good-quality CNB to construct TMA, of which 334 had ER-positive tumours treated by PET with a minimum of 6-month follow-up. A panel of biomarkers was measured by immunohistochemistry (ER, PgR, HER2, Ki-67, p53, CK5/6, CK 7/8, EGFR, BCL-2, MUC1, VEGF, LKB1, BRCA1, HER3, HER4, PTEN and AIB1). Expression of each biomarker was dichotomised into 'low' or 'high' based on breast cancer-specific survival (BCSS). RESULTS: From the panel of biomarkers, multivariate analysis showed: High ER (p = 0.003) and PgR (p = 0.002) were associated with clinical benefit of PET at 6 months, as opposed to progressive disease. High ER (p = 0.0023), PgR (p < 0.001) and BCL-2 (p = 0.043) and low LKB1 (p = 0.022) were associated with longer time to progression. High PgR (p < 0.001) and low MUC1 (p = 0.021) were associated with better BCSS. Expression of other biomarkers did not show any significant correlation. CONCLUSIONS: In addition to ER and PgR; MUC1, BCL-2 and LKB1 are important in determining the outcome of PET in this cohort.

Global evidence on occupational sun exposure and keratinocyte cancers: a systematic review.

Individual studies have suggested that the association between occupational exposure to solar ultraviolet radiation (UVR) and the development of keratinocyte cancers (KCs) may only be valid in populations of European ancestry living in certain geographical regions. Comparative global data are scarce and so this review aimed to summarize current evidence on the association between occupational exposure to solar UVR and the development of KCs, with a specific focus on geographical location and skin colour. Ovid MEDLINE, PubMed, Embase and Web of Science were searched for potentially relevant records. Extracted data were summarized by study, country and region. We included one prospective cohort study and 18 case-control studies (n = 15 233) from 12 countries in regions where the majority of the population is white skinned (Americas, Europe and Oceania). Eighteen of the 19 studies reported effect estimates suggesting an increased risk of basal cell carcinoma (BCC) and/or squamous cell carcinoma (SCC) among outdoor workers. Only 11 studies found a significantly increased risk and many had imprecise estimates. There was a significantly increased risk of BCC and SCC in individual studies in North America, Latin America and the Caribbean, Western Europe and Southern Europe, but not across regions or countries. Overall, 95% of studies reported higher risks among outdoor workers, although the increases in risk were statistically significant in just over half of the studies. Well-designed and sufficiently powered occupational case-control and cohort studies with adequate adjustment for confounding factors and other risk factors are required to provide more accurate risk estimates for occupational KC.

Development of a core outcome set for cutaneous squamous cell carcinoma trials: identification of core domains and outcomes.

BACKGROUND: The lack of uniformity in the outcomes reported in clinical studies of the treatment of cutaneous squamous cell carcinoma (cSCC) complicates efforts to compare treatment effectiveness across trials. OBJECTIVES: To develop a core outcome set (COS), a minimum set of agreed-upon outcomes to be measured in all clinical trials of a given disease or outcome, for the treatment of cSCC. METHODS: One hundred and nine outcomes were identified via a systematic literature review and interviews with 28 stakeholders. After consolidation of this long list, 55 candidate outcomes were rated by 19 physician and 10 patient stakeholders, in two rounds of Delphi exercises. Outcomes scored 'critically important' (score of 7, 8 or 9) by ≥ 70% of patients and ≥ 70% of physicians were provisionally included. At the consensus meeting, after discussion and voting of 44 international experts and patients, the provisional list was reduced to a final core set, for which consensus was achieved among all meeting participants. RESULTS: A core set of seven outcomes was finalized at the consensus meeting: (i) serious or persistent adverse events, (ii) patient-reported quality of life, (iii) complete response, (iv) partial response, (v) recurrence-free survival, (vi) progression-free survival and (vii) disease-specific survival. CONCLUSIONS: In order to increase the comparability of results across trials and to reduce selective reporting bias, cSCC researchers should consider reporting these core outcomes. Further work needs to be performed to identify the measures that should be reported for each of these outcomes.

Efficacy of galcanezumab in patients with migraine who did not benefit from commonly prescribed preventive treatments.

BACKGROUND: Galcanezumab is a calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) indicated for the preventive treatment of migraine. While galcanezumab has demonstrated efficacy in patients who did not respond to prior preventive medications in general, its efficacy in patients who did not benefit from individual, commonly prescribed preventive treatments due to inadequate efficacy or safety/tolerability remains unknown. METHODS: CONQUER was a 3-month, randomized, double-blind, placebo-controlled, phase 3b study that enrolled patients with episodic or chronic migraine who had 2 to 4 migraine preventive medication category failures in the past 10 years. Patients were randomly assigned 1:1 to receive placebo (N = 230) or galcanezumab 120 mg/month (240 mg loading dose; N = 232). Post hoc analyses were conducted to determine the efficacy of galcanezumab in patients who had not benefited from six of the most commonly prescribed migraine preventive medications. The mean change from baseline in monthly migraine headache days and ≥ 50 % response rates were assessed over months 1-3. Improvement in Migraine-Specific Questionnaire Role Function-Restrictive (MSQ-RFR) scores were assessed at month 3. The endpoints were estimated via mixed model with repeated measures. RESULTS: The most common treatment failures due to inadequate efficacy or safety/tolerability, which at least 20 % of patients reported trying without benefit, included topiramate, amitriptyline, propranolol, valproate or divalproex, onabotulinum toxin A, and metoprolol. Patients who had not previously benefited from these treatments had a greater mean reduction in monthly migraine headache days across months 1-3 in the galcanezumab group compared to placebo (all p < 0.01). More patients treated with galcanezumab experienced a ≥ 50 % reduction from baseline in monthly migraine headache days across months 1-3 compared to placebo (all p < 0.05). Galcanezumab-treated patients had a greater improvement in mean MSQ-RFR scores at month 3 compared to placebo (all p < 0.01). CONCLUSIONS: In this population, galcanezumab was effective in reducing monthly migraine headache days, improving response rates, and enhancing quality of life in patients who had not previously benefited from topiramate, amitriptyline, propranolol, valproate or divalproex, onabotulinum toxin A, and/or metoprolol due to inadequate efficacy or safety/tolerability. TRIAL REGISTRATION: ClinicalTrials.gov NCT03559257 (CONQUER).

Headache in Susac's Syndrome.

PURPOSE OF REVIEW: Provide an overview of the current diagnosis, pathophysiology, and treatment of Susac's syndrome (SuS), with special emphasis on summarizing what is currently known about headache as a symptom of disease activity. RECENT FINDINGS: The most recent literature in SuS has focused on furthering the understanding of the underlying pathology and efficacy of treatments for SuS. The importance of early recognition to facilitate timely treatment and avoid long-term disability has been highlighted. Headache, the most common symptom experienced by patients with SuS, can occur up to 6 months in advance of other symptoms, and exacerbations of headache can herald increased disease activity. Susac's syndrome (SuS) is a rare disorder classically characterized by triad of encephalopathy, branch retinal artery occlusion (BRAO), and sensory neuronal hearing loss (SNHL). The full triad is uncommon at initial presentation, which can confound efforts to make timely diagnosis and treatment decisions. Headache is the most common symptom in SuS, is often an early feature, and can help separate SuS from other diagnoses in the differential. However, the features and management of the headache associated with SuS have not been systematically defined in the literature.

High variability in anatomic patterns of cutaneous photodamage: a population-based study.

BACKGROUND: Skin cancer is strongly associated with photodamaged skin, but body sites are often referred to as 'exposed' or 'unexposed' to sun without recognizing extent of site-specific variation. OBJECTIVES: To assess whole-body patterns of photodamage in an Australian population. METHODS: A random sample of adult residents of Queensland underwent imaging across 10 body sites. Photodamage was graded from images using an ordinal photonumeric scale. We used cluster analysis to identify whole-body photodamage patterns and prevalence proportion ratios (PPRs) to assess associated factors. RESULTS: Of 190 adults (median age 52; 58% males), 58% showed severe or moderate-to-severe photodamage on most body sites. A higher proportion of woman had severe photodamage on the arms (upper: P = 0.002, lower: P = 0.034). A higher proportion of men had moderate or severe photodamage on the lower back (P = 0.004). We identified four photodamage patterns: 'severe general' (n = 24, 13%), 'moderate-severe general' (n = 86, 45%), 'moderate-severe v-neck' (n = 40, 21%) and 'mild-moderate upper body' (n = 12, 6%). All participants with 'severe-general' photodamage were >50 years and more likely to have past skin cancer (PPR: 2.54, 95% CI: 1.44-4.49) than those with 'moderate-severe v-neck' photodamage. Those with 'moderate-severe general' photodamage showed similar associations and were more likely female (PPR: 1.33, 95% CI: 1.04-1.69). Past or current smoking was associated with having higher levels of photodamage, with no smokers in those with 'mild-moderate upper body' photodamage. CONCLUSIONS: Moderate-to-severe photodamage across much of the body is common in Queensland adults and associated with age, sex, past skin cancer and smoking. Assuming a universal pattern of site-specific sun exposure could lead to spurious correlations, while accurate and objective assessment of site-specific photodamage can add to understanding of the development of sun-associated skin cancers, in particular site-specific skin carcinogenesis. Additionally, degree of site-specific photodamage has the potential to assist skin cancer screening.

Clinical utility of skin cancer and melanoma risk scores for population screening: TRoPICS study.

BACKGROUND: Screening for skin cancer can be cost-effective if focused on high-risk groups. Risk prediction tools have been developed for keratinocyte cancers and melanoma to optimize advice and management. However, few have been validated in a clinical setting over the past few years. OBJECTIVES: To assess the clinical utility of risk assessment tools to identify individuals with prevalent skin cancers in a volunteer-based screening clinic. METHODS: Participants were adults presenting for a skin check at a volunteer-based skin cancer screening facility. We used previously published tools, based on questionnaire responses, to predict melanoma and keratinocyte cancers [KCs; basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] and classified each participant into one of five risk categories. Participants subsequently underwent a full skin examination by a dermatologist. All suspicious lesions were biopsied, and all cancers were histopathologically confirmed. RESULTS: Of 789 people who presented to the clinic, 507 (64%) consented to the study. Twenty-two BCCs, 19 SCCs and eight melanomas were diagnosed. The proportion of keratinocyte cancers diagnosed increased according to risk category from <1% in the lowest to 24% in the highest risk category (P < 0.001). Subtype analysis revealed similar proportionate increases in BCC or SCC prevalence according to risk category. However, a similar proportion of melanoma cases were detected in the low-risk and high-risk groups. CONCLUSION: The risk prediction model for keratinocyte cancers can reliably identify individuals with a significant skin cancer burden prior to a skin examination in the community setting. The prediction tool for melanoma needs to be tested in a larger sample exposed to a wider range of environmental risk factors.

A broad-scale spatial analysis of the environmental benefits of fertiliser closed periods implemented under the Nitrates Directive in Europe.

Nutrient pollution from agriculture has been an ongoing challenge for decades, contributing to numerous negative environmental impacts. In the European Union policies have been developed to address nutrient pollution, including Nitrate Action Programmes under Council Directive 91/676/EEC. Although Member States report on progress on implementation, there have been few studies that explore how measures have been implemented; the environmental implications of any differences; and how they vary spatially on a European scale. This study aims to address this gap with respect to fertiliser closed periods (1155 different closed periods across 69 Nitrate Action Programmes). This included the development of an approach that can be applied using readily available spatial data. Each closed period was scored for its coverage of risk periods for losses of nitrate; organic material; nitrous oxide and ammonia. Closed periods were then matched to relevant combinations of spatial data for each environmental zone and fertiliser type. The scores for each combination were used to create maps and calculate spatial statistics. The results show that in addition to nitrate, closed periods also reduce the risk of organic material run-off, emissions of nitrous oxide and to a lesser extent ammonia. However, risk reduction is spatially variable across all the impacts and the scope for synergy is also variable (e.g. nitrate loss does not always correlate with nitrous oxide or ammonia risk reduction). Regions in the Atlantic, Lustanian and some areas within the Mediterranean zones appear to provide the greatest combined risk reduction, with other zones, especially in eastern Europe, having a lower combined risk reduction (due to a combination of different risk periods coupled with lower coverage of individual risks). The spatial analysis within this study is relatively simple; is based on a snapshot of closed periods during 2019-2020; and only explores one measure. However, it does provide some useful data and insights that could support policy development in the future. This includes scope for Member States and regions to learn from others where greater coverage of risk periods has been achieved; and highlighting how a more holistic perspective can be taken to the environmental management of nutrients. As we strive towards developing sustainable production systems, farmers and policy makers need to take a more integrated approach to incorporate additional environmental objectives; which increases the complexity of the challenge. Consequently, the demand for pragmatic approaches that take a more holistic approach is likely to increase in the future.

Indoor tanning prevalence after the International Agency for Research on Cancer statement on carcinogenicity of artificial tanning devices: systematic review and meta-analysis.

BACKGROUND: Exposure to artificial tanning devices is carcinogenic to humans, and government regulations to restrict or ban indoor tanning appear to be increasing. OBJECTIVES: We evaluated changes in the international prevalence of indoor tanning among adolescents and adults after artificial tanning devices were classified as carcinogenic by the International Agency for Research on Cancer (IARC) in 2009. METHODS: Systematic searches in PubMed and Web of Science databases were undertaken. Overall, 43 studies reporting 'ever' or 'past-year' indoor tanning exposure after 2009 were identified. We used metaregression analysis to evaluate the prevalence of indoor tanning over time. Random effects meta-analysis was used to summarize the prevalence of indoor tanning in adolescents and adults according to sex, region and presence of age prohibitions. RESULTS: Global prevalence of indoor tanning in adolescents for 2013-2018 was 6·5% [95% confidence interval (CI) 3·3-10·6], 70% lower than the 22·0% (95% CI 17·2-26·8) prevalence for 2007-2012. Among adults, the prevalence was 10·4% (95% CI 5·7-16·3) for 2013-2018, a decrease of 35% from 18·2% for 2007-2012. Since 2009, the overall past-year prevalence among adolescents was 6·7% (95% CI 4·4-9·6) and 12·5% (95% CI 9·5-15·6) among adults. The prevalence of tanning indoors in the past year was similar in North America (adults, 12·5%; adolescents, 7·6%) and Europe (adults, 11·1%; adolescents, 5·1%). In 2009, three countries had regulations restricting indoor tanning, compared with 26 countries today. CONCLUSIONS: Prevalence of indoor tanning has declined substantially and significantly in adolescents and adults since the 2009 IARC statement, reflecting the rise in regulations that limit this source of unnecessary exposure to carcinogenic ultraviolet radiation. What is already known about this topic? Indoor tanning is associated with an increased risk of melanoma. A meta-analysis of worldwide indoor tanning prevalence for 1986-2012 found a past-year prevalence of 18% in adolescents and 14% in adults, with higher prevalences during the period 2007-2012. Policies to regulate indoor tanning began to be implemented across the globe in 2009. Only one study carried out in the U.S.A. has evaluated the efficacy of such policies in reducing indoor tanning prevalence. What does this study add? For the period 2013-2018, we found indoor tanning prevalences of 6·7% in adolescents and 11·9% in adults. This implies a reduction in indoor tanning use of 70% in adolescents and 35% in adults during the last 10 years. Our study encourages policy makers to strengthen indoor tanning regulations that reduce sunbed use among the general population in order to produce maximum public health benefit.

Modifiable risk factors and the development of psoriatic arthritis in people with psoriasis.

BACKGROUND: Psoriatic arthritis (PsA) is a progressive and often destructive joint disease affecting approximately 20% of people with psoriasis. OBJECTIVES: To investigate associations between obesity, changes in body mass index (BMI), alcohol intake and smoking status and the development of PsA in people with psoriasis. METHODS: We undertook a cohort study involving incident cases of psoriasis identified from the U.K. Clinical Practice Research Datalink between 1998 and 2014. The associations between smoking, alcohol and BMI and development of PsA were assessed using generalized additive models. Additionally, the risks associated with a change in BMI during follow-up were investigated using distributed lag nonlinear models. RESULTS: We identified 90 189 incident cases of psoriasis (42% male, mean age 51 years), of whom 1409 had a subsequent record of PsA diagnosis. BMIs of 25·0-29·9, 30·0-34·9 and ≥ 35·0 kg m-2 were significantly associated with an increased risk of developing PsA compared with BMIs < 25·0 kg m-2 : adjusted odds ratios (95% confidence intervals) 1·79 (1·46-2·19), 2·10 (1·67-2·63) and 2·68 (2·09-3·43), respectively. Reducing BMI over a 10-year period (linearly) was associated with a reduction in the risk of developing PsA compared with BMI remaining constant over the same period. Increased risks of developing PsA were associated with moderate drinking but not with former or heavy drinking or with current or past smoking status. CONCLUSIONS: In this incident psoriasis cohort, increased BMI and moderate drinking, but not heavy drinking or smoking status, were associated with an increased risk of PsA in people with psoriasis. Importantly, we have shown that reducing weight may result in a reduction in the risk of developing PsA. What's already known about this topic? There is some evidence that increased body mass index is associated with an increased risk of developing psoriatic arthritis. There are conflicting results surrounding the relationship between smoking and the development of psoriatic arthritis among patients with psoriasis. What does this study add? Using a nonlinear and lagged effect of body mass index measured over time we have shown that reducing body mass index may be associated with a reduction in the risk of developing psoriatic arthritis. We have found no evidence that smoking alters the risk of developing psoriatic arthritis in patients with psoriasis.

Clinicopathological factors associated with death from thin (≤ 1·00 mm) melanoma.

BACKGROUND: Thin cutaneous melanomas (≤ 1·00 mm) are increasing worldwide, causing around a quarter of all melanoma deaths in the U.S.A. and Australia. Identification of predictive factors for potentially fatal thin melanomas could allow better use of resources for follow-up. OBJECTIVES: To identify the clinicopathological factors associated with fatal thin melanomas. METHODS: This large, nested case-case study extracted data from the population-based Queensland Cancer Registry, Australia. Our cohort consisted of Queensland residents aged 0-89 years who were diagnosed with a single, locally invasive thin melanoma (≤ 1·00 mm) between 1995 and 2014. Fatal cases (eligible patients who died from melanoma) were individually matched to three nonfatal cases (eligible patients who were not known to have died from melanoma) according to sex, age, year of diagnosis and follow-up interval. Using conditional logistic regression, we calculated odds ratios (ORs) for melanoma-specific death, adjusting for all collected clinicopathological variables. RESULTS: In the cohort, 27 660 eligible patients were diagnosed with a single, thin melanoma. The final case-case series included 424 fatal cases and 1189 nonfatal cases. Fatal cases were sixfold as likely to arise on the scalp as on the back [OR 6·39, 95% confidence interval (CI) 2·57-15·92] and six times as likely to be of thickness 0·80-1·00 mm as of < 0·30 mm (OR 6·00, 95% CI 3·55-10·17). CONCLUSIONS: Scalp location is a strong prognostic factor of death from thin melanoma. Further, this study provides support that melanomas with a thickness of 0·80-1·00 mm are the more hazardous thin lesions. Patients with these tumour characteristics require specific attention during follow-up. What's already known about this topic? Thin invasive melanomas (≤ 1·00 mm) contribute a substantial proportion of melanoma fatalities, owing to the high volume of disease. There is a need to find prognostic factors that will better identify fatal thin melanomas at the time of diagnosis. What does this study add? In this large population-based study, fatal thin tumours were sixfold as likely to be located on the scalp as on the back. Thin melanomas of 0·80-1·00 mm thickness were six times as likely to be associated with death as tumours < 0·30 mm. Scalp location and increasing thickness are strong predictive factors of fatal thin melanomas, indicating that patients with these tumour characteristics require close follow-up.

Statins may reduce disease recurrence in patients with ulcerated primary melanoma.

BACKGROUND: Statins may restrict the cellular functions required for melanoma growth and metastasis. OBJECTIVES: To determine whether long-term statin use commenced before diagnosis of a primary melanoma is associated with reduced risk of melanoma recurrence. METHODS: We prospectively followed a cohort of patients newly diagnosed between 2010 and 2014 with localized tumour-stage T1b to T4b melanoma in Queensland, Australia. We used Cox regression analyses to examine associations between long-term statin use and melanoma recurrence for the entire cohort, and then separately by sex and by presence of ulceration, due to evidence of effect modification. RESULTS: Among 700 patients diagnosed with stage T1b to T4b primary melanoma (mean age 62 years, 59% male, 28% with ulcerated tumours), 94 patients (13%) developed melanoma recurrence within 2 years. Long-term statin users (n = 204, 29%) had a significantly lower risk of disease recurrence than nonusers [adjusted hazard ratio (HRadj ) 0·55, 95% confidence Interval (CI) 0·32-0·97] regardless of statin subtype or potency. Compared with nonusers of statins, risk of recurrence was significantly decreased in male statin users (HRadj 0·39, 95% CI 0·19-0·79) but not in female statin users (HRadj 0·82, 95% CI 0·29-2·27) and in statin users with ulcerated (HRadj 0·17, 95% CI 0·05-0·52) but not nonulcerated (HRadj 0·91, 95% CI 0·46-1·81) primary melanoma. CONCLUSIONS: Statins commenced before melanoma diagnosis may reduce the risk of melanoma recurrence, especially in men and in those with ulcerated tumours. Clinical trial evaluation of the potential role of statins in improving the prognosis of high-risk melanoma is warranted.

Does polygenic risk influence associations between sun exposure and melanoma? A prospective cohort analysis.

BACKGROUND: Melanoma develops as the result of complex interactions between sun exposure and genetic factors. However, data on these interactions from prospective studies are scant. OBJECTIVES: To quantify the association between ambient and personal ultraviolet exposure and incident melanoma in a large population-based prospective study of men and women residing in a setting of high ambient ultraviolet radiation, and to examine potential gene-environment interactions. METHODS: Data were obtained from the QSkin Sun and Health Study, a prospective cohort study of men and women aged 40-69 years, randomly sampled from the Queensland population in 2011. Participants were genotyped and assessed for ultraviolet exposure. RESULTS: Among participants with genetic data (n = 15 373), 420 (2·7%) developed cutaneous melanoma (173 invasive, 247 in situ) during a median follow-up time of 4·4 years. Country of birth, age at migration, having > 50 sunburns in childhood or adolescence, and a history of keratinocyte cancer or actinic lesions were significantly associated with melanoma risk. CONCLUSIONS: An interaction with polygenic risk was suggested: among people at low polygenic risk, markers of cumulative sun exposure (as measured by actinic damage) were associated with melanoma. In contrast, among people at high polygenic risk, markers of high-level early-life ambient exposure (as measured by place of birth) were associated with melanoma (hazard ratio for born in Australia vs. overseas 3·16, 95% confidence interval 1·39-7·22). These findings suggest interactions between genotype and environment that are consistent with divergent pathways for melanoma development. What's already known about this topic? The relationship between sun exposure and melanoma is complex, and exposure effects are highly modified by host factors and behaviours. The role of genotype on the relationship between ultraviolet radiation exposure and melanoma risk is poorly understood. What does this study add? We found that country of birth, age at migration, sunburns in childhood or adolescence, and history of keratinocyte cancer or actinic lesions were significantly associated with melanoma risk, while other measures of continuous or more intermittent patterns of sun exposure were not. We found evidence for gene-environment interactions that are consistent with divergent pathways for melanoma development. Linked Comment: Cust. Br J Dermatol 2020; 183:205-206. Plain language summary available online.