The GENESIS-UV study on ultraviolet radiation exposure levels in 250 occupations to foster epidemiological and legislative efforts to combat nonmelanoma skin cancer.

BACKGROUND: Several hundred million of the 3 billion formally employed people worldwide are at risk from high levels of solar ultraviolet radiation (UVR). Chronic light damage to the skin can lead to nonmelanoma skin cancer (NMSC), especially when irradiation is too high and is acquired for decades. However, data with uniform metrics, high resolution over time and in-depth occupational profiles are not available. OBJECTIVES: To build a worldwide usable matrix of UVR exposure in occupations and to show use cases for the data. METHODS: One thousand test persons were recruited to wear electronic data logger dosimeters during their working time for 7 months each. The measurements yielded 3.7 billion data points for around 48 000 days with high-quality data capture covering more than 250 occupations and 650 activities. Scientific evaluation of the data included daily and half-hourly means, geographical transfer calculations to the world, threshold exceedance quotas, transcriptome effects, and occupational disease estimates. RESULTS: A compendium for global use is presented. In-depth analyses and the resulting implications for research have been elaborated to directly link exposure data to effects in the human body. Interestingly, the annual irradiances of the different occupations span a wide range of values: from about 650 to 50 standard erythemal doses, with different distributions over the months. Detailed exposure data per occupation were derived, and the risk on an occupational or activity basis assuming different exposure level quotas was quantified. This showed that, for example, in temperate latitudes, all activities with a duration of > 2 h outdoors are associated with increased NMSC risk. CONCLUSIONS: We offer our work to enable sound studies on the nature of ultraviolet-induced skin cancer, dose-response relationships, intermittency of skin exposure, and derivation of limit values. Sociological studies on prevention are now possible. Practitioners may use the findings for their daily work with employees.

Exposure to solar UV radiation in outdoor construction workers using personal dosimetry.

Occupational exposure to solar UV radiation (SUVR), a Group 1 carcinogen according to the IARC classification is at high exposure levels in outdoor construction workers, usually above the suggested occupational limits. Furthermore, there are no regulations related to this exposure in the EU, except for the artificial UVR. Also, the use of the ICNIRP exposure guideline in an outdoor setting poses problems of adequate dose assessment. In this context, the main purpose of the study was to perform direct measurements of the SUVR dose in outdoor workers from the construction sector, using individual SUVR dosimeters (GENESIS-UV system), for a period of 7 months, from April to October, in a prospective, observational study in two groups of 10 outdoor workers in Romania, located at two different geographic sites. In term of cumulative standard erythema dose (SED), our study population of outdoor construction workers received high levels of solar UV radiation, ranging from 165 SED to 453 SED during 7 months of occupational activity, from April to October. Our results, ranging from 1.28 SED (standard erythema dose) per day to 6.4 SED per day pose an alarm signal to the national and European health authorities to take preventive action for outdoor workers, as the ICNIRP suggested limit value of 1.33 SED for mean daily erythemal UV exposure is vastly exceeded. We suggest that personal dosimetry for SUVR, from simple devices to complex systems as GENESIS-UV should be regularly and mandatory used in outdoor workers, similarly to the usage of personal dosimetry in occupational exposure to ionizing radiations, which could be included in European and national legislation to reduce both, the level of exposure and the detrimental effects on outdoor workers' health.

Full-length Vpu and human CD4(372-433) in phospholipid bilayers as seen by magic angle spinning NMR.

HIV-1 Vpu and CD4(372-433), a peptide comprising the transmembrane and cytoplasmic domain of human CD4, were recombinantly expressed in Escherichia coli, uniformly labeled with 13C and 15N isotopes, and separately reconstituted into phospholipid bilayers. Highly resolved dipolar cross-polarization (CP)-based solid-state NMR spectra of the two transmembrane proteins were recorded under magic angle sample spinning. Partial assignment of 13C resonances was achieved. Site-specific assignments were obtained for 13 amino acid residues of CD4(372-433) and two Vpu residues. Additional amino acid type-specific assignments were achieved for 10 amino acid spin systems for both CD4(372-433) and Vpu. Further, structural flexibility was probed with different dipolar recoupling techniques, and the correct insertion of the transmembrane domains into the lipid bilayers was confirmed by proton spin diffusion experiments.

Risk of cutaneous squamous cell carcinoma due to occupational exposure to solar ultraviolet radiation: Protocol for a systematic review and meta-analysis.

Solar ultraviolet radiation (UVR) is the most significant occupational carcinogenic exposure in terms of the number of workers exposed (i.e., outdoor workers). Consequently, solar UVR-induced skin cancers are among the most common forms of occupational malignancies that are potentially expected globally. This systematic review is registered in PROSPERO (CRD42021295221) and aims to assess the risk of cutaneous squamous cell carcinoma (cSCC) associated to occupational solar UVR exposure. Systematic searches will be performed in three electronic literature databases (PubMed/Medline, EMBASE, and Scopus). Further references will be retrieved by a manual search (e.g., in grey literature databases, internet search engines, and organizational websites). We will include cohort studies and case-control studies. Risk of Bias assessment will be conducted separately for case-control and cohort studies. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) will be used for the certainty of assessment. In case quantitative pooling is not feasible, a narrative synthesis of results will be performed.

Digitally measuring solar ultraviolet radiation in outdoor workers: A study protocol for establishing the use of electronic personal dosimeters in Portugal.

Introduction: The rising incidence of skin cancer over the years has made it a significant public and occupational health issue. However, skin cancer is highly preventable, mainly through reduced exposure to solar ultraviolet radiation (UVR), which can be achieved by a variety of individual and collective protective measures and interventions. The relative risk associated with different patterns of exposure to solar UVR differs for the subtypes of keratinocyte cancers (KC). Specifically, whether the exposure is intermittent or continuous, and occurs in an occupational or leisure/recreational setting. The main aim of the study using this protocol is to contribute to raising public and policy awareness on solar UVR-inflicted occupational skin cancers in Lisbon. This will be achieved by performing direct measurements of the solar UVR dose received by outdoor workers using a digital platform. Results will likely contribute to further understanding the risk estimates for keratinocyte cancer estimations in this population. Methods: A prospective observational study will be conducted in Lisbon, Portugal. Personal electronic dosimeters (GENESIS-UV system) integrated with a digital platform will be used to assess occupational solar UVR doses of gardeners, masons, and gravediggers of the municipality of Lisbon. Two hundred and ten outdoor workers will be selected to wear the dosimeter for 1 month each, between April and October during their daily working hours. A digital web-based platform that offers private access to information through dashboard visualization will provide information for the outdoor workers and facilitate communication with the participants. Discussion: The expected results of the overall proposal comprise the occupational solar UVR doses, expressed in standard erythemal dose (SEDs) per day of outdoor work for 7 months. Study data will provide outdoor workers with information on their personal solar UVR exposure during their working hours and an estimate of their risk of developing skin cancer. It is expected that the occupational solar UVR doses of the outdoor workers in Portugal will be above the threshold of 1 to 1.33 SED/day, due to the latitude of Lisbon and the nature of the occupations. The results prospectively should flow into the design of adequate prevention campaigns for skin cancer in outdoor workers.

Probing Different Approaches in Ultraviolet Radiation Personal Dosimetry - Ball Sports and Visiting Parks.

Solar ultraviolet radiation (UVR) continues to be a decisive influencing factor for skin health. Besides acute damage (e.g. erythema), chronic light damage is of particular relevance. Skin cancer can develop on the basis of this light damage. Knowledge about irradiation is crucial for the choice of preventive measures, but has so far been incomplete in many occupational and leisure activities. Often a methodological problem in study design is the cause. Here we report on the clarification of two issues. First, further values are to be determined on the way to a comprehensive exposure register of leisure-related activities. Furthermore, it is to be determined to what extent the measurement setting can have an influence on the measurement campaigns. For long-term measurements, football referees were equipped with dosimeters over several months, selective measurements during visits to parks were carried out by on-site recruitment of test persons. It turned out that the choice of method also depends on the expected compliance of the test persons. Long-term measurements of specific activities such as playing football are particularly suitable for observing the course of UV exposure over the year and generating resilient mean values. Point measurements such as visits to parks can also do this if there are enough such events spread over the year. However, they are particularly suitable for such on-site campaigns, as they may be combined with awareness campaigns of the issue of skin cancer. They also allow many measurements to be taken at the same time in one place. Both playing football and visiting parks are associated with high levels of radiation, so specific prevention concepts need to be developed. We were able to determine that the sunburn dose for light skin types was reached or exceeded for both of the investigated activities.

UVR Exposure and Prevention of Street Construction Workers in Colombia and Germany.

(1) Solar ultraviolet radiation (UVR) poses a major risk factor for developing skin cancer after years of chronic exposure. The irradiation is strongly dependent upon the activity or occupation carried out, but also on the climate conditions at the workplace. Knowledge of both has been tested within the occupational group of road construction workers in Colombia and Germany. (2) The GENESIS-UV measurement system has been used at both locations for consistency. A number of workers in both countries wore an electronic data logging dosimeter for several months to deliver detailed information on UVR exposure. (3) It was found that in a tropical climate, UVR exposure remains constant throughout the year, while in a temperate climate seasonal effects are visible, superimposed by behavioural aspects e.g., in springtime. The daily distribution of the radiation shows a distinct dip, especially in the Colombian data. Derived data show the high fraction of working days exceeding a threshold set by the skin type. (4) Road construction work involves high UVR exposure. In both countries, preventive measures are required to reduce the personal exposure to a minimum. Exceedance of the minimal erythema dose (MED) suggests a possible enhancing effect, especially in fair skinned people. Intercomparison of UVR exposure at workplaces is possible between countries and climate zones, emphasizing efforts for global action against skin cancer.

NMR structure of the transmembrane and cytoplasmic domains of human CD4 in micelles.

The human cluster determinant 4 (CD4) is a type I transmembrane glycoprotein involved in T-cell signalling. It is expressed primarily on the surface of T helper cells but also on subsets of memory and regulatory T lymphocytes (CD4(+) cells). It serves as a coreceptor in T-cell receptor recognition of MHC II antigen complexes. Besides its cellular functions, CD4 serves as the main receptor for human immunodeficiency virus type I (HIV-1). During T-cell infection, the CD4 extracellular domain is bound by HIV-1 gp120, the viral surface glycoprotein, which triggers a number of conformational changes ultimately resulting in virion entry of the cell. Subsequently, CD4 is downregulated in infected cells by multiple strategies that involve direct interactions of the HIV-1 proteins VpU and Nef with the cytoplasmic part of CD4. In the present work, we describe the NOE-based solution structure of the transmembrane and cytoplasmic domains of the cystein-free variant of CD4 (CD4mut) in dodecylphosphocholine (DPC) micelles. Furthermore, we have characterized micelle-inserted CD4mut by paramagentic relaxation enhancement (PRE) agents and (1)H-(15)N heteronuclear NOE data. CD4mut features a stable and well-defined transmembrane helix from M372 to V395 buried in the micellar core and a cytoplasmic helix ranging from A404 to L413. Experimental data suggest the amphipathic cytoplasmic helix to be in close contact with the micellar surface. The role of the amphipathic helix and its interaction with the micellar surface is discussed with respect to the biological function of the full-length CD4 protein.

Criteria for Occupational Health Prevention for Solar UVR Exposed Outdoor Workers-Prevalence, Affected Parties, and Occupational Disease.

Non-melanoma skin cancer (NMSC) is the most common cancer in western countries. Legislative bodies and stakeholders like WHO and EU strongly promote protection against solar UVR, especially in workers. Occupational health prevention must be introduced as a strong instrument in workers protection also with regard to occupational disease issues. To date, criteria for both occupational health prevention and occupational disease are missing and the identification of risk groups has no metric basis. Here I report a criteria analysis based on the largest comprehensive data set of occupational ultraviolet radiation exposure of outdoor workers. With detailed research on occupation-specific dosimetric measurements of 45.000 measurement days in 176 occupations and sub-occupations, it is possible to map criteria for occupational health prevention specifically and to identify affected occupations. The number of employees affected can be elucidated worldwide. For the first time, a direct link to retrospective occupational disease criteria could be established. Of the 176 occupations and sub-occupations selected for this work, 153 (=87%) exceed the criterion for occupational health prevention and thus need special attention. This includes all occupations with annual exposures of more than 150 SED. Employment figures for the EU and the world yield the total number of affected workers to be 36.1 million and more than 500 million, respectively. These new criteria for occupational health prevention are valid and in good agreement with international research on limit values by WHO and ICNIRP. If applied correctly and consistently, these criteria can prevent occupational disease. It will be possible to identify occupations and sub-occupations that have an urgent need for prevention to avoid chronic skin damage leading to cancer. This research serves as a basis for policy making and clinical risk identification, as well as for daily practice of occupational physicians and employers responsible for risk assesment.

Bringing Light into Darkness-Comparison of Different Personal Dosimeters for Assessment of Solar Ultraviolet Exposure.

(1) Measuring personal exposure to solar ultraviolet radiation (UVR) poses a major challenges for researchers. Often, the study design determines the measuring devices that can be used, be it the duration of measurements or size restrictions on different body parts. It is therefore of great importance that measuring devices produce comparable results despite technical differences and modes of operation. Particularly when measurement results from different studies dealing with personal UV exposure are to be compared with each other, the need for intercomparability and intercalibration factors between different measurement systems becomes significant. (2) Three commonly used dosimeter types-(polysulphone film (PSF), biological, and electronic dosimeters)-were selected to perform intercalibration measurements. They differ in measurement principle and sensitivity, measurement accuracy, and susceptibility to inaccuracies. The aim was to derive intercalibration factors for these dosimeter types. (3) While a calibration factor between PSF and electronic dosimeters of about 1.3 could be derived for direct irradiation of the dosimeters, this was not the case for larger angles of incidence of solar radiation with increasing fractions of diffuse irradiation. Electronic dosimeters show small standard deviation across all measurements. For biological dosimeters, no intercalibration factor could be found with respect to PSF and electronic dosimeters. In a use case, the relation between steady-state measurements and personal measurements was studied. On average, persons acquired only a small fraction of the ambient radiation.

Personal ultraviolet radiation dosimetry and its relationship with environmental data: A longitudinal pilot study in Croatian construction workers.

OBJECTIVE: This pilot study aimed to estimate annual occupational ultraviolet radiation (UVR) exposures based on 5 consecutive months of dosimetry measurements in Croatian construction workers and assess its relationship with the environmental data collected during the same period. METHODS: Four male construction industry workers from the vicinity of Zagreb (lat. 45.8° N, alt. 128 m) participated in the study. The study was a part of the GENESIS-UV project, attempting to collect long-term dosimetry data for outdoor occupations across Europe. Workers wore personal dosimeters (model X2012-10, Gigahertz, Tuerkenfeld, Germany) on the left upper arm during working hours in the period from June to October 2017. Median exposure assessment period was 57 working days. RESULTS: Estimates of annual occupational UVR exposure ranged from 76 SED to 976 SED per worker, reflecting large differences in patterns of workers' exposure. Daily UVR doses received by the workers were comparable to the values of other studies at similar latitudes, reaching up to 12 SED in summer months. Measurements of workers with high exposure values (estimated >600 SED/year) showed moderate to high associations with environmental UVR and insolation data (Spearman's correlation coefficient ranging from 0.57 to 0.73). CONCLUSIONS: The results confirmed high occupational exposure of tested Croatian construction workers to solar UVR. However, more data are needed to explain the between-worker variability and develop prediction models with respect to specific work tasks. The use of environmental UVR for predicting long-term exposure should be considered, especially for high exposure tasks.

Is Occupational Skin Cancer More Aggressive than Sporadic Skin Cancer?

Background: Non-melanoma skin cancer (NMSC) represents the most frequently diagnosed cancer in humans. Occupational solar UV radiation exposure is associated with a higher-risk of developing NMSC, but still Romania does not acknowledge this affliction as an occupational disease. The study aims to determine if occupationally-induced NMSC is associated with more aggressive clinical and histopathological features compared to sporadic NMSC. Material and methods: A retrospective, analytical, comparative study was conducted during 2017-2019 in a University Department of Dermato-venereology in Bucharest, Romania, with focus on patients presenting with NMSC who underwent surgical excision of lesions followed by histopathological examination, classified as outdoor or indoor workers. High-risk clinical and histopathological characteristics were analysed and correlated with outdoor UV exposure. Outcomes: The study included 51 consecutive patients diagnosed with NMSC, of which 25 outdoor workers (OW) and 26 controls as indoor workers with no occupational UV exposure background. OW presented with 21 BCC and four SCC, while controls with 22 BCC and four SCC. Males were predominant in both groups and most patients came from urban environment. The mean age value was lower for the OW group compared to controls. OW had a 4.66 times higher risk of developing NMSC with aggressive location and size χ² (1, N=51) = 6.246, p=0.013, OR=4.66 (95% CI: 1.34, 16.23) and a 24-fold risk of developing NMSC with clinically poorly defined margins χ² (1, N=51) = 21.697, p<0.001, OR=24.44 (95% CI: 5.38,110.92). The risk of developing a high-risk histopathological subtype was 15 times greater for OW χ² (1, N=51) = 13.814, p<0.001, OR=15.27 (95% CI: 2.94,79.08). Moderate to severe desmoplastic reaction was 8.57 more frequent in controls χ² (1, N=51) = 12.244, p=0.001, OR=8.57 (95% CI: 2.42, 30.30). Grades 2 and 3 of actinic elastosis were significantly associated with outdoor work (χ² (1, N=51) = 33.382, p<0.001, OR=131.25 (95% CI: 13.60, 1266.37). The presence of ulceration and pigment association of tumors on the histopathological report were not significantly associated with outdoor working. Conclusion: 1. Occupational NMSC in Romania is associated with high-risk clinical features; 2. Poorly defined borders is a significant clinical high-risk factor associated with occupational UV exposure in NMSC; 3. High-risk histopathological subtypes are more frequently encountered in outdoor workers diagnosed with NMSC compared to indoor workers with no occupational UV exposure background; 4. Occupational NMSC is associated with significantly higher grades of desmoplastic reaction and of actinic elastosis compared to indoor workers.

In-Flight UV-A Exposure of Commercial Airline Pilots.

INTRODUCTION: Understanding UV exposure is essential for the assessment of its contribution to the occupational risk of pilots developing ocular and skin pathologies. The objective of this observational study was to measure the UV exposure of pilots flying between the United Kingdom and a range of destinations at three different seasons.METHODS: The in-flight UV exposure of pilots was measured on 322 Monarch Airlines short-haul flights on the Airbus A321-231 and Airbus A320-214 to 31 destinations, mostly in Europe, from 4 UK airports in September 2016-August 2017. The erythema effective and UV-A doses were compared with the ICNIRP guidance and typical recreational weekend exposure of UK office workers.RESULTS: The erythema effective radiant doses did not exceed 0.1 SED. For most of the flights, the UV-A exposure was also low. On 27 single sector flights, UV-A exposure could have exceeded the ICNIRP guidance if eye protection was not used.DISCUSSION: The UV exposure in a cockpit is mostly governed by the presence of direct sunlight and the duration of a flight. The average monthly exposures were low and significantly below weekend recreational exposures of UK office workers over a similar period. To assess the contribution of occupational UV exposure to the risk of developing sun-related ocular and cutaneous pathologies, it is important to consider the accumulative flight time, destinations, and UV attenuation of aircraft windshields. Additionally, leisure and recreational outdoor time needs to be considered before meaningful overall risk analysis can be undertaken.Baczynska KA, Brown S, Chorley AC, O'Hagan JB, Khazova M, Lyachev A, Wittlich M. In-flight UV-A exposure of commercial airline pilots. Aerosp Med Hum Perform. 2020; 91(6):501-510.

Integral membrane proteins in nanodiscs can be studied by solution NMR spectroscopy.

We present a two-dimensional solution NMR spectrum of an integral membrane protein (IMP) in a nanodisc. Solution NMR relies on rapid isotropic tumbling of the analyte with correlation times in the nanosecond range. IMPs in a cellular membrane do not satisfy this condition. Previous liquid-state NMR studies on IMPs were conducted in organic solvent or artificial membrane mimicking particles like detergent micelles. Nanodiscs are relatively small (150 kDa), detergent-free model membranes that are suitable for functional reconstitution of IMPs. Nanodiscs allow solubilization of integral membrane proteins in a nearly native lipid bilayer environment. The 70 residue polypeptide CD4mut was incorporated into nanodiscs. CD4mut features one transmembrane helix. The aliphatic (1)H-(13)C HSQC spectrum of nanodiscs with inserted, ((13)C, (15)N)-labeled CD4mut exhibits reasonably dispersed protein and lipid NMR signals. Our results demonstrate that IMPs in nanodiscs are amenable to liquid-state NMR methodology.

WHO/ILO work-related burden of disease and injury: Protocol for systematic reviews of occupational exposure to solar ultraviolet radiation and of the effect of occupational exposure to solar ultraviolet radiation on cataract.

BACKGROUND: The World Health Organization (WHO) and the International Labour Organization (ILO) are developing a joint methodology for estimating the national and global work-related burden of disease and injury (WHO/ILO joint methodology), with contributions from a large network of experts. Here, we present the protocol for two systematic reviews of parameters for estimating the number of disability-adjusted life years of cataracts from occupational exposure to solar ultraviolet radiation, to inform the development of the WHO/ILO joint methodology. OBJECTIVES: We aim to systematically review studies on occupational exposure to solar ultraviolet radiation (Systematic Review 1) and systematically review and meta-analyse estimates of the effect of occupational exposure to solar ultraviolet radiation on the development of cataract (Systematic Review 2), applying the Navigation Guide systematic review methodology as an organizing framework and conducting both systematic reviews in tandem and in a harmonized way. DATA SOURCES: Separately for Systematic Reviews 1 and 2, we will search electronic academic databases for potentially relevant records from published and unpublished studies, including Ovid Medline, PubMed, EMBASE, and Web of Sciences. We will also search electronic grey literature databases, Internet search engines and organizational websites; hand search reference list of previous systematic reviews and included study records; and consult additional experts. STUDY ELIGIBILITY AND CRITERIA: We will include working-age (≥15 years) workers in WHO and/or ILO Member States, but exclude children (<15 years) and unpaid domestic workers. For Systematic Review 1, we will include quantitative studies on the prevalence of relevant levels of occupational exposure to solar ultraviolet radiation and of the total working time spent outdoors from 1960 to 2018, stratified by sex, age, country and industrial sector or occupation. For Systematic Review 2, we will include randomized controlled trials, cohort studies, case-control studies and other non-randomized intervention studies with an estimate of the effect of any occupational exposure to solar ultraviolet radiation (i.e. ≥30 Jm-2/day of occupational solar UV exposure at the surface of the eye) on the prevalence or incidence of cataract, compared with the theoretical minimum risk exposure level (i.e. <30 Jm-2/day of occupational solar UV exposure at the surface of the eye). STUDY APPRAISAL AND SYNTHESIS METHODS: At least two review authors will independently screen titles and abstracts against the eligibility criteria at a first stage and full texts of potentially eligible records at a second stage, followed by extraction of data from qualifying studies. At least two review authors will assess risk of bias and the quality of evidence, using the most suited tools currently available. For Systematic Review 2, if feasible, we will combine relative risks using meta-analysis. We will report results using the guidelines for accurate and transparent health estimates reporting (GATHER) for Systematic Review 1 and the preferred reporting items for systematic reviews and meta-analyses guidelines (PRISMA) for Systematic Review 2. PROSPERO registration: CRD42018098897.

WHO/ILO work-related burden of disease and injury: Protocol for systematic reviews of occupational exposure to solar ultraviolet radiation and of the effect of occupational exposure to solar ultraviolet radiation on melanoma and non-melanoma skin cancer.

BACKGROUND: The World Health Organization (WHO) and the International Labour Organization (ILO) are developing a joint methodology for estimating the national and global work-related burden of disease and injury (WHO/ILO joint methodology), with contributions from a large network of experts. In this paper, we present the protocol for two systematic reviews of parameters for estimating the number of deaths and disability-adjusted life years from melanoma and non-melanoma skin cancer (or keratinocyte carcinoma) from occupational exposure to solar ultraviolet radiation, to inform the development of the WHO/ILO joint methodology. OBJECTIVES: We aim to systematically review studies on occupational exposure to solar ultraviolet radiation (Systematic Review 1) and systematically review and meta-analyse estimates of the effect of occupational exposure to solar ultraviolet radiation on melanoma and non-melanoma skin cancer (Systematic Review 2), applying the Navigation Guide systematic review methodology as an organizing framework and conducting both systematic reviews in tandem and in a harmonized way. DATA SOURCES: Separately for Systematic Reviews 1 and 2, we will search electronic academic databases for potentially relevant records from published and unpublished studies, including Ovid Medline, PubMed, EMBASE, and Web of Science. We will also search electronic grey literature databases, Internet search engines and organizational websites; hand-search reference list of previous systematic reviews and included study records and consult additional experts. STUDY ELIGIBILITY AND CRITERIA: We will include working-age (≥15 years) workers in the formal and informal economy in any WHO and/or ILO Member State, but exclude children (<15 years) and unpaid domestic workers. For Systematic Review 1, we will include quantitative studies on the prevalence of relevant levels of occupational exposure to solar ultraviolet radiation (i.e. <0.33 SED/d and ≥0.33 SED/d) and of the total working time spent outdoors, stratified by country, sex, age and industrial sector or occupation, in the years 1960 to 2018. For Systematic Review 2, we will include randomized controlled trials, cohort studies, case-control studies and other non-randomized intervention studies with an estimate of the effect of any occupational exposure to solar ultraviolet radiation (i.e., ≥0.33 SED/d) on the prevalence of, incidence of or mortality due to melanoma and non-melanoma skin cancer, compared with the theoretical minimum risk exposure level (i.e. <0.33 SED/d). STUDY APPRAISAL AND SYNTHESIS METHODS: At least two review authors will independently screen titles and abstracts against the eligibility criteria at a first stage and full texts of potentially eligible records at a second stage, followed by extraction of data from qualifying studies. At least two review authors will assess the risk of bias and the quality of evidence, using the most suited tools currently available. For Systematic Review 2, if feasible, we will combine relative risks using meta-analysis. We will report results using the guidelines for accurate and transparent health estimates reporting (GATHER) for Systematic Review 1 and the preferred reporting items for systematic reviews and meta-analyses guidelines (PRISMA) for Systematic Review 2. PROSPERO REGISTRATION NUMBER: CRD42018094817.

Structural characterization of the transmembrane and cytoplasmic domains of human CD4.

Cluster determinant 4 (CD4) is a type I transmembrane glycoprotein of 58 kDa. It consists of an extracellular domain of 370 amino acids, a short transmembrane region, and a cytoplasmic domain of 40 amino acids at the C-terminal end. We investigated the structure of the 62 C-terminal residues of CD4, comprising its transmembrane and cytoplasmic domains. The five cysteine residues of this region have been replaced with serine and histidine residues in the polypeptide CD4mut. Uniformly 15N and 13C labeled protein was recombinantly expressed in E. coli and purified. Functional binding activity of CD4mut to protein VpU of the human immunodeficiency virus type 1 (HIV-1) was verified. Close to complete NMR resonance assignment of the 1H, 13C, and 15N spins of CD4mut was accomplished. The secondary structure of CD4mut in membrane simulating dodecylphosphocholine (DPC) micelles was characterized based on secondary chemical shift analysis, NOE-based proton-proton distances, and circular dichroism spectroscopy. A stable transmembrane helix and a short amphipathic helix in the cytoplasmic region were identified. The fractional helicity of the cytoplasmic helix appears to be stabilized in the presence of DPC micelles, although the extension of this helix is reduced in comparison to previous studies on synthetic peptides in aqueous solution. The role of the amphipathic helix and its potentially variable length is discussed with respect to the biological functions of CD4.

Occupational UV-Exposure is a Major Risk Factor for Basal Cell Carcinoma: Results of the Population-Based Case-Control Study FB-181.

OBJECTIVE: The aim of this study was to investigate the role of occupational and nonoccupational ultraviolet (UV)-exposure concerning the development of basal cell carcinoma (BCC). METHODS: We undertook a population-based multicenter case-control study. Patients with first incident BCC (n = 836) were propensity score matched by age and sex to controls without skin cancer (n = 836). Sociodemographic characteristics, clinical characteristics, and lifetime UV-exposure were assessed by trained investigators. The differential estimation of occupational and nonoccupational UV-exposure dosages was based on validated instruments and established reference values. Associations were assessed using multivariable-adjusted conditional logistic regression models. RESULTS: Individuals with high levels of occupational UV-exposure were at significantly increased BCC-risk compared with individuals with low [odds ratio (OR) 1.84; 95% confidence interval (95% CI) 1.19 to 2.83 and moderate (OR 1.97; 95% CI 1.20 to 3.22) occupational UV-exposure. Nonoccupational UV-exposure was not independently associated with BCC. CONCLUSION: Skin cancer prevention strategies should be expanded to the occupational setting.

Mapping the interaction between the cytoplasmic domains of HIV-1 viral protein U and human CD4 with NMR spectroscopy.

Viral protein U (VpU) of HIV-1 plays an important role in downregulation of the main HIV-1 receptor CD4 from the surface of infected cells. Physical binding of VpU to newly synthesized CD4 in the endoplasmic reticulum is an early step in a pathway leading to proteasomal degradation of CD4. In this study, regions in the cytoplasmic domain of VpU involved in CD4 binding were identified by NMR spectroscopy. Amino acids in both helices found in the cytoplasmic region of VpU in membrane-mimicking detergent micelles experience chemical shift perturbations upon binding to CD4, whereas amino acids between the two helices and at the C-terminus of VpU show no or only small changes, respectively. The topology of the complex was further studied with paramagnetic relaxation enhancement. Paramagnetic spin labels were attached at three sequence positions of a CD4 peptide comprising the transmembrane and cytosolic domains of the receptor. VpU binds to a membrane-proximal region in the cytoplasmic domain of CD4.

NMR structural characterization of HIV-1 virus protein U cytoplasmic domain in the presence of dodecylphosphatidylcholine micelles.

The HIV-1 encoded virus protein U (VpU) is required for efficient viral release from human host cells and for induction of CD4 degradation in the endoplasmic reticulum. The cytoplasmic domain of the membrane protein VpU (VpUcyt) is essential for the latter activity. The structure and dynamics of VpUcyt were characterized in the presence of membrane simulating dodecylphosphatidylcholine (DPC) micelles by high-resolution liquid state NMR. VpUcyt is unstructured in aqueous buffer. The addition of DPC micelles induces a well-defined membrane proximal alpha-helix (residues I39-E48) and an additional helical segment (residues L64-R70). A tight loop (L73-V78) is observed close to the C-terminus, whereas the interhelical linker (R49-E63) remains highly flexible. A 3D structure of VpUcyt in the presence of DPC micelles was calculated from a large set of proton-proton distance constraints. The topology of micelle-associated VpUcyt was derived from paramagnetic relaxation enhancement of protein nuclear spins after the introduction of paramagnetic probes into the interior of the micelle or the aqueous buffer. Qualitative analysis of secondary chemical shift and paramagnetic relaxation enhancement data in conjunction with dynamic information from heteronuclear NOEs and structural insight from homonuclear NOE-based distance constraints indicated that micelle-associated VpUcyt retains a substantial degree of structural flexibility.