Harmful types of gambling: changes and emerging trends in longitudinal helpline data.

BACKGROUND: Gambling products differ in terms of their harm potential. Products are also constantly developing and changing. However, little research has addressed changes and trends in the types of gambling that are associated with harms. The current study explores trends in the gambling product categories identified as harmful in longitudinal helpline data from three Nordic countries. METHODS: We use data collected by national helplines in Denmark (StopSpillet), Finland (Peluuri) and Sweden (Stödlinjen) in their daily operations (N = 46 646). The data consist of information collected on gamblers and concerned significant others who have contacted these helplines between January 2019 and December 2022. We analyse which gambling products are mentioned as harmful by clients. The analysis uses linear regression with the interaction term (country) times time regressed over the outcome variable (proportion per month). RESULTS: The results show that an increased share of contacts concern online gambling. Online casino products have become the most harmful category across contexts. The share of reported harms from online betting and new emerging online forms is also increasing. The share of land-based products as a reported source of harms has decreased across 2019-22. CONCLUSIONS: The results suggest that online gamlbing environments, and particularly online casino products, are associated with increasing harms to help-seekers. The harmfulness of different gambling products may not be stable, but change over time. Further harm prevention efforts are needed to address the online gambling field, including emerging formats.

Drinking Water Criteria for Arsenic in High-Income, Low-Dose Countries: The Effect of Legislation on Public Health.

Due to the potential health risks at very low concentrations, the criterion for arsenic in drinking water has been debated. High-income, low-dose countries are uniquely positioned to follow WHO's recommendation of keeping concentrations "as low as reasonably possible." In this policy analysis, 47646 arsenic analyses from Denmark are used to follow the effect of lowering the national criterion from 50 to 5 µg/L. The first 3 years (2002-2004) following the criterion change, 106 waterworks were identified as noncompliant. An additional 64 waterworks were identified as noncompliant in the next 12 years (2005-2016). Of the 106 waterworks initially (2002-2004) aware of the violation, an average concentration drop from 6 to 3 µg/L was observed during a 6 year period following a lag time of 1 year. After this point, no further improvements were observed. Thirteen years after regulation was imposed, 25 of 170 waterworks were still in violation. The results suggest that legislation alone is insufficient to ensure better drinking water quality at some waterworks and that stakeholders' drivers and barriers to change also play an important role. In an exploration of five legislation scenarios, this study showed that a criterion of 1 µg/L would require action by more than 500 Danish waterworks, with treatment costs from 0.06 to 0.70 €/m3. These scenarios illustrate that it can be technically feasible and affordable to lower the arsenic criterion below 5 µg/L in low-dose, high-income countries. However, more information is needed to apply a cost-benefit model, and comparative studies from other counties are warranted.

Mapping an ancient city with a century of remotely sensed data.

The rapidly growing global population places cultural heritage at great risk, and the encroachment of modern settlement on archaeological sites means that valuable information about how past societies worked and interacted with the environment is lost. To manage and mitigate these risks, we require knowledge about what has been lost and what remains, so we can actively decide what should be investigated and what should be preserved for the future. Remote sensing provides archaeologists with some of the tools we need to do this. In this paper we explore the application of multitemporal, multisensor data to map features and chart the impacts of urban encroachment on the ancient city of Jerash (in modern Jordan) by combining archives of aerial photography dating back to 1917 with state-of-the-art airborne laser scanning. The combined results revealed details of the water distribution system and the ancient city plan. This demonstrates that by combining historical images with modern aerial and ground-based data we can successfully detect and contextualize these features and thus achieve a better understanding of life in a city in the past. These methods are essential, given that much of the ancient city has been lost to modern development and the historical imagery is often our only source of information.

Direct evidence of a large Northern European Roman period martial event and postbattle corpse manipulation.

New archaeological excavations at Alken Enge, Jutland, Denmark, have revealed a comprehensive assemblage of disarticulated human remains within a 75-ha wetland area. A minimum of 82 individuals have been uncovered. Based on the distribution, the total population is estimated to be greater than 380 individuals, exclusively male and predominantly adult. The chronological radiocarbon evidence of the human bones indicates that they belong to a single, large event in the early first century AD. The bones show a high frequency of unhealed trauma from sharp-edged weapons, which, together with finds of military equipment, suggests that the find is of martial character. Taphonomic traces indicate that the bones were exposed to animal gnawing for a period of between 6 mo and 1 y before being deposited in the lake. Furthermore, the find situations, including collections of bones, ossa coxae threaded onto a stick, and cuts and scraping marks, provide evidence of the systematic treatment of the human corpses after the time of exposure. The finds are interpreted as the remains of an organized and possibly ritually embedded clearing of a battlefield, including the physical manipulation of the partly skeletonized bones of the deceased fighters and subsequent deposition in the lake. The date places the finds in the context of the Germanic region at the peak of the Roman expansion northward and provides the earliest direct archaeological evidence of large-scale conflict among the Germanic populations and a demonstration of hitherto unrecognized postbattle practices.

Estimation of the celiac disease prevalence in Denmark and the diagnostic value of HLA-DQ2/DQ8.

The aims of the present study were to estimate the celiac disease (CD) prevalence in Denmark and the relevance of the test for human leukocyte antigen DQ2 and DQ8 haplotypes (HLA-DQ2/DQ8) for diagnosing CD. The plasma IgA transglutaminase antibody (TGA-IgA) and HLA-DQ2/DQ8 tests should normally be positive for a CD diagnosis. First, we estimated the CD and HLA-DQ2/DQ8 prevalence in the available blood samples collected at the North Zealand Hospital. Out of a total of 9754 patients, with symptoms suggestive of CD (such as malabsorption, diarrhea, steatorrhea, ion-deficiency anemia, and weight loss or growth failure), 153 patients had TGA-IgA positive results (i.e. TGA-IgA > 10 U/mL). In this cohort, the prevalence of CD was 0.912% and the prevalence of HLA-DQ2/DQ8 positive patients was estimated to be 62%. Based on the distribution of HLA-DQ2/DQ8 positive individuals in the general Danish population, a calculation of CD prevalence in Denmark was found to be maximum 0.77%. Second, we analysed for the HLA-DQ2/DQ8 haplotypes in 293 positive plasma TGA-IgA samples. Nearly all (99%) of the CD patients and non-CD patients were HLA-DQ2/DQ8 positive.

Soil fertility and flood regime are correlated with phylogenetic structure of Amazonian palm communities.

BACKGROUND AND AIMS: Identifying the processes that generate and maintain biodiversity requires understanding of how evolutionary processes interact with abiotic conditions to structure communities. Edaphic gradients are strongly associated with floristic patterns but, compared with climatic gradients, have received relatively little attention. We asked (1) How does the phylogenetic composition of palm communities vary along edaphic gradients within major habitat types? and (2) To what extent are phylogenetic patterns determined by (a) habitat specialists, (b) small versus large palms, and (c) hyperdiverse genera? METHODS: We paired data on palm community composition from 501 transects of 0.25 ha located in two main habitat types (non-inundated uplands and seasonally inundated floodplains) in western Amazonian rain forests with information on soil chemistry, climate, phylogeny and metrics of plant size. We focused on exchangeable base concentration (cmol+ kg-1) as a metric of soil fertility and a floristic index of inundation intensity. We used a null model approach to quantify the standard effect size of mean phylogenetic distance for each transect (a metric of phylogenetic community composition) and related this value to edaphic variables using generalized linear mixed models, including a term for spatial autocorrelation. KEY RESULTS: Overall, we recorded 112 008 individuals belonging to 110 species. Palm communities in non-inundated upland transects (but not floodplain transects) were more phylogenetically clustered in areas of low soil fertility, measured as exchangeable base concentration. In contrast, floodplain transects with more severe flood regimes (as inferred from floristic structure) tended to be phylogenetically clustered. Nearly half of the species recorded (44 %) were upland specialists while 18 % were floodplain specialists. In both habitat types, phylogenetic clustering was largely due to the co-occurrence of small-sized habitat specialists belonging to two hyperdiverse genera (Bactris and Geonoma). CONCLUSIONS: Edaphic conditions are associated with the phylogenetic community structure of palms across western Amazonia, and different factors (specifically, soil fertility and inundation intensity) appear to underlie diversity patterns in non-inundated upland versus floodplain habitats. By linking edaphic gradients with palm community phylogenetic structure, our study reinforces the need to integrate edaphic conditions in eco-evolutionary studies in order to better understand the processes that generate and maintain tropical forest diversity. Our results suggest a role for edaphic niche conservatism in the evolution and distribution of Amazonian palms, a finding with potential relevance for other clades.

Validation of plasma thyroxine and triiodothyronine methods on the ADVIA Centaur® XP.

Standardization programs for thyroid hormones have revealed bias between immunochemical methods and the reference method ED-ID-LC/MS. Lack of standardization between methods, suboptimal reference intervals and replacement of serum with plasma may compromise the capability of the immunochemical thyroid methods to diagnose thyroid disease. To accommodate the demand for faster turn-around times for laboratory replies, we replaced serum with plasma on some serum CE marked thyroid methods. This forced us to do on-board analytical correction for the plasma total T4 (TT4) method on ADVIA Centaur® XP. We, next, validated the capability of the ADVIA Centaur® XP thyroid methods on plasma by (1) first carrying out a prospective method comparison with the ED-ID-LC/MS reference method using collected plasma samples, (2) we verified the clinical reference intervals by analyzing collected plasma samples from healthy individuals, and (3) retrospectively compared laboratory results from two different time periods using serum TT4 and serum total triiodothyronine (TT3) versus plasma free thyroxine (FT4) and plasma TT3, respectively, to diagnose thyroid disease. The plasma FT4 method displayed a negative concentration-dependent bias against the reference method. This bias was apparently counteracted by a fitted reference interval for the plasma FT4 method. Indeed, overt hyperthyroid disease was found in 1.0% and 1.1% of the cases using serum and plasma and overt hypothyroid condition were in 1.3% and 0.6% of the cases using serum and plasma, respectively. In conclusion, the ADVIA Centaur® XP FT4 method displayed a negative bias at high plasma FT4 concentrations against the reference method, but the diagnostic performance was not compromised due to a fitted reference interval.

Verification study on the NORIP LDH reference intervals with a proposed new upper reference limit.

We verified the lactate dehydrogenase (LDH) reference interval (RI) provided by the Nordic Reference Interval Project (NORIP). The serum LDH concentration was analysed on the Dimension Vista 1500 system with an IFCC method with a bias of +2.1 % and +2.7 % against NFKK Reference Serum X and ERM-AD453/IFCC, respectively, showing verification of transference of the NORIP RI. Selective data mining in clinical laboratory information systems for retrospective serum LDH test results was used to calculate an indirect RI. For the adult age group (18 to <70 years) the limits of the interval was 127 U/L (90 % CI: 123-132 U/L) and 240 U/L (90 % CI: 234-243 U/L). However, the NORIP upper limit for the adult age group is 205 U/L (90 % CI: 198-210 U/L). Accordingly, 25.1 % of LDH test results were above the NORIPs upper limit of 205 U/L. If LDH analysis was requested by the hospital's medical departments, outpatient clinics or general practitioners 29.2 %, 26.2 % and 20.9 %, respectively, were above the 205 U/L limit. Differences in transport time before centrifugation of blood, and different transport principles could not explain the relative high percent of test results above the NORIP 205 U/L limit. The indirect finding of an upper limit of 240 U/L (90 % CI: 234-243 U/L), and the relative high number of test result >205 U/L, suggests that the NORIP upper limit should be adjusted.

Lithium in drinking water and the incidence of bipolar disorder: A nation-wide population-based study.

OBJECTIVE: Animal data suggest that subtherapeutic doses, including micro doses, of lithium may influence mood, and lithium levels in drinking water have been found to correlate with the rate of suicide. It has never been investigated whether consumption of lithium may prevent the development of bipolar disorder (primary prophylaxis). In a nation-wide population-based study, we investigated whether long-term exposure to micro levels of lithium in drinking water correlates with the incidence of bipolar disorder in the general population, hypothesizing an inverse association in which higher long-term lithium exposure is associated with lower incidences of bipolar disorder. METHODS: We included longitudinal individual geographical data on municipality of residence, data from drinking water lithium measurements and time-specific data from all cases with a hospital contact with a diagnosis of mania/bipolar disorder from 1995 to 2013 (N=14 820) and 10 age- and gender-matched controls from the Danish population (N= 140 311). Average drinking water lithium exposure was estimated for all study individuals. RESULTS: The median of the average lithium exposure did not differ between cases with a diagnosis of mania/bipolar disorder (12.7 µg/L; interquartile range [IQR]: 7.9-15.5 µg/L) and controls (12.5 µg/L; IQR: 7.6-15.7 µg/L; P=.2). Further, the incidence rate ratio of mania/bipolar disorder did not decrease with higher long-term lithium exposure, overall, or within age categories (0-40, 41-60 and 61-100 years of age). CONCLUSION: Higher long-term lithium exposure from drinking water was not associated with a lower incidence of bipolar disorder. The association should be investigated in areas with higher lithium levels than in Denmark.

Methylated DNA for monitoring tumor growth and regression: how do we get there?

A wide range of protein cancer biomarkers is currently recommended in international guidelines for monitoring the growth and regression of solid tumors. However, a number of these markers are also present in low concentrations in blood obtained from healthy individuals and from patients with benign diseases. In contrast, evidence has accumulated that suggests that modified methylated DNA is strongly related to the cancer phenotype. The modifications found in modified methylated DNA include a global loss of methylation in the genomes of the tumor cells as well as focal hypermethylation of gene promoters. Because tumor cells naturally secrete DNA and upon cell death leak DNA, modified methylated DNA can be detected in blood, urine, sputum and other body fluids. At present international guidelines do not include recommendations for monitoring modified methylated DNA. The low level of evidence can partly be explained by incomplete collection of serial blood samples, by analytical challenges, and by lack of knowledge of how monitoring studies should be designed and how serial marker data obtained from individual patients should be interpreted. Here, we review the clinical validity and utility of methylated DNA for monitoring the activity of malignant disease.

Iodine concentrations in Danish groundwater: historical data assessment 1933-2011.

In areas where water is a major source of dietary iodine (I), the I concentration in drinking water is an important factor for public health and epidemiological understandings. In Denmark, almost all of the drinking water is originating from groundwater. Therefore, understanding the I variation in groundwater and governing factors and processes are crucial. In this study, we perform uni- and multivariate analyses of all available historical Danish I groundwater data from 1933 to 2011 (n = 2,562) to give an overview on the I variability for first time and to discover possible geochemical associations between I and twenty other elements and parameters. Special attention is paid on the description and the quality assurance of this complex compilation of historical data. The high variability of I in Danish groundwater (

Development and Validation of a 1D Dynamic Model of an Injection Moulding Process and Design of a Model-Based Nozzle Pressure Controller.

A 1D model describing the dynamics of an injection moulding machine and the injection process is presented. The model describes an injection cylinder actuated by a dual-pump electro-hydraulic speed-variable drive and the filling, holding and cooling phases of the injection moulding process utilising amorphous polymers. The model is suggested as the foundation for the design of model-based pressure controllers of, e.g., the nozzle pressure. The focus is on using material, mould and machine properties to construct the model, making it possible to analyse and design the dynamic system prior to manufacturing hardware or conducting experiments. Both the presented model and the developed controller show good agreement with experimental results. The proposed method is general in nature and enables the design, analysis and evaluation of the machine, material and mould dynamics for controller design based solely on the physical properties of the system.

Association Between Estimated Geocoded Residential Maternal Exposure to Lithium in Drinking Water and Risk for Autism Spectrum Disorder in Offspring in Denmark.

Importance: Lithium is a naturally occurring and trace element that has mood-stabilizing effects. Maternal therapeutic use of lithium has been associated with adverse birth outcomes. In animal models, lithium modulates Wnt/ß-catenin signaling that is important for neurodevelopment. It is unknown whether exposure to lithium in drinking water affects brain health in early life. Objective: To evaluate whether autism spectrum disorder (ASD) in offspring is associated with maternal exposure to lithium in drinking water during pregnancy. Design, Setting, and Participants: This nationwide population-based case-control study in Denmark identified 8842 children diagnosed with ASD born from 2000 through 2013 and 43 864 control participants matched by birth year and sex from the Danish Medical Birth Registry. These data were analyzed from March 2021 through November 2022. Exposures: Geocoded maternal residential addresses during pregnancy were linked to lithium level (range, 0.6 to 30.7 µg/L) in drinking water estimated using kriging interpolation based on 151 waterworks measurements of lithium across all regions in Denmark. Main Outcomes and Measures: ASD diagnoses were ascertained using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes recorded in the Danish Psychiatric Central Register. The study team estimated odds ratios (ORs) and 95% CIs for ASD according to estimated geocoded maternal exposure to natural source of lithium in drinking water as a continuous (per IQR) or a categorical (quartile) variable, adjusting for sociodemographic factors and ambient air pollutants levels. The study team also conducted stratified analyses by birth years, child's sex, and urbanicity. Results: A total of 8842 participants with ASD (male, 7009 [79.3%]) and 43 864 control participants (male, 34 749 [79.2%]) were studied. Every IQR increase in estimated geocoded maternal exposure to natural source of lithium in drinking water was associated with higher odds for ASD in offspring (OR, 1.23; 95% CI, 1.17-1.29). Elevated odds among offspring for ASD were estimated starting from the second quartile (7.36 to 12.67 µg/L) of estimated maternal exposure to drinking water with lithium and the OR for the highest quartile (more than 16.78 µg/L) compared with the reference group (less than 7.39 µg/L) was 1.46 (95% CI, 1.35-1.59). The associations were unchanged when adjusting for air pollution exposures and no differences were apparent in stratified analyses. Conclusions and Relevance: Estimated maternal prenatal exposure to lithium from naturally occurring drinking water sources in Denmark was associated with an increased ASD risk in the offspring. This study suggests that naturally occurring lithium in drinking water may be a novel environmental risk factor for ASD development that requires further scrutiny.

Maternal exposure to arsenic in drinking water and risk of congenital heart disease in the offspring.

INTRODUCTION: Prenatal exposure to arsenic is suspected to impair fetal health, including congenital malformations. Few studies investigated an association between maternal exposure to arsenic and congenital heart disease. OBJECTIVE: To examine the association between maternal exposure to arsenic through drinking water and congenital heart disease among offspring. METHODS: This nationwide cohort study included all liveborn children in Denmark, 1997-2014. Maternal addresses at fetal age 4 weeks were linked to drinking water supply areas. Exposure was arsenic concentration in drinking water in first trimester in four categories (<0.5 µg/L, 0.5-0.9 µg/L, 1.0-4.9 µg/L, ≥5.0 µg/L). Outcomes were defined as congenital heart disease diagnosed within the first year of life, with sub-categorization of severe, septal defects and valvular heart defect. Associations between arsenic levels and congenital heart disease were analysed using logistic regression, presented as odds ratios (OR) with 95% confidence interval (CI), and adjusted for year of birth, mother's educational level and ethnicity. RESULTS: A total of 1,042,413 liveborn children were included of whom 1.0% had a congenital heart disease. The OR of congenital heart disease was higher among children exposed to all levels of arsenic above 0.5 µg/L; the OR was 1.13 (95% CI: 1.08-1.19) for exposure of 0.5-0.9 µg/L, 1.33 (95% CI: 1.27-1.39) for 1.0-4.9 µg/L and 1.42 (95% CI: 1.24-1.63) for ≥5.0 µg/L. Similar associations were observed for congenital septal defects. The OR was also higher for severe congenital heart disease but at the same level among all exposure levels ≥0.5 µg/L. The OR of congenital valvular heart defects was only higher among children with maternal exposure to arsenic in drinking water ≥5.0 µg/L. The associations were similar for boys and girls. CONCLUSION: The findings indicate that maternal exposure to arsenic in drinking water even at low concentrations (i.e., 0.5-0.9 µg/L) increased the risk of congenital heart disease in the offspring.

Long-Term Comparison of 7 SARS-CoV-2 Antibody Assays in the North Zealand Covid-19 Cohort.

BACKGROUND: Throughout the coronavirus disease 2019 (Covid-19) pandemic numerous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody assays have been approved through Emergency Use Authorization and require further evaluation of sensitivity and specificity in clinical laboratory settings prior to implementation. METHODS: We included 1733 samples from 375 PCR-confirmed SARS-CoV-2-positive individuals of the North Zealand Covid-19 Cohort in an 8-month period. We investigated diagnostic sensitivity and specificity against consensus and PCR and interassay agreement over time for 5 SARS-CoV-2 immunoassays [Roche-nucleocapsid (NC)-total, Roche-receptor binding domain (RBD)-total, Siemens-RBD-IgG, Siemens-RBD-total, Thermo Fisher Scientific (TFS)-RBD-IgG] commercially available on automated platforms and 2 ELISA assays (TFS-RBD-total, Wantai-RBD-total). RESULTS: Early interassay discrepancy in up to 49% of samples decreased steadily during the first 18 days. By day 18, all assays had reached a plateau between 82.3% and 90.5% seropositivity compared to PCR. Assays ranked by closest agreement with the consensus model beyond day 18 (sensitivity/specificity against consensus) were as follows: Roche-RBD-total, 99.8%/100.0%; Wantai-RBD-total, 99.8%/99.7%; Roche-NC-total, 97.8%/100.0%; Siemens-RBD-total, 98.0%/98.7%; TFS-RBD-total, 96.9%/99.7%; TFS-RBD-IgG, 91.5%/100.0%; and Siemens-RBD-IgG, 94.6%/89.9%. We found that 7.8% of PCR-positive patients remained seronegative in all assays throughout the study. CONCLUSIONS: All included assays had sensitivities against consensus >90% past day 18. For the current recommended use of antibody assays to detect former, undocumented Covid-19, our data suggest the use of total antibody assays rather than IgG-specific assays due to higher long-term sensitivity. Finally, a nonresponding subpopulation of 7.8% in our cohort with persistent seronegative results raises concern of a possible substantial number of people with continued low protection following natural SARS-CoV-2 infection.

A Roman provincial city and its contamination legacy from artisanal and daily-life activities.

Roman metal use and related extraction activities resulted in heavy metal pollution and contamination, in particular of Pb near ancient mines and harbors, as well as producing a global atmospheric impact. New evidence from ancient Gerasa (Jerash), Jordan, suggests that small-scale but intense Roman, Byzantine and Umayyad period urban, artisanal, and everyday site activities contributed to substantial heavy metal contamination of the city and its hinterland wadi, even though no metal mining took place and hardly any lead water pipes were used. Distribution of heavy metal contaminants, especially Pb, observed in the urban soils and sediments within this ancient city and its hinterland wadi resulted from aeolian, fluvial, cultural and post-depositional processes. These represent the contamination pathways of an ancient city-hinterland setting and reflect long-term anthropogenic legacies at local and regional scales beginning in the Roman period. Thus, urban use and re-use of heavy metal sources should be factored into understanding historical global-scale contaminant distributions.

Trace elements in drinking water and the incidence of attention-deficit hyperactivity disorder.

BACKGROUND: Trace elements have been suggested to have neurotoxic effects and increase the risk of neurodevelopmental disorders, but studies of a potential role of trace elements in relation to Attention-Deficit/Hyperactivity Disorder (ADHD) are very limited. The objective of this study was to conduct an exploratory analysis investigating the associations between 17 geogenic trace elements (Ba, Co, Eu, I, Li, Mo, Rb, Re, Rh, Sb, Sc, Se, Si, Sr, Ti, U and Y) found in Danish drinking water and the risk of developing ADHD. METHODS: In this cohort study, 284,309 individuals, born 1994-2007, were followed for incidence of ADHD from the age of five until the end of study, December 31, 2016. We conducted survival analyses, using Poisson regression to estimate incidence rate ratios (IRRs) with 95 % confidence intervals (CI) in three different confounder adjustment scenarios. RESULTS: In a model including adjustments for age, sex, calendar year, parental socio-economic status, neighborhood level socio-economic status and parental psychiatric illness, we found that six of the 17 trace elements (Sr, Rb, Rh, Ti, Sb and Re) were associated with an increased risk of ADHD, whereas two (Ba and I) were inversely associated with ADHD. However, when including region as a covariate in the model, most trace elements were no longer associated with ADHD or the association changed direction. Four trace elements (I, Li, Rb, and Y) remained significantly associated with ADHD but in an inverse direction and for three of these (I, Li and Y), we found significant interactions with region in their association with ADHD. CONCLUSION: The trace elements under investigation, at levels found in Danish drinking water, do not seem to contribute to the development of ADHD and our findings highlight the importance of examining consistency of associations across geographic areas.

Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials.

BACKGROUND: The phosphodiesterase-4 inhibitor roflumilast can improve lung function and prevent exacerbations in certain patients with chronic obstructive pulmonary disease (COPD). We therefore investigated whether roflumilast would reduce the frequency of exacerbations requiring corticosteroids in patients with COPD. METHODS: In two placebo-controlled, double-blind, multicentre trials (M2-124 and M2-125) with identical design that were done in two different populations in an outpatient setting, patients with COPD older than 40 years, with severe airflow limitation, bronchitic symptoms, and a history of exacerbations were randomly assigned to oral roflumilast (500 microg once per day) or placebo for 52 weeks. Primary endpoints were change in prebronchodilator forced expiratory volume in 1 s (FEV(1)) and the rate of exacerbations that were moderate (glucocorticosteroid-treated) or severe. Analysis was by intention to treat. The trials are registered with ClinicalTrials.gov, number NCT00297102 for M2-124, and NCT00297115 for M2-125. FINDINGS: Patients were assigned to treatment, stratified according to smoking status and treatment with longacting beta(2) agonists, and given roflumilast (n=1537) or placebo (n=1554). In both studies, the prespecified primary endpoints were achieved and were similar in magnitude. In a pooled analysis, prebronchodilator FEV(1) increased by 48 mL with roflumilast compared with placebo (p<0.0001). The rate of exacerbations that were moderate or severe per patient per year was 1.14 with roflumilast and 1.37 with placebo (reduction 17% [95% CI 8-25], p<0.0003). Adverse events were more common with roflumilast (1040 [67%]) than with placebo (963 [62%]); 219 (14%) patients in the roflumilast group and 177 (12%) in the placebo group discontinued because of adverse events. In the pooled analysis, the difference in weight change during the study between the roflumilast and placebo groups was -2.17 kg. INTERPRETATION: Since different subsets of patients exist within the broad spectrum of COPD, targeted specific therapies could improve disease management. This possibility should be explored further in prospective studies. FUNDING: Nycomed.

Loot box engagement and problem gambling among adolescent gamers: Findings from a national survey.

Loot boxes represent a form of microtransaction in many video games that have some resemblance with gambling. Research on this subject is still in its infancy, and particular there are few studies involving young people. Using cross-sectional survey data from a representative sample of 1,137 participants aged 12-16 years, this study examined loot box engagement patterns and links with problem gambling severity. Nearly half (45.6%) of the participants that were involved in gaming in the past year engaged in loot box activities at some level, and loot box users were predominantly male. The vast majority of the males (93%) had earned, bought, or sold items from a loot box whereas 15% of the females reported engagement with loot boxes. There was a significant positive correlation between loot box engagement and problem gambling severity when controlling for core demo-graphic factors. Compared to participants with no engagement or participants who solely obtained a loot box, the proportions of at-risk and problem gamblers were higher among those, who had purchased or sold items from a loot box. The findings provide new insights into the links between loot box engagement and problem gambling among adolescent populations. Specifically, the study provides new knowledge on different engagement patterns among loot box users and their implications. On this basis, different measures to reduce loot box purchases and reduce marketplace structures are discussed.

Exposure to Manganese in Drinking Water during Childhood and Association with Attention-Deficit Hyperactivity Disorder: A Nationwide Cohort Study.

BACKGROUND: Manganese (Mn) in drinking water may increase the risk of several neurodevelopmental outcomes, including attention-deficit hyperactivity disorder (ADHD). Earlier epidemiological studies on associations between Mn exposure and ADHD-related outcomes had small sample sizes, lacked spatiotemporal exposure assessment, and relied on questionnaire data (not diagnoses)-shortcomings that we address here. OBJECTIVE: Our objective was to assess the association between exposure to Mn in drinking water during childhood and later development of ADHD. METHODS: In a nationwide population-based registry study in Denmark, we followed a cohort of 643,401 children born 1992-2007 for clinical diagnoses of ADHD. In subanalyses, we classified cases into ADHD-Inattentive and ADHD-Combined subtypes based on hierarchical categorization of International Classification of Diseases (ICD)-10 codes. We obtained Mn measurements from 82,574 drinking water samples to estimate longitudinal exposure during the first 5 y of life with high spatiotemporal resolution. We modeled exposure as both peak concentration and time-weighted average. We estimated sex-specific hazard ratios (HRs) in Cox proportional hazards models adjusted for age, birth year, socioeconomic status (SES), and urbanicity. RESULTS: We found that exposure to increasing levels of Mn in drinking water was associated with an increased risk of ADHD-Inattentive subtype, but not ADHD-Combined subtype. After adjusting for age, birth year, and SES, females exposed to high levels of Mn (i.e., >100µg/L) at least once during their first 5 y of life had an HR for ADHD-Inattentive subtype of 1.51 [95% confidence interval (CI): 1.18, 1.93] and males of 1.20 (95% CI: 1.01, 1.42) when compared with same-sex individuals exposed to <5µg/L. When modeling exposure as a time-weighted average, sex differences were no longer present. DISCUSSION: Mn in drinking water was associated with ADHD, specifically the ADHD-Inattentive subtype. Our results support earlier studies suggesting a need for a formal health-based drinking water guideline value for Mn. Future Mn-studies should examine ADHD subtype-specific associations and utilize direct subtype measurements rather than relying on ICD-10 codes alone. https://doi.org/10.1289/EHP6391.