Urticaria and the risk of cancer: a Danish population-based cohort study.

BACKGROUND: Urticaria has been tentatively linked to cancer, but epidemiological evidence supporting this link is sparse and conflicting. We therefore conducted a population-based cohort study using healthcare databases of the Danish population (January 1980-December 2022). We followed 87,507 people for a median of 10.1 years after first hospital contact for urticaria. OBJECTIVES: To examine associations of a hospital diagnosis of urticaria with incident cancer. METHODS: We computed absolute risk of cancer and standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) standardized to Danish national cancer rates. In a cross-sectional analysis, we examined whether the extent of cancer spread differed between people with vs. without a previous urticaria diagnosis. RESULTS: The overall SIR for all types of cancer was 1.09 (95% CI, 1.06-1.11) based on 7,788 observed vs. 7,161 expected cases. The risk for any cancer was 0.7% (95% CI, 0.6-0.7) for the first year of follow-up. Cancer was diagnosed in 588 people with urticaria during the first year of follow-up (SIR 1.49, 95% CI, 1.38-1.62) and in 7,200 people thereafter (SIR 1.06, 95% CI, 1.04-1.09). During the first year of follow-up, we found strong associations with hematological cancers (e.g., non-Hodgkin lymphoma SIR 2.91, 95% CI, 1.92-4.23). Cancer stage was similar in people with vs. without previous urticaria diagnosis. CONCLUSIONS: At the time of urticaria diagnosis, or in the first year afterwards, we found a large increase in the risk for cancer. In subsequent years, a persistent 6% increase in risk remained. Diagnostic efforts may partly explain the elevated short-term risk, but occult cancer may promote urticaria, or cancer and urticaria share common risk factors.

Clinical presentation and genetics of tricho-rhino-phalangeal syndrome (TRPS) type 1: A single-center case series of 15 patients and seven novel TRPS1 variants.

Tricho-rhino-phalangeal syndrome (TRPS) is a rare malformation syndrome characterized by distinctive facial, ectodermal, and skeletal features. TRPS is divided into TRPS type I/III caused by pathogenic variants in TRPS1 and TRPS type II caused by contiguous gene deletions also spanning EXT1 and RAD21. Due to its rarity, knowledge of the clinical course of TRPS remains limited. Therefore, we collected and characterized a case series of 15 TRPS type I patients (median age at diagnosis 15 [interquartile range: 10-18] years, 11 females [73%]) seen at Aarhus University Hospital, Denmark, with a median follow-up period of 10 years. We estimated a minimum point prevalence of 0.5 in 100,000 (95% CI: 0.3-0.8 per 100,000) persons. Common craniofacial features included fine and sparse hair with a high anterior hairline, eyebrows with lateral thinning and a thicker medial part, prominent ears, a bulbous nose tip with small nasal alae, a low-hanging, and often wide columella, and a long philtrum with a thin upper vermillion. Specific skeletal features included short stature and deviating and short fingers with cone-shaped epiphyses and shortened metacarpals on radiographs. The most significant morbidity of the cohort was joint complaints, which were reported by all patients, often already before the TRPS diagnosis was established. We identified ten different TRPS1 variants including both frameshift/nonsense, missense, and splice-site variants, including seven variants not previously reported in the literature. In accordance with previous literature, no genotype-phenotype correlation was identified. The clinical trajectories were heterogeneous involving pediatrics, dermatology, orthopedic surgery, clinical genetics, and/or odontology, emphasizing that close multidisciplinary collaboration is essential for early diagnosis of TRPS and to ensure proper and timely patient care and counseling.

Autoimmune blistering disorders and cardiovascular risks: A population-based cohort study.

BACKGROUND: Autoimmune blistering disorders (ABDs) might elevate cardiovascular risk, but studies are lacking. OBJECTIVE: The objective of this study was to examine if ABDs elevate the risk of atherosclerotic cardiovascular disease, heart failure, arrhythmia, venous thromboembolism, and cardiovascular death. METHODS: A population-based cohort of Danish patients with ABD (≥18 years of age) diagnosed during 1996-2021 (n = 3322) was compared with an age- and sex-matched comparison cohort from the general population (n = 33,195). RESULTS: Compared with the general population, patients with ABDs had higher 1-year risks of atherosclerotic cardiovascular disease (3.4% vs 1.6%), heart failure (1.9% vs 0.7%), arrhythmia (3.8% vs 1.3%), venous thromboembolism (1.9% vs 0.3%), and cardiovascular death (3.3% vs 0.9%). The elevated risk persisted after 10 years for all outcomes but arrhythmia. The hazard ratios associating ABDs with the outcomes during the entire follow-up were 1.24 (1.09-1.40) for atherosclerotic cardiovascular disease, 1.48 (1.24-1.77) for heart failure, 1.16 (1.02-1.32) for arrhythmia, 1.87 (1.50-2.34) for venous thromboembolism, and 2.01 (1.76-2.29) for cardiovascular death. The elevated cardiovascular risk was observed for both pemphigus and pemphigoid. LIMITATIONS: Our findings might only generalize to patients with ABDs without prevalent cardiovascular diseases. CONCLUSION: Patients with ABDs had an elevated cardiovascular risk compared with age- and sex-matched controls.

Prevalence and Patient Characteristics of Ectodermal Dysplasias in Denmark.

Importance: Ectodermal dysplasias constitute a group of rare genetic disorders of the skin and skin appendages with hypodontia, hypotrichosis, and hypohidrosis as cardinal features. There is a lack of population-based research into the epidemiology of ectodermal dysplasias. Objective: To establish a validated population-based cohort of patients with ectodermal dysplasia in Denmark and to assess the disease prevalence and patient characteristics. Design, Setting, and Participants: This nationwide cohort study used individual-level registry data recorded across the Danish universal health care system to identify patients with ectodermal dysplasias from January 1, 1995, to August 25, 2021. A 3-level search of the Danish National Patient Registry and the Danish National Child Odontology Registry was conducted to identify patients with diagnosis codes indicative of ectodermal dysplasias; patients registered in the Danish RAREDIS Database, the Danish Database of Genodermatoses, and local databases were also added. The search results underwent diagnosis validation and review of clinical data using medical records. Of 844 patient records suggestive of ectodermal dysplasias, 791 patients (93.7%) had medical records available for review. Positive predictive values of the diagnosis coding were computed, birth prevalence was estimated, and patient characteristics were identified. Data analysis was performed from May 4 to December 22, 2023. Results: The identified and validated study cohort included 396 patients (median [IQR] age at diagnosis, 13 [4-30] years, 246 females [62.1%]), of whom 319 had confirmed ectodermal dysplasias and 77 were likely cases. The combined positive predictive value (PPV) for ectodermal dysplasia-specific diagnosis codes was 67.0% (95% CI, 62.7%-71.0%). From 1995 to 2011, the estimated minimum birth prevalence per 100 000 live births was 14.5 (95% CI, 12.2-16.7) for all ectodermal dysplasias and 2.8 (95% CI, 1.8-3.8) for X-linked hypohidrotic ectodermal dysplasias. A molecular genetic diagnosis was available for 241 patients (61%), including EDA (n = 100), IKBKG (n = 55), WNT10A (n = 21), TRPS1 (n = 18), EDAR (n = 10), P63 (n = 9), GJB6 (n = 9), PORCN (n = 7), and other rare genetic variants. Conclusions and Relevance: The findings of this nationwide cohort study indicate that the prevalence of ectodermal dysplasias was lower than previously reported. Furthermore, PPVs of the search algorithms emphasized the importance of diagnosis validation. The establishment of a large nationwide cohort of patients with ectodermal dysplasias, including detailed clinical and molecular data, is a unique resource for future research in ectodermal dysplasias.

Occupational exposure to epoxy components and risk of dermatitis: A registry-based follow-up study of the wind turbine industry.

BACKGROUND: Allergic contact allergy and dermatitis are frequently reported among epoxy-exposed workers. OBJECTIVES: To determine the risk of dermatitis associated with epoxy exposure. METHODS: We followed 825 epoxy-exposed and 1091 non-exposed blue-collar workers, and 493 white-collar workers of a Danish wind turbine blade factory during 2017-2022 with linked data from national health registers on diagnoses, patch testing, or fillings of prescriptions for topical corticosteroids. Incidence rate ratios of dermatitis or a first-time topical corticosteroid prescription were estimated with Poisson regression using non-exposed blue-collar workers as reference. We similarly estimated incidence rate ratios for the duration of epoxy exposure and current epoxy exposure. RESULTS: Epoxy-exposed blue-collar workers showed a dermatitis incidence rate of 2.1 per 100 000 person days, a two-fold increased risk of dermatitis and a 20% increased risk of filling a prescription for topical corticosteroids. Incidence rate ratios were higher during early exposure and declined with further exposure for both outcomes. White-collar workers had generally lower risks. CONCLUSION: We observed an increased risk of dermatitis following epoxy exposure confirming previous case reports and cross-sectional studies emphasizing the need for intensified focus on preventive efforts for this group of workers.

Use of methotrexate and risk of skin cancer: a nationwide case-control study.

BACKGROUND: Methotrexate (MTX) use has been suspected of increasing the risk of skin cancer. The aim of this investigation was to examine the association between the use of MTX and the risk of basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC) and cutaneous malignant melanoma (CMM). METHODS: In a nationwide Danish case-control study, we identified incident, histologically verified cases of BCC (n = 131,447), cSCC (n = 18,661) or CMM (26,068) from 2004 to 2018. We matched 10 controls to each case on sex and birth year using risk-set sampling and computed crude and adjusted odds ratios (ORs) using conditional logistic regression for the use of MTX (≥2.5 g) compared with never-use. RESULTS: Use of MTX was associated with increased risk of BCC, cSCC and CMM with adjusted ORs of (95% confidence interval) 1.29 (1.20-1.38), 1.61 (1.37-1.89) and 1.35 (1.13-1.61), respectively. For BCC and cSCC, ORs increased with higher cumulative doses. When restricting the study population to patients with psoriasis, the ORs were 1.43 (1.23-1.67), 1.18 (0.80-1.74) and 1.15 (0.77-1.72), respectively. CONCLUSIONS: We observed an increased risk of BCC and cSCC associated with the use of MTX with evidence of a dose-response pattern; however, the association was not consistent when restricting the study population to patients with psoriasis.

Prevalence of skin sensitization and dermatitis among epoxy-exposed workers in the wind turbine industry.

BACKGROUND: A high prevalence of skin sensitization and dermatitis has been reported among workers exposed to epoxy components. OBJECTIVES: To estimate the risk of skin sensitization and dermatitis among workers exposed to epoxy components during production of wind turbine blades while using comprehensive safety measures. METHODS: A cross-sectional study of 180 highly epoxy-exposed production workers and 41 nonexposed office workers was conducted at two wind turbine blade factories in Denmark. Participants underwent a skin examination, were tested with a tailored patch test panel including epoxy-containing products used at the factories, and answered a questionnaire. RESULTS: Sixteen production workers (8·9%) were sensitized to an epoxy component compared with none of the office workers. Skin sensitization was more frequent within the first year of exposed employment. Strong selection bias by atopic status was indicated. Among nonatopic workers, the prevalence of dermatitis was higher among production workers (16·4%) than among office workers [6·5%, odds ratio (OR) 2·3, 95% confidence interval (CI) 0·6-9·1] and higher among the sensitized workers (43·8%) than the nonsensitized workers (14·6%, OR 4·5, 95% CI 1·6-12·7). Resins based on diglycidyl ether of bisphenol A and F were the most frequent sensitizers. One of the four workers sensitized to epoxy components used at the factories did not react to the epoxy resin of the TRUE test® panel. CONCLUSIONS: Despite comprehensive skin protection, sensitization and dermatitis are prevalent among highly epoxy-exposed workers in the wind turbine industry in Denmark. Our findings document the need for intensified preventive efforts and emphasize the importance of tailored patch testing. What is already known about this topic? Epoxy components are well-known sensitizers of the skin. A high prevalence of skin sensitization and dermatitis has been reported among workers exposed to epoxy components. Comprehensive protective equipment is recommended when working with epoxy components. What does this study add? Despite comprehensive skin protection, skin sensitization and dermatitis are prevalent among epoxy-exposed workers. We found that 40% of workers sensitized to epoxy products had dermatitis. Only 75% of the sensitized workers were detected by the epoxy resin of the TRUE test® , which emphasizes the importance of tailored testing.

Incident Herpes Zoster and Risk of Dementia: A Population-Based Danish Cohort Study.

BACKGROUND AND OBJECTIVES: Herpes zoster is caused by reactivation of the neurotrophic varicella-zoster virus. Zoster may contribute to development of dementia through neuroinflammation, cerebral vasculopathy, or direct neural damage, but epidemiological evidence is limited. We used data from linked nationwide Danish registries to conduct a cohort study of the association between zoster and dementia during 1997 to 2017. As secondary aims, we examined if associations were more pronounced for zoster involving cranial nerves (mainly ophthalmic zoster) or the central nervous system and Alzheimer's disease as an outcome. METHODS: We included people aged ≥40 years with zoster and a general population comparison cohort matched 5:1 by sex and birth year. We identified zoster and dementia in the registries using prescription records in the community and hospital diagnoses. We used Cox regression to compute confounder-adjusted hazard ratios (HR) with 95% confidence intervals (CIs) for dementia associated with zoster during 0-1 year and 1-21 years of follow-up. We compared the cumulative incidence of dementia, inverse probability-weighted for confounders. RESULTS: The study included 247,305 people with zoster and 1,235,890 matched general population comparators (median age 64 years; 61% female). The HR of all-cause dementia was 0.98 (95% CI: 0.92-1.04) during the first year and 0.93 (95% CI: 0.90-0.95) thereafter in people with zoster versus matched comparators. Dementia was diagnosed in 9.7% of zoster patients and 10.3% of matched comparators by end of follow-up. We observed no increased long-term risk of dementia in subgroup analyses, except possibly in people with central nervous system infection (HR 1.94; 95% CI: 0.78-4.80). Analyses of Alzheimer's disease as a separate outcome showed similar results. DISCUSSION: Herpes zoster is not associated with increased risk of dementia, and contrary to expectation we found a small decrease in risk. The explanation for this finding is unclear, and systematic errors should be considered. Patients with central nervous system involvement had almost two-fold increased relative risk of dementia. The population attributable fraction of dementia due to this rare complication is estimated at 0.014%. Therefore, universal vaccination against varicella-zoster virus in the elderly is unlikely to reduce dementia risk.

Validation of the Danish Comorbidity Index for Acute Myocardial Infarction for predicting one-year mortality in patients with venous thromboembolism.

INTRODUCTION: The Danish Comorbidity Index for Acute Myocardial Infarction (DANCAMI) was developed to predict one-year mortality after myocardial infarction. We validated DANCAMI in predicting one-year mortality after venous thromboembolism (VTE). MATERIALS AND METHODS: We identified all first-time VTE patients in Denmark during 2000-2015. Using Cox regression, we assessed the performance of DANCAMI to predict one-year all-cause mortality using Nagelkerke's R2, Harrell's C-Statistic, the net reclassification index (NRI), and the integrated discrimination improvement (IDI). We compared the performance of DANCAMI with the Charlson Comorbidity Index (CCI) and the Elixhauser Comorbidity Index (ECI) and evaluated whether DANCAMI comorbidities not included in the CCI predicted one-year mortality. We stratified the analyses by type (deep vein thrombosis [DVT] and pulmonary embolism [PE]) and presence of provoking risk factors. RESULTS: We identified 108,824 VTE patients of whom 20,649 (19%) died within one year. The R2, C-Statistic, NRI, and IDI for DANCAMI were 0.35, 0.76, 0.63, and 0.098 for VTE overall; 0.43, 0.80, 0.70, and 0.105 for DVT; and 0.24, 0.71, 0.54, and 0.083 for PE. The R2 and C-Statistic for VTE overall were 0.35 and 0.76 for CCI and 0.33 and 0.75 for ECI. After adjusting for age, sex, and all CCI comorbidities, seven DANCAMI comorbidities, not included in the CCI, predicted increased mortality. DANCAMI performed better than the CCI and ECI in predicting mortality after provoked VTE, including provoked DVT and PE. CONCLUSION: DANCAMI performed comparable to existing comorbidity indices in predicting one-year mortality after first-time VTE overall, but better after provoked VTE.

Fever of Unknown Origin and Incidence of Cancer.

BACKGROUND: Diagnostic tools for determining causes of fever of unknown origin (FUO) have improved over time. We examined if cancer incidence among these patients changed over a 20-year period. METHODS: Population-based cohort study using nationwide Danish registries. We identified individuals diagnosed with FUO (1998-2017) to quantify their excess risk of cancer compared with the general population. Follow-up for cancer started 1 month after FUO. We computed absolute risks and standardized incidence ratios (SIRs) of cancer, and mortality rate ratios adjusted for age, sex, and cancer stage. RESULTS: Among 6620 patients with FUO (46.9% male; median age: 39 years), 343 were diagnosed with cancer (median follow-up: 6.5 years). The 1- to <12-month risk was 1.2%, and the SIR was 2.3 (95% CI, 1.8-2.9). The increased 1- to <12-month SIR was mainly due to an excess of Hodgkin lymphoma (SIR = 41.7) non-Hodgkin lymphoma (SIR = 16.1), myelodysplastic syndrome/chronic myeloproliferative diseases (SIR = 6.0), lower gastrointestinal cancer (SIR = 3.3), and urinary tract cancer (SIR = 2.9). Beyond 1-year follow-up, malignant melanoma, hepatobiliary tract/pancreatic cancer, and brain/CNS/eye cancer were diagnosed more often than expected. The 1- to <12-month cancer SIR attenuated over time, and for the 2013-2017 period we found no excess risk. Patients diagnosed with cancer ≤1 year after FUO had similar mortality to cancer patients without this diagnosis. CONCLUSIONS: Patients with FUO have a higher 1- <12-month cancer SIR; thereafter, the incidence for most cancers equals that of the general population. Decreasing SIRs over time suggests improvements in the initial diagnostic workup for FUO.

Flecainide and risk of skin neoplasms: Results of a large nested case-control study in Spain and Denmark.

Background: A previous study in Denmark suggested an increased melanoma risk associated with the use of flecainide. Objective: To study the association between flecainide use and the risk of melanoma and non-melanoma skin cancer in Spain and Denmark. Methods: We conducted a multi-database case-control study in (database/study period) Spain (SIDIAP/2005-2017 and BIFAP/2007-2017) and Denmark (Danish registries/2001-2018). We included incident cases of melanoma or non-melanoma skin cancer (NMSC) aged ≥18 with ≥2 years of previous data (≥10 years for Denmark) before the skin cancer and matched them to controls (10:1 by age and sex). We excluded persons with immunosuppression or previous cancer. We defined ever-use as any prescription fill and high-use as a cumulative dose of at least 200 g (reference: never-use). We categorized a cumulative dose for a dose-response assessment. We used conditional logistic regression to compute ORs (95% CI) adjusted for photosensitizing, anti-neoplastic, disease-specific drugs and comorbidities. Results: The total numbers of melanoma/NMSC cases included were 7,809/64,230 in SIDIAP, 4,661/31,063 in BIFAP, and 27,978/152,821 in Denmark. In Denmark, high-use of flecainide was associated with increased adjusted ORs of skin cancer compared with never-use [melanoma: OR 1.97 (1.38-2.81); NMSC: OR 1.34 (1.15-1.56)]. In Spain, an association between high-use of flecainide and NMSC was also observed [BIFAP: OR 1.42 (1.04-1.93); SIDIAP: OR 1.19 (0.95-1.48)]. There was a non-significant dose-response pattern for melanoma in Denmark and no apparent dose-response pattern for NMSC in any of the three databases. We found similar results for ever-use of flecainide. Conclusion: Flecainide use was associated with an increased risk of melanoma (Denmark only) and NMSC (Denmark and Spain) but without substantial evidence of dose-response patterns. Further studies are needed to assess for possible unmeasured confounders.

Validity of First-Time Diagnoses of Darier's Disease in the Danish National Patient Registry.

PURPOSE: Darier's disease (DD) is a rare genetic skin disease, characterized by yellow-brown, scaly, crusted papules in seborrheic areas and specific nail changes. This study aimed to validate all first-time diagnoses of DD in Danish National Patient Registry (DNPR). The intent of the study is validation of DNPR for epidemiological and clinical studies on DD. PATIENTS AND METHODS: We identified all patients in DNPR who received their first-time diagnosis of DD between January 1, 1977 and December 31, 2018 (International Classification of Diseases [ICD]-8 code 75721 until the end of 1993: ICD-10 code Q828F thereafter). We restricted to diagnoses from departments of dermatology, where these patients are managed. We validated diagnoses against information from medical records, using predefined data extraction sheets and validation criteria. We classified diagnoses as probable when characteristic clinical features were present; confirmed when there was also genetic confirmation, histopathological confirmation and/or positive family history, or rejected (remaining patients). We estimated positive predictive values (PPVs) with 95% confidence intervals (CIs) for diagnoses overall and stratified by ICD classification, sex, age at diagnosis, year of diagnosis, type of diagnosis, and type of contact. RESULTS: We identified 277 first-time diagnoses of DD, of which 229 (82.7%) stemmed from departments of dermatology. Medical records were available for 196 (85.6%) of these. The overall PPVs for probable and confirmed DD were 89.3% (95% CI: 84.2-92.9) and 81.1% (95% CI: 75.1-86.0), respectively. The PPV for probable ICD-8 diagnosis (95.8% (95% CI: 82.1-99.5)) was slightly higher than that of probable ICD-10 diagnosis (88.4% (95% CI: 82.7-92.3)). CONCLUSION: The validity of first-time diagnoses of DD recorded by departments of dermatology in the DNPR is relatively high, making DNPR suitable for epidemiological studies on DD in Denmark, as well as a useful source for recruitment to clinical studies on DD.

Adverse outcomes after partner bereavement in people with reduced kidney function: Parallel cohort studies in England and Denmark.

OBJECTIVES: To investigate whether partner bereavement is associated with adverse cardiovascular and kidney-related events in people with reduced kidney function. DESIGN: Two parallel matched cohort studies using linked routinely collected health data. SETTING: England (general practices and hospitals using linked Clinical Practice Research Datalink, Hospital Episode Statistics, and Office of National Statistics) and Denmark (hospitals and community pharmacies using the Danish National Patient, Prescription and Education Registries and the Civil Registration System). PARTICIPANTS: Bereaved people with reduced kidney function (estimated glomerular filtration rate (eGFR) <60mL/min/1.73m2 (England) or hospital-coded chronic kidney disease (Denmark)) and non-bereaved people with reduced kidney function similarly defined, matched on age, sex, general practice (England), and county of residence (Denmark) and followed-up from the bereavement date of the exposed person. MAIN OUTCOME MEASURES: Cardiovascular disease (CVD) or acute kidney injury (AKI) hospitalization, or death. RESULTS: In people with reduced kidney function, we identified 19,820 (England) and 5,408 (Denmark) bereaved individuals and matched them with 134,828 (England) and 35,741 (Denmark) non-bereaved individuals. Among the bereaved, the rates of hospitalizations (per 1000 person-years) with CVD were 31.7 (95%-CI: 30.5-32.9) in England and 78.8 (95%-CI: 74.9-82.9) in Denmark; the rates of hospitalizations with AKI were 13.2 (95%-CI: 12.5-14.0) in England and 11.2 (95%-CI: 9.9-12.7) in Denmark; and the rates of death were 70.2 (95%-CI: 68.5-72.0) in England and 126.4 (95%-CI: 121.8-131.1) in Denmark. After adjusting for confounders, we found increased rates of CVD (England, HR 1.06 [95%-CI: 1.01-1.12]; Denmark, HR 1.10 [95%-CI: 1.04-1.17]), of AKI (England, HR 1.20 [95%-CI: 1.10-1.31]; Denmark HR 1.36 [95%-CI: 1.17-1.58]), and of death (England, HR 1.10 [95%-CI: 1.05-1.14]; Denmark HR 1.20 [95%-CI: 1.15-1.25]) in bereaved compared with non-bereaved people. CONCLUSIONS: Partner bereavement is associated with an increased rate of CVD and AKI hospitalization, and death in people with reduced kidney function. Additional supportive care for this at-risk population may help prevent serious adverse events.

Association Between Atopic Dermatitis and Educational Attainment in Denmark.

IMPORTANCE: Atopic dermatitis (AD) may affect academic performance through multiple pathways, including poor concentration associated with itching, sleep deprivation, or adverse effects of medications. Because educational attainment is associated with health and well-being, any association with a prevalent condition such as AD is of major importance. OBJECTIVE: To examine whether a childhood diagnosis of AD is associated with lower educational attainment. DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study used linked routine health care data from January 1, 1977, to June 30, 2017 (end of registry follow-up), in Denmark. The study population included all children born in Denmark on June 30, 1987, or earlier with an inpatient or outpatient hospital clinic diagnosis of AD recorded before their 13th birthday (baseline) and a comparison cohort of children from the general population matched by birth year and sex. A secondary analysis included exposure-discordant full siblings as a comparison cohort to account for familial factors. Data were analyzed from September 11, 2019, to January 21, 2021. EXPOSURES: Hospital-diagnosed AD. MAIN OUTCOMES AND MEASURES: Estimated probability or risk of not attaining specific educational levels (lower secondary, upper secondary, and higher) by 30 years of age among children with AD compared with children in the matched general population cohort. Corresponding risk ratios (RRs) were computed using Poisson regression that was conditioned on matched sets and adjusted for age. The sibling analysis was conditioned on family and adjusted for sex and age. RESULTS: The study included a total of 61 153 children, 5927 in the AD cohort (3341 male [56.4%]) and 55 226 from the general population (31 182 male [56.5%]). Compared with matched children from the general population, children with AD were at increased risk of not attaining lower secondary education (150 of 5927 [2.5%] vs 924 of 55 226 [1.7%]; adjusted RR, 1.50; 95% CI, 1.26-1.78) and upper secondary education (1141 of 5777 [19.8%] vs 8690 of 52 899 [16.4%]; RR, 1.16; 95% CI, 1.09-1.24), but not higher education (2406 of 4636 [51.9%] vs 18 785 of 35 408 [53.1%]; RR, 0.95; 95% CI, 0.91-1.00). The absolute differences in probability were less than 3.5%. The comparison of 3259 children with AD and 4046 of their full siblings yielded estimates that were less pronounced than those in the main analysis (adjusted RR for lower secondary education, 1.29 [95% CI, 0.92-1.82]; adjusted RR for upper secondary education, 1.05 [95% CI, 0.93-1.18]; adjusted RR for higher education, 0.94 [95% CI, 0.87-1.02]). CONCLUSIONS AND RELEVANCE: This population-based cohort study found that hospital-diagnosed AD was associated with reduced educational attainment, but the clinical importance was uncertain owing to small absolute differences and possible confounding by familial factors in this study. Future studies should examine for replicability in other populations and variation by AD phenotype.

Associations of Lifestyle and Anthropometric Factors With the Risk of Herpes Zoster: A Nationwide Population-Based Cohort Study.

The role of lifestyle in development of herpes zoster remains unclear. We examined whether smoking status, alcohol consumption, body mass index, or physical activity were associated with zoster risk. We followed a population-based cohort of 101,894 respondents to the 2010 Danish National Health Survey (baseline, May 1, 2010) until zoster diagnosis, death, emigration, or July 1, 2014, whichever occurred first. We computed hazard ratios for zoster associated with each exposure, using Cox regression with age as the time scale and adjusting for potential confounders. Compared with never smokers, hazards for zoster were increased in former smokers (1.17, 95% confidence interval (CI): 1.06, 1.30), but not in current smokers (1.00, 95% CI: 0.89, 1.13). Compared with low-risk alcohol consumption, neither intermediate-risk (0.95, 95% CI: 0.84, 1.07) nor high-risk alcohol consumption (0.99, 95% CI: 0.85, 1.15) was associated with zoster. We also found no increased hazard associated with weekly binge drinking versus not (0.93, 95% CI: 0.77, 1.11). Risk of zoster varied little by body mass index (referent = normal weight) and physical activity levels (referent = light level), with hazard ratios between 0.96 and 1.08. We observed no dose-response association between the exposures and zoster. The examined lifestyle and anthropometric factors thus were not risk factors for zoster.

Atopic eczema in adulthood and mortality: UK population-based cohort study, 1998-2016.

BACKGROUND: Atopic eczema affects up to 10% of adults and is becoming more common globally. Few studies have assessed whether atopic eczema increases the risk of death. OBJECTIVE: We aimed to determine whether adults with atopic eczema were at increased risk of death overall and by specific causes and to assess whether the risk varied by atopic eczema severity and activity. METHODS: The study was a population-based matched cohort study using UK primary care electronic health care records from the Clinical Practice Research Datalink with linked hospitalization data from Hospital Episode Statistics and mortality data from the Office for National Statistics from 1998 to 2016. RESULTS: A total of 526,736 patients with atopic eczema were matched to 2,567,872 individuals without atopic eczema. The median age at entry was 41.8 years, and the median follow-up time was 4.5 years. There was limited evidence of increased hazard for all-cause mortality in those with atopic eczema (hazard ratio = 1.04; 99% CI = 1.03-1.06), but there were somewhat stronger associations (8%-14% increased hazard) for deaths due to infectious, digestive, and genitourinary causes. Differences on the absolute scale were modest owing to low overall mortality rates. Mortality risk increased markedly with eczema severity and activity. For example, patients with severe atopic eczema had a 62% increased hazard (hazard ratio = 1.62; 99% CI = 1.54-1.71) for mortality compared with those without eczema, with the strongest associations for infectious, respiratory, and genitourinary causes. CONCLUSION: The increased hazards for all-cause and cause-specific mortality were largely restricted to those with the most severe or predominantly active atopic eczema. Understanding the reasons for these increased hazards for mortality is an urgent priority.

The DANish Comorbidity Index for Acute Myocardial Infarction (DANCAMI): Development, Validation and Comparison with Existing Comorbidity Indices.

OBJECTIVE: To develop and validate the DANish Comorbidity index for Acute Myocardial Infarction (DANCAMI) for adjustment of comorbidity burden in studies of myocardial infarction prognosis. METHODS: Using medical registries, we identified patients with first-time myocardial infarction in Denmark during 2000-2013 (n=36,685). We developed comorbidity indices predicting 1-year all-cause mortality from all comorbidities (DANCAMI) and restricted to non-cardiovascular comorbidities (rDANCAMI). For variable selection, we eliminated comorbidities stepwise using hazard ratios from multivariable Cox models. We compared DANCAMI/rDANCAMI with Charlson and Elixhauser comorbidity indices using standard performance measures (Nagelkerke's R2, Harrell's C-statistic, the Integrated Discrimination Improvement, and the continuous Net Reclassification Index). We assessed the significance of the novel DANCAMI variables not included in the Charlson Comorbidity Index. External validation was performed in patients with myocardial infarction in New Zealand during 2007-2016 (n=75,069). RESULTS: The DANCAMI included 24 comorbidities. The rDANCAMI included 17 non-cardiovascular comorbidities. In the Danish cohort, the DANCAMI indices outperformed both the Charlson and the Elixhauser comorbidity indices on all performance measures. The DANCAMI indices included multiple variables that were significant predictors of 1-year mortality even after controlling for all variables in the Charlson Comorbidity Index. These novel variables included valvular heart disease (hazard ratio for 1-year mortality=1.25, 95% CI: 1.14-1.35), coagulopathy (1.13, 95% CI: 1.05-1.22), alcohol and drug abuse (1.35, 95% CI: 1.15-1.58), schizophrenia (1.60, 95% CI: 1.46-1.76), affective disorder (1.29, 95% CI: 1.22-1.36), epilepsy (1.26, 95% CI: 1.05-1.50), neurodegenerative disorder (1.30, 95% CI: 1.10-1.54) and chronic pancreatitis (1.71, 95% CI: 1.14-2.56). The results were supported by the external validation in New Zealand. CONCLUSION: DANCAMI assessed comorbidity burden of patients with first-time myocardial infarction, outperformed existing comorbidity indices, and was generalizable to patients outside Denmark. DANCAMI is recommended as a standard approach for comorbidity adjustment in studies of myocardial infarction prognosis.

Estimation of the diagnostic accuracy of real-time reverse transcription quantitative polymerase chain reaction for SARS-CoV-2 using re-analysis of published data.

INTRODUCTION: As the coronavirus disease 2019 (COVID-19) epidemic evolves and test strategies change, understanding the concepts of testing (gold standard and test performance measures) becomes essential. The challenge of any novel disease is that the gold standard has yet to be defined. METHODS: We reanalysed published data on real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR) of severe acute respiratory syndrome coronavirus-2 to illustrate how predictive values vary with disease prevalence, sensitivity (set to values between 30% and 95%) and specificity (set to 99% or 99.98%). We used published data on chest CT and RT-qPCR to examine the potential of latent class analysis to estimate the sensitivity and specificity of RT-qPCR when no single gold standard exists. RESULTS: For the various sensitivity values, the negative predictive value of a RT-qPCR test remained above 92% until a COVID-19 prevalence of > 10%. The positive predictive value (PPV) was more variable. For a sensitivity of 95% and a specificity of 99%, the PPV was less-than 10% at a prevalence of 0.1%, increasing to about 90% at a prevalence of 10%. This improved to a PPV of 85% and almost 100%, respectively, when specificity increased to 99.98%. In a restricted latent class analysis, the sensitivity was 97.1% and the specificity was 99.9%, which is similar to figures from the Danish Health Authority. However, derived predictive values depended on model specification. CONCLUSIONS: A high risk of false-positives should be considered when extending the testing strategy, whereas false-negatives may occur during local outbreaks. This may have consequences for, e.g., containment strategies and research. A confirmatory test (e.g., demonstrating seroconversion or repeated RT-qPCR) may be warranted. FUNDING: none. TRIAL REGISTRATION: not relevant.

Validity of First-Time Diagnoses of Inherited Ichthyosis in the Danish National Patient Registry and the Danish Pathology Registry.

PURPOSE: Inherited ichthyosis is a monogenetic disease characterized by hyperkeratosis and scaling of the skin, with large interindividual variation in severity. It can affect quality of life for patients and their families. Population-based data on inherited ichthyosis are lacking, which hampers studies into its epidemiology. PATIENTS AND METHODS: Based on medical record review, we validated diagnoses of inherited ichthyosis in two nationwide population-based registries commonly used for epidemiological research: The Danish National Patient Registry and the Danish Pathology Registry. The study period was January 1, 1977, through December 31, 2015. Validation samples were taken from one regional hospital without a specialized dermatological department and two specialized dermatological departments. Positive predictive values (PPVs) were estimated overall and for each coding system (ICD-8, ICD-10 and SNOMED), including for specific ICD-10 codes. RESULTS: We identified 1772 first-time diagnoses of inherited ichthyosis; 363 patients were diagnosed at the departments selected for validation, and 307 of these patients (84.6%) had medical records enabling validation. We observed an overall PPV of 73.3% (95% CI: 68.1-77.9). For ICD-8, ICD-10, and SNOMED diagnoses, the PPVs were 73.2% (95% CI: 58.1-84.3), 74.7% (95% CI: 69.0-79.7), and 46.2% (95% CI: 22.1-71.7), respectively. In analyses for ICD-10 diagnoses, we observed much higher validity of diagnoses from the specialized departments (PPV 79.7%; 95% CI: 74.1-84.3) than the regional hospital (PPV 5.9%; 95% CI: 0.6-24.3). The PPVs for specific diagnoses were 80.1% for ichthyosis vulgaris and 96.6% for X-linked ichthyosis but below 45% for remaining, rarer, subtypes. CONCLUSION: The PPV of first-time diagnosis of inherited ichthyosis made at specialized dermatological departments in the Danish National Patient Registry is approximately 80%. Diagnoses from the Danish Pathology Registry had low PPVs precluding their use for research.