Undiagnosed adrenal insufficiency as a cause of premature death in glucocorticoid users.

Objective: It is unknown whether glucocorticoid (GC)-induced adrenal insufficiency may cause premature mortality in GC users. We conducted a retrospective cohort study to investigate if undiagnosed and undertreated GC-induced adrenal insufficiency is a contributor to premature death in GC users. Methods: Information on dispensed prescriptions in West Sweden from 2007 to 2014 was obtained from the Swedish Prescribed Drug Register. Cause of death was collected from the Swedish Cause of Death Register. Of 223,211 patients who received oral GC prescriptions, 665 died from sepsis within 6 months of their last prescription. Three hundred of these patients who had died in hospital were randomly selected for further investigation. Medical records were initially reviewed by one investigator. Furthermore, two additional investigators reviewed the medical records of patients whose deaths were suspected to be caused by GC-induced adrenal insufficiency. Results: Of 300 patients (121 females, 40%), 212 (75%) were prescribed GC treatment at admission. The mean age was 76 ± 11 years (range 30-99). Undiagnosed or undertreated GC-induced adrenal insufficiency was considered a probable contributor to death by at least two investigators in 11 (3.7%) patients. In five of these 11 cases, long-term GC therapy was abruptly discontinued during hospitalization. Undiagnosed or undertreated GC-induced adrenal insufficiency was considered a possible contributing factor to death in a further 36 (12%) patients. Conclusion: GC-induced adrenal insufficiency is an important contributor to premature death in GC users. Awareness of the disorder during intercurrent illness and following cessation of GC treatment is essential.

Impact of chronic oral glucocorticoid treatment on mortality in patients with COVID-19: analysis of a population-based cohort.

OBJECTIVES: While glucocorticoid (GC) treatment initiated for COVID-19 reduces mortality, it is unclear whether GC treatment prior to COVID-19 affects mortality. Long-term GC use raises infection and thromboembolic risks. We investigated if patients with oral GC use prior to COVID-19 had increased mortality overall and by selected causes. DESIGN: Population-based observational cohort study. SETTINGS: Population-based register data in Sweden. PARTICIPANTS: All patients infected with COVID-19 in Sweden from January 2020 to November 2021 (n=1 200 153). OUTCOME MEASURES: Any prior oral GC use was defined as ≥1 GC prescription during 12 months before index. High exposure was defined as ≥2 GC prescriptions with a cumulative prednisolone dose ≥750 mg or equivalent during 6 months before index. GC users were compared with COVID-19 patients who had not received GCs within 12 months before index. We used Cox proportional hazard models and 1:2 propensity score matching to estimate HRs and 95% CIs, controlling for the same confounders in all analyses. RESULTS: 3378 deaths occurred in subjects with any prior GC exposure (n=48 806; 6.9%) and 14 850 among non-exposed (n=1 151 347; 1.3%). Both high (HR 1.98, 95% CI 1.87 to 2.09) and any exposure (1.58, 1.52 to 1.65) to GCs were associated with overall death. Deaths from pulmonary embolism, sepsis and COVID-19 were associated with high GC exposure and, similarly but weaker, with any exposure. High exposure to GCs was associated with increased deaths caused by stroke and myocardial infarction. CONCLUSION: Patients on oral GC treatment prior to COVID-19 have increased mortality, particularly from pulmonary embolism, sepsis and COVID-19.

Intermittent high-dose glucocorticoid treatment does not cause adrenal insufficiency in patients with diffuse large B-cell lymphoma - a prospective study.

Glucocorticoid (GC) treatment suppresses the hypothalamic-pituitary-adrenal axis and can cause GC-induced adrenal insufficiency. In this study we investigated the incidence of GC-induced adrenal insufficiency in patients receiving intermittent short-term high-dose oral GC treatment for newly diagnosed diffuse large B-cell lymphoma. Cosyntropin stimulation test was used to assess adrenal function at study entry (baseline), at 2 months (before the 5th cycle), and 6 months from baseline (3 months after the last cycle). Ten patients were included (40% women). Mean age was 61 years. The mean (range) plasma morning cortisol was 407 (320-530) nmol/L at baseline, 373 (260-610) nmol/L at 2 months, and 372 (230-520) nmol/L 6 months from baseline. All patients had normal response to cosyntropin stimulation at baseline as well as 2 and 6 months from baseline. Thus, none of the patients developed biochemically verified adrenal insufficiency. Therefore, short-term high-dose GC therapy, a commonly used adjuvant treatment in patients with malignant hematological diseases, does not seem to down-regulate the hypothalamic-pituitary-adrenal axis.

Topical clobetasol treatment for oral lichen planus can cause adrenal insufficiency.

OBJECTIVE: Glucocorticoids suppress the hypothalamic-pituitary-adrenal axis, which may lead to glucocorticoid-induced adrenal insufficiency. The study aimed to investigate the prevalence of this state in patients with oral lichen planus treated with topical clobetasol propionate. METHODS: In this cross-sectional study, 30 patients with oral lichen planus receiving long-term (>6 weeks) clobetasol propionate gel 0.025% were invited to participate. Adrenal function was assessed by measuring morning plasma cortisol after a 48-h withdrawal of clobetasol treatment. In patients with plasma cortisol <280 nmol/L, a cosyntropin stimulation test was performed. RESULTS: Twenty-seven patients were included. Twenty-one (78%) patients presented with plasma cortisol ≥280 nmol/L (range 280-570 nmol/L), and six (22%) <280 nmol/L (range 13-260 nmol/L). Five of these six patients underwent cosyntropin stimulation that revealed severe adrenal insufficiency in two patients (cortisol peak 150 nmol/L and 210 nmol/L) and mild adrenal insufficiency in three patients (cortisol peak 350-388 nmol/L). CONCLUSION: In this study, approximately 20% of patients receiving intermittent topical glucocorticoid treatment for oral lichen planus had glucocorticoid-induced adrenal insufficiency. It is essential for clinicians to be aware of this risk and to inform patients about the potential need for glucocorticoid stress doses during intercurrent illness.

High Mortality Rate in Oral Glucocorticoid Users: A Population-Based Matched Cohort Study.

Objective: The aim of the study was to investigate all-cause and disease-specific mortality in a large population-based cohort of oral glucocorticoid (GC) users. Methods: This was a retrospective, matched cohort study. Information on dispensed prescriptions was obtained from the Swedish Prescribed Drug Register. The cause of death was obtained from the Swedish Cause-of-Death Registry. Patients receiving prednisolone ≥5 mg/day (or equivalent dose of other GC) for ≥21 days between 2007-2014 were included. For each patient, one control subject matched for age and sex was included. The study period was divided into 3-month periods and patients were divided into groups according to a defined daily dose (DDD) of GC used per day. The groups were: Non-users (0 DDD per day), low-dose users (>0 but <0.5 DDD per day), medium-dose users (0.5-1.5 DDD per day) and high-dose users (>1.5 DDD per day). Hazard ratios (HRs), unadjusted and adjusted for age, sex and comorbidities, were calculated using a time-dependent Cox proportional hazard model. Results: Cases (n=223 211) had significantly higher all-cause mortality compared to controls (HR adjusted for age, sex and comorbidities 2.08, 95% confidence interval 2.04 to 2.13). After dividing the cases into subgroups, adjusted HR was 1.31 (1.28 to 1.34) in non-users, 3.64 (3.51 to 3.77) in low-dose users, 5.43 (5.27 to 5.60) in medium-dose users and, 5.12 (4.84 to 5.42) in high-dose users. The highest adjusted hazard ratio was observed in high-dose users for deaths from sepsis 6.71 (5.12 to 8.81) and pulmonary embolism 7.83 (5.71 to 10.74). Conclusion: Oral GC users have an increased mortality rate compared to the background population, even after adjustment for comorbidities. High-dose users have an increased risk of dying from sepsis, and pulmonary embolism compared to controls. Whether the relationship between GC exposure and the excess mortality is causal remains to be elucidated.

The prevalence, seriousness, and causes of teenage work accidents: A gender difference?

BACKGROUND: Teenage workers are prone to a higher injury risk than adult workers, and adult men are prone to a higher risk of work injuries than adult women. OBJECTIVES: This study aims to examine whether gender differences exist in teenage work accidents, the level of the accidents, their causes, and the types of the injuries. METHODS: A survey was sent to a sample of 2,800 13-19-year-olds, randomly selected from Registers Iceland. The response rate was 48.6%. A chi-square test, CI 95%, was applied to measure gender differences. RESULTS: In total, 16.3%of the respondents had at least one work accident, and 1.2%, an accident that lead to more than one week's absence from work. No gender differences were observed in the level of the accidents, but appeared in the types of injuries and their causes. Cuts were the most common injuries of the boys, but burns of the girls. Bone fractures were the most serious injuries of the boys, but sprains of the girls. CONCLUSION: Work accidents among teenagers are a particular threat to public health. Therefore, all stakeholders need to work together to prevent teenage work accidents in the future; and to keep in mind the gender diversity of the group.

[The association of mental symptoms with teenage work in Iceland].

INTRODUCTION: Adolescent mental health problems have increased in recent years, and such problems may predispose the adolescent to long-term mental illness in adulthood. In past decades it has become more common for Icelandic teenagers to work while attending school (term-time work). Nevertheless, research is missing on the association between the level of termtime work and mental health. The aim is to examine the association between six types of mental symptoms (tiredness after an adequate night's sleep, difficulty sleeping, depression, stress/anxiety, worries/sadness, and multiple symptoms) and level of term-time work, by gender, age, and family's financial status. MATERIAL AND METHODS: A survey applying a Nordic questionnaire based on self-assessed mental symptoms, was conducted among 2800 randomly selected adolscents, aged 13-19. The response rate was 48.6%. Participants were asked how often they felt symptoms of poor mental health. They were divided into three groups consisting of: non term-time workers, moderate term-time workers, and intensive term-time workers. A Chi-square test was used to test statistical significance: 95% confidence interval (CI). Results show gender difference in the association between level of term-time work and the mental symptoms. Intensive female workers are more likely to suffer symptoms of poor mental health than female non-workers, but no relationship was examined amongst boys. Furthermore, some association between term-time work and poor mental health is found amongst 13-15-year-olds, and for those whose parents are financially well-off. CONCLUSION: It is important that all stakeholders promote moderate term-time work for adolescents, and that the young people themselves receive occupational health and safety education to better understand the connection between work and mental health.

The nature of Neanderthal introgression revealed by 27,566 Icelandic genomes.

Human evolutionary history is rich with the interbreeding of divergent populations. Most humans outside of Africa trace about 2% of their genomes to admixture from Neanderthals, which occurred 50-60 thousand years ago1. Here we examine the effect of this event using 14.4 million putative archaic chromosome fragments that were detected in fully phased whole-genome sequences from 27,566 Icelanders, corresponding to a range of 56,388-112,709 unique archaic fragments that cover 38.0-48.2% of the callable genome. On the basis of the similarity with known archaic genomes, we assign 84.5% of fragments to an Altai or Vindija Neanderthal origin and 3.3% to Denisovan origin; 12.2% of fragments are of unknown origin. We find that Icelanders have more Denisovan-like fragments than expected through incomplete lineage sorting. This is best explained by Denisovan gene flow, either into ancestors of the introgressing Neanderthals or directly into humans. A within-individual, paired comparison of archaic fragments with syntenic non-archaic fragments revealed that, although the overall rate of mutation was similar in humans and Neanderthals during the 500 thousand years that their lineages were separate, there were differences in the relative frequencies of mutation types-perhaps due to different generation intervals for males and females. Finally, we assessed 271 phenotypes, report 5 associations driven by variants in archaic fragments and show that the majority of previously reported associations are better explained by non-archaic variants.

High prescription rate of oral glucocorticoids in children and adults: A retrospective cohort study from Western Sweden.

OBJECTIVE: Glucocorticoids (GCs) are a cornerstone in treating various common and uncommon diseases. The aim of this study was to estimate the prevalence of GC use in terms of doses associated with risk of tertiary adrenal insufficiency in adults and children, and treatment indications. METHODS: This was a retrospective cohort study. Information on dispensed prescriptions was obtained from the Swedish Prescribed Drug Register. Patients with prescriptions of prednisolone (or equivalent dose of other GCs) ≥5 mg daily for ≥21 days between 2007 and 2014 were included. Information on concurrent diseases was obtained from the Swedish National Patient Register and the Västra Götaland Regional Healthcare Database. RESULTS: Of 1 585 335 inhabitants in Västra Götaland County, 223 211 were included in the study (women 55.6%). Mean age was 48 ± 24 years. Period prevalence of oral GC use during the 8-year study period was 14.1%. The highest prevalence (27.4%) was in men aged 80-89 years and lowest (7.5%) in men 10-19 years of age. The period prevalence in children 0-9 years of age was 10.6%. COPD and asthma were the most common indications for treatment (17.2%) followed by allergy (12.5%) and malignant neoplasms (11.5%). Allergy was the most frequent indication (20.5%) in children and adolescents. CONCLUSION: Between 2007 and 2014, every seventh inhabitant in western Sweden received a GC prescription at doses associated with risk of developing tertiary adrenal insufficiency. These findings illustrate the importance of awareness of the potential development of tertiary adrenal insufficiency in both paediatric and adult patients.

OHS education and safety training of teenage workers in Iceland.

BACKGROUND: We sought to investigate the extent and quality of occupational health and safety (OHS) education and safety training of Icelandic teenagers. METHODS: Mixed methods were used to obtain data. Initially, 12 group and 7 individual interviews with a total of 45 teenagers were conducted. Supplemental qualitative data was collected to corroborate the interviews. Following this, a survey was sent to a sample of 2800 13 to 19-year-olds, randomly selected from Registers Iceland. RESULTS: The response rate was 48.6% (N = 1339). Severe inadequacy in the quality and quantity of both OHS education and safety training was found. In total, 30% received OHS education at school and 14% obtained safety training at work. OHS education was considered unsystematic, and the safety training low engagement. Participants noted that safety training was especially inadequate in jobs in the retail sector and restaurants. CONCLUSIONS: OHS education needs to be taught systematically within all levels of the Icelandic school system, and authorities should be more active in educating employers on their responsibilities on health and safety at work.

[The association of musculoskeletal symptoms with teenage work in Iceland].

INTRODUCTION: Musculoskeletal symptoms are common in adolescence, and may predispose a person to more occurrences in adulthood. Musculoskeletal problems have increased in the adult work force in recent years, becoming one of the most common causes of workers' disability, particularly among women. However, there is a lack of research on the association between musculoskeletal symptoms and teenage work. The aim of this research is to examine the association between four types of musculoskeletal symptoms (aches in joints and/or muscles, aches in the neck or shoulders, backache, and myalgia) and the level of term-time work among Icelandic teenagers, by gender, age, and educational status of the parents. MATERIAL AND METHODS: A survey was carried out in the first half of 2018 amongst 2800 teenagers, aged 13-19, randomly selected from the Registers Iceland. The response rate was 48.6%. The young people were asked how often they had experienced musculoskeletal symptoms in the last 12 months, and then were divided into three groups according to their level of term-time work: non-workers; moderate workers (≤ 12 h/w and/or in irregular work); and intensive workers (> 12) h/w and in regular work). A Chi-square test was used to test statistical significance: 95% confidence interval (CI). The results show that intensive term-time workers are more prone to suffer from all four types of musculoskeletal symptoms than non-workers. The association persists for backache independent of demographic factors, and for all measured musculoskeletal symptoms among girls. Conclusion is that the working conditions of Icelandic teenagers need to be improved so that they do not give rise to musculoskeletal symptoms. In particular, the working conditions of young females need to be examined, as well as the conditions that lead to occupational backache.

Antiepileptic drugs are associated with central hypothyroidism.

OBJECTIVE: Studies in children have shown an increased frequency of central hypothyroidism (CH) with long-term use of antiepileptic drugs (AEDs). The aim of this study was to search for CH in adults treated with AEDs and find whether the type of AEDs used matters. MATERIALS AND METHODS: Adult epileptic patients treated at the neurology outpatient clinic at Landspitali University Hospital (LSH) from 1998 to 2011 were included. Patients were invited for a blood test if serum levels for TSH (s-TSH) or free-T4 (s-fT4 ) had not already been obtained. CH was defined as s-fT4 below the reference range (12-22 pmol/L) and normal s-TSH levels (0.30-4.20 mIU/L). Data were analyzed using logistic regression and Mann-Whitney test. RESULTS: We identified 165 patients (92 women), mean age 45.6 (±15.5, range: 20-92) years. The mean s-fT4 -level in our group was 14.2 (±2.9, range: 8.1-24.4) pmol/L compared with 16.9 (±6.1) pmol/L in a sample of 13248 measurements at LSH during one year (LSH-group) (P < 0.001). The difference in s-fT4 -level between men and the LSH-group was significant and also for women (P < 0.001 and P < 0.001, respectively). Thirty-five patients (21%) had CH. A significant association with the use of carbamazepine or oxcarbazepine was found, odds ratio for women 15.0 (95% CI: 4.6-49.5) and 1.8 (95% CI: 0.4-8.3) for men. CONCLUSION: 21% of patients treated with AEDs had CH, more often patients taking carbamazepine or oxacarbazepine, and more often women. The s-fT4 -level was lower among patients treated with AEDs.

Ancient genomes from Iceland reveal the making of a human population.

Opportunities to directly study the founding of a human population and its subsequent evolutionary history are rare. Using genome sequence data from 27 ancient Icelanders, we demonstrate that they are a combination of Norse, Gaelic, and admixed individuals. We further show that these ancient Icelanders are markedly more similar to their source populations in Scandinavia and the British-Irish Isles than to contemporary Icelanders, who have been shaped by 1100 years of extensive genetic drift. Finally, we report evidence of unequal contributions from the ancient founders to the contemporary Icelandic gene pool. These results provide detailed insights into the making of a human population that has proven extraordinarily useful for the discovery of genotype-phenotype associations.

Reconstructing an African haploid genome from the 18th century.

A genome is a mosaic of chromosome fragments from ancestors who existed some arbitrary number of generations earlier. Here, we reconstruct the genome of Hans Jonatan (HJ), born in the Caribbean in 1784 to an enslaved African mother and European father. HJ migrated to Iceland in 1802, married and had two children. We genotyped 182 of his 788 descendants using single-nucleotide polymorphism (SNP) chips and whole-genome sequenced (WGS) 20 of them. Using these data, we reconstructed 38% of HJ's maternal genome and inferred that his mother was from the region spanned by Benin, Nigeria and Cameroon.

Low-dose rate brachytherapy with I-125 seeds has an excellent 5-year outcome with few side effects in patients with low-risk prostate cancer.

BACKGROUND: Low-dose rate brachytherapy (LDR-BT) has been used in Sweden for more than a decade for treatment of low-risk prostate cancer. This study presents the outcome for patients treated with LDR-BT at a single institution with focus on the association between dose and biochemical failure-free survival (BFFS). METHODS: In total 195 patients were treated with LDR-BT between 2004 and 2008. The patients were followed systematically for side effects for at least one year. PSA levels were followed regularly from three months and for at least five years. Outcome was analyzed in relation to clinical variables at baseline and to radiotherapy data. RESULTS: Kaplan-Meier estimated BFFS at five years was 95.7%. Dose to the prostate in terms of D90% was significantly associated with BFFS [HR 0.90 (95%CI 0.83-0.96), p = 0.002]. CONCLUSION: Out data confirmed that absorbed dose is a predictive factor for BFFS for low-risk patients without androgen deprivation therapy. With our treatment routines and dosimetry, a D90% in the range of 170-180 Gy gives excellent outcomes with acceptable toxicity for patients with low-risk prostate cancer.

[Work injuries of 13-17-year-old Icelanders: causes and consequences]. / Vinnuslys ungmenna: Orsakir og alvarleiki.

INTRODUCTION: The aim of the research is to investigate work injuries among 13-17-year-old teenagers in Iceland, their causes and seriousness. Firstly, the prevalence of work injuries among the age-group is examined, as is the length of their absence from work, as well as the gender and age differences of both factors. Secondly, the type and the cause of the injuries are investigated. Thirdly, the most serious injuries and their causes are studied further. MATERIAL AND METHODS: A survey was carried out amongst 2000 teenagers, aged 13-17, randomly selected from the Registers Iceland. The response rate was 48.4%. The teenagers were asked in a closed question about whether they had had an accident at work, and in an open one about the type and cause of the injury. A Chi-square test was used to test statistical significance: 95% confidence interval (CI). RESULTS: A fifth of the young people had had an accident at work, one quarter of the injured workers were absent from work because of the injury of which 5.9% for more than a week. The percentage of injured workers increases with age and has reached 30,7% among the 17-year-olds. Cuts and sprains were the most common injuries, whereas back injuries and bone fractures caused the longest absences. Sharp instruments were the most common cause of an injury, but lifting/carrying a (heavy) object as well as a fall of an object caused the longest absences. CONCLUSION: The prevalence of young workers' injuries and the seriousness of some of these injuries are of concern. In addition to education on occupational health and safety (OHS) and OHS training, future research must analyse if their labour market position threaten the young people's safety, and if it is the case, how to prevent it.

[Elective splenectomy at landspitali university hospital 1993-2004 efficacy and long-term outcome]. / Valmitistökur á landspítala 1993-2004 arangur og langtímaeftirfylgd.

OBJECTIVE: To evaluate the long-term outcome of elective splenectomy, with emphasis on the incidence of complications, vaccine immunization and patient´s knowledge about asplenia. MATERIAL AND METHODS: Medical reports of all patients, who underwent elective splenectomy during the time period of 1993-2004, were reviewed. Questionnaire was sent to 96% (44/46) patients alive. RESULTS: The average age was 50 (8-83) years. Thirty-five patients were male and 32 were female. Eighty percent responded to the questionnaire. Most of the patients (31) had idiopathic thrombocytopenic purpura (ITP). Complete response was obtained in 60% (18/30) and partial response in 23% (7/30). Five patients had spherocytosis and all of them had complete response. None of the three patients with autoimmune hemolytic anemia had any response to the splenectomy. Patients were vaccinated against pneumococci in 92% of the cases. In 44% of the cases revaccination was done. Only 41% of those who answered experienced that they had got a good education about the consequences of asplenia. Sixteen percent of the patients (10/64) had major postoperative complications. One patient with metastatic cancer and thrombocytopenia died within 30 days of surgery. Five patients had long-term complications. Two had pneumococcal sepsis, one of them was unvaccinated and the other had not been revaccinated. CONCLUSION: Splenectomy has a good long-term outcome for spherocytosis and ITP patients. The incidence of complications is high. It is possible that better guidelines and better patient´s education can lower the complication rate and improve the outcome.

[The Iron-man: a case-report]. / Járnmadurinn--sjúkratilfelli.

The most common cause of microcytic anemia is iron deficiency. We report a 29 year old man with history of dyspnea, fatigue and severe microcytic anemia despite iron therapy for 3 years. Blood transfusions elevated the hemoglobin levels temporarily, but iv iron did not. Bone marrow showed sideroblastic anemia. The anemia resolved with pyridoxine treatment but severe iron overload necessitated multiple phlebotomies. Today the patient is asymptomatic on pyridoxine with a normal hemoglobin level.

Towards accurate in vivo spectroscopy of the human prostate.

The recent interest in photodynamic therapy of human prostate cancer is accompanied by a need for techniques for in vivo monitoring of optical and physiological characteristics. We propose time-of-flight (TOF) spectroscopy in combination with Monte Carlo evaluation as a reliable optical technique for quantitative assessment of absorption, scattering, hemoglobin content and tissue oxygenation in the human prostate. For the first time, we demonstrate Monte Carlo-based evaluation of in vivo TOF photon migration data. We show that this approach is crucial in order to avoid the large errors associated with the use of time-resolved diffusion theory of light propagation in prostate-like tissues. This progress also allows us to present the first in vivo scattering spectroscopy of human prostate tissue. Furthermore, TOF spectroscopy, in contrast to the more common steady-state approach, is insensitive to bleedings, and has been found highly reliable (100% success rate).