Long Term Nationwide Analysis of HIV and AIDS in Iceland, 1983-2012.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.Introduction: Iceland is well suited for epidemiological research due to well-kept patient records, easy followup of patients and nation-wide health care databases. This study provides a nationwide 30-year epidemiological overview of the HIV epidemic in the country. Materials and methods: Retrospective study on all HIV positive individuals in Iceland, 1983-2012. Clinical data, CD4+ T-cell counts, plasma HIV RNA, proportion of late presenters and effectiveness of combined antiretroviral therapy (cART) were compared by different time intervals. Results: In total, 313 were diagnosed with HIV in 1983-2012, thereof 222 (71%) men and 91 (29%) women. Most infections (65%) were acquired outside the country. Mean incidence of HIV was 3.7/100,000 inhabitants/year, with a significant increase in 2010-2012 (p=0.0113), related to misuse of the prescription drug methylphenidate among intravenous drug users. Official prescriptions for this drug increased from 3.5 in 2002 to 17.4 defined daily doses/ 1,000 inhabitants/day in 2012. Mortality decreased by 70% during the study period (p=0.0275). Proportion of late presenters decreased from 74% in the first decade to 36% during the third (p=0.0001). After 6 months of ART, CD4+ T-cells increased by only 26 cells/µl on average during the monotherapy era (1987-1995; p=0,174), by 107 cells/µl during the early-cART era (1996-2004; p<0.0001) and by 159 cells/µl during the late-cART era (2005-2012; p<0,0001). Similarly, progressively greater reductions in plasma HIV RNA were observed from 1996-2004 to 2005-2012 (p<0.0001). Conclusions: HIV incidence remained relatively low in Iceland until 2010, when it increased significantly due to spread among IDUs. The majority of HIV infections diagnosed in Iceland were imported. With ever more effective drug treatments on CD4+ T-cells and plasma HIV RNA, the number of AIDS diagnoses and deaths has decreased dramatically.University of Iceland Research Fund, Gilead Nordic fellowshi

Incidence of and risk factors of chronic kidney disease: Results of a nationwide study in Iceland

Background - Information on the incidence of chronic kidney disease (CKD) in the general population is scarce. This study examined the incidence and risk factors of CKD stages 1–5 in Iceland, based on multiple markers of kidney damage. Methods - All serum creatinine (SCr) values, urine protein measurements and diagnosis codes for kidney diseases and comorbid conditions for people aged ≥18 years were obtained from electronic medical records of all healthcare institutions in Iceland in 2008–2016. CKD was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria as evidence for kidney damage and/or estimated glomerular filtration rate (eGFR) 3 months. Alternatively, CKD was defined using age-adapted eGFR thresholds. Mean annual age-standardized incidence of CKD was calculated for persons without CKD at study entry. Risk factor assessment was based on International Classification of Diseases diagnosis codes. Incidence was reported per 100 000 population. Results - We retrieved 1 820 990 SCr values for 206 727 persons. Median age was 45 years (range, 18–106) and 47% were men. Mean annual age-standardized incidence of CKD per 100 000 was 649 in men and 694 in women, and 480 in men and 522 in women using age-adapted eGFR thresholds. The incidence reached over 3000 in men and women aged >75 years. Traditional CKD risk factors, such as acute kidney injury, diabetes, hypertension and cardiovascular disease, as well as less well characterized risk factors, including chronic lung disease, malignancy and major psychiatric illness were associated with increased risk of CKD, and the same was true for obesity and sleep apnoea in women. Conclusion - The annual incidence of CKD, with strict adherence to the KDIGO criteria, was <0.7% but markedly lower using age-adapted eGFR thresholds. Apart from acute kidney injury, the observed risk factors comprised chronic and potentially modifiable disorders

Association of eGFR and mortality with use of a joint model: results of a nationwide study in Iceland

Objectives. Prior studies on the association of estimated glomerular filtration rate (eGFR) and mortality have failed to include methods to account for repeated eGFR determinations. The aim of this study was to estimate the association between eGFR and mortality in the general population in Iceland employing a joint model. Methods. We obtained all serum creatinine and urine protein measurements from all clinical laboratories in Iceland in the years 2008–16. Clinical data were obtained from nationwide electronic medical records. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation and categorized as follows: 0–29, 30–44, 45–59, 60–74, 75– 89, 90–104 and >104 mL/min/1.73 m2. A multiple imputation method was used to account for missing urine protein data. A joint model was used to assess risk of all-cause mortality. Results. We obtained 2 120 147 creatinine values for 218 437 individuals, of whom 84 364 (39%) had proteinuria measurements available. Median age was 46 (range 18–106) years and 47% were men. Proteinuria associated with increased risk of death for all eGFR categories in persons of all ages. In persons ≤65 years, the lowest risk was observed for eGFR of 75–89 mL/min/1.73 m2 without proteinuria. For persons aged >65 years, the lowest risk was observed for eGFR of 60–74 mL/min/1.73 m2 without proteinuria. eGFR of 45–59 mL/min/1.73 m2 without proteinuria did not associate with increased mortality risk in this age group. eGFR >104 mL/min/1.73 m2 associated with increased mortality. Conclusions. These results lend further support to the use of age-adapted eGFR thresholds for defining chronic kidney disease. Very high eGFR needs to be studied in more detail with regard to mortalit

Intravenous calcitriol therapy in an early stage prevents parathyroid gland growth

Background. Both the phenotypic alterations of parathyroid (PT) cells, e.g. down-regulation of the calcium-sensing receptor, and the increase of the PT cell number in nodular hyperplasia are the main causes of refractory secondary hyperparathyroidism. It is of great importance to prevent PT growth in an early stage

No significant effect on bone mineral density by high doses of vitamin D3 given to overweight subjects for one year

<p>Abstract</p> <p>Background</p> <p>In meta-analyses supplementation with vitamin D appears to reduce incidence of fractures, and in cross-sectional studies there is a positive association between serum 25-hydroxyvitamin D (25(OH)D) levels and bone mineral density (BMD). However, the effect of supplementation with high doses of vitamin D on BMD is more uncertain and could in theory have both positive and negative effects.</p> <p>Methods</p> <p>The study was a one year, double blind placebo-controlled intervention trial performed at the University Hospital of North Norway. 421 subjects, 21 - 70 years old, were included and 312 completed the study. The subjects were randomized to vitamin D₃40.000 IU per week (DD group), vitamin D₃20.000 IU per week (DP group), or placebo (PP group). All subjects were given 500 mg calcium daily. Serum 25(OH)D, osteoprotegrin (OPG), receptoractivator of nuclear factor-kappaB ligand (RANKL), and BMD at the lumbar spine and the hip were measured before and at the end of the study.</p> <p>Results</p> <p>At baseline the mean serum 25(OH)D levels were 58 nmol/L (all subjects) and increased to 141 and 100 nmol/L in the DD and DP groups, respectively. After one year, no significant differences were found between the three groups regarding change in BMD, serum OPG or RANKL.</p> <p>Conclusions</p> <p>Supplementation with high doses of vitamin D for one year does not appear to have a negative effect on BMD in healthy subjects. In order to disclose a positive effect, subjects with low BMD and/or low serum 25(OH)D levels need to be studied.</p> <p>Trial registration</p> <p>The trial was registered at ClinicalTrials.gov (NCT00243256).</p

Association of Variants at UMOD with Chronic Kidney Disease and Kidney Stones—Role of Age and Comorbid Diseases

Chronic kidney disease (CKD) is a worldwide public health problem that is associated with substantial morbidity and mortality. To search for sequence variants that associate with CKD, we conducted a genome-wide association study (GWAS) that included a total of 3,203 Icelandic cases and 38,782 controls. We observed an association between CKD and a variant with 80% population frequency, rs4293393-T, positioned next to the UMOD gene (GeneID: 7369) on chromosome 16p12 (OR = 1.25, P = 4.1×10−10). This gene encodes uromodulin (Tamm-Horsfall protein), the most abundant protein in mammalian urine. The variant also associates significantly with serum creatinine concentration (SCr) in Icelandic subjects (N = 24,635, P = 1.3×10−23) but not in a smaller set of healthy Dutch controls (N = 1,819, P = 0.39). Our findings validate the association between the UMOD variant and both CKD and SCr recently discovered in a large GWAS. In the Icelandic dataset, we demonstrate that the effect on SCr increases substantially with both age (P = 3.0×10−17) and number of comorbid diseases (P = 0.008). The association with CKD is also stronger in the older age groups. These results suggest that the UMOD variant may influence the adaptation of the kidney to age-related risk factors of kidney disease such as hypertension and diabetes. The variant also associates with serum urea (P = 1.0×10−6), uric acid (P = 0.0064), and suggestively with gout. In contrast to CKD, the UMOD variant confers protection against kidney stones when studied in 3,617 Icelandic and Dutch kidney stone cases and 43,201 controls (OR = 0.88, P = 5.7×10−5)

Comparison of total parathyroidectomy without autotransplantation and without thymectomy versus total parathyroidectomy with autotransplantation and with thymectomy for secondary hyperparathyroidism: TOPAR PILOT-Trial

<p>Abstract</p> <p>Background</p> <p>Secondary hyperparathyroidism (sHPT) is common in patients with chronic renal failure. Despite the initiation of new therapeutic agents, several patients will require parathyroidectomy (PTX). Total PTX with autotransplantation of parathyroid tissue (TPTX+AT) and subtotal parathyroidectomy (SPTX) are currently considered as standard surgical procedures in the treatment of sHPT. Recurrencerates after TPTX+AT or SPTX are between 10% and 12% (median follow up: 36 months).</p> <p>Recent retrospective studies demonstrated a lower rate of recurrent sHPT of 0–4% after PTX without autotransplantation and thymectomy (TPTX) with no higher morbidity when compared to the standard procedures. The observed superiority of TPTX is flawed due to different definitions of outcomes, varying follow up periods and different surgical treatment strategies (with and without thymectomy).</p> <p>Methods/Design</p> <p>Patients with sHPT (intact parathyroid hormone > 10 times above the upper limit of normal) on long term dialysis (>12 months) will be randomized either to TPTX or TPTX+AT and followed for 36 months. Outcome parameters are recurrence rates of sHPT, frequencies of reoperations due to refractory hypoparathyroidism or recurrent/persistent hyperparathyroidism, postoperative morbidity and mortality and quality of life. 50 patients per group will be randomized in order to obtain relevant frequencies of outcome parameters that will form the basis for a large scale confirmatory multicentred randomized controlled trial.</p> <p>Discussion</p> <p>sHPT is a disease with a high incidence in patients with chronic renal failure. Even a small difference in outcomes will be of clinical relevance. To assess sufficient data about the rate of recurrent sHPT after both methods, a multicentred, randomized controlled trial (MRCT) under standardized conditions is mandatory.</p> <p>Due to the existing uncertainties the calculated number of patients necessary in each treatment arm (n > 4000) makes it impossible to perform this study as a confirmatory trial. Therefore estimates of different outcomes are performed using a pilot MRCT comparing 50 versus 50 randomized patients in order to establish a hypothesis that can be tested thereafter.</p> <p>If TPTX proves to have a lower rate of recurrent sHPT, no relevant disadvantages and no higher morbidity than TPTX+AT, current surgical practice may be changed.</p> <p>Trial registration</p> <p>International Standard Randomized Controlled Trial Number Registration (ISRCTN86202793)</p

Sequence variants in malignant hyperthermia genes in Iceland: classification and actionable findings in a population database.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadMalignant hyperthermia (MH) susceptibility is a rare life-threatening disorder that occurs upon exposure to a triggering agent. MH is commonly due to protein-altering variants in RYR1 and CACNA1S. The American College of Medical Genetics and Genomics recommends that when pathogenic and likely pathogenic variants in RYR1 and CACNA1S are incidentally found, they should be reported to the carriers. The detection of actionable variants allows the avoidance of exposure to triggering agents during anesthesia. First, we report a 10-year-old Icelandic proband with a suspected MH event, harboring a heterozygous missense variant NM_000540.2:c.6710G>A r.(6710g>a) p.(Cys2237Tyr) in the RYR1 gene that is likely pathogenic. The variant is private to four individuals within a three-generation family and absent from 62,240 whole-genome sequenced (WGS) Icelanders. Haplotype sharing and WGS revealed that the variant occurred as a somatic mosaicism also present in germline of the proband's paternal grandmother. Second, using a set of 62,240 Icelanders with WGS, we assessed the carrier frequency of actionable pathogenic and likely pathogenic variants in RYR1 and CACNA1S. We observed 13 actionable variants in RYR1, based on ClinVar classifications, carried by 43 Icelanders, and no actionable variant in CACNA1S. One in 1450 Icelanders carries an actionable variant for MH. Extensive sequencing allows for better classification and precise dating of variants, and WGS of a large fraction of the population has led to incidental findings of actionable MH genotypes.deCODE Genetics/Amgen Inc