Selenium supplementation and placebo are equally effective in improving quality of life in patients with hypothyroidism.

PURPOSE: We investigated whether selenium supplementation improves quality-of-life (QoL) in patients with autoimmune thyroiditis (ID:NCT02013479). METHODS: We included 412 patients ≥18 years with serum thyroid peroxidase antibody (TPOAb) level ≥100 IU/mL in a multicentre double-blinded randomised clinical trial. The patients were allocated 1:1 to daily supplementation with either 200 µg selenium as selenium-enriched yeast or matching placebo tablets for 12 months, as add-on to levothyroxine (LT4) treatment. QoL, assessed by the Thyroid-related Patient-Reported-Outcome questionnaire (ThyPRO-39), was measured at baseline, after six weeks, three, six, 12, and 18 months. RESULTS: In total, 332 patients (81%) completed the intervention period, of whom 82% were women. Although QoL improved during the trial, no difference in any of the ThyPRO-39 scales was found between the selenium group and the placebo group after 12 months of intervention. In addition, employing linear mixed model regression no difference between the two groups was observed in the ThyPRO-39 composite score (28.8 [95%CI:24.5-33.6] and 28.0 [24.5-33.1], respectively; P=0.602). Stratifying the patients according to duration of the disease at inclusion, ThyPRO-39 composite score, TPOAb level, or selenium status at baseline did not significantly change the results. TPOAb levels after 12 months of intervention were lower in the selenium group than in the placebo group (1995 [95%CI:1512-2512] vs. 2344 kIU/L [1862-2951]; P=0.016) but did not influence LT4 dosage or free triiodothyronine/free thyroxin ratio. CONCLUSION: In hypothyroid patients on LT4 therapy due to autoimmune thyroiditis, daily supplementation with 200 µg selenium or placebo for 12 months improved QoL to the same extent.

Patient and families' perspectives on telepalliative care: A systematic integrative review.

BACKGROUND: Telepalliative care is increasingly used in palliative care, but has yet to be examined from a patient and family perspective. A synthesis of evidence may provide knowledge on how to plan and provide telepalliative care that caters specifically to patients and families' needs. OBJECTIVE: To synthesise evidence on patients and families' perspectives on telepalliative care. DESIGN: A systematic integrative review (PROSPERO #CRD42022301206) reported in accordance with PRISMA 2020 guidelines. Inclusion criteria; primary peer-reviewed studies published 2011-2022, patient and family perspective, >18 years, telepalliative care and English/Danish language. Quality was appraised using the mixed-methods appraisal tool, version 2020. Guided by Toronto and Remington, data were extracted, thematically analysed and synthesised. DATA SOURCES: MEDLINE, EMBASE, PsycINFO and CINAHL were searched in March 2022 and updated in February 2023. RESULTS: Forty-four studies were included. Analysis revealed five themes; the effect of the Covid-19 pandemic on telepalliative care, adding value for patients and families, synchronous and asynchronous telepalliative care, the integration of telepalliative care with other services and the tailoring and timing of telepalliative care. CONCLUSION: Enhanced access to care and convenience, as attributes of telepalliative care, are highly valued. Patients and families have varying needs during the illness trajectory that may be addressed by early integration of telepalliative care based on models of care that are flexible and combine synchronous and asynchronous solutions. Further research should examine telepalliative care in a post-pandemic context, use of models of care and identify meaningful outcome measures from patient and family perspectives for evaluation of telepalliative care.

Isotopic Tracing of Nucleotide Sugar Metabolism in Human Pluripotent Stem Cells.

Metabolism not only produces energy necessary for the cell but is also a key regulator of several cellular functions, including pluripotency and self-renewal. Nucleotide sugars (NSs) are activated sugars that link glucose metabolism with cellular functions via protein N-glycosylation and O-GlcNAcylation. Thus, understanding how different metabolic pathways converge in the synthesis of NSs is critical to explore new opportunities for metabolic interference and modulation of stem cell functions. Tracer-based metabolomics is suited for this challenge, however chemically-defined, customizable media for stem cell culture in which nutrients can be replaced with isotopically labeled analogs are scarcely available. Here, we established a customizable flux-conditioned E8 (FC-E8) medium that enables stem cell culture with stable isotopes for metabolic tracing, and a dedicated liquid chromatography mass-spectrometry (LC-MS/MS) method targeting metabolic pathways converging in NS biosynthesis. By 13C6-glucose feeding, we successfully traced the time-course of carbon incorporation into NSs directly via glucose, and indirectly via other pathways, such as glycolysis and pentose phosphate pathways, in induced pluripotent stem cells (hiPSCs) and embryonic stem cells. Then, we applied these tools to investigate the NS biosynthesis in hiPSC lines from a patient affected by deficiency of phosphoglucomutase 1 (PGM1), an enzyme regulating the synthesis of the two most abundant NSs, UDP-glucose and UDP-galactose.

Prevalence and incidence of chronic kidney disease stage 3-5 - results from KidDiCo.

BACKGROUND: Chronic kidney disease (CKD) is a global challenge. CKD prevalence estimation is central to management strategies and prevention. It is necessary to predict end stage kidney disease (ESKD) and, subsequently, the burden for healthcare systems. In this study we characterize CKD stage 3-5 prevalence and incidence in a cohort covering the majority of the Region of Southern Denmark and investigate individuals' demographic, socioeconomic, and comorbidity status. METHODS: We used data from the Kidney Disease Cohort (KidDiCo) combining laboratory data from Southern Denmark with Danish national databases. Chronic kidney disease was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. RESULTS: The prevalence varied between 4.83 and 4.98% and incidence rate of CKD was 0.49%/year. The median age was 76.4 years. The proportion of individuals with CKD stage 3-5 in the entire population increased consistently with age. The percentage of women in the CKD 3-5 group was higher than in the background population. Diabetes mellitus, hypertension and cardiovascular disease were more prominent in patients with CKD. CKD stage 5 and ESKD were more frequent as incident CKD stages in the 18-49 year olds when compared to older individuals. CKD patients tended to have a lower socioeconomic status. CONCLUSION: Chronic kidney disease stage 3-5 is common, especially in the elderly. Patients with CKD stage 3-5 are predominantly female. The KidDiCo data suggests an association between lower socioeconomic status and prevalence of CKD.

Referral rate of chronic kidney disease patients to a nephrologist in the Region of Southern Denmark: results from KidDiCo.

Background: Data on the referral rate of chronic kidney disease (CKD) patients to specialists are sparse. Investigating referral rates and characterizing patients with kidney disease not followed by a nephrologist are relevant for future measures in order to optimize public health and guideline implementation. Methods: Data were extracted from the Kidney Disease Cohort of Southern Denmark (KidDiCo). Referral rates for all incident CKD patients below 60 mL/min/1.73 m² and referral rates according to the KDIGO guidelines based on glomerular filtration rates below 30 mL/min/1.73 m² were calculated. Information on contact with one of the nephrologist outpatient clinics in the Region of Southern Denmark was collected from the Danish National Patient Registry. The individual follow-up time for nephrology contact was 12 months. Additional data were accessed via the respective national databases. CKD patients on dialysis and kidney transplanted patients were excluded. Results: A total of 3% of patients with an eGFR <60 mL/min/1.73 m²-16% of patients with an eGFR <30 mL/min/1.73 m² and 35% of patients with an eGFR <15 mL/min/1.73 m² were in contact with a nephrologist in the outpatient settings. Younger age, male sex, diabetes, hypertension, higher education and proximity to a nephrology outpatient clinic increased the chance of nephrology follow-up. Conclusion: Only a small fraction of CKD patients are followed by a nephrologist. More studies should be performed in order to find out which patients will profit the most from renal referral and how to optimize the collaboration between nephrologists and general practitioners.

The application of resilience assessment grid in healthcare: A scoping review.

BACKGROUND: The Resilience Assessment Grid (RAG) has attracted increasing interest in recent healthcare discourse as an instrument to understand and measure the resilience performance of socio-technical systems. Despite its growing popularity in healthcare, its applicability and utility remain unclear. This scoping review aims to understand the practical application of RAG method and its outcomes in healthcare. METHOD: We followed the Arksey and O'Malley, and the Levac and colleagues' framework for scoping reviews and the PRISMA-ScR Checklist. We conducted searches of three electronic databases [Medline, Embase and Web of Science] in May 2021. Supplementary searches included Google Scholar, web and citation searches, and hand searches of the nine seminal edited books on Resilience Engineering and Resilient Health Care. All English language, empirical studies of RAG application in the healthcare setting were included. Open Science Framework [Registration-DOI. 10.17605/OSF.IO/GTCZ3]. RESULTS: Twelve studies met the inclusion criteria. Diversities were found across study designs and methodologies. Qualitative designs and literature reviews were most frequently used to develop the RAG and applied it in practice. Eight of the studies had qualitative designs, three studies had mixed-methods designs and one study had a quantitative design. All studies reported that the RAG was very helpful for understanding how frontline healthcare professionals manage the complexity of everyday work. While the studies gained insights from applying the RAG to analyze organizational resilience and identify areas for improvement, it was unclear how suggestions were implemented and how they contributed to quality improvement. CONCLUSION: The RAG is a promising tool to manage some of the current and future challenges of the healthcare system. To realise the potential benefits of the RAG, it is important that we move beyond the development phase of the RAG tool and use it to guide implementation and management of quality initiatives.

Rate and Risk Factors of Acute Myocardial Infarction after Debut of Chronic Kidney Disease-Results from the KidDiCo.

Chronic kidney disease (CKD) is a known risk factor for cardiovascular disease, including acute myocardial infarction. However, whether this risk is only associated with severe kidney disease or is also related to mildly impaired kidney function is still under debate. The incidence rate and risk factors of incident acute myocardial infarction (AMI) in patients with CKD are sparse. Potential differences in risk factor profiles between CKD patients with incident AMI and CKD patients with a prior AMI have not been sufficiently investigated. Furthermore, important factors such as albuminuria and socio-economic factors are often not included. The primary aim of this study was to establish the incidence rate of AMI after CKD debut. Secondly, to evaluate the importance of different CKD stages and the risk of having an AMI. Finally, to identify individuals at risk for AMI after CKD debut adjusted for prevalent AMI. Based on data from the kidney disease cohort of Southern Denmark (KidDiCo), including 66,486 CKD patients, we established incidence rates and characteristics of incident AMI among patients within a 5-year follow-up period after CKD debut. A Cox regression was performed to compute the cause-specific hazard ratios for the different risk factors. The incidence rate for CKD stage G3−5 patients suffering acute myocardial infarction is 2.5 cases/1000 people/year. In patients without a previous myocardial infarction, the risk of suffering a myocardial infarction after CKD debut was only significant in CKD stage G4 (HR = 1.402; (95% CI: 1.08−1.81); p-value = 0.010) and stage G5 (HR = 1.491; (95% CI: 1.01−2.19); p-value = 0.042). This was not the case in patients who had suffered an acute myocardial infarction prior to their CKD debut. In this group, a previous myocardial infarction was the most critical risk factor for an additional myocardial infarction after CKD debut (HR = 2.615; (95% CI: 2.241−3.05); p-value < 0.001). Irrespective of a previous myocardial infarction, age, male sex, hypertension, and a low educational level were significant risk factors associated with an acute myocardial infarction after CKD debut. The incidence rate of AMI in patients with CKD stage G3−5 was 2.5 cases/1000 people/year. Risk factors associated with incident AMI in CKD stage G3−5 patients were CKD stage, age, and hypertension. Female sex and higher educational levels were associated with a lower risk for AMI. Prior AMI was the most significant risk factor in patients with and without previous AMI before fulfilling CKD stage G3−5 criteria. Only age, sex, and a medium-long educational level were significant risk factors in this group.

Time to End-of-Life of Patients Starting Specialised Palliative Care in Denmark: A Descriptive Register-Based Cohort Study.

Increasing numbers of patients are being referred to specialised palliative care (SPC) which, in order to be beneficial, is recommended to last more than three months. This cohort study aimed to describe time to end-of-life after initiating SPC treatment and to explore potential regional variations. We used national register data from all Danish hospital SPC teams. We included patients who started SPC treatment from 2015-2018 to explore if time to end-of-life was longer than three months. Descriptive statistics were used to summarise the data and a generalised linear model was used to assess variations among the five Danish regions. A total of 27,724 patients were included, of whom 36.7% (95% CI 36.2-37.1%) had over three months to end-of-life. In the Capital Region of Denmark, 40.1% (95% CI 39.0-41.3%) had over three months to end-of-life versus 32.5% (95% CI 30.9-34.0%) in North Denmark Region. We conclude that most patients live for a shorter period of time than the recommended three months after initiating SPC treatment. This is neither optimal for patient care, nor the healthcare system. A geographical variation between regions was shown indicating different practices, patient groups or resources. These results warrant further investigation to promote optimal SPC treatment.

The resilient potential behaviours in an Internal Medicine Department: Application of resilience assessment grid.

BACKGROUND: The healthcare system is frequently subject to unpredictable conditions such as organisational changes and pandemics. In order to perform as required under these conditions (i.e. exhibiting resilient behaviour), it is necessary to know the current position of the organisation with respect to the four resilient potentials i.e. respond, monitor, learn and anticipate. The study aimed to understand and assess resilient performance of an Internal Medicine Department in a public hospital in Denmark using the resilience assessment grid (RAG). METHODS: A modified Delphi method was used to develop the context specific RAG, using interviews to generate items, two rounds of expert panel reviews and pilot testing the developed RAG questionnaire. The four sets of structured RAG questions were tested and revised until satisfactory face and content validity for application was achieved. The final version of the RAG (28-item Likert scale) questionnaire was sent electronically to 87 healthcare professionals (clinicians and managers) in January 2021 and 2022. The data was statistically analysed and illustrated in radar charts to assist in interpreting the resilience profiles. RESULTS: While the resilience profiles in 2021 and 2022 were similar, the scores in 2022 were slightly lower for some of the sub-indicators. The results indicate areas for improvement, especially related to the Internal Medicine Department's potential to respond and learn. The results from the RAG were presented to the chief clinical consultants and managers to identify initiatives for quality improvement and for planning a new workflow at the Internal Medicine Department. CONCLUSION: The RAG is a managerial tool to assess the potential resilient performance of the organisation in respect to the four resilience potentials, i.e., responding, monitoring, learning, and anticipating. It can be used to construct the resilience profile of the system over time to manage organisational changes.

Statin use before and after the KDIGO Lipids in chronic kidney disease guideline: A population-based interrupted time series analysis.

In November 2013, the Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease was published, recommending statins for all individuals 50 years or older with an estimated glomerular filtration rate below 60 ml/min/1.73 m2 to lower the risk of major cardiovascular events. We quantified the prevalence of statin use among the target population before and after the guideline publication in a large Danish cohort of individuals with an estimated glomerular filtration rate below 60 ml/min/1.73 m2 , to investigate the effect of the guideline, but found no difference in the prevalence of statin use prior to and after the guideline publication.

Expectations and Experiences of Patients Recently Initiated to Centre-Based Dialysis Treatment.

Existing studies display a huge disparity in terms of the number of patients who regret having engaged in dialysis. Modifiable care processes such as providing sufficient information and education prior to decision-making have been shown to have a greater impact on patient satisfaction. Despite the importance of regret as a measure of the quality of the dialysis decision-making process, few studies have examined regret following dialysis initiation. Aim: To explore the expectations and experiences of patients who have recently started centre-based dialysis treatment. Methods: A qualitative explorative study of centre-based dialysis patients was performed. Data were collected using focus group discussions of 2-4 patients. The study was guided by interpretive description and thematic analysis was used to analyse data. Results: Three focus group discussions were performed. Participants (n = 8) consisted of six men and two women aged 54 to 80 years of age with a median age of 72. Three themes emerged from the data: 1. transition from being a non-dialysis patient to becoming a dialysis patient, 2. physical condition following initiation of dialysis treatment, and 3. limitations and social disruptions. Conclusion: The initiation of dialysis disrupted daily life in terms of fluctuating fatigue, strict schedules, and time lost. There was a loss of independence, and participants did not view dialysis as an active choice. Nurses may have a significant impact on the perception of dialysis. This study highlights the need for further research to develop interventions to support newly initiated centre-based dialysis patients to transition from non-dialysis to dialysis patients.

Today's referral is tomorrow's repeat patient: referrals to and between medical outpatient clinics in a hospital.

BACKGROUND: Unnecessary referrals in Danish hospitals may be contributing to inefficient use of health services already stretched and under pressure and may lead to delayed treatment for patients. Despite a growing awareness in the literature and in practice of issues related to referrals, there has been relatively little research on referrals between specialists in hospital outpatient clinics and how it can be improved. This study aimed to describe the referral patterns to and within the Medical Department at the University Hospital of Southern Denmark. The Medical Department consists of the following medical specialist outpatient clinics; nephrology, pulmonology, endocrinology, cardiovascular, wound outpatient clinic, and a day hospital. METHODS: Two specialist physicians assessed all referrals to the medical specialist outpatient clinics over one month (from 01 September 2019 to 30 September 2019) using data drawn from the Danish electronic patient record system (Cosmic). Data on referral pattern, and patient age and sex, were statistically analysed to identify and characterise patterns of referral. RESULTS: Four hundred seventy-one (100%) referrals were included in the study. 49.5% (233) of the referrals were from the hospital and 50.5% (238) from general practitioners (GPs). Of the 233 referrals from the hospitals, 31% (72) were from the Medical Department. CONCLUSION: The high rate of referrals (31%) from own Medical Department or outpatient clinics may reflect an inefficient internal referral process within the department. Improved collaboration between specialists could have the potential to improve health outcomes, timely access to care and more appropriate healthcare resource utilisation.

Troponin Cut-Offs for Acute Myocardial Infarction in Patients with Impaired Renal Function-A Systematic Review and Meta-Analysis.

Identifying acute myocardial infarction in patients with renal disease is notoriously difficult, due to atypical presentation and chronically elevated troponin. The aim of this study was to identify a specific troponin T/troponin I cut-off value for diagnosis of acute myocardial infarction in patients with renal impairment via meta-analysis. Two investigators screened 2590 publications from MEDLINE, Embase, PubMed, Web of Science, and the Cochrane library. Only studies that investigated alternative cut-offs according to renal impairment were included. Fifteen articles fulfilled the inclusion criteria. Six studies were combined for meta-analysis. The manufacturer's upper reference level for troponin T is 14 ng/L. Based on the meta-analyses, cut-off values for troponin in patients with renal impairment with myocardial infarction was 42 ng/L for troponin I and 48 ng/L for troponin T. For patients on dialysis the troponin T cut-off is even higher at 239 ng/L. A troponin I cut-off value for dialysis patients could not be established due to lack of data. The 15 studies analyzed showed considerable diversity in study design, study population, and the definition of myocardial infarction. Further studies are needed to define a reliable troponin cut-off value for patients with kidney disease, especially in dialysis patients, and to allow necessary subanalysis.

Urinary Dipstick Is Not Reliable as a Screening Tool for Albuminuria in the Emergency Department-A Prospective Cohort Study.

Albuminuria is a sensitive marker for renal dysfunction. Urinary dipstick tests are frequently used to screen for urinary abnormalities in the emergency department (ED). The aim of this prospective cohort study is to evaluate the usefulness of urinary dipstick testing as a screening tool for albuminuria in the ED setting and to determine the persistency of albuminuria identified in the acute setting. Urinary dipstick tests and spot urine samples were obtained simultaneously for analysis of the urinary albumin-creatinine ratio (ACR). Participants with positive dipsticks for protein were invited for a second urinalysis four to six weeks after admission. The study included 234 patients admitted to the ED. Urinalysis was performed on 178 patients of which 46% (n = 82) had positive urinary dipstick tests for proteinuria. The sensitivity and specificity of the dipstick test were low (72.7% and 55.7% respectively) when compared to the ACR. Of the 82 patients with positive dipsticks at admission, 35 were available for follow-up. We observed a significant reduction in ACR at follow-up when compared to ACR at admission (p = 0.004). This paper concludes that urinary dipstick tests are not a reliable means to screen for albuminuria in the ED setting.

Lanthanum Carbonate Opacities-A Systematic Review.

BACKGROUND: Lanthanum carbonate is a phosphate binder used in advanced kidney disease. Its radiopaque appearance has been described in many case studies and case series. Misinterpretation of this phenomenon leads to unnecessary diagnostic tests and procedures. The objectives of this study were to summarize the literature on lanthanum carbonate opacities and present a visual overview. METHODS: A systematic search was conducted using MEDLINE, Embase, and Web of Science. We included all types of studies, including case reports/studies, describing radiological findings of lanthanum carbonate opacities in patients with chronic kidney disease. No filter for time was set. RESULTS: A total of 36 articles were eligible for data extraction, and 33 articles were included in the narrative synthesis. Lanthanum carbonate opacities were most commonly reported in the intestines (26 studies, 73%), stomach (8 studies, 21%), and the aerodigestive tract (2 studies, 6%). The opacities in the intestine were most frequently described as multiple, scattered radiopaque densities, compared with the aerodigestive tract, where the opacities were described as a single, round foreign body. Suspicion of contrast medium or foreign bodies was the most common differential diagnosis. LC opacities in patients with CKD are commonly misinterpreted as foreign bodies or suspect contrast media. CONCLUSIONS: CKD patients treated with LC may have opacities throughout the digestive tract that can vary in appearance. Stopping LC treatment or changing to an alternative phosphate binder prior to planned image studies can avoid diagnostic confusion. If this is not an option, knowledge of the presentation of LC opacities is important.

Protocol for an integrative review: patient and families' perspectives on telehealth in palliative care.

INTRODUCTION: Increases in the use of telehealth in palliative care (telepalliative care) prior to, and during, the COVID-19 pandemic have resulted in a proliferation of studies on the topic. While knowledge is building on how providers and recipients adapt to telepalliative care, no reviews have, as of yet, examined telepalliative care from a patient and family perspective. Therefore, the aim of this integrative review is to explore patients and families' perspectives on telepalliative. METHODS AND ANALYSIS: An integrative review will be performed inspired by the methodology of Remmington and Toronto from March 2022 to December 2022. Medline, Embase, PsycINFO and CINAHL will be searched for primary peer-reviewed studies that describe telepalliative care from patient and families' perspectives. Limiters will be used for age; 18 years+, time; 10 years, and language; English and Danish. Hand searches of authors of included articles and reference lists of included articles will be performed. Two reviewers will independently screen and appraise selected articles using the Mixed Method Appraisal Tool. Conflicts will be resolved through discussions with a third reviewer. Data will be extracted independently by two reviewers into a data matrix with predefined headings and analysed using thematic analysis. Findings will be reported thematically, summarised into a thematic synthesis and discussed in relation to relevant literature. ETHICS AND DISSEMINATION: Ethical approval is not required for this review. Results will be published in an international peer-reviewed journal and presented at a relevant international conference. Reporting of this protocol was guided by the Preferred Reporting Items for Systematic reviews and Meta-Analyses Protocol checklist and prospectively reported to PROSPERO (CRD42022301206).

Kidney Disease Cohort (KidDiCo) of Southern Denmark: Design, Coverage, Generalizability and Implications for Use.

BACKGROUND: This article provides a description of a large register of a population from the Region of Southern Denmark, the Kidney Disease Cohort (KiDiCo). Coverage and representativeness according to gender and education level are discussed. METHODS: Data for KiDiCo were obtained using laboratory databases from participating laboratories in the Region of Southern Denmark and were linked to individual personal 10-digit personal identification numbers. The study population includes individuals over 18 years of age living in Denmark, whose serum creatinine was analysed in one of the 27 participating laboratories in the Region of Southern Denmark during the period of 8 years from 1st January 2006 to 31st December 2013. Individually linked data consist of diagnosis codes, date and cause of death, dispensed medicine data, socioeconomic data and demographic data. RESULTS: In total, n = 669,929 individuals had their blood tested for creatinine between 2007 and 2013 in a defined geographical area. The estimated geographical coverage was 78%. The median age of the background population was 6 years lower. The cohort had a slightly higher percentage of females (53%) compared to the background population (49%). Differences in educational levels reflect the minor age gap. CONCLUSION: Based on coverage of 78% together with similar characteristics in terms of gender and age, the KiDiCo is a representative cohort of patients in the Region of Southern Denmark. Combining laboratory data with high-quality Danish administrative registers makes diverse research feasible.

Increased risk of dementia in hypothyroidism: A Danish nationwide register-based study.

OBJECTIVE: Globally, the prevalence of individuals with dementia is increasing, and identification of risk factors is of paramount interest. Using population-based registers, we evaluated whether hypothyroidism is a risk factor for dementia. DESIGN: Register-based cohort study. PATIENTS AND METHODS: Risk of dementia was evaluated in two cohorts. The DNPR cohort comprises 111,565 hypothyroid patients, diagnosed between 1995 and 2012, and 446,260 euthyroid age- and sex-matched individuals (median follow-up 6.2 years). The OPENTHYRO cohort comprises 233,844 individuals with at least one measurement of serum thyrotropin (TSH) between 1995 and 2011, of whom 2,894 had hypothyroidism (median follow-up 7.2 years). Primary outcome was dementia defined as an International Classification of Diseases 10 code, or prescription of medicine for dementia. RESULTS: In the DNPR cohort, risk of dementia was significantly increased in subjects with hypothyroidism (HR 1.22; 95% CI: 1.17-1.27), which attenuated after adjusting for pre-existing comorbidity (HR 0.82; 95% CI: 0.79-0.86). Stratification of age into ≤56 and >56 years showed an inverse relationship between age and risk of dementia (HR≤56 years. 2.03; 95% CI: 1.62-2.53 and HR>56 years . 1.00; 95% CI: 0.96-1.05). In the OPENTHYRO cohort, the risk of dementia was significantly increased for each 6 months of elevated TSH (HR 1.12; 95% CI: 1.07-1.16). CONCLUSIONS: Hypothyroidism is associated with increased risk of dementia. The association is influenced by comorbidity and age. Every 6 months of elevated TSH increased the risk of dementia by 12%, suggesting that also the length of hypothyroidism influences the risk of dementia.

A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction.

COX16 is involved in the biogenesis of cytochrome-c-oxidase (complex IV), the terminal complex of the mitochondrial respiratory chain. We present the first report of two unrelated patients with the homozygous nonsense variant c.244C>T(p. Arg82*) in COX16 with hypertrophic cardiomyopathy, encephalopathy and severe fatal lactic acidosis, and isolated complex IV deficiency. The absence of COX16 protein expression leads to a complete loss of the holo-complex IV, as detected by Western blot in patient fibroblasts. Lentiviral transduction of patient fibroblasts with wild-type COX16 complementary DNA rescued complex IV biosynthesis. We hypothesize that COX16 could play a role in the copper delivery route of the COX2 module as part of the complex IV assembly. Our data provide clear evidence for the pathogenicity of the COX16 variant as a cause for the observed clinical features and the isolated complex IV deficiency in these two patients and that COX16 deficiency is a cause for mitochondrial disease.

Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction.

NGLY1 encodes the enzyme N-glycanase that is involved in the degradation of glycoproteins as part of the endoplasmatic reticulum-associated degradation pathway. Variants in this gene have been described to cause a multisystem disease characterized by neuromotor impairment, neuropathy, intellectual disability, and dysmorphic features. Here, we describe four patients with pathogenic variants in NGLY1. As the clinical features and laboratory results of the patients suggested a multisystem mitochondrial disease, a muscle biopsy had been performed. Biochemical analysis in muscle showed a strongly reduced ATP production rate in all patients, while individual OXPHOS enzyme activities varied from normal to reduced. No causative variants in any mitochondrial disease genes were found using mtDNA analysis and whole exome sequencing. In all four patients, variants in NGLY1 were identified, including two unreported variants (c.849T>G (p.(Cys283Trp)) and c.1067A>G (p.(Glu356Gly)). Western blot analysis of N-glycanase in muscle and fibroblasts showed a complete absence of N-glycanase. One patient showed a decreased basal and maximal oxygen consumption rates in fibroblasts. Mitochondrial morphofunction fibroblast analysis showed patient specific differences when compared to control cell lines. In conclusion, variants in NGLY1 affect mitochondrial energy metabolism which in turn might contribute to the clinical disease course.