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The association between the MCM6-13910-C/T polymorphism and lactose intolerance in individuals of European descent is well known. However, the notion that having a single versus a double allelic mutation might influence one's phenotype has been hypothesized. This study investigated whether patients with the three genotypes C/C, C/T, T/T differed in response to a lactose tolerance test (LTT) in a Danish setting. Anonymized data on 603 individuals with results for both genetic test and LTT were investigated. Mean delta glucose values were plotted for the time points of the LTT (0, 15, 30, 45 and 60 min) for the C/C, C/T and T/T genotype, respectively. Further, the agreement between the three genotypes and the diagnostic interpretation of the LTT were examined using a cut-off of > 1.4 mmol/L rise in glucose. In subjects with the C/C genotype, mean glucose delta levels were markedly lower compared to both the C/T and T/T genotypes at all time points. Overall, a difference between mean glucose delta values among the C/T and T/T genotype could not be shown. Using a LTT cut-off of > 1.4 mmol/L, the proportions of lactose intolerant LTT results for each genotype were as follows: 58% among C/C, 5% among C/T, and 7% among T/T. In a Danish healthcare setting, the C/C genotype was on average associated with a smaller glucose response during a LTT when compared to the C/T and T/T genotypes. A marked difference in the LTT response among the C/T and T/T genotype was not observed.

Objective: To evaluate the impact of a compulsory pop-up form on the ordering pattern of proBNP blood tests by general practitioners in the Capital Region of Denmark., Design: A follow-up study comparing the average number of proBNP tests ordered before and after the implementation of an intervention., Setting and Subjects: From 2016 to 2021, the average number of proBNP tests increased by over 300%. In March 2022, a compulsory pop-up form was introduced in the electronic request system (WebReq), requiring general practitioners to select one of three indications for ordering proBNP, as recommended by the Danish Society of Cardiology. The study included 528 general practitioners in the Capital Region of Denmark, with data available from January 2020 to 2023, encompassing 83,576 proBNP results from 56,645 patients., Main Outcome Measure: The average number of proBNP tests ordered per month and the median level of proBNP before and after the intervention., Results: Following the intervention, the average number of proBNP tests per month decreased by 60% over a 22-month follow-up period. The highest reduction was seen among general practitioners who previously ordered the most tests (≥3 per 1000 biochemical tests). In this group, the median proBNP level increased from 12.1 pmol/L before the intervention to 13.5 pmol/L after the intervention ( p  < 0.0001)., Conclusions: This study demonstrates a significant decrease in the number of proBNP requests from general practitioners in the Capital Region of Denmark after the introduction of a pop-up form in the requisition system containing the current guidelines.

Aims: Plasma levels of Vitamin D (25(OH)D) have been suggested as a predictor for developing type 2 diabetes. The purpose of this study was therefore to investigate if a measurement of plasma 25(OH)D could predict the development of type 2 diabetes in a cohort of 222,311 individuals from primary healthcare in Denmark., Methods: The CopD-study database containing data from the Copenhagen General Practitioners Laboratory on blood tests conducted from April 2004 to January 2012 was used for identification of the study population. Incident type 2 diabetes was then defined as having at least two redeemed prescriptions of antidiabetics or at least two hospital contacts due to type 2 diabetes or one redeemed prescription and one hospital contact regarding type 2 diabetes., Results: A total of 222,311 individuals were included in the study, of whom 7652 (3.4%) developed type 2 diabetes during the follow-up period of minimum one year. Individuals who developed type 2 diabetes had a significantly lower median 25(OH)D level than persons in the non-diabetes group. The hazard ratio for development of type 2 diabetes increased by 15% per 10 n mol/L decrease in 25(OH)D level., Conclusion: In this study of 222,311 persons from primary health care in Denmark, we found a clear inverse relationship between 25(OH)D and the risk of developing type 2 diabetes. Further studies should be conducted to clarify the mechanisms behind the relationship between 25(OH)D and type 2 diabetes and the effect of oral vitamin D supplementation on the development of type 2 diabetes., (© 2024. The Author(s).)

Purpose: This aim of this study was to assess the possible association between diurnal oscillations and biochemical markers associated with calcium homeostasis. This included the markers parathyroid hormone (PTH), total calcium, total alkaline phosphatase, phosphate, and 25-hydroxyvitamin D (25-OH-D). By examining the influence of circadian rhythms on these parameters, the study aimed to deepen the understanding of calcium metabolism dynamics and its clinical implications., Patients and Methods: Blood samples from 24 Caucasian male volunteers aged 20 to 40 (mean age 26) with normal pulse, blood pressure, and BMI were analyzed for biochemical markers related to calcium homeostasis. Data was obtained from the Bispebjerg study of diurnal variations. Blood samples were collected every three hours over a 24-hour period. Patients were fasting from 22:00 to 09:00. The participants spent 24 h in the hospital ward, receiving regular meals and engaging in low-intensity activities. They experienced 15 h of daylight and 9 h of complete darkness during sleep. Diurnal oscillations were analyzed using cosinor analysis with statistical significance set at p  < 0.05., Results: Total calcium, phosphate, and PTH exhibited significant diurnal variations. Total calcium and PTH were inversely synchronized while PTH and phosphate oscillated in synchronization. The three parameters showed relatively large amplitude/reference range ratios from 25.4% to 41.5%., Conclusion: This study found notable fluctuations in total calcium, phosphate, and PTH levels over a 24-hour cycle, while 25-OH-D and total alkaline phosphatase remained consistent. It highlights the importance of considering sampling times for total calcium, PTH, and phosphate in clinical settings.

Recurrent pregnancy loss (RPL) affects 1-2 % of all couples trying to conceive and is a challenging heterogeneous condition. This study aimed to evaluate the prevalence and impact of various risk factors in patients suffering from RPL. We performed a prospective cohort study including patients at the tertiary RPL Unit in the Capital Region of Denmark between 1st January 2000 and 1st January 2023. The main outcome of the study was the first pregnancy after referral and whether the pregnancy was ongoing at least to the 22nd gestational week. A total of 2555 patients were included in the study, out of whom 1892 patients achieved a pregnancy after referral to the RPL Unit. This resulted in 1103 live births (58.3 %) and 718 pregnancy losses (37.9 %). Maternal age, BMI, smoking status and the number of prior pregnancy losses were negatively correlated with the likelihood of achieving pregnancy. Furthermore, maternal age, prior pregnancy losses, antiphospholipid syndrome (APS) and uterine malformations were associated with reduced birth rates. Patients with secondary RPL had a higher birth rate compared to those with primary RPL, and patients with APS treated with low-molecular-weight heparin (LMWH) demonstrated a significantly increased birth rate compared to untreated APS patients. These findings suggest that certain risk factors significantly impact the likelihood of achieving pregnancy and live birth following RPL, which can be used in patient guidance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article, (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The diagnosis of multiple myeloma requires detection of paraproteinemia and confirmation of monoclonal bone marrow infiltration, along with signs of end-organ damage. Despite the increasing prevalence, serum paraproteinemia is not routinely measured. We examined the relationship between alterations in routine hematological parameters and the development of paraproteinemia in a case-control study. Data was retrieved from a laboratory database in the capital region of Denmark between 01/01/2012 and 31/12/2022. Patients were included if they had a test for paraproteinemia (n = 134,740) and at least one prior hematological parameter (white blood cells, hemoglobin and platelet count) with a minimum follow-up of 1 year.Between 96,999 and 103,590 patients were included in each of the three hematological groups. We found white blood cell count and the presence of paraproteinemia followed an inverse J-shaped curve, with the highest presence below 3 × 10 9 /L and above > 9 × 10 9 /L. The adjusted OR below and above the nadir of 4 × 10 9 /L was 1.61 (95% CI 1.25; 2.08, p < 0.0001) and 1.03 (95% CI 1.03; 1.04, p < 0.0001). Hemoglobin levels were inversely associated the presence of paraproteinemia, with the highest association below 6 mmol/L with an OR of 1.30 (95% CI 1.28; 1.32, p < 0.0001) adjusted for age and gender. Platelet count followed a U-shaped curve with the highest association at < 100 × 10 9 /L. The adjusted OR below and above the nadir of 250 × 10 9 /L was 1.13 (95% CI 1.10; 1.17, p < 0.0001) and 1.10 (95% CI 1.08; 1.12, p < 0.0001) respectively. In conclusion, all three parameters showed significant association with later paraproteinemia., (© 2024. The Author(s).)

Context: It is not clear if antagonizing the GIP (glucose-dependent insulinotropic polypeptide) receptor (GIPR) for treatment of obesity is likely to increase the risk of fractures, or to lower bone mineral density (BMD) beyond what is expected with rapid weight loss., Objective: The objective of this study was to investigate the risk of fracture and BMD of sequence variants in GIPR that reduce the activity of the GIP receptor and have been associated with reduced body mass index (BMI)., Methods: We analyzed the association of 3 missense variants in GIPR, a common variant, rs1800437 (p.Glu354Gln), and 2 rare variants, rs139215588 (p.Arg190Gln) and rs143430880 (p.Glu288Gly), as well as a burden of predicted loss-of-function (LoF) variants with risk of fracture and with BMD in a large meta-analysis of up to 1.2 million participants. We analyzed associations with fractures at different skeletal sites in the general population: any fractures, hip fractures, vertebral fractures and forearm fractures, and specifically nonvertebral and osteoporotic fractures in postmenopausal women. We also evaluated associations with BMD at the lumbar spine, femoral neck, and total body measured with dual-energy x-ray absorptiometry (DXA), and with BMD estimated from heel ultrasound (eBMD)., Results: None of the 3 missense variants in GIPR was significantly associated with increased risk of fractures or with lower BMD. Burden of LoF variants in GIPR was not associated with fractures or with BMD measured with clinically validated DXA, but was associated with eBMD., Conclusion: Missense variants in GIPR, or burden of LoF variants in the gene, are not associated with risk of fractures or with lower BMD., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: In orthopaedics, anterior cruciate ligament (ACL) reconstructions are among the most common surgical interventions. Two methods are preferably used: autografts from the hamstring tendon (HT) or patella tendon (PT). The purpose of this meta-analysis was to compare these two methods when returning to sports., Methods: Eleven studies were included based on a literature search conducted in PubMed. The primary outcome was return to preinjury sport level in athletes. Post-operative results such as the Lysholm score, the International Knee Documentation Committee (IKDC) subjective score, the Tegner Activity Score and KT-1000 arthrometry and autograft re-rupture rates were analysed as secondary outcomes., Results: The analysis showed no significant difference in return to preinjury sports level at a two-year follow-up between patients operated with hamstring or patella autograft. Considering the secondary outcomes, no significant differences were recorded in Lysholm score, IKDC score or re-rupture rate. The Tegner Activity Scale demonstrated a significantly higher activity level in the PT group than in the HT group (OR 0.79, p = 0.003). At the two-year follow-up, the KT-1000 arthrometer analysis also showed a significant difference in laxity, which was higher for the HT autografts (OR -0.31, p = 0.02)., Conclusion: This study showed no significant differences between hamstring and patella autografts. Even so, the choice of method when operated for ACL rupture remains crucial for the individual and should be a weighted decision made jointly by the patient and the physician., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

In order to estimate the likelihood of 1, 3, 6 and 12 month mortality in patients with hip fractures, we applied a variety of machine learning methods using readily available, preoperative data. We used prospectively collected data from a single university hospital in Copenhagen, Denmark for consecutive patients with hip fractures, aged 60 years and older, treated between September 2008 to September 2010 (n = 1186). Preoperative biochemical and anamnestic data were used as predictors and outcome was survival at 1, 3, 6 and 12 months after the fracture. After feature selection for each timepoint a stratified split was done (70/30) before training and validating Random Forest models, extreme gradient boosting (XGB) and Generalized Linear Models. We evaluated and compared each model using receiver operator characteristic (ROC), calibration slope and intercept, Spiegelhalter's z- test and Decision Curve Analysis. Using combinations of between 10 and 13 anamnestic and biochemical parameters we were able to successfully estimate the likelihood of mortality with an area under the curve on ROC curves of 0.79, 0.80, 0.79 and 0.81 for 1, 3, 6 and 12 month, respectively. The XGB was the overall best calibrated and most promising model. The XGB model most successfully estimated the likelihood of mortality postoperatively. An easy-to-use model could be helpful in perioperative decisions concerning level of care, focused research and information to patients. External validation is necessary before widespread use and is currently underway, an online tool has been developed for educational/experimental purposes ( https://hipfx.shinyapps.io/hipfx/ )., (© 2024. The Author(s).)

Background and Aims: Pancreatic walled-off necrosis (WON) carries significant mortality and morbidity risks, often necessitating intensive care unit (ICU) admission. This retrospective study aimed to evaluate whether routine biochemical parameters at the time of the index endoscopic procedure could predict ICU admission and 1-year mortality following endoscopic treatment of WON., Materials and Methods: We retrospectively identified 201 consecutive patients who underwent endoscopic drainage for WON between January 1, 2010, and December 31, 2020. Associations between routine biochemical blood tests and outcomes were assessed using logistic regression models., Results: Within 1 year of the index endoscopy, 31 patients (15.4%) died, and 40 (19.9%) were admitted to the ICU due to sepsis. Preoperative electrolyte disturbances were more prevalent among ICU-admitted patients and nonsurvivors. Hyperkalemia, hypoalbuminemia, and elevated urea were significant predictors of 1-year mortality, while hypernatremia, elevated serum creatinine, and hypoalbuminemia predicted ICU admission. Predictive models exhibited good discriminative ability, with an AUC of 0.84 (95% CI,0,75-0.93) for 1-year mortality and 0.86 (95%CI, 0.79-0.92) for ICU admission., Conclusions: Preoperative imbalances in routine blood tests effectively predict adverse outcomes in endoscopically treated WON patients., Competing Interests: Potential competing interests: M.E., M.P.W., N.A., S.N., and H.L.J. have no conflicts of interest to declare. J.G.K. is a consultant for Boston Scientific, Ambu, and SNIPR Biome., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Glucagon is secreted from pancreatic alpha cells in response to low blood glucose and increases hepatic glucose production. Furthermore, glucagon enhances hepatic protein and lipid metabolism during a mixed meal. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from gut endocrine cells during meals and control glucose homeostasis by potentiating insulin secretion and inhibiting food intake. Both glucose homeostasis and food intake have been reported to be affected by circadian rhythms and vice versa. In this study, we investigated whether the secretion of glucagon, GLP-1 and GIP was affected by circadian rhythms., Methods: A total of 24 healthy men with regular sleep schedules were examined for 24 h at the hospital ward with 15 h of wakefulness and 9 h of sleep. Food intake was standardized, and blood samples were obtained every third hour. Plasma concentrations of glucagon, GLP-1 and GIP were measured, and data were analyzed by rhythmometric statistical methods. Available data on plasma glucose and plasma C-peptide were also included., Results: Plasma concentrations of glucagon, GLP-1, GIP, C-peptide and glucose fluctuated with a diurnal 24-h rhythm, with the highest levels during the day and the lowest levels during the night: glucagon (p < 0.0001, peak time 18:26 h), GLP-1 (p < 0.0001, peak time 17:28 h), GIP (p < 0.0001, peak time 18:01 h), C-peptide (p < 0.0001, peak time 17.59 h), and glucose (p < 0.0001, peak time 23:26 h). As expected, we found significant correlations between plasma concentrations of C-peptide and GLP-1 and GIP but did not find correlations between glucose concentrations and concentrations of glucagon, GLP-1 and GIP., Conclusions: Our results demonstrate that under meal conditions that are similar to that of many free-living individuals, plasma concentrations of glucagon, GLP-1 and GIP were observed to be higher during daytime and evening than overnight. These findings underpin disturbed circadian rhythm as a potential risk factor for diabetes and obesity., Trial Registration: ClinicalTrials.gov Identifier: NCT06166368. Registered 12 December 2023., (© 2024. The Author(s).)

Free ionized calcium (fCa) is considered the gold standard for assessing calcium status in patients, but it is relatively expensive and is associated with several preanalytical and analytical error sources. We investigated the feasibility of using a reflex test that involves first measuring total calcium (tCa) and if out of reference range, then measure fCa, with expectation of reducing the number of fCa measurements. We used data from 1815 unique patients with concurrent measurement of fCa, tCa and albumin adjusted calcium (aCa). Patients were stratified by albumin level, and the association of fCa to tCa and aCa respectively was assessed with linear regression. The regression analysis showed the best linearity for tCa and aCa at albumin <35 g/L ( R 2 : 0.80-0.90), and the poorest at albumin >40 g/L ( R 2 : tCa 0.58; aCa 0.59). We examined the accuracy of hypo- and hypercalcemia classifications for tCa, aCa and the reflex test. aCa had more misclassifications of hypo- and hypercalcemia than tCa, with respectively 25% and 21%. Implementation of the reflex test would correct any false hypo- or hypercalcemia classified by tCa, leaving only false negative results corresponding to 9% of all tCa measurements. False negative results were on average 0.04 mmol/L above or below the reference range of fCa. Implementation of the reflex test reduces the number of fCa by 68% without major errors diagnosing hyper- or hypocalcemia.

Importance: Gram-negative bacteremia is a global health concern, and optimizing the transition from intravenous (IV) to oral antibiotics is a critical step in improving patient treatment and resource utilization., Objective: To assess the association of switching to oral antibiotics within 4 days after initial blood culture with 90-day all-cause mortality compared with prolonged IV antibiotic treatment for patients with uncomplicated gram-negative bacteremia., Design, Setting, and Participants: This cohort study conducted using the target trial emulation framework included observational data from adults with uncomplicated gram-negative bacteremia in 4 hospitals in Copenhagen, Denmark, from January 1, 2018, through December 31, 2021. The duration of follow-up was 90 days. Eligibility criteria included a blood culture positive for growth of gram-negative bacteria, clinical stability within 4 days of initial blood culture, an available susceptibility report on day 4, and initiation of appropriate empirical IV antibiotic treatment within 24 hours of blood culture., Exposure: Switching to oral antibiotics within 4 days after initial blood culture compared with continuing IV antibiotic treatment for at least 5 days after initial blood culture., Main Outcomes and Measures: The main outcome was 90-day all-cause mortality. Inverse probability of treatment weighting was applied to adjust for confounding. Intention-to-treat and per-protocol analyses were performed using pooled logistic regression to estimate absolute risk, risk difference (RD), and risk ratio (RR); 95% CIs were computed using bootstrapping., Results: A total of 914 individuals were included in the target trial emulation analysis (512 [56.0%] male; median age, 74.5 years [IQR, 63.3-83.2 years]); 433 (47.4%) transitioned early to oral antibiotic treatment, and 481 (52.6%) received prolonged IV treatment. Ninety-nine individuals (10.8%) died during follow-up. The proportion of individuals who died was higher in the group receiving prolonged IV treatment (69 [14.3%] vs 30 [6.9%]). In the intention-to-treat analysis, 90-day all-cause mortality risk was 9.1% (95% CI, 6.7%-11.6%) for the early-switch group and 11.7% (95% CI, 9.6%-13.8%) for the group receiving prolonged IV treatment; the RD was -2.5% (95% CI, -5.7% to 0.7%) and RR was 0.78 (95% CI, 0.60-1.10). In the per-protocol analysis, the RD was -0.1% (95% CI, -3.4% to 3.1%) and RR was 0.99 (95% CI, 0.70-1.40)., Conclusions and Relevance: In this cohort study of uncomplicated gram-negative bacteremia, early transition to oral antibiotics within 4 days of initial blood culture was associated with 90-day all-cause mortality risk comparable to that of continuing IV antibiotic treatment and may be an effective alternative to prolonged IV treatment.

The aim of this study was to assess the possible association between P-Mg and subsequent high levels of HbA 1c. The study involves data from primary health care patients and data from patients treated in hospitals located in the capital region of Denmark. P-Mg and HbA 1c levels were analyzed from 121,575 patients in the period 2010-2022. Patients were categorized in a diabetic and non-diabetic group. Out of 121,575 patients, 8,532 were categorized as diabetic. A reverse J-shaped association between P-Mg and HbA 1c levels ≥ 48 mmol/mol was observed with nadir at P-Mg of 0.90 mmol/L. The unadjusted hazard ratio (HR) for having a first HbA 1c measurement ≥ 48 mmol/mol is 1.54 (95% Cl 1.50; 1.57) per 0.1 mmol/L decrease in P-Mg when P-Mg is lower than 0.90 mmol/L. After adjusting for age and gender, the HR remained significant at 1.45 (95% Cl 1.41; 1.48).For P-Mg levels above 0.90 mmol/L, the unadjusted HR per 0.1 mmol/L increase in P-Mg was 1.04 (95% Cl 1.02; 1.06). After adjusting for age and gender the HR remained significant at 1.06 (95% Cl 1.05; 1.08). In conclusion, this study found that patients with dysmagnesemia have a higher risk of developing diabetes even after adjusting for age and gender. Hyper- or hypomagnesemia in patients could be a biomarker for predicting the risk of developing diabetes.

Background: Major abdominal surgery is associated with considerable mortality in the elderly. Anemia has been linked to increased mortality in other types of surgery, such as hip and cardiac surgery. This study aimed to assess the impact of preoperative anemia on mortality in the elderly undergoing major abdominal surgery, and how allogeneic red cell blood transfusion influences mortality in these patients., Materials and Methods: We conducted a single-center, register-based retrospective study on patients, who were aged beyond 60 years and underwent one of 81 open abdominal surgical procedures. Patients operated on during the period from January 1, 2000, to May 31, 2013, were consecutively identified in the Danish National Patient Registry. Plasma hemoglobin was measured within 30 days prior to surgery and the primary endpoint was 30-day postoperative mortality. Information about patient transfusions from the hospital blood bank was available from 1998 to 2010., Results: A total of 3199 patients were included of whom 85% underwent emergency surgery. The total mortality after 30 days was 20%. The median preoperative hemoglobin value of survivors was 7.7 mmol/L vs 6.9 mmol/L in those who died. The difference in hemoglobin values, between those who survived or died, decreased from the pre- to the post-operative phase. The 30-day postoperative mortality was 28%, 20%, and 12% in patients with a preoperative hemoglobin level in the lower, median, and upper quartile respectively. Transfusion therapy was associated with higher postoperative mortality, except in patients with very low hemoglobin values., Conclusion: Preoperative anemia has a clear association with surgically related mortality. The distribution of hemoglobin values in patients with a fatal outcome differs significantly from that of survivors. Red cell transfusion is associated with increased mortality, except in patients with very low hemoglobin values which supports recent guidelines suggesting a restrictive transfusion strategy., (© 2023. The Author(s).)

Background: Caregiving in Alzheimer's disease (AD) is often provided by informal care partners, who spend more hours per week on average than care partners of individuals with conditions other than AD. However, the burden of care in partners of individuals with AD has not been systematically compared to that of other chronic diseases., Objective: The current study therefore aims to compare the care partner burden of AD to that of other chronic diseases through a systematic literature review., Methods: Data was collected from journal articles published in the last 10 years, using two unique search strings in PubMed and analysed using pre-defined patient-reported outcome measures (PROMs) including the EQ-5D-5L, GAD-7, GHQ-12, PHQ-9, WPAI and the ZBI. The data was grouped according to the included PROMs and the diseases studied. The number of participants in the studies reporting burden of caregiving in AD was adjusted to reflect the number of participants in studies reporting care partner burden in other chronic diseases., Results: All results in this study are reported as a mean value and standard deviation (SD). The ZBI measurement was the most frequently used PROM to collect care partner burden (15 studies) and showed a moderate burden (mean 36.80, SD 18.35) on care partners of individuals with AD, higher than most of the other included diseases except for those characterized by psychiatric symptoms (mean scores 55.92 and 59.11). Other PROMs such as PHQ-9 (six studies) and GHQ-12 (four studies) showed a greater burden on care partners of individuals with other chronic diseases such as heart failure, haematopoietic cell transplantations, cancer and depression compared to AD. Likewise, GAD-7 and EQ-5D-5L measurements showed a lesser burden on care partners of individuals with AD compared to care partners of individuals with anxiety, cancer, asthma and chronic obstructive pulmonary disease. The current study suggests that care partners of individuals with AD experience a moderate burden, but with some variations depending on the PROMs used., Conclusion: The results of this study were mixed with some PROMs indicating a greater burden for care partners of individuals with AD versus other chronic diseases, and other PROMs showing a greater burden for care partners of individuals with other chronic diseases. Psychiatric disorders imposed a greater burden on care partners compared to AD, while somatic diseases in the musculoskeletal system resulted in a significantly smaller burden on care partners compared to AD., (© 2023. The Author(s).)

Objective: To examine whether education level influences screening, monitoring, and treatment of hypercholesterolemia., Design: Epidemiological cohort study., Setting: Department of Clinical Biochemistry, Copenhagen University Hospital Hvidovre., Subjects: Cholesterol blood test results ordered by general practitioners in Greater Copenhagen were retrieved from 2000-2018. Using the International Standard Classification of Education classification, the population was categorized by length of education in three groups (basic education; up to 10 years, intermediate education; 11-12 years, advanced education; 13 years or more). The database comprised 13,019,486 blood sample results from 653,903 patients., Main Outcome Measures: Frequency of lipid measurement, prevalence of statin treatment, age and comorbidity at treatment initiation, total cholesterol threshold for statin treatment initiation, and achievement of treatment goal., Results: The basic education group was measured more frequently (1.46% absolute percentage difference of total population measured [95% CI 0.86%-2.05%] in 2000 and 9.67% [95% CI 9.20%-10.15%] in 2018) over the period compared to the intermediate education group. The advanced education group was younger when receiving first statin prescription (1.87 years younger [95% CI 1.02-2.72] in 2000 and 1.06 years younger [95% CI 0.54-1.58 in 2018) compared to the intermediate education group. All education groups reached the treatment goals equally well when statin treatment was initiated., Conclusion: Higher education was associated with earlier statin prescription, although the higher educated group was monitored less frequently. There was no difference in reaching treatment goal between the three education groups. These findings suggest patients with higher education level achieve an earlier dyslipidemia prevention intervention with an equally satisfying result compared to lower education patients.Key PointsLittle is known about the role of social inequality as a possible barrier for managing hypercholesterolemia in general practice.Increasing education level was associated to less frequent measurement and less frequent statin treatment.Patients with higher education level were younger, and less comorbidity at first statin prescription.Education level had no effect on frequency of statin treatment-initiated patients reaching the treatment goal was found.

Vitamin D was investigated as a prognostic biomarker in COVID-19, in relation to both disease susceptibility and outcomes in infected individuals. Patients admitted to the hospital with a confirmed COVID-19 diagnosis were included if they had a vitamin D measurement prior to hospitalization. Using age- and sex-matched controls, vitamin D levels were investigated for an association with COVID-19 related hospitalizations. Further, vitamin D levels were investigated for an association with 30-day mortality in hospitalized COVID-19 patients. Additionally, three meta-analyses were conducted, investigating the association of vitamin D with the following outcomes: Having a positive SARS-CoV-2 test, hospitalization with COVID-19, and mortality in COVID-19 patients. A total of 685 hospitalized COVID-19 patients were included in the single-center study. Compared to controls, they had higher vitamin D levels. Unadjusted analysis of these 685 cases found higher vitamin D levels associated with increased 30-day mortality. This association disappeared after adjusting for age. In the fully adjusted model, no association between vitamin D and 30-day mortality was found. The meta-analyses found significant associations between lower vitamin D and having a positive SARS-CoV-2 test, and mortality among hospital-admitted COVID-19 patients. The relationship between lower vitamin D and COVID-19 related hospital admissions trended towards being positive but was not statistically significant. Many factors seem to influence the associations between vitamin D and COVID-19 related outcomes. Consequently, we do not believe that vitamin D in and of itself is likely to be a clinically useful and widely applicable predictor for the susceptibility and severity of COVID-19 infections.

Background: Long-term preventive treatment such as treatment with statins should be reassessed among patients approaching end of life. The aim of the study was to describe the rate of discontinuation of statin treatment and factors associated with discontinuation in the 6 months before death., Methods: This study is a retrospective cohort study using national registers and blood test results from primary health care patients. Patients in the Copenhagen municipality, Denmark who died between 1997 and 2018 and were statin users during the 10-year period before death were included. We calculated the proportion who remained statin users in the 6-month period before death. Factors associated with discontinuation were tested using logistic regression., Results: A total of 55,591 decedents were included. More patients continued treatment (64%, n = 35,693) than discontinued (36%, n = 19,898) the last 6 months of life. The 70 and 80 age groups had the lowest odds of discontinuing compared to the 90 (OR 1.59, 95% CI 0.93-2.72) and 100 (OR 3.11, 95% CI 2.79-3.47) age groups. Increasing comorbidity score (OR 0.89, 95% CI 0.87; 0.90 per 1-point increase) and use of statins for secondary prevention (OR 0.89, 95% CI 0.85; 0.93) reduced the likelihood of discontinuation as did a diagnosis of dementia, heart failure, or cancer., Conclusion: A substantial portion of patients continued statin treatment near end of life. Efforts to promote rational statin use and discontinuation are required among patients with limited life expectancy, including establishing clear, practical recommendations about statin discontinuation, and initiatives to translate recommendations into clinical practice., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Postoperative acute kidney injury is common and associated with increased length of hospital stay, costs and mortality. The impact from postoperative subclinical changes in plasma concentration of creatinine (p-creatinine) on postoperative mortality has received less attention. In this study, the association between the postoperative change of p-creatinine and all-cause mortality was investigated., Methods: A single-centre register-based, retrospective study was conducted including patients ≥60 years undergoing open abdominal surgery from 2000 to 2013. Postoperative p-creatinine change was analysed for association with 30-day mortality following adjustment for age, gender, surgical setting and surgical procedure. Main findings A total of 3,460 patients were included in the study of whom 67.6% underwent emergency surgery. The 30-day mortality rate was 18.3%, and a given 10μmol/L daily postoperative increase in p-creatinine was associated with an increased mortality risk with an odds ratio (OR) of 2.67 (95% CI; 2.28-3.14, P<0.001). In patients undergoing emergency surgery, a daily 10μmol/L increase in p-creatinine increased the risk for a fatal outcome a 2.39 OR (CI 95%; 2.05-2.78), P<0.001). In patients undergoing elective surgery, a similar increase in p-creatinine increased risk of postoperative death with a 28.85 OR (CI 95%; 10.25-81.19)., Conclusion: Even a minor postoperative p-creatinine increase following open abdominal surgery below the criteria for acute kidney injury was associated with increased 30-day mortality in patients aged 60 years or above., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Research Question: Is low-grade inflammation, detected by C-reactive protein (CRP), a marker of IVF outcome addressing both blastocyst quality and pregnancy outcome?, Design: This sub-study of a multicentre randomized controlled trial included 440 women undergoing IVF treatment with a gonadotrophin-releasing hormone (GnRH) antagonist protocol. Serum CRP was measured on cycle day 2-3 (baseline) and on the day of ovulation triggering. The association between CRP concentrations and reproductive outcomes (number of retrieved oocytes, number of good-quality blastocysts, pregnancy, pregnancy loss and live birth), were analysed, adjusting for relevant confounders., Results: A negative association was found between higher baseline CRP concentrations and live birth rate (odds ratio [OR] 0.77, 95% confidence interval [CI] 0.62-0.96, P = 0.02) and higher CRP concentrations at baseline were associated with pregnancy loss among women who conceived (OR 1.37, 95% CI 1.07-1.76, P = 0.01). When testing for a specific cut-off, CRP concentrations above 2.34 (the highest quartile) were more likely to be associated with pregnancy loss (P = 0.02) and a lower chance of live birth (P = 0.04) compared with the lowest quartile. No associations were found between CRP concentrations and pregnancy outcomes on the day of ovulation triggering, and there were no associations between CRP concentrations and the number of good-quality blastocysts., Conclusions: Higher CRP concentrations at cycle day 2-3, before starting ovarian stimulation, are negatively associated with chance of live birth, possibly because of an increased risk of pregnancy loss. No association was found between the number of good-quality blastocysts and CRP concentration. More studies are needed to investigate the impact of low-grade inflammation., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: In patients with chronic pancreatitis, pancreatic duct leakage is associated with a prolonged disease course and serious complications. We aimed to assess the efficacy of this multimodal treatment of pancreatic duct leakage., Methods: In a retrospective design, patients with chronic pancreatitis, an amylase content greater than 200 U/L in either ascites or pleural fluid and treated between 2011 and 2020, were evaluated. The primary end point was treatment success., Results: Twenty-seven patients (22 males, median age 60, median American Society of Anesthesiologists score 3) were included.Endoscopic retrograde pancreatography was performed in 23 patients (85%) with transpapillary stenting of the main pancreatic duct in 22 patients (96%). Pancreatic sphincterotomy and dilation of the main pancreatic duct were done in 14 patients (61%) and 17 patients (74%), respectively. Twelve patients (44%) were treated with somatostatin analogs, parenteral nutrition, and were "nil by mouth" for a median of 11 days (range, 4-34 days). Six patients (22%) had extracorporeal shock wave lithotripsy due to pancreatic duct stones. One patient (4%) was referred for surgery. All 23 patients (100%) were treated with success after a median of 21 days (range, 5-80 days)., Conclusions: Multimodal treatment of pancreatic duct leakage is effective, with minimal need for surgery., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The association between ferritin and transferrin saturation (TS), respectively, and all-cause mortality is unclear. Furthermore, the influence of concurrent inflammation has not been sufficiently elucidated. We investigated these associations and the effect of concurrently elevated C-reactive protein (CRP), and accordingly report the levels associated with lowest all-cause mortality for females and males with and without inflammation.Blood test results from 161,921 individuals were included. Statistical analyses were performed in sex-stratified subpopulations, with ferritin or TS level as continuous exposure variables, and were adjusted for age, co-morbidity and inflammation status using CRP. An interaction was used to investigate whether the effect of ferritin or TS on all-cause mortality was modified by inflammation status (CRP ≥ 10 mg/L or CRP < 10 mg/L). Low and high ferritin and TS levels were respectively associated with increased all-cause mortality in females and in males. These associations persisted with concurrent CRP ≥ 10 mg/L. The ferritin level associated with lowest mortality was 60 µg/L for females and 125 µg/L for males with CRP < 10 mg/L. It was 52 µg/L for females and 118 µg/L for males with CRP ≥ 10 mg/L. The TS level associated with lowest mortality was 33.9% for females and 32.3% for males with CRP < 10 mg/L. It was 28.7% for females and 30.6% for males with CRP ≥ 10 mg/L.Our findings can nuance clinical interpretation and further aid in defining recommended ranges for ferritin and TS.

The aim of this study was to assess the possible association between P-Albumin and 30-day mortality in hip fracture patients. The study is based on information from a database of hip fracture patients, established and collected at Bispebjerg University Hospital (Copenhagen, Denmark). This database includes all femoral neck (DS720), pertrochanteric (DS721) and subtrochanteric fractures (DS722) admitted to Bispebjerg Hospital between 1996 and 2012. We further identified all surgically treated hip fracture patients aged >60 years with an available P-Albumin at admission. 1856 patients were eligible for inclusion in this study (73.7% female, 26.3% male). 11.8% of these had died within 30 days. Differences between continuous variables were tested using unpaired t -tests while differences in the distribution of categorical variables were tested using chi square tests. After adjusting for co-variates in a logistic regression model, the association between P-Albumin and 30-day mortality remained increased, (OR 1.09, 95% CI 1.05;1.11 ( p  < 0.0001)). This study shows an increased 30-day mortality risk among surgically treated hip fracture patients with decreasing levels of P-Albumin even after adjusting for age, sex, BMI, CCI and fracture type. Routine screening of patients for hypoalbuminemia at hospital admission may be beneficial in the management of hip fracture patients.

Introduction: Approximately 25% of the patients with hospital acquired anemia (HAA) develop moderate to severe HAA during hospitalization. This is related to an increased risk of prolonged stay, readmission and mortality. The primary aim was during one year to characterize a population with very frequent phlebotomies based on a university hospital in the Capital Region of Denmark and the related general practitioners., Material and Methods: We conducted a retrospective cohort study using administrative data on phlebotomies from 1 January 2019 to 31 December 2019 analyzed at a university hospital., Results: A total of 203,811 patients had 10,083,207 requisitions and 1,373,013 tubes. One percent, 1985 patients, had an extreme of frequent phlebotomies >60 tubes and formed the basis for the study population. The study population was significantly older as compared to the excluded patients (<60 tubes) (mean 65.7 vs. 51.6 years, p  < .001).The likelihood of hemoglobin decrease per 100 mL blood drawn were calculated at four levels of decreases: Hemoglobin decrease of 2 mmol/L (adjusted OR; 95%; 2.03, CI 1.79-2.31), hemoglobin decrease of 3 mmol/L (adjusted OR; 95%, 1.36, CI 1.28-1.45), hemoglobin decrease of 4 mmol/L, (adjusted OR; 95%, 1.27, CI 1.19-1.35) and hemoglobin decrease of 5 mmol/L, (adjusted OR; 95% 1.22, CI 1.13-1.31)., Conclusions: Moderate to severe HAA occurred in a limited group with excessive many phlebotomies. It was a worrisome trend that the frailest patients had the highest risk of developing HAA.

Purpose: Excess mortality among hip fracture patients is well documented. Less is known, however, about the causes of death in this group of patients, although existing literature suggests that bronchopneumonia and cardiovascular diseases constitute the leading causes of death. In this study, we investigated the causes of death in Danish hip fracture patients, who died within 30-days after sustaining a hip fracture, with a focus on differences in causes of death between men and women and between different age groups. Furthermore, the frequency of potentially preventable causes of death such as pneumonia, urinary tract infections and thromboembolic events was examined., Methods: All Danish patients aged 18 or more suffering from a hip fracture in the period 2002-2012 were examined for inclusion into the study. Data were collected from the Danish National Patient registry. The last month of 2012 being December was left out since we were looking at 30-days mortality. Logistic regression analysis was used to test the association between 30-day mortality with each of the causes of death adjusted for age, sex and CCI in multivariable models with results presented as odds ratios (OR) with 95% confidence intervals., Results: During this period, 93,637 patients sustained a hip fracture. Of these, 9504 patients died within 30-days and were included in the study. For patients dead within 30-days after sustaining a hip fracture, the two leading medical causes of death were cardiovascular disease (21.1%) and pneumonia (10.5%) when looking at both genders. A frequent cause of death especially in the younger age group of women less than 50 years old were infections (other than pneumonia) (18.2%) especially urinary tract infections. Pulmonary embolism accounted for 3.9% of causes of deaths in hip fracture patients., Conclusion: In this study, cardiovascular disease and pneumonia were overall the leading medical causes of death in patients dead within 30-days after sustaining a hip fracture. Apart from pneumonia, another potentially preventable infection in younger female hip fracture patients was urinary tract infections. Pulmonary embolism, another potentially preventable cause of death might be underreported in Danish death certificates., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: The aim was to report the prevalence of diabetes status in patients hospitalized with COVID-19 and assess the association between the glucometabolic status at admission and 90-day mortality., Methods: Consecutive patients hospitalized with COVID-19 were included in the study. All participants included had an HbA 1c measurement 60 days prior to or within 7 days after admission. We studied the association between diabetes status, the glycemic gap (difference between admission and habitual status), admission plasma-glucose, and mortality using Cox proportional hazards regression., Results: Of 674 patients included, 114 (17%) had normal glucose level, 287 (43%) had pre-diabetes, 74 (11%) had new-onset, and 199 (30%) had diagnosed diabetes. No association between diabetes status, plasma-glucose at admission, and mortality was found. Compared to the 2nd quartile (reference) of glycemic-gap, those with the highest glycemic gap had increased mortality (3rd (HR 2.38 [1.29-4.38], p = 0.005) and 4th quartile (HR 2.48 [1.37-4.52], p = 0.002)., Conclusion: Abnormal glucose metabolism was highly prevalent among patients hospitalized with COVID-19. Diabetes status per se or admission plasma-glucose was not associated with a poorer outcome. However, a high glycemic gap was associated with increased risk of mortality, suggesting that, irrespective of diabetes status, glycemic stress serves as an important prognostic marker for mortality., (Copyright © 2022 Elsevier B.V. All rights reserved.)

As healthcare costs continue to rise throughout the world, critical assessment of the appropriateness of expenses gain focus., Objectives: We aimed to describe the developments in test numbers of the 10 most frequently requested tests, and to simulate the effect of introducing minimal retesting intervals., Design & Methods: Data from the blood tests - albumin, alanine transaminase, cholesterol, creatinine, C-reactive protein, hemoglobin, hemoglobin A 1c , potassium, sodium, and thyrotropin - from 2,687,589 patients handled by the Capital Region of Denmark from 2010 to 2019 was used. Tallies of each test per year were graphed. A simulation of the effect of minimal retesting intervals on test count and blood sampling volume was performed by virtually removing requests made prior to a set of possible minimal retesting intervals., Results: Increases in requests were observed both from hospitals and general practitioners. The number of requests for hemoglobin A 1c increased more than the other tests. The increases could not be accounted for by an increase in population size and aging of the population, and therefore suggests possible inappropriate increase in monitoring of patients. The simulated effect of applying minimal retesting intervals showed large reductions in tests and blood sampled., Conclusions: For hospitals, the simulation suggested that applying minimal retesting intervals could lead to significant reductions in both the number of blood tests performed and in the amount of blood drawn for testing. For general practitioners, the simulation showed only minimal reductions in number of tests and blood volume drawn., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Lipid levels in blood have decreased considerably during the past decades in the general population partly due to use of statins. This study aims to investigate the trends in lipid levels between 2001 and 2018 in a statin-free population from primary health care, overall and by sex and age., Methods: In a cohort of 634,119 patients from general practice with no diagnoses or medical treatments that affected lipid levels of total cholesterol (TC; n = 1,574,339) between 2001 and 2018 were identified. Similarly, measurements of low-density lipoprotein cholesterol (LDL-C; n = 1,302,440), high-density lipoprotein cholesterol (HDL-C; n = 1,417,857) and triglycerides (TG; n = 1,329,477) were identified., Results: Mean TC decreased from 5.64 mmol/L (95% CI: 5.63-5.65) in 2001 to 5.17 mmol/L (95% CI: 5.16-5.17) in 2018 while LDL-C decreased from 3.67 mmol/L (95% CI: 3.66-3.68) to 3.04 mmol/L (95% CI: 3.03-3.04). Women aged 70-74 years experienced the largest decreases in TC levels corresponding to a decrease of 0.7 mmol/L. The decrease in LDL-C levels was most pronounced in men ≥85 years with a decrease of 0.9 mmol/L. For both genders, TC and LDL-C levels increased with advancing age until around age 50. After menopause the women had higher TC and LDL-C levels than the men. The median (geometric mean) TG level decreased by 0.4 mmol/L from 2001 to 2008, after which it increased slightly by 0.1 mmol/L until 2018. During life the TG levels of the men were markedly higher than the women's until around age 65-70. HDL-C levels showed no trend during the study period., Conclusions: The levels of TC and LDL-C decreased considerably in a statin-free population from primary health care from 2001 to 2018. These decreases were most pronounced in the elderly population and this trend is not decelerating. For TG, levels have started to increase, after an initial decrease., (© 2021. The Author(s).)

VIP/VPAC2-receptor signaling is crucial for functioning of the circadian clock in the suprachiasmatic nucleus (SCN) since the lack results in disrupted synchrony between SCN cells and altered locomotor activity, body temperature, hormone secretion and heart rhythm. Endocrine glands, including the thyroid, show daily oscillations in clock gene expression and hormone secretion, and SCN projections target neurosecretory hypothalamic thyroid-stimulating hormone (TSH)-releasing hormone cells. The aim of the study was to gain knowledge of mechanisms important for regulation of the thyroid clock by evaluating the impact of VIP/VPAC2-receptor signaling. Quantifications of mRNAs of three clock genes ( Per1 , Per2 and Bmal1 ) in thyroids of wild type (WT) and VPAC2-receptor deficient mice were done by qPCR. Tissues were taken every 4 th h during 24-h 12:12 light-dark (LD) and constant darkness (DD) periods, both genders were used. PER1 immunoreactivity was visualized on sections of both WT and VPAC2 lacking mice during a LD cycle. Finally, TSH and the thyroid hormone T4 levels were measured in the sera by commercial ELISAs. During LD, rhythmic expression of all three mRNA was found in both the WT and knockout animals. In VPAC2-receptor knockout animals, the amplitudes were approximately halved compared to the ones in the WT mice. In the WT, Per1 mRNA peaked around "sunset", Per2 mRNA followed with approximately 2 h, while Bmal1 mRNA was in antiphase with Per1 . In the VPAC2 knockout mice, the phases of the mRNAs were advanced approximately 5 h compared to the WT. During DD, the phases of all the mRNAs were identical to the ones found during LD in both groups of mice. PER1 immunoreactivity was delayed compared to its mRNA and peaked during the night in follicular cells of both the thyroid and parathyroid glands in the WT animals. In WT animals, TSH was high around the transition to darkness compared to light-on, while T4 did not change during the 24 h cycle. In conclusion, sustained and identical rhythms (phases and amplitudes) of three clock genes were found in VPAC2 deficient mice during LD and DD suggesting high degree of independence of the thyroid clock from the master SCN clock., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Georg, Fahrenkrug, Jørgensen and Hannibal.)

Purpose: The aim of this study is to assess the possible association between thyroid-stimulating hormone (TSH) and mortality in hip fracture patients., Patients and Methods: The study is based on a hip fracture database from Bispebjerg University Hospital (Copenhagen, Denmark). This database includes all hip fracture patients (ICD-10 codes DS720 (femoral neck), DS721 (pertrochanteric), and DS722 (subtrochanteric)) admitted to Bispebjerg Hospital from 1996 to 2012. From this database, we identified all surgically treated hip fracture patients aged > 60 years with available plasma TSH-measurements at admission., Results: Of the 914 included patients (24% men and 76% women), 10.5% died within 30 days. At inclusion, 161 (17.6%) of the patients were hyperthyroid (TSH < 0.65 mIU/L), 58 (6.4%) were hypothyroid (TSH > 4.8 mIU/L), while 695 (76.0%) were euthyroid (0.65 < TSH < 4.80 mIU/L), p = 0.03. Mortality was significantly higher in the two higher quartiles of TSH [Q3 (13.0%) and Q4 (15.4%)] compared to the two lower quartiles [Q1 (7.4%) and Q2 (6.2%), p = 0.0003. After adjustment for age, sex and Charlson Comorbidity Index (CCI) in a Cox proportional hazard model, the risk of 30-day mortality continued to be increased in patients with TSH above the median as compared to patients with TSH below the median (HR 2.1 (1.4-3.3), p = 0.0006]., Conclusion: The study demonstrates increased 30-day mortality in surgically treated hip fracture patients with plasma TSH levels above the median (1.41 mIU/L) at admission, even after adjusting for age, sex and CCI., (© 2019. Springer-Verlag GmbH Germany, part of Springer Nature.)

It has recently been hypothesized that vitamin K could play a role in COVID-19. We aimed to test the hypotheses that low vitamin K status is a common characteristic of patients hospitalized with COVID-19 compared to population controls and that low vitamin K status predicts mortality in COVID-19 patients. In a cohort of 138 COVID-19 patients and 138 population controls, we measured plasma dephosphorylated-uncarboxylated Matrix Gla Protein (dp-ucMGP), which reflects the functional vitamin K status in peripheral tissue. Forty-three patients died within 90 days from admission. In patients, levels of dp-ucMGP differed significantly between survivors (mean 877; 95% CI: 778; 995) and non-survivors (mean 1445; 95% CI: 1148; 1820). Furthermore, levels of dp-ucMGP (pmol/L) were considerably higher in patients (mean 1022; 95% CI: 912; 1151) compared to controls (mean 509; 95% CI: 485; 540). Cox regression survival analysis showed that increasing levels of dp-ucMGP (reflecting low vitamin K status) were associated with higher mortality risk (sex- and age-adjusted hazard ratio per doubling of dp-ucMGP was 1.49, 95% CI: 1.03; 2.24). The association attenuated and became statistically insignificant after adjustment for co-morbidities (sex, age, CVD, diabetes, BMI, and eGFR adjusted hazard ratio per doubling of dp-ucMGP was 1.22, 95% CI: 0.82; 1.80). In conclusion, we found that low vitamin K status was associated with mortality in patients with COVID-19 in sex- and age-adjusted analyses, but not in analyses additionally adjusted for co-morbidities. Randomized clinical trials would be needed to clarify a potential role, if any, of vitamin K in the course of COVID-19.

Background and Purpose: The outbreak of the COVID-19 pandemic has resulted in an overall decline in fractures. However, the amount of hip fractures has remained relatively stable throughout the period. The objective of this study is to investigate the impact of perioperative COVID-19 infections on mortality among hip fracture patients., Methods: A meta-analysis was performed by collecting current data available through a systematic literature search in the PubMed database. The search was performed Oct 18 2020., Results: The meta-analysis was conducted on a trial population consisting of 1.272 hip fracture patients with a pooled prevalence of COVID-19 of 18%. Mortality among hip fracture patients without a perioperative COVID-19 infection was 7.49%. Mortality among hip fracture patients infected with COVID-19 perioperatively was associated with an odds ratio of 6.70 [(95% CI 4.64-9.68), p < 0.00001, I 2  = 41%]. A sensitivity analysis showed no major impact of assumptions regarding varying definitions of COVID-19 statuses among the included studies., Conclusion: Perioperative infections with COVID-19 in hip fracture patients are correlated with a significantly increased mortality. The meta-analysis showed a pooled odds ratio of 6.70 [(95% CI 4.64-9.68), p < 0.00001, I 2  = 41%].

Background: Major abdominal surgery in older and frail patients is associated with considerable morbidity and mortality. Plasma albumin is routinely measured in the clinic and has been proposed as an indicator of frailty. This study aimed to investigate if plasma albumin is a predictor of mortality in older patients undergoing open abdominal surgery., Materials and Methods: We conducted a single-center, register-based retrospective study of patients, aged ⩾60 years who underwent one of 81 open abdominal surgical procedures. Patients operated on during the period from January 1 st , 2000 to May 31 st , 2013 were consecutively identified in the Danish National Patient Registry. Plasma albumin was measured within 30 days prior to surgery and the primary endpoint was 30-day postoperative mortality., Results: 3,639 patients were included of whom 68.2% underwent emergency surgery. The rate of severe hypoalbuminemia (plasma albumin < 28 g/L) was 43.4%. Preoperative plasma albumin was lower in patients with a fatal 30-day outcome (mean 20.6 g/L vs 30.1 g/L in survivors, p < 0.0001). Other independent predictive parameters of 30-day mortality were age, male sex, and emergency surgery. We present an algorithm including these four variables for the prediction of 30-day mortality for patients aged ⩾60 years undergoing open abdominal surgery., Conclusion: Preoperative plasma albumin is a predictor of 30-day mortality in patients above 60 years of age following open abdominal surgery. Assessment of plasma albumin in conjunction with other risk factors such as age, sex, and surgical priority may improve preoperative decision-making.

Background: Vitamin D has a role in bone turnover and potentially bone-metastatic spread of prostate cancer (PCa). The aim of this observational study was to address the association between levels of serum vitamin D, diagnosis of PCa and subsequent mortality in men who underwent a biopsy of the prostate., Methods: All men who underwent prostatic biopsy in the Danish PCa Registry (DaPCaR) and who had a serum vitamin D measurement during the period 2004 to 2010 ( n  = 4,065) were identified. Men were categorized by clinical cut-offs based on seasonally adjusted serum vitamin D levels in <25 (deficient), 25-50 (insufficient), 50-75 (sufficient) and >75 nmol/L (high) serum vitamin D. Logistic regression model for association between vitamin D and risk of PCa diagnosis and multivariate survival analyses were applied., Results: No association between serum vitamin D and risk of PCa was found. Overall survival was lowest for serum vitamin D deficiency and a significantly higher PCa specific mortality (HR: 2.37, 95%CI: 1.45-3.90, p  < .001) and other cause mortality (HR: 2.08, 95%CI: 1.33-3.24, p  = .001) was found for PCa patients with serum vitamin D deficiency compared to serum vitamin D sufficiency., Conclusion: No association was found between serum vitamin D categories and risk of PCa in men who underwent biopsy of the prostate. Men with PCa and serum vitamin D deficiency had a higher overall and PCa specific mortality compared to men with a sufficient level of serum vitamin D.

Background: In hospitalized patients, abnormal plasma electrolyte concentrations are frequent and have been linked to poor outcomes following acute surgery. The aim of this study was to assess whether preoperative plasma levels of potassium, sodium, and creatinine at the time of admission were associated with 30-day mortality in patients following open abdominal surgery., Methods: This was a single-center register-based retrospective study. By means of electronic search in a maintained surgery database, all patients (n = 4177) aged ≥ 60 years old undergoing open surgery in our department from January 2000 to May 2013 were identified. Plasma was assessed within 30 days prior to surgery. The primary endpoint was 30-day postoperative mortality. The association between mortality and plasma levels of potassium, sodium, and creatinine were examined using Cox proportional hazard models., Results: A total of 3690 patients were included in the study cohort. The rates of abnormal preoperative plasma levels were 36, 41, and 38% for potassium, sodium, and creatinine, respectively. The overall 30 day mortality was 20%. A predictive algorithm for 30 day mortality following abdominal surgery was constructed by means of logistic regression showing excellent distinction between patients with and without a fatal postoperative outcome., Conclusion: Apart from demographic factors (age, sex, and emergency surgery), preoperative imbalance in potassium, sodium and creatinine levels were significant independent predictors of early mortality following open abdominal surgery.

Objective: To investigate the frequency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in parturient women, their partners, and their newborns and the association of such antibodies with obstetric and neonatal outcomes., Methods: From April 4 to July 3, 2020, in a single university hospital in Denmark, all parturient women and their partners were invited to participate in the study, along with their newborns. Participating women and partners had a pharyngeal swab and a blood sample taken at admission; immediately after delivery, a blood sample was drawn from the umbilical cord. The swabs were analyzed for SARS-CoV-2 RNA by polymerase chain reaction, and the blood samples were analyzed for SARS-CoV-2 antibodies. Full medical history and obstetric and neonatal information were available., Results: A total of 1,313 parturient women (72.5.% of all women admitted for delivery at the hospital in the study period), 1,188 partners, and 1,206 newborns participated in the study. The adjusted serologic prevalence was 2.6% in women and 3.5% in partners. Seventeen newborns had SARS-CoV-2 immunoglobulin G (IgG) antibodies, and none had immunoglobulin M antibodies. No associations between SARS-CoV-2 antibodies and obstetric or neonatal complications were found (eg, preterm birth, preeclampsia, cesarean delivery, Apgar score, low birth weight, umbilical arterial pH, need for continuous positive airway pressure, or neonatal admission), but statistical power to detect such differences was low. Full serologic data from 1,051 families showed an absolute risk of maternal infection of 39% if the partner had antibodies., Conclusion: We found no association between SARS-CoV-2 infection and obstetric or neonatal complications. Sixty-seven percent of newborns delivered by mothers with antibodies had SARS-CoV-2 IgG antibodies. A limitation of our study is that we lacked statistical power to detect small but potentially meaningful differences between those with and without evidence of infection., Competing Interests: Financial Disclosure Henriette Svarre Nielsen has received speaker's fees from Ferring Pharmaceuticals, Merck Denmark A/S and Ibsa Nordic (outside the submitted work). Nina la Cour Freiesleben has received a grant from Gedeon Richter (outside the submitted work). Astrid Marie Kolte has received speaker's fees from Merck (outside the submitted work). The other authors did not report any potential conflicts of interest., (Copyright © 2020 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Study Question: Does maternal infection with severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) in first trimester pregnancy have an impact on the fetal development as measured by nuchal translucency thickness and pregnancy loss?, Summary Answer: Nuchal translucency thickness at the first trimester scan was not significantly different in pregnant women with versus without SARS-CoV-2 infection in early pregnancy and there was no significantly increased risk of pregnancy loss in women with SARS-CoV-2 infection in the first trimester., What Is Known Already: Pregnant women are more vulnerable to viral infections. Previous coronavirus epidemics have been associated with increased maternal morbidity, mortality and adverse obstetric outcomes. Currently, no evidence exists regarding possible effects of SARS-CoV-2 in first trimester pregnancies., Study Design, Size, Duration: Cohort study of 1019 women with a double test taken between 17 February and 23 April 2020, as a part of the combined first trimester risk assessment, and 36 women with a first trimester pregnancy loss between 14 April and 21 May 2020, prior to the double test. The study period was during the first SARS-CoV-2 epidemic wave in Denmark., Participants/materials, Setting, Methods: Cohort 1 included pregnant women with a double test taken within the study period. The excess serum from each double test was analyzed for SARS-CoV-2 antibodies. Results were correlated to the nuchal translucency thickness and the number of pregnancy losses before or at the time of the first trimester scan. Cohort 2 included women with a pregnancy loss before the gestational age for double test sample. Serum from a blood test taken the day the pregnancy loss was identified was analyzed for SARS-CoV-2 antibodies. The study was conducted at a public university hospital serving ∼12% of pregnant women and births in Denmark. All participants in the study provided written informed consent., Main Results and the Role of Chance: Eighteen (1.8%) women had SARS-CoV-2 antibodies in the serum from the double test suggestive of SARS-CoV-2 infection in early pregnancy. There was no significant difference in nuchal translucency thickness for women testing positive for previous SARS-CoV-2 infection (n = 16) versus negative (n = 966) (P = 0.62). There was no significantly increased risk of pregnancy loss for women with antibodies (n = 1) (OR 3.4, 0.08-24.3 95% CI, P = 0.27). None of the women had been hospitalized due to SARS-CoV-2 infection. None of the women with pregnancy loss prior to the double test (Cohort 2) had SARS-CoV-2 antibodies., Limitations, Reasons for Caution: These results may only apply to similar populations and to patients who do not require hospitalization due to SARS-CoV-2 infection. A limitation of the study is that only 1.8% of the study population had SARS-CoV-2 antibodies suggestive of previous infection., Wider Implication of the Findings: Maternal SARS-CoV-2 infection had no effect on the nuchal translucency thickness and there was no significantly increased risk of pregnancy loss for women with SARS-CoV-2 infection in first trimester pregnancy. Evidence concerning COVID-19 in pregnancy is still limited. These data indicate that infection with SARS-CoV-2 in not hospitalized women does not pose a significant threat in first trimester pregnancies. Follow-up studies are needed to establish any risk to a fetus exposed to maternal SARS-CoV-2 infection., Study Funding/competing Interest(s): Prof. H.S.N. and colleagues received a grant from the Danish Ministry of Research and Education for research of COVID-19 among pregnant women. The Danish government was not involved in the study design, data collection, analysis, interpretation of data, writing of the report or decision to submit the paper for publication. A.I., J.O.-L., J.B.-R., D.M.S., J.E.-F. and E.R.H. received funding from a Novo Nordisk Foundation (NNF) Young Investigator Grant (NNF15OC0016662) and a Danish National Science Foundation Center Grant (6110-00344B). A.I. received a Novo Scholarship. J.O.-L. is funded by an NNF Pregraduate Fellowship (NNF19OC0058982). D.W. is funded by the NNF (NNF18SA0034956, NNF14CC0001, NNF17OC0027594). A.M.K. is funded by a grant from the Rigshospitalet's research fund. H.S.N. has received speaker's fees from Ferring Pharmaceuticals, Merck Denmark A/S and Ibsa Nordic (outside the submitted work). N.l.C.F. has received a grant from Gedeon Richter (outside the submitted work). A.M.K. has received speaker's fee from Merck (outside the submitted work). The other authors did not report any potential conflicts of interest., Trial Registration Number: N/A., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Cholecystokinin (CCK) is a gut hormone which regulates gallbladder contraction and pancreatic enzyme secretion. In addition, CCK is also a major intestinal satiety signal. The knowledge about CCK in circulation, however, has been limited by difficulties in accurate measurement of the concentrations in plasma. Thus, CCK circulates in low concentrations and furthermore, it is structurally homologous to the antral hormone, gastrin, which circulates in higher concentrations. Therefore, most antibodies raised against CCK cross-react in immunoassays with gastrin. However, using highly sensitive and entirely specific in-house radioimmunoassays, which meet these challenges, we have now measured the daily concentration-variations of CCK and gastrin in plasma from young healthy men ( n  = 24). Plasma was sampled every third hour from each person during 24 h. The results show that the gastrointestinal secretion of both CCK and gastrin in man display significant circadian variations.

Objective: Healthcare costs, including costs for laboratory tests, are increasing worldwide. One example is the measurement of vitamin D. General practitioners in the Capital Region of Denmark include a vitamin D status in approximately 20% of all laboratory requisitions. This study intended to examine the effect of a compulsory pop-up form in the electronic request system on the number of vitamin D tests and to monitor the indications., Design: From 1 January 2017, we introduced a compulsory pop-up form in which the general practitioners had to state the indication for measuring vitamin D, choosing from a predefined set of indications. Intervention practitioners were compared with control practitioners before and after the intervention., Setting: General practices in the Capital Region of Denmark., Subjects: In total, 572 general practitioners and 383,964 patients were included in the period from 1 January 2016 to 31 December 2018., Main Outcome Measures: Number of vitamin D tests and distribution of indications., Results: We observed a drop in number of vitamin D requisitions to 70% (in 2017) and 75% (in 2018) relative to 2016. During the same period, the number of requisitions increased by 33% in a non-intervention group of practitioners. The indication 'Monitoring of treatment with vitamin D' was the most frequently used indication, recorded in 121,475 patients., Conclusion: A compulsory pop-up form reduces the number of vitamin D requests from general practitioners by 25%. The implication is that pop-up forms can be used to decrease healthcare costs.

Study Question: Is the fetal fraction (FF) of circulating cell-free DNA (cfDNA) affected in pregnancies following ART treatment with either fresh or frozen embryo transfer (ET) compared with natural conception?, Summary Answer: This study shows a significant reduction in the FF in ART patients compared with naturally conceived pregnancies, which seems to be more pronounced after fresh ET compared with frozen ET., What Is Known Already: Non-invasive prenatal testing (NIPT) is based on cfDNA in maternal blood, of which about 10% is of placental origin and thus represents the fetal karyotype. Validation studies have demonstrated a high sensitivity, specificity and positive predictive value of NIPT for the detection of fetal trisomy 21, 18 and 13. Nevertheless, the FF of cfDNA is an important factor for NIPT test accuracy. Several studies have found a reduction in FF for pregnancies following ART in comparison with natural conception. However, knowledge on how the FF is affected in ART pregnancies after fresh ET compared with frozen ET is very limited., Study Design, Size, Duration: The study was designed as a case-control study. A total of 54 women with an ongoing pregnancy following ART treatment were included. After exclusion for different reasons, statistical analyses were based on 23 NIPT samples from pregnant women treated with fresh ET and 26 NIPT samples from pregnant women treated with frozen-thawed ET in a modified natural cycle. Women were included between February 2018 and November 2018. The results were compared with a control group of 238 naturally conceived pregnancies with a high-risk result from the combined first trimester screening (cFTS)., Participants/materials, Setting, Methods: The study included women from the Fertility Clinics at Copenhagen University Hospital Hvidovre and Copenhagen University Hospital Rigshospitalet. Blood samples for NIPT analysis were drawn between 11 + 0 and 14 + 2 weeks of gestation and were all analyzed at the NIPT Center at Copenhagen University Hospital Hvidovre. The NIPT-test was performed by massive-parallel whole-genome sequencing. The FF was determined using the SeqFF algorithm., Main Results and the Role of Chance: We found a reduction in FF in ART patients compared with naturally conceived pregnancies, and the reduction was more pronounced for ART pregnancies after fresh ET (mean FF = 0.049) compared with frozen ET (mean FF = 0.063) (multivariate analysis adjusted for maternal BMI, P = 0.02). Another multivariate analysis, adjusted for BMI and multiples of median (MoM) values for pregnancy-associated plasma protein-A (PAPP-A), demonstrated a significantly reduced FF for ART pregnancies (mean FF = 0.056) compared with naturally conceived pregnancies (mean FF = 0.072) (P < 0.0001). We found that FF was significantly reduced with increasing maternal BMI (P < 0.0001) and with decreasing MoM values of PAPP-A (P = 0.003)., Limitations, Reasons for Caution: A limitation of our study design was the relatively small sample size. Another limitation was that the control group was not matched with the ART-treated women. The majority of the women from the control group had a high risk from cFTS, thereby their biochemical markers were diverging. However, the biochemical markers for the ART-treated women with fresh or frozen ET were not divergent within the subgroups., Wider Implications of the Findings: Concurrent with other studies demonstrating a reduced FF for singleton pregnancies after ART treatment compared with naturally conceived pregnancies, we found a reduction in FF between the two groups. This is one of the first studies to examine FF in ART pregnancies after fresh ET compared with frozen ET, hence the existing knowledge is limited. We find that FF is even more reduced in pregnancies following fresh ET compared with frozen ET, which might possibly reflect the predisposition of being small for gestational age after fresh ET compared with natural cycle frozen ET., Study Funding/competing Interest(s): The study was supported by the A.P. Møller og Hustru Chastine Mc-Kinney Møllers Fond til almene Formaal (the A.P. Møller Foundation for General Purposes). All authors declare no conflicts of interest., Trial Registration Number: NA., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The peptide hormone insulin-like factor 3 (INSL3) is a marker for Leydig cell function and the clinical use of serum INSL3 measurements has been suggested by several groups., Aim: (1) To establish a reference range for liquid chromatography-tandem mass spectrometry (LC-MS/MS) of serum INSL3 in healthy boys and men; and (2) to compare the associations of serum INSL3 and testosterone (T) to pubertal stage, lifestyle factors, diurnal variation, body composition, and human chorionic gonadotropin (hCG) stimulation., Results: In a reference range based on LC-MS/MS analysis of serum from 1073 boys and men, INSL3 increased from levels close to the detection limit (0.03 µg/L) in prepubertal boys to a maximum mean level of 1.3 µg/L (95% CI, 0.9-2.7) in young men (19-40 years of age) and decreased slightly in older men (0.1 µg/L per decade). Serum T, but not INSL3, was associated with body mass index or body fat percentage and with alcohol consumption. Smoking was positively associated with serum T, but negatively associated with INSL3. There were significant diurnal variations in both INSL3 and T in men (P < 0.001), but serum INSL3 varied substantially less, compared with serum T (± 11% vs ± 26%). Mean serum INSL3 increased after hCG stimulation, but less than T (+ 17% vs + 53%). In both healthy men and in patients suspected of testicular failure, baseline serum INSL3 was more closely associated to the hCG-induced increase in serum T than baseline T itself., Conclusion: Measurement of serum INSL3 by LC-MS/MS has promise as a marker of testicular disorders., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The first case of coronavirus disease 2019 (COVID-19) disease caused by severe acute respiratory syndrome coronavirus-2 occurred in Denmark on 27 February 2020. On 10 March, the first case of COVID-19 pneumonia was admitted to Hvidovre Hospital., Methods: Retrospective case review of individuals 18 years or older who were admitted consecutively to Hvidovre Hospital from 10 March through 23 April 2020., Results: A total of 175 individuals were admitted with COVID-19 pneumonia. The median age was 71 years, 48.6% were male and 71% had at least one co-morbidity. The most commonly presenting symptoms were dyspnoea, dry cough, and fever. The majority of patients had lymphopenia, elevated liver function tests and C-reactive protein. Nearly two in three presented with multilobar infiltration by chest X-ray. Respiratory failure leading to invasive mechanical ventilation developed in 27 patients (15.4%). By 20 April, 23 of 175 (13.1%) patients remained hospitalised, 43 (24.6%) had died and 109 (62.3%) had been discharged., Conclusions: The manifestations of COVID-19 at presentation were similar to those seen in other reports. Our population was older, slightly overrepresented by women and had a high level of co-morbidity. COVID-19 admittance was associated with frequent need of intensive care and mechanical ventilation that was associated with a very high mortality., Funding: none., Trial Registration: not relevant., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Purpose: To evaluate the predictive value of pre-fracture medication usage on 30-day mortality following a hip fracture., Methods: Information on age, sex, fracture type, time of death and Charlson co-morbidity index (CCI) was collected from the Danish National Patient Registry on all patients above 60 years, sustaining a hip fracture during the period January 1995 to December 2013. Information on drug usage was obtained from the Danish National Prescription Database. Hazard ratios were calculated with 30-day mortality as the outcome. A univariate and 3 multivariate analyses were conducted with increasing adjustments, starting with age, sex and fracture type, adding co-morbidity and dose in the latter., Results: 141,201 patients were included and a total of 12 drugs/drug groups were identified for analysis. Increased mortality was evident in all analyses for antiarrhythmics, beta blockers, proton pump inhibitors, loop diuretics, opioids, acetaminophen and for psycholeptics. For ACE-inhibitors, increased mortality was found in all analyses, except after adjustment for co-morbidity and dose. For thiazide diuretics, a significantly reduced mortality was evident in all but the univariate analyses while NSAIDs and statins were associated with a significantly reduced mortality in all analyses. For calcium channel blockers, an insignificant decrease was found after adjustment for dose. Further analysis showed a dose-response relationship for all drugs except ACE-inhibitors and calcium channel blockers., Conclusion: The study shows a correlation between pre-fracture usage of certain drugs and 30 day mortality after a hip fracture.

Purpose: The purpose of this study was to examine the possible association between mortality following a hip fracture and known biochemical markers of inflammation., Methods: The study population was identified using two local databases from Bispebjerg Hospital (Copenhagen, Denmark): the Hip Fracture Database containing all patients admitted to the hospital with a fractured hip from 1996 to 2012 and the Hip Fracture Biobank, containing whole blood, serum and plasma taken in relation to admission on a subgroup of patients from the Hip Fracture Database, consecutively collected over a period of 2.5 years from 2008 to 2011. The following biochemical markers of inflammation were included: C-reactive protein (CRP), the soluble urokinase plasminogen activating receptor (suPAR), ferritin and transferrin. The association between the blood markers and mortality was examined using Cox proportional hazards models. Hazard ratios (HR) were expressed per quartile increase in the biochemical markers., Results: A total of 698 patients were included, 69 (9.9%) died within 30 days after sustaining a hip fracture. The HR for 30-day mortality was significantly increased with increasing quartiles of suPAR, CRP and ferritin and with decreasing quartiles of transferrin., Conclusion: This study shows that 30-day mortality after a hip fracture is associated with elevated levels of suPAR, CRP and ferritin as well as with lower levels of transferrin. This excess inflammatory response is likely caused by muscle damage associated with the hip fracture. However, this needs to be further clarified.

Purpose: This nationwide study assessed associations between comorbidity and mortality after hip fracture in young and middle-aged patients., Methods: Data on 19,682 patients aged 18 to 65 years were extracted from Danish registries out of 154,047 patients who experienced a hip fracture between 1996 and 2012. Mortality and comorbidity were assessed using information on vital status, hospital admissions, and prescriptions., Results: Of the 19,682 patients 17,722 (90.0%) were middle-aged (40-65 years) and 1960 (10.0%) were young (18-39 years). The 30-day mortality rates were 3.2% (n = 570) and 1.6% (n = 32), respectively. Indicators of multi-trauma (hazard ratio (HR), 3.5 95% confidence interval (CI) [1.6-7.8], n = 2056) and having diabetes (HR, 4.4 [1.2-11.3], n = 59) and heart disease (HR, 4.4[1.3-14.8], n = 57) increased 30-day mortality in the young patients, while having cancer (HR, 5.0 [4.2-5.9], n = 1958) increased 30-day mortality in the middle-aged patients., Conclusion: Heart disease and diabetes were associated with high mortality in the young patients while having cancer was associated with high mortality in the middle-aged patients.

Hemoglobin A 1c (HbA 1c ) is a long-term measure for glucose concentration in plasma. Since its introduction as a diabetes monitoring tool, and its more recent application as a diagnostic tool, the number of measurements of HbA 1c have risen dramatically. However, HbA 1c change is slow, so repeating measurements should not be done too often. We use a large, unfiltered dataset from 52,017 patients to determine the possible rate of change in HbA 1c concentration. In our laboratory, the critical difference between HbA 1c measurements is 8.5%. Our data show that a 1-unit HbA 1c rise takes 4 weeks to occur, hence, at a HbA 1c concentration around 50 mmol/mol Hgb, a critically increased HbA 1c concentration cannot be determined until after 16 weeks. Conversely a critically lower HbA1c can manifest itself after 2 weeks, but after 7 weeks the dropping tendency stops. The amount of measurements that can be cancelled because they were taken sooner than 16 weeks is 23 percent.