Correction to: Sex differences in the association between plasma copeptin and incident type 2 diabetes: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study.

The values given for copeptin levels in men in quartiles 1 and 2 (Table 1) were incorrect, and should have read.

'It just has to click': Internists' views of: what constitutes productive interactions with chronically ill patients.

BACKGROUND: According to the Chronic Care Model, productive interactions are crucial to patient outcomes. Despite productive interactions being at the heart of the Model, however, it is unclear what constitutes such an interaction. The aim of this study was to gain a better understanding of physician views of productive interactions with the chronically ill. METHOD: We conducted a qualitative study and interviewed 20 internists working in an academic hospital. The data were analyzed using a constructivist approach of grounded theory. To categorize the data, a coding process within which a code list was developed and tested with two other coders was conducted. RESULTS: The participants engaged in goal-directed reasoning when reflecting on productive interactions. This resulted in the identification of four goal orientations: (a) health outcome; (b) satisfaction; (c) medical process; and (d) collaboration. Collaboration appeared to be conditional for reaching medical process goals and ultimately health outcome and satisfaction goals. Achieving rapport with the patient ('clicking,' in the term of the participants) was found to be a key condition that catalyzed collaboration goals. Clicking appeared to be seen as a somewhat unpredictable phenomenon that might or might not emerge, which one had to accept and work with. Goal orientations were found to be related to the specific medical context (i.e., a participant's subspecialty and the nature of a patient's complaint). CONCLUSIONS: The participants viewed a productive interaction as essentially goal-directed, catalyzed by the two parties clicking, and dependent on the nature of a patient's complaint. Using the findings, we developed a conceptual process model with the four goal orientations as wheels and with clicking in the center as a flywheel. Because clicking was viewed as important, but somewhat unpredictable, teaching physicians how to click, while taking account of the medical context, may warrant greater attention.

Stressful life events and leukocyte telomere attrition in adulthood: a prospective population-based cohort study.

BACKGROUND: Telomere attrition might be one of the mechanisms through which psychosocial stress leads to somatic disease. To date it is unknown if exposure to adverse life events in adulthood is associated with telomere shortening prospectively. In the current study we investigated whether life events are associated with shortening of telomere length (TL). METHOD: Participants were 1094 adults (mean age 53.1, range 33-79 years) from the PREVEND cohort. Data were collected at baseline (T1) and at two follow-up visits after 4 years (T2) and 6 years (T3). Life events were assessed with an adjusted version of the List of Threatening Events (LTE). TL was measured by monochrome multiplex quantitative PCR at T1, T2, and T3. A linear mixed model was used to assess the effect of recent life events on TL prospectively. Multivariable regression analyses were performed to assess whether the lifetime life events score or the score of life events experienced before the age of 12 predicted TL cross-sectionally. All final models were adjusted for age, sex, body mass index, presence of chronic diseases, frequency of sports, smoking status, and level of education. RESULTS: Recent life events significantly predicted telomere attrition prospectively (B = -0.031, p = 0.007). We were not able to demonstrate a significant cross-sectional relationship between the lifetime LTE score and TL. Nor did we find exposure to adverse life events before the age of 12 to be associated with TL in adulthood. CONCLUSIONS: Exposure to recent adverse life events in adulthood is associated with telomere attrition prospectively.

Effects of adverse life events on heart rate variability, cortisol, and C-reactive protein.

OBJECTIVE: Our objective was to assess whether self-reported adverse life events during childhood or over the lifespan are associated with altered activity of the autonomic nervous system (ANS), the hypothalamic-pituitary-adrenal axis (HPA axis), and the immune system. METHOD: This study was performed in a population-based cohort of 1094 adults aged 33-79 years, 46.3% male, average age 53 (SD 11.4). Two waves of data were collected at a 2-year interval, enabling replication of the analyses. Cumulative exposure to adverse life events was assessed by means of the List of Threatening Experiences. ANS function was assessed by spectral analysis of heart rate variability in the high-frequency band (HRV-HF). HPA axis function was assessed by 24-h urinary free cortisol (24-h UFC) excretion. Inflammation was assessed by high-sensitive C-reactive protein (hsCRP). RESULTS: Multiple linear regression analyses did not reveal any significant associations, with the exception of one significant negative association between the lifetime score of adverse life events and HRV-HF ß = -0.028; P = 0.037 at baseline, but not at follow up 2 years later. CONCLUSION: In a large population-based cohort, adverse life events were not consistently associated with HRV-HF, 24-h UFC or (hsCRP).

Intraperitoneal insulin infusion: treatment option for type 1 diabetes resulting in beneficial endocrine effects beyond glycaemia.

Continuous intraperitoneal insulin infusion (CIPII) is a treatment option for patients with type 1 diabetes mellitus who fail to reach adequate glycaemic control despite intensive subcutaneous (SC) insulin therapy. CIPII has clear advantages over SC insulin administration in terms of pharmacokinetic and pharmacodynamic properties and has been shown to improve glycaemic regulation. Due to the delivery of insulin predominantly in the portal vein, as opposed to systemically, CIPII offers a unique research model to investigate the effects of insulin on endocrine and metabolic parameters in vivo. The aim of the present article is to provide an overview of the literature with respect to the effects of CIPII on glucose management, quality of life, complications and costs, with additional focus on metabolic and endocrine aspects. Finally, future use and research objectives are discussed.

Sex differences in the association between plasma copeptin and incident type 2 diabetes: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study.

AIMS/HYPOTHESIS: Vasopressin plays a role in osmoregulation, glucose homeostasis and inflammation. Therefore, plasma copeptin, the stable C-terminal portion of the precursor of vasopressin, has strong potential as a biomarker for the cardiometabolic syndrome and diabetes. Previous results were contradictory, which may be explained by differences between men and women in responsiveness of the vasopressin system. The aim of this study was to evaluate the usefulness of copeptin for prediction of future type 2 diabetes in men and women separately. METHODS: From the Prevention of Renal and Vascular Endstage Disease (PREVEND) study, 4,063 women and 3,909 men without diabetes at baseline were included. A total of 208 women and 288 men developed diabetes during a median follow-up of 7.7 years. RESULTS: In multivariable-adjusted models, we observed a stronger association of copeptin with risk of future diabetes in women (OR 1.49 [95% CI 1.24, 1.79]) than in men (OR 1.01 [95% CI 0.85, 1.19]) (p (interaction) < 0.01). The addition of copeptin to the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) clinical model improved the discriminative value (C-statistic,+0.007, p = 0.02) and reclassification (integrated discrimination improvement [IDI] = 0.004, p < 0.01) in women. However, we observed no improvement in men. The additive value of copeptin in women was maintained when other independent predictors, such as glucose, high sensitivity C-reactive protein (hs-CRP) and 24 h urinary albumin excretion (UAE), were included in the model. CONCLUSIONS/INTERPRETATION: The association of plasma copeptin with the risk of developing diabetes was stronger in women than in men. Plasma copeptin alone, and along with existing biomarkers (glucose, hs-CRP and UAE), significantly improved the risk prediction for diabetes in women.

Endogenous plasma erythropoietin, cardiovascular mortality and all-cause mortality in renal transplant recipients.

Cardiovascular disease (CVD) is the main cause of mortality in renal transplant recipients (RTR). Classical factors only partly explain the excess risk. We hypothesized that high EPO--a marker for inflammation, angiogenesis and hypoxia--is associated with CVD in RTR. A total of 568 RTR (51±12 years; 45% female; creatinine clearance (CrCl) 57±20 mL/min/1.73 m(2)) were included at median 6 [IQR 3-11] years after transplantation. Subjects on exogenous EPO and ferritin-depleted subjects were excluded. Median EPO level was 17.3 [IQR 11.9-24.2] IU/L. Gender-stratified tertiles of age-corrected EPO were positively associated with waist circumference (but not BMI), CVD history, time since transplantation, diuretics, azathioprine, CRP, mean corpuscular volume and triglyceride levels, and inversely with CrCl, RAAS-inhibition, cyclosporine, hemoglobin, total- and HDL-cholesterol. During follow-up for 7 [6-7] years, 121 RTR (21%) died, 64 of cardiovascular (CV) causes. Higher EPO (per 10 IU/L) was associated with total (HR1.16 [1.04-1.29], p = 0.01) and CV mortality (HR1.22 [1.06-1.40], p = 0.005), independent of age, gender, hemoglobin, inflammation, renal function and Framingham risk factors. Thus, EPO and mortality are linked in RTR, independent of potential confounders. This suggests that yet other mechanisms are involved. Dissecting determinants of EPO in RTR may improve understanding of mechanisms behind excess CV risk in this population.

Trough anti-Xa activity after intermediate dose nadroparin for thrombosis prophylaxis in critically ill patients with COVID-19 and acute kidney injury.

Our objective was to assess the incidence of drug bioaccumulation in critically ill COVID-19 patients with AKI receiving intermediate dose nadroparin for thrombosis prophylaxis. We conducted a Prospective cohort study of critically ill COVID-19 patients. In patients on intermediate dose nadroparin (5700 IU once daily) we assessed the incidence of bioaccumulation (trough anti-Xa level > 0.2 IU/mL) stratified according to presence of AKI. We quantified this association using multilevel analyses. To assess robustness of our observations, we explored the association between AKI and anti-Xa activity in patients receiving high dose nadroparin (> 5700 IU). 108 patients received intermediate dose nadroparin, of whom 24 had AKI during 36 anti-Xa measurements. One patient with AKI (4.2% [95%CI 0.1-21%]) and 1 without (1.2% [95%CI 0.03-6.5%]) developed bioaccumulation (p = 0.39). Development of AKI was associated with a mean increase of 0.04 (95%CI 0.02-0.05) IU/ml anti-Xa activity. There was no statistically significant association between anti-Xa activity and AKI in 51 patients on high dose nadroparin. There were four major bleeding events, all in patients on high dose nadroparin. In conclusion, Bioaccumulation of an intermediate dose nadroparin did not occur to a significant extent in critically ill patients with COVID-19 complicated by AKI. Dose adjustment in AKI may be unnecessary.

Flash Glucose Monitoring in the Netherlands: Increased monitoring frequency is associated with improvement of glycemic parameters.

AIMS: To evaluate the association between Flash Glucose Monitoring (FLASH) frequency and glycemic parameters during real-life circumstances in the Netherlands. METHODS: Obtained glucose readings were de-identified and uploaded to a dedicated database when FLASH reading devices were connected to internet. Data between September 2014 and March 2020, comprising 16,331 analyzable readers (163,762 sensors) were analyzed. Scan rate per reader was determined and each reader was sorted into 20 equally sized rank ordered groups (n = 817 each). RESULTS: Users performed a median of 11.5 [IQR 7.7-16.7] scans per day. Those in the lowest and highest ventiles scanned on average 3.7 and 40.0 times per day and had an eHbA1c of 8.6% (71 mmol/mol) and 6.9% (52 mmol/mol), respectively. Increasing scan rates were associated with more time in target range (3.9-10 mmol/L), less time in hyperglycemia (>10 mmol/L), and a lower standard deviation of glucose. An eHbA1c of 7.0% (53 mmol/mol) translated in approximately 65% time in target range, 30% time in hyperglycemia and 5% time in hypoglycemia (<3.9 mmol/L). CONCLUSIONS: These outcomes among Dutch FLASH users suggest that with higher scan rate glycemic control improves.

A polymorphism in the gene encoding carnosinase (CNDP1) as a predictor of mortality and progression from nephropathy to end-stage renal disease in type 1 diabetes mellitus.

AIMS/HYPOTHESIS: Homozygosity for a five leucine repeat (5L-5L) in the carnosinase gene (CNDP1) has been found to be cross-sectionally associated with a low frequency of diabetic nephropathy (DN), mainly in type 2 diabetes. We prospectively investigated in patients with type 1 diabetes whether: (1) 5L-5L is associated with mortality; (2) there is an interaction of 5L-5L with DN or sex for prediction of mortality; and (3) 5L-5L is associated with progression to end-stage renal disease (ESRD). METHODS: In this prospective study in white European patients with type 1 diabetes, individuals with DN were defined by persistent albuminuria ≥ 300 mg/24 h. Controls without nephropathy were defined by persistent (>15 years) normoalbuminuria < 30 mg/24 h. Leucine repeats were assessed with a fluorescent DNA analysis system. Onset of ESRD was defined by need to start chronic dialysis or kidney transplantation. RESULTS: The study involved 916 patients with DN and 1,170 controls. During follow-up for 8.8 years, 107 patients (14%) with 5L-5L died compared with 182 patients (13.8%) with other genotypes (p = 0.99). There was no significant interaction of 5L-5L with DN for prediction of mortality (p = 0.57), but a trend towards interaction with sex (p = 0.08). In patients with DN, HR for ESRD in 5L-5L vs other genotypes was not constant over time, with increased risk for 5L-5L beyond 8 years of follow-up (p = 0.03). CONCLUSIONS/INTERPRETATION: CNDP1 polymorphism was not associated with mortality, and nor was there an interaction of this polymorphism with DN for prediction of mortality in patients with type 1 diabetes. CNDP1 polymorphism predicts progression to ESRD in patients with DN, but only late after baseline measurements.

Markers of the hepatic component of the metabolic syndrome as predictors of mortality in renal transplant recipients.

Cardiovascular disease (CVD) is a leading cause of mortality in renal transplant recipients (RTRs). Metabolic syndrome (MS) is highly prevalent in RTRs. Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic component of MS. We investigated associations of NAFLD markers with MS and mortality. RTRs were investigated between 2001 and 2003. NAFLD markers, alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT) and alkaline phosphatase (AP) were measured. Bone and nonbone fractions of AP were also determined. Death was recorded until August 2007. Six hundred and two RTRs were studied (age 52+/-12 years, 55% men). At baseline 388 RTRs had MS. Prevalence of MS was positively associated with liver enzymes. During follow-up for 5.3[4.5-5.7] years, 95 recipients died (49 cardiovascular). In univariate Cox regression analyses, GGT (HR=1.43[1.21-1.69], p<0.001) and AP (HR=1.34[1.11-1.63], p=0.003) were associated with mortality, whereas ALT was not. Similar associations were found for cardiovascular mortality. Adjustment for potential confounders, including MS, diabetes and traditional risk factors did not materially change these associations. Results for nonbone AP mirrored that for total AP. ALT, GGT and AP are associated with MS. Of these three enzymes, GGT and AP are associated with mortality, independent of MS. These findings suggest that GGT and AP are independently related to mortality in RTRs.

The importance of contextual aspects in the care for patients with functional somatic symptoms.

Functional somatic symptoms refer to physical symptoms that cannot be (bio) medically explained. The pattern or clustering of such symptoms may lead to functional syndromes like chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, among many others. Since the underlying pathophysiology remains unknown, several explanatory models have been proposed, nearly all including social and psychological parameters. These models have stimulated effectiveness studies of several psychological and psychopharmacological therapies. While the evidence for their effectiveness is steadily growing, effect-sizes are at most moderate and many patients do not benefit. We hypothesize that the context in which interventions for functional somatic symptoms are delivered substantially influences their effectiveness. Although this hypothesis is in line with explanatory models of functional somatic symptoms, to our knowledge, studies primarily focusing on the influence of contextual aspects on treatment outcome are scarce. Contextual research in the field of somatic symptoms has (irrespective whether these symptoms can be medically explained or not), however, just begun and already yielded some valuable results. These findings can be organized according to Duranti's and Goodwin's theoretical approach to context in order to substantiate our hypothesis. Based on this approach, we categorized empirical findings in three contextual aspects, i.e. 1) the setting, 2) the behavioural environment, and 3) the language environment. Collectively, some support is found for the fact that early identification of patients with functional somatic symptoms, starting treatment as soon as possible, having a neat appearance and an organized office interior, a warm and friendly nonverbal approach and a language use without defensiveness are contextual parameters which enhance the assessment by the patient of the physician's competence to help. Nonetheless, in vivo studies addressing the most aspects, i.e. nonverbal behaviour and language, are needed for better understanding of these contextual aspect. Moreover, future research should address to what extent optimizing contextual aspects improve care for functional somatic symptoms.

Point-of-care Ultrasound (PoCUS) for the internist in Acute Medicine: a uniform curriculum.

The use of Point-of-care Ultrasound (PoCUS) is rapidly increasing in internal medicine as it is useful in the primary assessment of acutely ill internal medicine patients for enhanced diagnostics and resuscitation. PoCUS can be taught in a modular fashion including basic core applications and advanced applications which can be combined for a symptom-based approach. Several PoCUS curriculum guidelines, especially for emergency medicine, exist throughout the world but a clear Dutch guideline for internists has not been developed. In this review we propose 'core' ultrasound competencies for internists that may also be incorporated into the European Training Requirements Internal Medicine. We suggest the use of an Entrustable Professional Activities (EPA) competencybased training system with EPAs specifically designed for ultrasound.

Treatment with intramuscular vascular endothelial growth factor gene compared with placebo for patients with diabetes mellitus and critical limb ischemia: a double-blind randomized trial.

Despite advances in revascularization techniques, limb salvage and relief of pain cannot be achieved in many diabetic patients with diffuse peripheral vascular disease. Our objective was to determine the effect of intramuscular administration of phVEGF165 (vascular endothelial growth factor gene-carrying plasmid) on critical limb ischemia (CLI) compared with placebo (0.9% NaCl). A double-blind, placebo-controlled study was performed in 54 adult diabetic patients with CLI. The primary end point was the amputation rate at 100 days. Secondary end points were a 15% increase in pressure indices (ankle-to-brachial index and toe-to-brachial index), clinical improvement (skin, pain, and Quality of Life score), and safety. In patients (n=27) treated with placebo versus phVEGF165-treated patients (n=27) the following results were found: 6 amputations versus 3 (p=not significant [NS]); hemodynamic improvement in 1 versus 7 (p=0.05); improvement in skin ulcers, 0 versus 7 (p=0.01); decrease in pain, 2 versus 5 (p=NS); and overall, 3 versus 14 responding patients (p=0.003). No grade 3 or 4 adverse effects were seen in these patients. We conclude that this small, randomized gene therapy study failed to meet the primary objective of significant amputation reduction. However, significant and meaningful improvement was found in patients treated with a VEGF165-containing plasmid. There were no substantial adverse events.

[The diagnosis of pulmonary embolism based on clinical probability: D-dimer test and spiral CT]]. / Diagnostiek van longembolie op grond van klinische waarschijnlijkheid, D-dimeertest en spiraal-CT.

Recently, an algorithm encompassing a dichotomized clinical score, D-dimer and helical CT has proved to be a valid tool in confirming or rejecting a clinical diagnosis of pulmonary embolism. The diagnosis can be rejected in the context of low clinical suspicion and a negative D-dimer test. In all other situations the diagnostic accuracy of helical CT for the diagnosis of pulmonary embolism compares favourably with pulmonary angiography, with regard to the occurrence of recurrent venous thromboembolism or fatal pulmonary embolism if anticoagulation is withheld in cases of negative findings. For final diagnosis of pulmonary embolism, pulmonary angiography is only necessary if CT-scan results are suboptimal or inconclusive. This new algorithm may increase the compliance in general practice of applying guideline recommendations in patients in whom thromboembolic disease is suspected. However the proposed clinical score must first be validated for use in general practice.

Glucose and potassium derangements by glucose-insulin-potassium infusion in acute myocardial infarction.

BACKGROUND: High-dose glucose-insulin-potassium infusion (GIK) has been suggested to be beneficial in acute myocardial infarction (MI). Recently new large trials have shown no effect of GIK on mortality. To investigate whether metabolic derangement could have negated the potential beneficial effect, we studied the relation between systemic glucose and potassium levels and outcome. METHODS: Patients with signs and symptoms of ST-segment-elevation MI and treated with primary percutaneous coronary intervention (PCI) were randomised to no infusion or high-dose GIK, i.e. 80 mmol potassium chloride in 500 ml 20% glucose at a rate of 3 ml/kg/hour and 50 units short-acting insulin in 50 ml 0.9% sodium chloride for 12 hours. RESULTS: A total of 6991 glucose values and 7198 potassium values were obtained in 476 GIK patients and 464 controls. Mean serum glucose was significantly higher in the GIK group (9.3±4.5 mmol/l vs. 8.4±2.9 mmol/l, p<0.001). Mean potassium level was significantly higher in the GIK group (4.2±0.5 mmol/l vs. 3.9±0.4 mmol/l, p<0.001). Incidence of hyperglycaemia (glucose >11.0 mmol/l) occurred in 70.8% of GIK patients and 33.8% of controls (p<0.001). Hypokalaemia was less common in the GIK group (23.5 vs. 41.2%, p<0.001). Incidence of hyperkalaemia and hypoglycaemia did not differ significantly between the two groups. In multivariate analysis age, previous cardiovascular disease, Killip class >1, unsuccessful PCI and mean glucose after admission were associated with increased one-year mortality. CONCLUSION: In ST-segment-elevation MI patients treated with primary PCI, high-dose GIK induced hyperglycaemia and prevented hypokalaemia. Derangement of the glucose metabolism was related to one-year mortality.

Effects of intraperitoneal insulin versus subcutaneous insulin administration on sex hormone-binding globulin concentrations in patients with type 1 diabetes mellitus.

AIMS: Elevated sex hormone-binding globulin (SHBG) concentrations have been described in patients with type 1 diabetes mellitus (T1DM), probably due to low portal insulin concentrations. We aimed to investigate whether the route of insulin administration, continuous intraperitoneal insulin infusion (CIPII), or subcutaneous (SC), influences SHBG concentrations among T1DM patients. METHODS: Post hoc analysis of SHBG in samples derived from a randomized, open-labeled crossover trial was carried out in 20 T1DM patients: 50% males, mean age 43 (±13) years, diabetes duration 23 (±11) years, and hemoglobin A1c (HbA1c) 8.7 (±1.1) (72 (±12) mmol/mol). As secondary outcomes, testosterone, 17-ß-estradiol, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were analyzed. RESULTS: Estimated mean change in SHBG was -10.3nmol/L (95% CI: -17.4, -3.2) during CIPII and 3.7nmol/L (95% CI: -12.0, 4.6) during SC insulin treatment. Taking the effect of treatment order into account, the difference in SHBG between therapies was -6.6nmol/L (95% CI: -17.5, 4.3); -12.7nmol/L (95% CI: -25.1, -0.4) for males and -1.7nmol/L (95% CI: -24.6, 21.1) for females, respectively. Among males, SHBG and testosterone concentrations changed significantly during CIPII; -15.8nmol/L (95% CI: -24.2, -7.5) and -8.3nmol/L (95% CI: -14.4, -2.2), respectively. The difference between CIPII and SC insulin treatment was also significant for change in FSH 1.2U/L (95% CI: 0.1, 2.2) among males. CONCLUSIONS: SHBG concentrations decreased significantly during CIPII treatment. Moreover, the difference in change between CIPII and SC insulin therapy was significant for SHBG and FSH among males. These findings support the hypothesis that portal insulin administration influences circulating SHBG and sex steroids.