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.

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.

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.

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.

'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.

Intraperitoneal versus subcutaneous insulin therapy in the treatment of type 1 diabetes mellitus.

BACKGROUND: Continuous intraperitoneal insulin infusion (CIPII), a last-resort type 1 diabetes mellitus (T1DM) treatment, has only been investigated in small or controlled studies. We aimed to investigate glycaemia and quality of life (QoL) with CIPII versus subcutaneous (SC) insulin therapy during usual T1DM care. METHODS: A prospective, observational case-control study. CIPII-treated cases were matched to SC controls. The primary endpoint was a non-inferiority assessment (pre-defined margin of -5.5 mmol÷mol) of the baseline adjusted difference in HbA1c between groups during a 26-week follow-up. Secondary outcomes included QoL, clinical and biochemical measurements. RESULTS: In total, 183 patients were analysed (CIPII n = 39 and SC n = 144). The HbA1c difference between treatment groups was -3.0 mmol÷mol (95% CI -5.0, -1.0), being lower in the SC group. Patients using SC insulin therapy spent less percentage of time in hyperglycaemia (-9.3% (95% CI -15.8, -2.8)) and more in euglycaemia (6.9% (95% CI 1.2, 12.5) as compared with CIPII-treated patients. Besides a 3.6 U÷l (95% CI 1.2, 6.0) lower concentration of alanine aminotransferase with CIPII, no biochemical and clinical differences were present. Most QoL scores were lower at baseline among CIPII-treated patients. However, besides lower health status, there were no differences in the baseline-adjusted general and diabetes-specific QoL and treatment satisfaction. CONCLUSION: Although patients using CIPII had a higher glycaemic profile compared with patients using SC insulin therapy, the HbA1c difference was non-inferior. Overall, health status was lower among CIPII-treated patients, although diabetes-specific QoL and treatment satisfaction was similar to subcutaneously treated patients.

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.

Sex specific association between carnosinase gene CNDP1 and cardiovascular mortality in patients with type 2 diabetes (ZODIAC-22).

INTRODUCTION: Homozygosity for a 5-leucine repeat (5L-5L) in the carnosinase gene (CNDP1) has been associated with a reduced prevalence of diabetic nephropathy in cross-sectional studies in patients with type 2 diabetes, particularly in women. Prospective studies on mortality are not available. This study investigated whether 5L-5L was associated with mortality and progression of renal function loss and to what extent this effect is modified by sex. METHODS: In a prospective cohort of patients with type 2 diabetes, a Cox proportional hazard model was used to compare 5L-5L with other genotypes regarding (cardiovascular) mortality. Renal function slopes were obtained by within-individual linear regression of the estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) equation, and were compared between 5L-5L and other genotypes. RESULTS: 871 patients were included (38% with 5L-5L). After 9.5 years of follow-up, hazards ratios (HR) for all-cause and cardiovascular mortality in 5L-5L versus other genotypes were 1.09 [95% confidence interval (CI) 0.88-1.36] and 1.12 (95% CI 0.79-1.58), respectively. There was a significant interaction between CNDP1 and sex for the association with cardiovascular mortality (p = 0.01), not for all-cause mortality (p = 0.32). Adjusted HR in 5L-5L for cardiovascular mortality was 0.69 (95% CI 0.39-1.23) in men and 1.77 (95% CI 1.12-2.81) in women. The slopes of eGFR-MDRD did not significantly differ between 5L-5L and other genotypes. CONCLUSIONS: The association between CNDP1 and cardiovascular mortality was sex-specific, with a higher risk in women with 5L-5L genotype. CNDP1 was not associated with all-cause mortality or change in eGFR.

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).

Report of a 7 year case-control study of continuous intraperitoneal insulin infusion and subcutaneous insulin therapy among patients with poorly controlled type 1 diabetes mellitus: favourable effects on hypoglycaemic episodes.

AIMS: Continuous intraperitoneal insulin infusion (CIPII) is a last-resort treatment option for patients with type 1 diabetes mellitus (T1DM) who fail to reach adequate glycaemic control with subcutaneous (SC) insulin therapy. Aim was to compare the long-term effects of CIPII and SC insulin therapy among patients with T1DM in poor glycaemic control. METHODS: Patients in which CIPII was initiated in 2006 were compared with a control group of T1DM patients who continued SC therapy. Linear mixed models were used to calculate differences between the baseline (2006) and final (2013) measurements within and between groups. RESULTS: A total of 95 patients of which 21 were using CIPII and 74 using SC insulin were included. Within the CIPII group, the number of hypoglycaemic episodes decreased with -5 (95% CI -8 to -3) per 2 weeks while it remained stable among SC patients. Over time, only the number of hypoglycaemic episodes decreased more with CIPII as compared to SC insulin treatment (difference: -6 (95% CI -9 to -4)). There were no differences between treatment groups regarding clinical parameters and quality of life scores over time. Pump or catheter dysfunction led to ketoacidosis in 6 patients: 2 using CIPII and 4 SC insulin. CONCLUSIONS: After 7 years of follow-up, there is a persistent decline of hypoglycaemic events among CIPII treated T1DM patients. Besides less hypoglycaemic episodes with CIPII therapy, there are no differences between long-term CIPII and SC insulin therapy.

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.

Current concepts in the management of diabetic nephropathy.

Although much progress has been made in slowing the progression of diabetic nephropathy, renal dysfunction and development of end-stage renal disease (ESRD) remain major concerns in diabetes. In addition, diabetic patients with microalbuminuria have an increased cardiovascular mortality. Therefore, new treatment modalities or strategies are needed to prevent or slow the progression of diabetic nephropathy and prevent cardiovascular disease in diabetes. In this review we describe current concepts in pathophysiology, treatment goals and we discuss future developments in the treatment of diabetic nephropathy. Common risk factors for diabetic nephropathy and its progression are longer duration, poor glycaemic control, hypertension and the presence of albuminuria. Available treatment options, especially renin-angiotensin aldosterone system (RAAS) blockade, but also better blood pressure and blood glucose control, decrease the incidence of cardiovascular disease and renal disease in diabetes. It is important that treatment goals are tailored to the individual patient with individual treatment goals of glycaemic control and blood pressure, depending on age, type of diabetes and diabetes duration. Aggressive treatment of glucose control and blood pressure might not always be best practice for every patient. Since the proportion of ESRD due to diabetic nephropathy remains high, optimisation of RAAS blockade is advocated and can be achieved by adequate sodium restriction and/or diuretic treatment. Moreover, aldosterone blockade might be a valuable strategy, which has potency to slow the progression of diabetic renal disease. Other possible future interventions are under investigation, but large clinical trials have to be awaited to confirm the safety and efficacy of these drugs.

Educational disparities in mortality among patients with type 2 diabetes in The Netherlands (ZODIAC-23).

BACKGROUND: Relative mortality differences between educational level in mortality have been reported among diabetic as well as among non-diabetic subjects in Europe, but data on absolute differences are lacking. We studied the effect of educational disparities on mortality in a Dutch prospective cohort of type 2 diabetes mellitus (T2DM) patients. METHODS: This study was part of the ZODIAC study, a prospective observational study of patients with T2DM. Data on educational level were first collected on 19 May 1998, and from this date on, 858 patients were included in 1998; educational level was known for 656 patients. Vital status was assessed in 2009. The relationship between mortality and educational level was studied using a Cox proportional hazard model, the relative index of inequality (RII), slope index of inequality (SII) and the population attributable risk (PAR). Educational level was divided into four categories; the highest educational level was used as reference. RESULTS: After a median follow-up time of 9.7 years, 365 out of 858 patients had died. The hazard ratio of primary education for total mortality was 3.02 (95% CI 1.44-6.34). The RII was 2.85 (95% CI 1.21-6.67), the absolute difference in the risk for mortality (SII) was 384 deaths (95% CI 49-719) per 10,000 follow-up years. PAR for patients with the lowest level of education was 51.4%. CONCLUSIONS: A low educational level had a higher impact on mortality than having a macrovascular complication. Given the substantial differences in mortality between educational levels in T2DM, more understanding of underlying (modifiable) mechanisms is necessary.

What do professionals recommend regarding the frequency of self-monitoring of blood glucose?

BACKGROUND: Patients' adherence to guidelines regarding self-monitoring of blood glucose (SMBG) is limited. However, there are no previous reports about the recommendations that are given in clinical practice concerning SMBG. The aim of this study was to investigate what healthcare providers recommend to insulin-treated patients with diabetes regarding frequency and timing of SMBG. METHODS: In this cross-sectional descriptive study, primary care assistants, diabetes specialised nurses and doctors in the Netherlands were invited via e-mail to complete an internet survey. RESULTS: A total of 980 (14%) professionals returned the questionnaire. Insulin pump users and patients with type 1 diabetes (T1DM) on 4 injections a day were advised to perform SMBG daily by 96% and 63% of the professionals, respectively. The majority of the professionals advised these patients to perform 3-4 measurements per day. There was less agreement on the timing (pre- and÷or postprandial). Patients with type 2 diabetes (T2DM) on four injections were advised to perform SMBG less frequently. There was a wide variation in recommendations that were given to patients with T2DM on less intensive insulin regimens. CONCLUSION: This study investigated SMBG from a professional's perspective. A considerable and relevant variation in the recommendations about the number and timing of SMBG was observed. The most striking differences were found in patients with T2DM on less intensive insulin regimes, also with respect to the frequency of SMBG. Well-designed studies are necessary in order to give a more evidence-based advice on the basic frequency and timing of SMBG.

[Calcium suppletion for patients who use gastric acid inhibitors: calcium citrate or calcium carbonate?]. / Calciumsuppletie bij patiënten met maagzuurremmers: calciumcitraat of calciumcarbonaat?

Various calcium supplements are available for patients who have an indication for calcium suppletion. American guidelines and UpToDate recommend prescribing calcium citrate to patients who use antacids The rationale for this advice is that water-insoluble calcium carbonate needs acid for adequate absorption. No convincing scientific evidence supporting the advice to prescribe calcium citrate instead of calcium carbonate to patients who also take antacids is available, and therefore deserves further investigation. On the contrary, the fact that calcium carbonate does not need acid in order to be absorbed, has also not been proven. In clinical practise, it appears important that calcium is taken with meals in order to improve its absorption.

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.