The Incidence of Pulmonary Embolism in Hospitalized Non-ICU Patients with COVID-19 during the First Wave: A Multicenter Retrospective Cohort Study in the Netherlands.

INTRODUCTION: During the first COVID-19 outbreak in 2020 in the Netherlands, the incidence of pulmonary embolism (PE) appeared to be high in COVID-19 patients admitted to the intensive care unit (ICU). This study was performed to evaluate the incidence of PE during hospital stay in COVID-19 patients not admitted to the ICU. METHODS: Data were retrospectively collected from 8 hospitals in the Netherlands. Patients admitted between February 27, 2020, and July 31, 2020, were included. Data extracted comprised clinical characteristics, medication use, first onset of COVID-19-related symptoms, admission date due to COVID-19, and date of PE diagnosis. Only polymerase chain reaction (PCR)-positive patients were included. All PEs were diagnosed with computed tomography pulmonary angiography (CTPA). RESULTS: Data from 1,852 patients who were admitted to the hospital ward were collected. Forty patients (2.2%) were diagnosed with PE within 28 days following hospital admission. The median time to PE since admission was 4.5 days (IQR 0.0-9.0). In all 40 patients, PE was diagnosed within the first 2 weeks after hospital admission and for 22 (55%) patients within 2 weeks after onset of symptoms. Patient characteristics, pre-existing comorbidities, anticoagulant use, and laboratory parameters at admission were not related to the development of PE. CONCLUSION: In this retrospective multicenter cohort study of 1,852 COVID-19 patients only admitted to the non-ICU wards, the incidence of CTPA-confirmed PE was 2.2% during the first 4 weeks after onset of symptoms and occurred exclusively within 2 weeks after hospital admission.

Hepatic Fat and Macrophages Are Increased in Livers of Diabetic Patients without Non-Alcoholic Fatty Liver Disease.

INTRODUCTION: Diabetes mellitus (DM), especially type 2, is strongly associated with non-alcoholic fatty liver disease (NAFLD). Recent studies indicate that particularly in DM patients, "simple" liver steatosis can progress into more severe disease. However, little is known about putative hepatic histopathological changes in DM patients without NAFLD. In this study, we therefore analysed fat content and inflammatory cell infiltration in the livers of deceased DM and non-DM patients without NAFLD, and analysed age/sex effects hereon. METHODS: Hepatic fat and inflammatory cells were studied through (immuno)histochemical analysis in liver tissue from 24 DM patients and 66 non-diabetic controls, without histopathological characteristics of NAFLD. RESULTS: We observed a 2-fold increase in fat percentage/mm2 and a near 5-fold increase in the number of fat-containing cells/mm2 in DM patients compared to non-diabetic controls. Fat content was significantly higher in patients with type 2 DM, but not type 1 DM, compared to non-diabetic controls, while the number of CD68+ cells/mm2 was significantly elevated in both DM groups. CONCLUSION: Hepatic fat and number of macrophages are increased in patients with DM without NAFLD, which may reflect a higher risk on development of steatosis and steatohepatitis.

Liraglutide treatment attenuates inflammation markers in the cardiac, cerebral and renal microvasculature in streptozotocin-induced diabetic rats.

BACKGROUND: Diabetes mellitus (DM) induces cardiac and cerebral microvascular dysfunction via increased glycation, oxidative stress and endothelial activation. Liraglutide, a glucagon-like peptide-1 analogue, inhibited NOX2 and adhesion molecules in isolated endothelial cells. Here, we have studied how Liraglutide affects advanced glycation, NOX expression and inflammation of the cardiac, cerebral and renal microvasculature in diabetic rats. METHODS: DM was induced in Sprague-Dawley rats (n = 15) via intraperitoneal streptozotocin (STZ) injection (60 mg/kg bodyweight). Ten control rats remained nondiabetic. From day 9 post-STZ injection, Liraglutide (200 µg/kg bodyweight; n = 7) or vehicle (n = 8) was injected subcutaneously daily until termination on day 29. The advanced glycation endproduct N-ε-(carboxymethyl)lysine (CML), NOX2, NOX4, ICAM-1 and VCAM-1 were subsequently immunohistochemically analysed and quantified to compare Liraglutide treatment with placebo. RESULTS: In the heart, Liraglutide treatment significantly reduced the DM-increased scores/cm2 for CML in both ventricles (from 253 ± 53 to 72 ± 12; p = .003) and atria (343 ± 29 to 122 ± 8; p = .0001) and for NOX2, ICAM-1 and VCAM-1, but not for NOX4. Also in the cerebrum and cerebellum of the brain, Liraglutide significantly reduced the scores/cm2 for CML (to 60 ± 7 (p = .0005) and 47 ± 13 (p = .02), respectively), and for NOX2 and NOX4. In the kidney, the DM-induced expression of ICAM-1 and VCAM-1 was decreased in the blood vessels and glomeruli by Liraglutide treatment. Liraglutide did not affect blood glucose levels or bodyweight. CONCLUSIONS: Our study implies that Liraglutide protects the cardiac, cerebral and renal microvasculature against diabetes-induced dysfunction, independent of lowering blood glucose in a type 1 diabetes rat model.

Eosinopenia and increased markers of endothelial damage are characteristic of COVID-19 infection at time of hospital admission.

In December 2019, a new virus has been discovered, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), leading to coronavirus disease 2019 (COVID-19). COVID-19 has been defined as an evolving disease with different phases. It starts with a mild or asymptomatic phase in which there is minimal disease. Thereafter, most patients recover, however, in 20% of the cases the infection worsens. It is hypothesized that eosinopenia, endothelial injury and the presence of smooth muscle autoantibodies are associated with the severity of the COVID-19. In a subset of 75 blood samples of patients with a SARS-CoV-2 infection at time of hospitalization and 30 healthy control samples concentrations of eosinophils, VEGF, VCAM, endothelin and smooth muscle autoantibodies were determined with hemocytometry, ELISA and immunofluorescence assays. In the group of patients with COVID-19 eosinophils (IQR = 0.0-0.01*109/L) were significantly decreased (p < .001), whereas markers of endothelial damage VCAM (IQR = 740-1120 ng/mL) and endothelin (IQR = 2.0-3.4 pg/mL) were significantly increased (p < .001) compared to the group of healthy controls (eosinophils IQR = 0.09-0.19*109/L, VCAM IQR = 362-561 ng/mL, endothelin IQR = 0.5-1.0 pg/mL). From the multivariate analysis, it is concluded that at time of hospitalization a combination of eosinopenia and increased markers of endothelial damage VCAM and endothelin are characteristic of COVID-19.

Faecal microbiota transplantation halts progression of human new-onset type 1 diabetes in a randomised controlled trial.

OBJECTIVE: Type 1 diabetes (T1D) is characterised by islet autoimmunity and beta cell destruction. A gut microbiota-immunological interplay is involved in the pathophysiology of T1D. We studied microbiota-mediated effects on disease progression in patients with type 1 diabetes using faecal microbiota transplantation (FMT). DESIGN: Patients with recent-onset (<6 weeks) T1D (18-30 years of age) were randomised into two groups to receive three autologous or allogenic (healthy donor) FMTs over a period of 4 months. Our primary endpoint was preservation of stimulated C peptide release assessed by mixed-meal tests during 12 months. Secondary outcome parameters were changes in glycaemic control, fasting plasma metabolites, T cell autoimmunity, small intestinal gene expression profile and intestinal microbiota composition. RESULTS: Stimulated C peptide levels were significantly preserved in the autologous FMT group (n=10 subjects) compared with healthy donor FMT group (n=10 subjects) at 12 months. Small intestinal Prevotella was inversely related to residual beta cell function (r=-0.55, p=0.02), whereas plasma metabolites 1-arachidonoyl-GPC and 1-myristoyl-2-arachidonoyl-GPC levels linearly correlated with residual beta cell preservation (rho=0.56, p=0.01 and rho=0.46, p=0.042, respectively). Finally, baseline CD4 +CXCR3+T cell counts, levels of small intestinal Desulfovibrio piger and CCL22 and CCL5 gene expression in duodenal biopsies predicted preserved beta cell function following FMT irrespective of donor characteristics. CONCLUSION: FMT halts decline in endogenous insulin production in recently diagnosed patients with T1D in 12 months after disease onset. Several microbiota-derived plasma metabolites and bacterial strains were linked to preserved residual beta cell function. This study provides insight into the role of the intestinal gut microbiome in T1D. TRIAL REGISTRATION NUMBER: NTR3697.

Safety and effectiveness of replacement with biosimilar growth hormone in adults with growth hormone deficiency: results from an international, post-marketing surveillance study (PATRO Adults).

PURPOSE: To evaluate safety and effectiveness of biosimilar recombinant human growth hormone (rhGH; Omnitrope®) in adults with growth hormone deficiency (GHD), using data from the PATRO Adults study. METHODS: PATRO Adults was a post-marketing surveillance study conducted in hospitals and specialized endocrinology units across Europe. The primary objective was to assess the safety of rhGH in adults treated in routine clinical practice. All adverse events (AEs) were monitored and recorded for the complete duration of Omnitrope® treatment. Effectiveness was evaluated as a secondary objective. RESULTS: As of January 2020, 1447 patients (50.9% male) had been enrolled from 82 centers in 9 European countries. Most patients had adult-onset GHD (n = 1179; 81.5%); 721 (49.8%) were rhGH-naïve at study entry. Overall, 1056 patients (73.0%) reported adverse events (AEs; n = 5397 events); the majority were mild-to-moderate in intensity. Treatment-related AEs were reported in 117 patients (8.1%; n = 189 events); the most commonly reported (MedDRA preferred terms) were arthralgia (n = 19), myalgia (n = 16), headache (n = 14), and edema peripheral (n = 10). In total, 495 patients (34.2%) had serious AEs (SAEs; n = 1131 events); these were considered treatment-related in 28 patients (1.9%; n = 35 events). Mean (standard deviation) IGF-I SDS increased from - 2.34 (1.47) at baseline to - 0.23 (1.65) at 12 months, and remained relatively stable thereafter (up to 3 years). Body mass index remained stable between baseline and 3 years. CONCLUSION: Data from PATRO Adults indicate biosimilar rhGH (Omnitrope®) is not associated with any unexpected safety signals, and is effective in adults with GHD treated in real-world clinical practice.

Early warning scores to assess the probability of critical illness in patients with COVID-19.

OBJECTIVE: Validated clinical risk scores are needed to identify patients with COVID-19 at risk of severe disease and to guide triage decision-making during the COVID-19 pandemic. The objective of the current study was to evaluate the performance of early warning scores (EWS) in the ED when identifying patients with COVID-19 who will require intensive care unit (ICU) admission for high-flow-oxygen usage or mechanical ventilation. METHODS: Patients with a proven SARS-CoV-2 infection with complete resuscitate orders treated in nine hospitals between 27 February and 30 July 2020 needing hospital admission were included. Primary outcome was the performance of EWS in identifying patients needing ICU admission within 24 hours after ED presentation. RESULTS: In total, 1501 patients were included. Median age was 71 (range 19-99) years and 60.3% were male. Of all patients, 86.9% were admitted to the general ward and 13.1% to the ICU within 24 hours after ED admission. ICU patients had lower peripheral oxygen saturation (86.7% vs 93.7, p≤0.001) and had a higher body mass index (29.2 vs 27.9 p=0.043) compared with non-ICU patients. National Early Warning Score 2 (NEWS2) ≥ 6 and q-COVID Score were superior to all other studied clinical risk scores in predicting ICU admission with a fair area under the receiver operating characteristics curve of 0.740 (95% CI 0.696 to 0.783) and 0.760 (95% CI 0.712 to 0.800), respectively. NEWS2 ≥6 and q-COVID Score ≥3 discriminated patients admitted to the ICU with a sensitivity of 78.1% and 75.9%, and specificity of 56.3% and 61.8%, respectively. CONCLUSION: In this multicentre study, the best performing models to predict ICU admittance were the NEWS2 and the Quick COVID-19 Severity Index Score, with fair diagnostic performance. However, due to the moderate performance, these models cannot be clinically used to adequately predict the need for ICU admission within 24 hours in patients with SARS-CoV-2 infection presenting at the ED.

Oral butyrate does not affect innate immunity and islet autoimmunity in individuals with longstanding type 1 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: The pathophysiology of type 1 diabetes has been linked to altered gut microbiota and more specifically to a shortage of intestinal production of the short-chain fatty acid (SCFA) butyrate, which may play key roles in maintaining intestinal epithelial integrity and in human and gut microbial metabolism. Butyrate supplementation can protect against autoimmune diabetes in mouse models. We thus set out to study the effect of oral butyrate vs placebo on glucose regulation and immune variables in human participants with longstanding type 1 diabetes. METHODS: We administered a daily oral dose of 4 g sodium butyrate or placebo for 1 month to 30 individuals with longstanding type 1 diabetes, without comorbidity or medication use, in a randomised (1:1), controlled, double-blind crossover trial, with a washout period of 1 month in between. Participants were randomly allocated to the 'oral sodium butyrate capsules first' or 'oral placebo capsules first' study arm in blocks of five. The clinical investigator received blinded medication from the clinical trial pharmacy. All participants, people doing measurements or examinations, or people assessing the outcomes were blinded to group assignment. The primary outcome was a change in the innate immune phenotype (monocyte subsets and in vitro cytokine production). Secondary outcomes were changes in blood markers of islet autoimmunity (cell counts, lymphocyte stimulation indices and CD8 quantum dot assays), glucose and lipid metabolism, beta cell function (by mixed-meal test), gut microbiota and faecal SCFA. The data was collected at the Amsterdam University Medical Centers. RESULTS: All 30 participants were analysed. Faecal butyrate and propionate levels were significantly affected by oral butyrate supplementation and butyrate treatment was safe. However, this modulation of intestinal SCFAs did not result in any significant changes in adaptive or innate immunity, or in any of the other outcome variables. In our discussion, we elaborate on this important discrepancy with previous animal work. CONCLUSIONS/INTERPRETATION: Oral butyrate supplementation does not significantly affect innate or adaptive immunity in humans with longstanding type 1 diabetes. TRIAL REGISTRATION: Netherlands Trial Register: NL4832 (www.trialregister.nl). DATA AVAILABILITY: Raw sequencing data are available in the European Nucleotide Archive repository (https://www.ebi.ac.uk/ena/browse) under study PRJEB30292. FUNDING: The study was funded by a Le Ducq consortium grant, a CVON grant, a personal ZONMW-VIDI grant and a Dutch Heart Foundation grant.

Amplified prevalence and incidence of cardiovascular disease in patients with inflammatory arthritis and coexistent autoimmune disorders.

OBJECTIVE: This study aims to assess the prevalence proportion and incidence rate of cardiovascular morbidity in patients with inflammatory arthritis compared with that in controls, and to determine whether the co-existence of multiple autoimmune disorders is associated with an amplified risk of cardiovascular disease. METHODS: Data from the Nivel Primary Care Database were used to assess prevalence proportion and incidence rate of cardiovascular disease in patients with inflammatory arthritis only, patients with inflammatory arthritis coexistent with another autoimmune disorder, and controls. Hazard ratios were calculated using Cox regression models. RESULTS: The prevalence proportions in inflammatory arthritis patients were increased for type 1 diabetes [odds ratio (OR) 1.80, 95% CI: 1.27, 2.55], hypothyroidism (OR 1.49, 95% CI: 1.37, 1.61), psoriasis (OR 2.72, 95% CI: 2.49, 2.97) and IBD (OR 2.64, 95% CI: 2.28, 3.07) compared with that in controls. Cardiovascular disease prevalence (OR 1.34, 95% CI: 1.28, 1.41) and incidence rates (incidence rate ratio 1.3, 95% CI: 1.23, 1.41) were higher in inflammatory arthritis patients compared with that in controls, and were further increased in the presence of a second autoimmune disorder. The hazard ratio for cardiovascular disease was 1.32 (95% CI: 1.23, 1.41) for patients with inflammatory arthritis only, and 1.49 (95% CI: 1.31, 1.68) for patients with inflammatory arthritis co-existent with another autoimmune disorder. CONCLUSION: The amplification of cardiovascular disease risk in inflammatory arthritis patients with multiple autoimmune disorders warrants greater awareness, and since autoimmune disorders often co-exist, the need for cardiovascular risk management in these patients is once again emphasized.

No increased risk of glucose metabolism disorders in adults with growth hormone deficiency undergoing long-term treatment with biosimilar somatropin (Omnitrope®): data from an observational, longitudinal study.

BACKGROUND: To evaluate the impact of treatment with recombinant human growth hormone (rhGH; Omnitrope®) on the risk of diabetes mellitus in adults with growth hormone deficiency (GHD), using data from the ongoing PATRO Adults post-marketing surveillance study. METHODS: PATRO Adults is an ongoing post-marketing surveillance study being conducted in hospitals and specialized endocrinology clinics across Europe. All enrolled patients who receive ≥1 dose of Omnitrope® are included in the safety population. Patient profiles, containing all available study database information for each specific patient, were generated for all patients with adverse events (AEs) of diabetes mellitus while participating in the study. Diabetes mellitus was confirmed if fasting plasma glucose was ≥7.0 mmol/L or 2-h plasma glucose ≥11.1 mmol/L during oral glucose tolerance test or glycated hemoglobin ≥6.5%. RESULTS: Up to July 2018, 1293 patients had been enrolled in the study, and 983 (76.0%) remained active. Just under half (n = 687, 49.3%) of the patients were growth hormone (GH) treatment-naïve on entering the study, and most (n = 1128, 87.2%) had multiple pituitary hormone deficiency (MPHD). Diabetes mellitus/inadequate control (worsening) of diabetes mellitus was reported in 21 patients (22 events). The cases were newly diagnosed in 15 patients (age 29-84 years; incidence rate 3.61 per 1000 patient-years) and occurred in 6 patients with pre-existing diabetes mellitus at baseline (age 45-72 years). Most cases of newly diagnosed diabetes mellitus occurred in patients with adult-onset MPHD (n = 13); the remaining cases of new-onset diabetes mellitus occurred in a patient with childhood-onset MPHD who had previously received GH replacement therapy (n = 1), and a patient with adulthood-onset isolated GHD who was naïve to GH replacement therapy (n = 1). All cases of inadequate control/worsening of diabetes mellitus occurred in patients with adult-onset MPHD. CONCLUSIONS: Based on this snapshot of data from PATRO Adults, Omnitrope® treatment is tolerated in adult patients with GHD in a real-life clinical practice setting. No signals of an increased risk for diabetes mellitus have been noted so far, although continued follow-up (both during and after rhGH therapy) is required to confirm this. TRIAL REGISTRATION: Not applicable.

Study protocol: a randomised placebo-controlled clinical trial to study the effect of vitamin D supplementation on glycaemic control in type 2 Diabetes Mellitus SUNNY trial.

BACKGROUND: Besides the classical role of vitamin D on calcium and bone homeostasis, vitamin D deficiency has recently been identified as a contributing factor in the onset of insulin resistance in type 2 diabetes mellitus. However, it is uncertain whether vitamin D deficiency and poor glycaemic control are causally interrelated or that they constitute two independent features of type 2 diabetes mellitus. There are limited clinical trials carried out which measured the effect of vitamin D supplementation on glycaemic control.The objective of this study is to investigate the effect of vitamin D supplementation on glycaemic control and quality of life in patients with type 2 diabetes mellitus. METHODS/DESIGN: In a randomised double-blind placebo-controlled trial conducted in five general practices in the Netherlands three hundred patients with type 2 diabetes mellitus treated with lifestyle advises or metformin or sulphonylurea-derivatives are randomised to receive either placebo or 50,000 IU Vitamin D3 at monthly intervals. The primary outcome measure is the change in glycated haemoglobin level between baseline and six months. Secondary outcome measures include blood pressure, anthropometric parameters, lipid profile, insulin resistance, quality of life, advanced glycation end products and safety profiles. Quality of life will be measured by The Short Form (SF-36) Health Survey questionnaire. Advanced glycation end products are measured by an AGE-reader. DISCUSSION: This trial will be the first study exploring the effect of vitamin D supplementation on both glycaemic control and quality of life in patients with type 2 diabetes mellitus. Our findings will contribute to the knowledge of the relationship between vitamin D status and insulin resistance in patients with type 2 diabetes mellitus. TRIAL REGISTRATION: The Netherlands trial register: NTR3154.

Temporal evolution of liver function parameters predicts clinical outcome in chronic heart failure patients (Bio-SHiFT study).

BACKGROUND: Liver dysfunction contributes to worse clinical outcomes in heart failure (HF) patients. However, studies exploring temporal evolutions of liver function parameters in chronic HF (CHF) pa- tients, and their associations with clinical outcome, are scarce. Detailed temporal patterns of alkaline phosphatase (ALP), gamma glutamyl transpeptidase (GGTP), total bilirubin (TBIL) and albumin (ALB) were investigated, and their relation with clinical outcome, in patients with stable CHF with reduced ejection fraction. METHODS: Tri-monthly plasma samples were collected from 250 patients during 2.2 (1.4-2.5) years of follow-up. ALP, GGTP, ALB, and TBIL were measured in 749 selected samples and the relationship between repeatedly measured biomarker levels and the primary endpoint (PEP; composite of cardiovas- cular death, heart transplantation, left ventricular assist device implantation, and hospitalization for worsened HF) was evaluated by joint models. RESULTS: Mean age was 66 ± 13 years; 74% were men, 25% in New York Heart Association class III-IV. 66 (26%) patients reached the PEP. Repeatedly measured levels of TBIL, ALP, GGTP, and ALB were associated with the PEP after adjustment for N-terminal prohormone B-type natriuretic peptide and high sensitivity troponin T (hazard ratio [95% confidence interval] per doubling of biomarker level: 1.98 [1.32; 2.95], p = 0.002; 1.84 [1.09; 3.05], p = 0.018, 1.33 [1.08; 1.63], p = 0.006 and 1.14 [1.09; 1.20], p < 0.001, respectively). Serial levels of ALP and GGTP, and slopes of the temporal evolutions of ALB and TBIL, adjusted for clinical variables, were also significantly associated with the PEP. CONCLUSIONS: Changes in serum levels of TBIL, ALP, GGTP, and ALB precede adverse cardiovascular events in patients with CHF. These routine liver function parameters may provide additional prognostic information in heart failure with reduced ejection fraction patients in clinical practice.

Lanreotide versus placebo for tumour reduction in patients with a 68Ga-DOTATATE PET-positive, clinically non-functioning pituitary macroadenoma (GALANT study): a randomised, multicentre, phase 3 trial with blinded outcome assessment.

Background: No established medical treatment options currently exist for patients with non-functioning pituitary macroadenoma (NFPMA). Somatostatin analogues may prevent tumour growth, but randomised controlled trials are lacking. In vivo somatostatin receptor assessment with 68Ga-DOTATATE PET could help in selecting patients for treatment. We aimed to determine the effect of the somatostatin analogue lanreotide on tumour size in patients with a 68Ga-DOTATATE PET-positive NFPMA. Methods: The GALANT study was an investigator-initiated, multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial with recruitment at three academic hospitals in the Netherlands. Adult patients with a suprasellar extending NFPMA, either surgery-naïve or postoperative remnant ≥10 mm, were eligible for inclusion. Important exclusion criteria were previous sellar radiotherapy and use of dopamine receptor agonists. Somatostatin receptor expression in the NFPMA was determined through 68Ga-DOTATATE PET/CT, co-registered with MRI. A predefined sample of 44 patients with PET-positive NFPMA were randomly assigned (1:1) to lanreotide acetate 120 mg or placebo, both administered as deep subcutaneous injections every 28 days for 72 weeks. Primary outcome was the change in cranio-caudal tumour diameter measured on pituitary MRI from baseline to end-of-treatment in the intention-to-treat population. Participants, investigators and outcome assessors were masked to treatment allocation. The trial is registered with the Netherlands Trial Registry, NL5136, and EudraCT, 2015-001234-22. Findings: Between Nov 3, 2015, and Dec 10, 2019, 49 patients were included in the study. Forty-four patients with a 68Ga-DOTATATE PET-positive NFPMA were randomly assigned to lanreotide (22 [50%]) or placebo (22 [50%]). Study treatment was completed in 13 (59%) lanreotide and 19 (86%) placebo participants. The mean (SD) change from baseline in cranio-caudal tumour diameter after treatment was +1·2 (2·5) mm with lanreotide and +1·3 (1·5) mm with placebo; adjusted mean difference versus placebo -0·1 mm (95% CI -1·3 to 1·2, p = 0·93). Adverse events occurred in 22 (100%, 147 events) lanreotide and 21 (95%, 94 events) placebo participants. Gastrointestinal complaints were most common, reported by 18 (82%) lanreotide and 8 (36%) placebo participants. There were no treatment-related serious adverse events. Interpretation: Compared with placebo, lanreotide treatment did not reduce tumour size or growth in patients with 68Ga-DOTATATE PET-positive NFPMA. Funding: Ipsen Farmaceutica BV.

Cardiovascular protective properties of incretin-based therapies in type 2 diabetes.

PURPOSE OF REVIEW: Type 2 diabetes mellitus is a chronic dysmetabolic condition characterized by hyperglycemia and accompanied by dyslipidemia (low HDL, high triglycerides), and hypertension associated with insulin resistance in obesity. In addition to the glucose-reducing effects, incretin-based therapies have been found to have cardiovascular protective properties. This review summarizes the best available evidence favoring these positive pleiotropic effects of incretin mimetics as well as incretin enhancers. RECENT FINDINGS: Studies in animals and humans are accumulating showing the direct as well as indirect actions of the glucagon-like peptide 1 analogues and dipeptidyl peptidase 4 inhibitors on the cardiovascular system. This class of agents appear to have effects on the cardiomyocytes, blood vessels, adipose tissue, regulation of blood pressure, and postprandial intestinal lipoprotein metabolism. SUMMARY: Long-term hard outcome trials are under way that investigate the effects of incretin-based treatments on elevated cardiovascular risks in patients with type 2 diabetes.

Procalcitonin-Guided Antibiotic Prescription in Patients With COVID-19: A Multicenter Observational Cohort Study.

BACKGROUND: Despite the low rate of bacterial coinfection, antibiotics are very commonly prescribed in hospitalized patients with COVID-19. RESEARCH QUESTION: Does the use of a procalcitonin (PCT)-guided antibiotic protocol safely reduce the use of antibiotics in patients with a COVID-19 infection? STUDY DESIGN AND METHODS: In this multicenter cohort, three groups of patients with COVID-19 were compared in terms of antibiotic consumption, namely one group treated based on a PCT-algorithm in one hospital (n = 216) and two control groups, consisting of patients from the same hospital (n = 57) and of patients from three similar hospitals (n = 486) without PCT measurements during the same period. The primary end point was antibiotic prescription in the first week of admission. RESULTS: Antibiotic prescription during the first 7 days was 26.8% in the PCT group, 43.9% in the non-PCT group in the same hospital, and 44.7% in the non-PCT group in other hospitals. Patients in the PCT group had lower odds of receiving antibiotics in the first 7 days of admission (OR, 0.33; 95% CI, 0.16-0.66 compared with the same hospital; OR, 0.42; 95% CI, 0.28-0.62 compared with the other hospitals). The proportion of patients receiving antibiotic prescription during the total admission was 35.2%, 43.9%, and 54.5%, respectively. The PCT group had lower odds of receiving antibiotics during the total admission only when compared with the other hospitals (OR, 0.23; 95% CI, 0.08-0.63). There were no significant differences in other secondary end points, except for readmission in the PCT group vs the other hospitals group. INTERPRETATION: PCT-guided antibiotic prescription reduces antibiotic prescription rates in hospitalized patients with COVID-19, without major safety concerns.

Colchicine and diabetes in patients with chronic coronary artery disease: insights from the LoDoCo2 randomized controlled trial.

Introduction: Despite optimal treatment, patients with chronic coronary artery disease (CAD) and diabetes mellitus (DM) are at high risk of cardiovascular events, emphasizing the need for new treatment options. The Low-Dose Colchicine 2 (LoDoCo2) trial demonstrated that colchicine reduces cardiovascular risk in patients with chronic CAD. This analysis determines the efficacy of colchicine in patients with chronic CAD and DM as well as the effect of colchicine on the development of new-onset type 2 diabetes mellitus (T2DM). Methods: The LoDoCo2 trial randomized 5,522 patients to placebo or colchicine 0.5 mg once daily, with a median follow-up of 28.6 months. The primary composite endpoint was cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven revascularization. The effect of its treatment in patients with and without DM was evaluated by including an interaction term in the model. Results: A total of 1,007 participants (18.2%) had T2DM at baseline. The adjusted hazard ratio (HR) [(95% confidence interval (CI)] for the primary endpoint in the T2DM group was 1.52 (1.15-2.01, p < 0.01) compared with the group without T2DM. The HR for the treatment effect on the primary endpoint was 0.87 (0.61-1.25) in participants with T2DM and 0.64 (0.51-0.80) in participants without diabetes (pinteraction = 0.14). The incidence of new-onset T2DM was 1.5% (34 out of 2,270) in the colchicine group and 2.2% (49 out of 2,245) in the placebo group (p = 0.10). Discussion: In conclusion, based on the current evidence, the beneficial effects of colchicine on cardiovascular endpoints are consistent regardless of DM status. The potential benefits of colchicine in preventing new-onset DM need further investigation. These findings are only hypothesis-generating and require larger prospective trials to confirm the results.

Determinants and mediating mechanisms of quality of life and disease-specific symptoms among thyroid cancer patients: the design of the WaTCh study.

BACKGROUND: Thyroid cancer (TC) patients are understudied but appear to be at risk for poor physical and psychosocial outcomes. Knowledge of the course and determinants of these deteriorated outcomes is lacking. Furthermore, little is known about mediating biological mechanisms. OBJECTIVES: The WaTCh-study aims to; 1. Examine the course of physical and psychosocial outcomes. 2. Examine the association of demographic, environmental, clinical, physiological, and personality characteristics to those outcomes. In other words, who is at risk? 3. Reveal the association of mediating biological mechanisms (inflammation, kynurenine pathway) with poor physical and psychological outcomes. In other words, why is a person at risk? DESIGN AND METHODS: Newly diagnosed TC patients from 13 Dutch hospitals will be invited. Data collection will take place before treatment, and at 6, 12 and 24 months after diagnosis. Sociodemographic and clinical information is available from the Netherlands Cancer Registry. Patients fill-out validated questionnaires at each time-point to assess quality of life, TC-specific symptoms, physical activity, anxiety, depression, health care use, and employment. Patients are asked to donate blood three times to assess inflammation and kynurenine pathway. Optionally, at each occasion, patients can use a weighing scale with bioelectrical impedance analysis (BIA) system to assess body composition; can register food intake using an online food diary; and can wear an activity tracker to assess physical activity and sleep duration/quality. Representative Dutch normative data on the studied physical and psychosocial outcomes is already available. IMPACT: WaTCh will reveal the course of physical and psychosocial outcomes among TC patients over time and answers the question who is at risk for poor outcomes, and why. This knowledge can be used to provide personalized information, to improve screening, to develop and provide tailored treatment strategies and supportive care, to optimize outcomes, and ultimately increase the number of TC survivors that live in good health.

What is the aetiology of dysnatraemia in COVID-19 and how is this related to outcomes in patients admitted during earlier and later COVID-19 waves? A multicentre, retrospective observational study in 11 Dutch hospitals.

OBJECTIVES: To evaluate the relationship among dysnatraemia at hospital presentation and duration of admission, risk of intensive care unit (ICU) admission and all-cause mortality and to assess the underlying pathophysiological mechanism of hyponatraemia in patients with COVID-19. Our hypothesis is that both hyponatraemia and hypernatraemia at presentation are associated with adverse outcomes. DESIGN: Observational study. SETTING: Secondary care; 11 Dutch hospitals (2 university and 9 general hospitals). PARTICIPANTS: An analysis was performed within the retrospective multicentre cohort study COVIDPredict. 7811 patients were included (60% men, 40% women) between 24 February 2020 and 9 August 2022. Patients who were ≥18 years with PCR-confirmed COVID-19 or CT with COVID-19 reporting and data system score≥4 and alternative diagnosis were included. Patients were excluded when serum sodium levels at presentation were not registered in the database or when they had been transferred from another participating hospital. OUTCOME MEASURES: We studied demographics, medical history, symptoms and outcomes. Patients were stratified according to serum sodium concentration and urinary sodium excretion. RESULTS: Hyponatraemia was present in 2677 (34.2%) patients and hypernatraemia in 126 (1.6%) patients. Patients with hyponatraemia presented more frequently with diarrhoea, lower blood pressure and tachycardia. Hyponatraemia was, despite a higher risk for ICU admission (OR 1.27 (1.11-1.46; p<0.001)), not associated with mortality or the risk for intubation. Patients with hypernatraemia had higher mortality rates (OR 2.25 (1.49-3.41; p<0.001)) and were at risk for ICU admission (OR 2.89 (1.83-4.58)) and intubation (OR 2.95 (1.83-4.74)). CONCLUSIONS: Hypernatraemia at presentation was associated with adverse outcomes in patients with COVID-19. Hypovolaemic hyponatraemia was found to be the most common aetiology of hyponatraemia. Hyponatraemia of unknown aetiology was associated with a higher risk for ICU admission and intubation and longer duration of admission.