Bihormonal fully closed-loop system for the treatment of type 1 diabetes: a real-world multicentre, prospective, single-arm trial in the Netherlands.

BACKGROUND: Management of insulin administration for intake of carbohydrates and physical activity can be burdensome for people with type 1 diabetes on hybrid closed-loop systems. Bihormonal fully closed-loop (FCL) systems could help reduce this burden. In this trial, we assessed the long-term performance and safety of a bihormonal FCL system. METHODS: The FCL system (Inreda AP; Inreda Diabetic, Goor, Netherlands) that uses two hormones (insulin and glucagon) was assessed in a 1 year, multicentre, prospective, single-arm intervention trial in adults with type 1 diabetes. Participants were recruited in eight outpatient clinics in the Netherlands. We included adults with type 1 diabetes aged 18-75 years who had been using flash glucose monitoring or continuous glucose monitors for at least 3 months. Study visits were integrated into standard care, usually every three months, to evaluate glycaemic control, adverse events, and person-reported outcomes. The primary endpoint was time in range (TIR; glucose concentration 3·9-10·0 mmol/L) after 1 year. The study is registered in the Dutch Trial Register, NL9578. FINDINGS: Between June 1, 2021, and March 2, 2022, we screened 90 individuals and enrolled 82 participants; 78 were included in the analyses. 79 started the intervention and 71 were included in the 12 month analysis. Mean age was 47.7 (SD 12·4) years and 38 (49%) were female participants. The mean preintervention TIR of participants was 55·5% (SD 17·2). After 1 year of FCL treatment, mean TIR was 80·3% (SD 5·4) and median time below range was 1·36% (IQR 0·80-2·11). Questionnaire scores improved on Problem Areas in Diabetes (PAID) from 30·0 (IQR 18·8-41·3) preintervention to 10·0 (IQR 3·8-21·3; p<0·0001) at 12 months and on World Health Organization-Five Well-Being Index (WHO-5) from 60·0 (IQR 44·0-72·0) preintervention to 76·0 (IQR 60·0-80·0; p<0·0001) at 12 months. Five serious adverse events were reported (one cerebellar stroke, two severe hypoglycaemic, and two hyperglycaemic events). INTERPRETATION: Real-world data obtained in this trial demonstrate that use of the bihormonal FCL system was associated with good glycaemic control in patients who completed 1 year of treatment, and could help relieve these individuals with type 1 diabetes from making treatment decisions and the burden of carbohydrate counting. FUNDING: Inreda Diabetic.

Complete Genome Sequence of Novel Polerovirus-Associated RNA Infecting Pepper (Capsicum spp.) in South Africa.

The complete genome sequence of a novel polerovirus-associated RNA infecting pepper in South Africa was determined. The nucleotide sequence identity of 78.3% with closely related species suggested that this associated RNA was novel, and the name pepper vein yellows virus-associated RNA is proposed for this RNA fragment.

Visual Analytics for Hypothesis-Driven Exploration in Computational Pathology.

Recent advances in computational and algorithmic power are evolving the field of medical imaging rapidly. In cancer research, many new directions are sought to characterize patients with additional imaging features derived from radiology and pathology images. The emerging field of Computational Pathology targets the high-throughput extraction and analysis of the spatial distribution of cells from digital histopathology images. The associated morphological and architectural features allow researchers to quantify and characterize new imaging biomarkers for cancer diagnosis, prognosis, and treatment decisions. However, while the image feature space grows, exploration and analysis become more difficult and ineffective. There is a need for dedicated interfaces for interactive data manipulation and visual analysis of computational pathology and clinical data. For this purpose, we present IIComPath, a visual analytics approach that enables clinical researchers to formulate hypotheses and create computational pathology pipelines involving cohort construction, spatial analysis of image-derived features, and cohort analysis. We demonstrate our approach through use cases that investigate the prognostic value of current diagnostic features and new computational pathology biomarkers.

REducing STEroids in Relapsing Nephrotic syndrome: the RESTERN study- protocol of a national, double-blind, randomised, placebo-controlled, non-inferiority intervention study.

INTRODUCTION: Oral corticosteroids are the first-line treatment for idiopathic childhood nephrotic syndrome. Most children experience several relapses, needing repeated courses of corticosteroid therapy. This exposes them to side effects and long-term complications. For most patients, long-term prognosis is for complete resolution of the disease over time and maintenance of normal kidney function. Therefore, it is vital to focus on minimising adverse events of the disease and its therapy. Unfortunately, no randomised controlled trials are available to determine the optimal corticosteroid treatment of an infrequent relapse of nephrotic syndrome. Recent studies show that treatment schedules for the first episode can safely be shortened to 2 months. The hypothesis of the REducing STEroids in Relapsing Nephrotic syndrome (RESTERN) study is that a 4-week reduction of alternate-day steroids after inducing remission is effective and safe, reduces steroid exposure by 35% on average and is therefore preferable. METHODS AND ANALYSIS: The RESTERN study is a nationwide, double-blind, randomised, placebo-controlled, non-inferiority intervention study. Children aged 1-18 years with a relapse of steroid-sensitive nephrotic syndrome are eligible for this study. Study subjects (n=144) will be randomly assigned to either current standard therapy in the Netherlands or a reduced prednisolone schedule. The primary outcome of the RESTERN study is the time to first relapse after the final prednisolone dose. The secondary outcomes are the number or relapses, progression to frequent relapsing or steroid dependent nephrotic syndrome and the cumulative dosage of prednisolone during the study period. ETHICS AND DISSEMINATION: This non-inferiority trial will be performed in accordance with the Declaration of Helsinki and has been approved by the medical ethical committee of Arnhem-Nijmegen and the Dutch Competent Authority (Central Committee on Research Involving Human Subjects, CCMO). After completion of this study, results will be published in national and international peer-reviewed scientific journals. Papers will be published according to CCMO guidelines. The final report will be made available to trial participants. TRIAL REGISTRATION NUMBER: NTR5670, EudraCT no 2016-002430-76.

Modelling the temperature evolution of bone under high intensity focused ultrasound.

Magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) has been clinically shown to be effective for palliative pain management in patients suffering from skeletal metastasis. The underlying mechanism is supposed to be periosteal denervation caused by ablative temperatures reached through ultrasound heating of the cortex. The challenge is exact temperature control during sonication as MR-based thermometry approaches for bone tissue are currently not available. Thus, in contrast to the MR-HIFU ablation of soft tissue, a thermometry feedback to the HIFU is lacking, and the treatment of bone metastasis is entirely based on temperature information acquired in the soft tissue adjacent to the bone surface. However, heating of the adjacent tissue depends on the exact sonication protocol and requires extensive modelling to estimate the actual temperature of the cortex. Here we develop a computational model to calculate the spatial temperature evolution in bone and the adjacent tissue during sonication. First, a ray-tracing technique is used to compute the heat production in each spatial point serving as a source term for the second part, where the actual temperature is calculated as a function of space and time by solving the Pennes bio-heat equation. Importantly, our model includes shear waves that arise at the bone interface as well as all geometrical considerations of transducer and bone geometry. The model was compared with a theoretical approach based on the far field approximation and an MR-HIFU experiment using a bone phantom. Furthermore, we investigated the contribution of shear waves to the heat production and resulting temperatures in bone. The temperature evolution predicted by our model was in accordance with the far field approximation and agreed well with the experimental data obtained in phantoms. Our model allows the simulation of the HIFU treatments of bone metastasis in patients and can be extended to a planning tool prior to MR-HIFU treatments.

Increased prevalence of impaired fasting glucose in MEN1 gene mutation carriers.

OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary syndrome characterized by parathyroid, gastroenteropancreatic, pituitary and adrenal tumours. Cardiovascular disease has been identified as an important cause of death in MEN1 patients. Menin, the product of the MEN1 gene, is a co-activator for peroxisome proliferator-activated receptor-γ and the vitamin D receptor, which are involved in glucose metabolism. We aimed to compare insulin sensitivity and prevalence of impaired fasting glucose and diabetes mellitus between MEN1 patients and controls. DESIGN: Cross-sectional study. PATIENTS: Sixty-three MEN1 gene mutation carriers (44% men, mean age 41 years) from 22 kindreds and 126 unrelated controls matched for gender, age and BMI. MEASUREMENTS: Fasting glucose levels were categorized and compared using WHO criteria. Homeostasis model assessment (HOMA) was used as a measure of insulin resistance. RESULTS: Homeostasis model assessment was significantly increased in MEN1 patients compared with controls (3·0 ± 2·0 vs 2·0 ± 1·0, P < 0·05). In MEN1 patients, HOMA was associated with BMI, but not with age, calcium and gastrin levels. Using logistic regression analysis, the presence of hyperparathyroidism, pancreatic lesions and various other manifestations was not associated with HOMA. Impaired fasting glucose was more prevalent in MEN1 compared with controls (17%vs 6%, P < 0·05). Three MEN1 patients (5%) compared with four controls (3%) were diabetic (not significant). CONCLUSIONS: Multiple endocrine neoplasia type 1 patients had decreased insulin sensitivity and higher prevalence of impaired fasting glucose compared with controls, which was unrelated to MEN1 manifestations. Impaired glucose metabolism may result in increased risk of cardiovascular disease in MEN1 patients.

Compressed Adjacency Matrices: Untangling Gene Regulatory Networks.

We present a novel technique-Compressed Adjacency Matrices-for visualizing gene regulatory networks. These directed networks have strong structural characteristics: out-degrees with a scale-free distribution, in-degrees bound by a low maximum, and few and small cycles. Standard visualization techniques, such as node-link diagrams and adjacency matrices, are impeded by these network characteristics. The scale-free distribution of out-degrees causes a high number of intersecting edges in node-link diagrams. Adjacency matrices become space-inefficient due to the low in-degrees and the resulting sparse network. Compressed adjacency matrices, however, exploit these structural characteristics. By cutting open and rearranging an adjacency matrix, we achieve a compact and neatly-arranged visualization. Compressed adjacency matrices allow for easy detection of subnetworks with a specific structure, so-called motifs, which provide important knowledge about gene regulatory networks to domain experts. We summarize motifs commonly referred to in the literature, and relate them to network analysis tasks common to the visualization domain. We show that a user can easily find the important motifs in compressed adjacency matrices, and that this is hard in standard adjacency matrix and node-link diagrams. We also demonstrate that interaction techniques for standard adjacency matrices can be used for our compressed variant. These techniques include rearrangement clustering, highlighting, and filtering.

Interactive density maps for moving objects.

Density maps show trends in objects' trajectories. Density map creation involves aggregating smoothed trajectories in a density field and visualizing the field. Using an interactive distribution map, users can define subsets and, supported by graphics hardware, get fast feedback for these computationally expensive density field calculations.

Pyuria is absent during urinary tract infections in neutropenic patients.

To investigate the diagnostic significance of a normal urine sediment in the work-up for fever of unknown origin in neutropenia. Urinary tract infection was defined as ≥10(5) urinary pathogens in the absence of another focus. Pyuria was found in only 1/23 neutropenic episodes compared to 21/31 in controls (P < 0.0001).

Mannose binding lectin deficiency and triglyceride-rich lipoprotein metabolism in normolipidemic subjects.

Mannose binding lectin (MBL) is one of the three initiators of complement activation and is therefore closely linked to inflammation. MBL deficiency has been associated with the generation of atherosclerosis. Since atherosclerosis, the complement system and postprandial lipemia are linked to inflammation, we studied postprandial lipoprotein metabolism in MBL deficiency. An observational study was carried out in 107 volunteers (21% MBL deficient). Classical cardiovascular risk factors were not different between subjects with and without MBL deficiency. Oral fat loading tests in 8 MBL deficient and 14 MBL sufficient subjects showed similar postprandial triglyceride, free fatty acid, hydroxybutyric acid and complement component 3 concentrations. MBL deficient subjects had 2.4 times lower postprandial Sf>400 (chylomicron)-apoB48 concentrations, but in contrast a 2-3.5 times increased Sf 60-400 (VLDL1-TG) and Sf 60-400-apoB100 response. MBL activity was inversely related to the postprandial Sf 60-400-TG increase. Despite lower postprandial Sf>400-apoB48 concentrations, MBL deficient subjects show an accumulation of Sf 60-400 lipoproteins.

Rectocele repair by anterolateral rectopexy: long-term functional outcome.

INTRODUCTION: Rectoceles are frequently associated with feelings of pelvic discomfort and symptoms of obstructed defaecation (OD). Repair by a transvaginal or transanal approach might result in de novo dyspareunia in up to approximately 40% of the cases. This study was designed to investigate whether anterolateral rectopexy provides an adequate rectocele repair without dyspareunia as a side effect. METHOD: A consecutive series of 33 women (median age 55 years; range: 37-73) with a symptomatic rectocele (depth > 3 cm) underwent anterolateral rectopexy. Before the operation, all patients underwent evacuation proctography (EP), which was repeated 6 months after the repair in all but three patients. A standardized questionnaire concerning pelvic discomfort, OD and dyspareunia was used to assess the long-term effect of rectocele repair. The response rate was 91%. RESULTS: Six months after the procedure, EP revealed a recurrent or persistent rectocele in six patients (20%). However, in four of these six patients, the depth of the rectocele was < 3 cm. The median duration of follow-up was 74 months (range: 2-96). Among the patients with an adequate repair, signs of OD persisted in 55%. None of the patients encountered de novo dyspareunia after the procedure. CONCLUSION: Anterolateral rectopexy provides an effective tool for anatomical correction of rectoceles and does not result in dyspareunia as a side effect. However, despite adequate repair, OD persist in the majority of patients.

[A boy with cyclic vomiting and an alleged furosemide allergy on the basis of a subpelvic stenosis]. / Een jongen met cyclisch braken en een vermeende furosemideallergie op basis van een subpelviene stenose.

An 8-year-old boy, known with a Diamond-Blackfan anaemia, was admitted to the hospital because of frequent vomiting since 3 days and loin pain. In previous years, he had been admitted several times for the same complaints but no cause had been identified. Ultrasound examination of the abdomen performed at admittance showed dilatation of the left renal pelvis. A renal scintigraphy was discussed with the mother, and she refused the injection of furosemide, because her son was allegedly allergic to furosemide: previous furosemide treatments during blood transfusions for his anaemia had always resulted in stomach-ache and vomiting, which may be attributed, however, to an acute dilatation of the renal pelvis due to the diuretic effect of furosemide. Scintigraphy without furosemide showed a significant obstruction and asymmetric renal function, so a pyeloplasty was performed after which he has been symptom-free. In patients with cyclic vomiting, an intermittent uretero-pelvic junction obstruction should be considered and can only be ruled out when ultrasound during the complaints and renal scintigraphy under adequate hydration and after furosemide are normal.

Enterocele repair by abdominal obliteration of the pelvic inlet: long-term outcome on obstructed defaecation and symptoms of pelvic discomfort.

OBJECTIVE: Enterocele is defined as a herniation of the peritoneal sac between the vagina and the rectum. This may contain either sigmoid colon or small bowel. It has been reported that enterocele is associated with obstructed defaecation and symptoms of pelvic discomfort. The aim of the present study was to evaluate the long-term effect of enterocele repair. METHOD: In the time period between 1994 and 2003, 54 women (median age 54 years; range: 31-80) with a symptomatic enterocele underwent obliteration of the pelvic inlet with a U-shaped Mersilene mesh. All patients underwent evacuation proctography (EP), which was repeated 6 months after the repair. In addition, they were contacted over the telephone to assess the long-term effect of enterocele repair. Forty-nine patients were willing to answer questions over the telephone. Five patients were lost to follow-up (response rate: 91%). RESULTS: Six months after the procedure, EP revealed a recurrent or persistent enterocele in five (9%) patients, which was symptomatic in two, both of whom underwent a second repair. Among the 49 patients without an enterocele after 6 months, 10 (23%) women encountered recurrent symptoms of pelvic discomfort at a median follow-up of 85 months (range: 3-137). Despite adequate correction of the enterocele, obstructed defaecation persisted in 21 (75%) patients of 28, who presented with this problem before the procedure. De novo dyspareunia occurred in 5% of the women after the procedure. CONCLUSION: Obliteration of the pelvic inlet with a U-shaped Mersilene mesh provides an effective tool for anatomical correction of enteroceles. However, in the long term one of four patients encounters recurrent symptoms of pelvic discomfort. It seems unlikely that enterocele contributes to obstructed defaecation, as evacuation difficulties persist in around three quarters of the patients.

Weekend versus working day: differences in telemetric blood pressure in male Wistar rats.

Blood pressure (BP) is a frequently monitored parameter in research. Various methods are used to obtain BP values in animal models, but telemetry is the method of choice because it allows for continuous monitoring in conscious and freely moving animals. However, factors due to the animal facility, like activities and sound, can still influence measurements. We, therefore, retrospectively compared BP values in adult male Wistar rats during working hours with values from non-working days. Telemetry devices were implanted according to standard protocol. Values were obtained at the age of 6 and 12 months during working hours (Friday 10:00-16:00 h, lights on 06:00-18:00 h) and compared with data from the average of Saturday 10:00-16:00 h and Sunday 10:00-16:00 h, representing non-working days. Data were available from 12 and 7 rats at 6 months and 12 months of age respectively. Relative differences in heart rate, spontaneous locomotor activity, systolic and diastolic BP were 2.2% (P<0.001), 32.9% (P<0.05), 3.2% (P<0.05) and 3.7% (P<0.05), respectively, with no differences between the age groups. We have shown a significant and important difference between BP values obtained during working hours and non-working days using telemetry in adult male Wistar rats. This phenomenon has implications for the interpretation of BP measurements in animals.

Influence of intrauterine growth restriction on renal function in the adult rat.

Intrauterine growth restriction (IUGR) has been shown to influence renal development and lead to fewer nephrons. Data on long term renal function after IUGR are limited. We studied the effect on renal function of IUGR in aging rats. IUGR was induced using a model of bilateral uterine artery ligation in pregnant Wistar rats. Renal function was studied at the age of 18 months. In male IUGR rats, estimated glomerular filtration rate was significantly decreased compared to male control rats [1.1 (SD 0.3) 1.7 (SD 0.3) ml x min(-1), p<0.05]. Female IUGR rats showed an increased urinary protein excretion compared with female control rats [84 (SD 73) vs. 12 (SD 13) mg x 24h(-1), p<0.01]. All male rats showed heavy proteinuria (p<0.01 vs. female rats from same experimental group), with no significant differences between the groups. Tubular reabsorption of phosphorus was lower in females, but showed no differences between the experimental groups. In conclusion, IUGR impairs renal function in the rat. It is suggested that a low nephron endowment leads to proteinuria as a sign of glomerular damage, and ends with a decrease in glomerular filtration rate as a sign of glomerular loss.

Effects of rosiglitazone on postprandial leukocytes and cytokines in type 2 diabetes.

OBJECTIVE: We postulated that in type 2 diabetes, the postprandial phase is a pro-inflammatory state that can be modulated by PPAR-gamma agonists. For this purpose, we determined the effects of rosiglitazone (8 mg/d) on postprandial leukocyte counts and pro-inflammatory cytokines (IL-6 and IL-8) in patients with type 2 diabetes. METHODS AND RESULTS: A randomized, 8-week, cross-over, placebo-controlled, double-blind clinical trial was performed in 19 patients with type 2 diabetes. Standardized 6-h oral fat-loading tests were performed after each treatment period. During placebo treatment, blood leukocytes increased to a maximum 6-h postprandially, due to significant increases in neutrophils and lymphocytes. Concomitant postprandial increases were observed for IL-6 and IL-8, the major chemokines responsible for leukocyte recruitment. Rosiglitazone reduced the incremental area under the curves (dAUCs) for IL-6 (-63%, p<0.01) and IL-8 (-16%, p<0.05). The dAUC for leukocytes decreased with 37% (p<0.05), due to a specific reduction of neutrophils (-39%, p<0.05). CONCLUSIONS: Rosiglitazone attenuated the postprandial increases of neutrophils, IL-6 and IL-8 in patients with type 2 diabetes. Since inflammation is a major force driving atherosclerosis, and man lives in a postprandial period most part of the day, a reduced inflammatory response after a meal may delay progression of atherosclerosis. CONDENSED ABSTRACT: We postulated that in type 2 diabetes, the postprandial phase is a pro-inflammatory state that can be modulated by PPAR-gamma agonists. Rosiglitazone attenuated the postprandial increases of neutrophils, IL-6 and IL-8 in patients with type 2 diabetes. These effects may contribute to cardiovascular risk reduction.

[Schimke's immuno-osseous dysplasia as an explanation for the rare combination of disproportionately short stature and the nephrotic syndrome]. / Immuno-ossale dysplasie van Schimke als zeldzame oorzaak van de combinatie van kleine lichaamslengte en nefrotisch syndroom.

A 10-year-old Turkish boy with consanguineous parents was presented with a disproportionately short stature and a nephrotic syndrome. The mild form of Schimke's immuno-osseous dysplasia was diagnosed as the common cause. This rare, autosomal recessive osteochondrodysplasia is characterised by spondyloepiphyseal dysplasia, facial dysmorphism, T-cell immunodeficiency and progressive renal failure due to focal segmental glomerulosclerosis. In Schimke's immuno-osseous dysplasia, a severe early-onset form and a milder later-onset form can be distinguished on the basis of the clinical course. The patient was treated by fluid and salt restriction, enalapril and later also losartan, which led to a decrease in the proteinuria and an increase in serum albumin concentration. Two years later, the renal function was still normal.

[The polypill: not an effective strategy for reduction of cardiovascular disease]. / De 'polypil': geen effectieve strategie tegen hart- en vaatziekten.

The implementation of the intriguing concept of the polypill to prevent cardiovascular events remains doubtful due to a lack of evidence, expected adherence problems, the inevitable overtreatment and undertreatment of individuals, and potential side effects. Lifestyle changes and individual interventions are more preferable strategies.