Preclinical validation of the advection diffusion flow estimation method using computational patient specific coronary tree phantoms.

Coronary computed tomography angiography (CCTA) does not allow the quantification of reduced blood flow due to coronary artery disease (CAD). In response, numerical methods based on the CCTA image have been developed to compute coronary blood flow and assess the impact of disease. However to compute blood flow in the coronary arteries, numerical methods require specification of boundary conditions that are difficult to estimate accurately in a patient-specific manner. We describe herein a new noninvasive flow estimation method, called Advection Diffusion Flow Estimation (ADFE), to compute coronary artery flow from CCTA to use as boundary conditions for numerical models of coronary blood flow. ADFE uses image contrast variation along the tree-like structure to estimate flow in each vessel. For validating this method we used patient specific software phantoms on which the transport of contrast was simulated. This controlled validation setting enables a direct comparison between estimated flow and actual flow and a detailed investigation of factors affecting accuracy. A total of 10 CCTA image data sets were processed to extract all necessary information for simulating contrast transport. A spectral element method solver was used for computing the ground truth simulations with high accuracy. On this data set, the ADFE method showed a high correlation coefficient of 0.998 between estimated flow and the ground truth flow together with an average relative error of only 1 % . Comparing the ADFE method with the best method currently available (TAFE) for image-based blood flow estimation, which showed a correlation coefficient of 0.752 and average error of 20 % , it can be concluded that the ADFE method has the potential to significantly improve the quantification of coronary artery blood flow derived from contrast gradients in CCTA images.

Extrapolating empirical long-term survival data: the impact of updated follow-up data and parametric extrapolation methods on survival estimates in multiple myeloma.

BACKGROUND: In economic evaluations, survival is often extrapolated to smooth out the Kaplan-Meier estimate and because the available data (e.g., from randomized controlled trials) are often right censored. Validation of the accuracy of extrapolated results can depend on the length of follow-up and the assumptions made about the survival hazard. Here, we analyze the accuracy of different extrapolation techniques while varying the data cut-off to estimate long-term survival in newly diagnosed multiple myeloma (MM) patients. METHODS: Empirical data were available from a randomized controlled trial and a registry for MM patients treated with melphalan + prednisone, thalidomide, and bortezomib- based regimens. Standard parametric and spline models were fitted while artificially reducing follow-up by introducing database locks. The maximum follow-up for these locks varied from 3 to 13 years. Extrapolated (conditional) restricted mean survival time (RMST) was compared to the Kaplan-Meier RMST and models were selected according to statistical tests, and visual fit. RESULTS: For all treatments, the RMST error decreased when follow-up and the absolute number of events increased, and censoring decreased. The decline in RMST error was highest when maximum follow-up exceeded six years. However, even when censoring is low there can still be considerable deviations in the extrapolated RMST conditional on survival until extrapolation when compared to the KM-estimate. CONCLUSIONS: We demonstrate that both standard parametric and spline models could be worthy candidates when extrapolating survival for the populations examined. Nevertheless, researchers and decision makers should be wary of uncertainty in results even when censoring has decreased, and the number of events has increased.

The diagnosis and management of CMV colitis in IBD patients shows high practice variation: a national survey among gastroenterologists.

BACKGROUND: Clinical guidelines on cytomegalovirus (CMV) colitis in inflammatory bowel disease (IBD) are hampered by the low quality of evidence. In this study, we aim to explore the attitude and management of CMV colitis in IBD among gastroenterologists. METHODS: A web-based survey was distributed to adult and pediatric gastroenterologists and trainees in academic and general hospitals in the Netherlands. The survey comprised data collection on respondents' demographics, attitudes towards the importance of CMV infection in IBD on a visual analogue scale (from 0 to 100), and diagnostic and therapeutic strategies. RESULTS: A total of 73/131 invited respondents from 32 hospitals completed the survey (response rate of 56%). The importance of CMV infection was scored at a median 74/100. Respondents indicated CMV testing as appropriate in the clinical setting of steroid-refractory colitis (69% of respondents), hospitalized patients with active colitis (64%), immunomodulator or biological refractory colitis (55%) and active colitis irrespective of medication use (14%). CMV diagnostics include histology of colonic biopsies (88% of respondents), tissue CMV PCR (43%), serum CMV PCR (60%), CMV serology (25%) and fecal CMV PCR (4%). 82% of respondents start antiviral therapy after a positive CMV test on colonic biopsies (histology or PCR). CONCLUSIONS: Most Dutch gastroenterologists acknowledge the importance of CMV colitis in IBD. Strategies vary greatly with regard to the indication for testing and diagnostic method, as well as indication for the start of antiviral therapy. These findings underline the need for pragmatic clinical studies on different management strategies, in order to reduce practice variation and improve the quality of care. Summary of the established knowledge on this subject:The clinical significance of CMV-associated colitis in IBD remains a matter of debateRecommendations regarding CMV colitis in current international guidelines are based on low to moderate evidence levels and different diagnostic strategies are proposed What are the significant and/or new findings of this study?We show that there is a high practice variation of diagnosis and management of CMV colitis in IBD amongst adult and pediatric gastroenterologistsThis study underlined the need for pragmatic studies and guidelines on different management strategies including cut-off values to start therapy.

Driven-Dissipative Time Crystalline Phases in a Two-Mode Bosonic System with Kerr Nonlinearity.

For the driven-dissipative system of two coupled bosonic modes in a nonlinear cavity resonator, we demonstrate a sequence of phase transitions from a trivial steady state to two distinct dissipative time crystalline phases. These effects are already anticipated at the level of the semiclassical analysis of the Lindblad equation using the theory of bifurcations and are further supported by the full quantum treatment. The system is predicted to exhibit different dynamical phases characterized by an oscillating nonequilibrium steady state with nontrivial periodicity, which is a hallmark of time crystals. We expect that these phases can be directly probed in various cavity QED experiments.

Correction to: Implementing a hospital-wide protocol for Staphylococcus aureus bacteremia.

The article "Implementing a hospital-wide protocol for Staphylococcus aureus bacteremia", written by K. Bolhuis, L. J. Bakker, J. T. Keijer, and P. J. de Vries was originally published electronically on 31 May 2018 with incorrect copyright line in the publisher's internet portal.

Implementing a hospital-wide protocol for Staphylococcus aureus bacteremia.

Staphylococcus aureus bacteraemia (SAB) is associated with high-mortality and complication rates. A multidisciplinary approach is needed to predict, detect and treat complications. In this pre- and post-intervention study, we investigated the effects of a hospital-wide protocol for diagnosis, classification and treatment of SAB. It was hypothesized that complications and endocarditis would be better identified and treated. Medical records of SAB patients admitted in 2011 and 2012 (pre) were analysed. In 2013, a protocol, describing risk factors, diagnostic classification and recommended treatment, was implemented. In 2014 and 2015 (post), SAB patients were followed prospectively. Transthoracic (TTE) or transoesophageal cardiac ultrasound (TEE) was chosen following a decision tree. A resident internal medicine acted as contact person. Pre-intervention, 98 patients were eligible for analysis compared to 85 patients post-intervention. Age and number of risk factors were slightly higher post-intervention; other baseline characteristics were similar. Most SAB-patients were classified as complicated (89 and 82% pre- and post-intervention, respectively). Follow-up blood cultures drawn within 2 days after initiating treatment increased from 51 to 85%. Cardiac ultrasounds increased from 44 to 83% for TTE and 13 to 24% for TEE. Endocarditis was more frequently diagnosed (4 vs. 12%). Additionally, duration of antibiotic therapy increased. The 3-month mortality did not change significantly (33% pre-intervention vs. 35% post-intervention; p > 0.05). Introduction of a hospital-wide protocol for SAB management increased standard of care, created awareness among clinicians to properly classify SAB, search for endocarditis and adapt duration of antibiotic treatment. Mortality did not decrease.

Bone-site-specific responses to zoledronic acid.

OBJECTIVES: Bisphosphonates are widely used to treat bone diseases such as osteoporosis. However, they may cause osteonecrosis of the jaw. Here, we investigated whether in vivo exposure to bisphosphonates has a different effect on long bone and jaw osteoclasts, and on the turnover of these different bones. MATERIALS AND METHODS: Zoledronic acid (0.5 mg kg-1 weekly) was administered intraperitoneally to 3-month-old female mice for up to 6 months. The effects on the number of osteoclasts, bone mineralization and bone formation were measured in the long bones and in the jaw. RESULTS: Long-term treatment with zoledronic acid reduced the number of jaw bone marrow cells, without affecting the number of long bone marrow cells. Zoledronic acid treatment did not affect the number of osteoclasts in vivo. Yet, the bisphosphonate increased bone volume and mineral density of both long bone and jaw. Interestingly, 6 months of treatment suppressed bone formation in the long bones without affecting the jaw. Unexpectedly, we showed that bisphosphonates can cause molar root resorption, mediated by active osteoclasts. CONCLUSIONS: Our findings provide more insight into bone-site-specific effects of bisphosphonates and into the aetiology of osteonecrosis of the jaw. We demonstrated that bisphosphonates can stimulate osteoclast activity at the molar roots.

HDL functionality in South Asians as compared to white Caucasians.

BACKGROUND AND AIMS: South Asians have an exceptionally high risk of developing cardiovascular disease compared to white Caucasians. A contributing factor might be dysfunction of high density lipoprotein (HDL). We aimed to compare HDL function in different age groups of both ethnicities. METHODS AND RESULTS: HDL functionality with respect to cholesterol efflux, anti-oxidation and anti-inflammation was determined using fasting, apoB-depleted, plasma samples from South Asian and white Caucasian neonates (n = 14 each), adolescent healthy men (n = 12 each, 18-25 y), and adult overweight men (n = 12 each, 40-50 y). Adolescents were subjected to a 5-day high fat high calorie diet (HCD) and adults to an 8-day very low calorie diet (LCD). Additionally, HDL composition was measured in adolescents and adults using (1)H-NMR spectroscopy. Anti-oxidative capacity was lower in South Asian adults before LCD (19.4 ± 2.1 vs. 25.8 ± 1.2%, p = 0.045, 95%-CI = [0.1; 12.7]) and after LCD (16.4 ± 2.4 vs. 27.6 ± 2.7%, p = 0.001, 95%-CI = [4.9; 17.5]). Anti-inflammatory capacity was reduced in South Asian neonates (23.8 ± 1.2 vs. 34.9 ± 1.3%, p = 0.000001, 95%-CI = [-14.6; -7.5]), and was negatively affected by an 8-day LCD only in South Asian adults (-12.2 ± 4.3%, p = 0.005, 95%-CI = [-5.9; -1.2]). Cholesterol efflux capacity was increased in response to HCD in adolescents (South Asians: +6.3 ± 2.9%, p = 0.073, 95%-CI = [-0.02; 0.46], Caucasians: +11.8 ± 3.4%, p = 0.002, 95%-CI = [0.17;0.65]) and decreased after LCD in adults (South Asians: -10.3 ± 2.4%, p < 0.001, 95%-CI = [-0.57; -0.20], Caucasians: -13.7 ± 1.9%, p < 0.00001, 95%-CI = [-0.67; -0.33]). Although subclass analyses of HDL showed no differences between ethnicities, cholesterol efflux correlated best with cholesterol and phospholipid within small HDL compared to other HDL subclasses and constituents. CONCLUSION: Impaired HDL functionality in South Asians may be a contributing factor to their high CVD risk. CLINICAL TRIAL REGISTRATION: NTR 2473 (URL: http://www.trialregister.nl/).

Cardiovascular flexibility in middle-aged overweight South Asians vs. white Caucasians: response to short-term caloric restriction.

BACKGROUND AND AIMS: South Asians have a higher risk of developing cardiovascular disease than white Caucasians. The underlying cause is unknown, but might be related to higher cardiac susceptibility to metabolic disorders. Short-term caloric restriction (CR) can be used as a metabolic stress test to study cardiac flexibility. We assessed whether metabolic and functional cardiovascular flexibility to CR differs between South Asians and white Caucasians. METHODS AND RESULTS: Cardiovascular function and myocardial triglycerides were assessed using a 1.5T-MRI/S-scanner in 12 middle-aged overweight male South Asians and 12 matched white Caucasians before and after an 8-day very low calorie diet (VLCD). At baseline South Asians were more insulin resistant than Caucasians. Cardiac dimensions were smaller, despite correction for body surface area, and pulse wave velocity (PWV) in the distal aorta was higher in South Asians. Systolic and diastolic function, myocardial triglycerides and pericardial fat did not differ significantly between groups. After the VLCD body weight reduced on average by 4.0 ± 0.2 kg. Myocardial triglycerides increased in both ethnicities by 69 ± 18%, and diastolic function decreased although this was not significant in South Asians. However, pericardial fat and PWV in the proximal and total aorta were reduced in Caucasians only. CONCLUSION: Myocardial triglyceride stores in middle-aged overweight and insulin resistant South Asians are as flexible and amenable to therapeutic intervention by CR as age-, sex- and BMI-matched but less insulin resistant white Caucasians. However, paracardial fat volume and PWV showed a differential effect in response to an 8-day VLCD in favor of Caucasians. CLINICAL TRIAL REGISTRATION: NTR 2473 (URL: http://www.trialregister.nl/trialreg/admin/rctsearch.asp?Term=2473).

Impact of transition from microscopy to molecular screening for detection of intestinal protozoa in Dutch patients.

Detection of intestinal protozoa by PCR methods has been described as being sensitive and specific, and as improving the diagnostic yield. Here we present the outcome of the transition from microscopy to molecular screening for detection of a select group of intestinal protozoa in faeces in our laboratory. Introduction of molecular screening for intestinal protozoa resulted in higher sensitivity, reduced hands-on-time, reduced time-to-results, leading to improved diagnostic efficiency.

Radioactive iodine in the treatment of medullary thyroid carcinoma: a controlled multicenter study.

OBJECTIVE: Radioactive iodine (RAI) therapy in medullary thyroid carcinoma (MTC) is applied in some centers, based on the assumption that cross-irradiation from thyroid follicular cells may be beneficial. However, no systematic studies on the effect of RAI treatment in MTC have been performed. The aim of this study was to analyze the effect of RAI treatment on survival in MTC patients. DESIGN: Retrospective multicenter study in eight University Medical Centers in The Netherlands. METHODS: Two hundred and ninety three MTC patients without distant metastases who had undergone a total thyroidectomy were included between 1980 and 2007. Patients were stratified by clinical appearance, hereditary stage, screening status, and localization. All patients underwent regular surgical treatment with additional RAI treatment in 61 patients. Main outcome measures were disease-free survival (DFS) and disease-specific survival (DSS). Cure was defined as biochemical and radiological absence of disease. RESULTS: In multivariate analysis, stratification according to clinical appearance (P=0.72), hereditary stage (P=0.96), localization (P=0.69), and screening status (P=0.31) revealed no significant effects of RAI treatment on DFS. Multivariate analysis showed no significant difference in DSS for the two groups stratified according to clinical appearance (P=0.14). Owing to limited number of events, multivariate analysis was not possible for DSS in the other groups of stratification. CONCLUSIONS: Based on the results of the present analysis, we conclude that RAI has no place in the treatment of MTC.

[Treatment for chronic depression: cognitive behavioral analysis system of psychotherapy (CBASP)]. / Behandeling voor chronische depressie: 'cognitive behavioral analysis system of psychotherapy' (CBASP).

BACKGROUND: Chronic depression is a common disorder in secondary care. Treatment results for this group of depressed patients are often disappointing and the existing treatment protocols are insufficiently tailored to chronic MDD. For this reason, an effective psychotherapeutic treatment will constitute a welcome addition to the range of treatments currently available for chronically depressed patients. AIM: To describe 'cognitive behavioral analysis system of psychotherapy' (CBASP), the first form of psychotherapy specifically designed for the treatment of chronic depression. METHOD: This article describes the evidence, rational and the most important techniques of CBASP. RESULTS: In the United States CBASP has proven to be effective in one trial. As a result of these findings, CBASP is recommended in the Dutch treatment guidelines as an evidence-based treatment option for chronic depression. However, the findings have not yet been replicated and little is known about possible ways of implementing CBASP in the Netherlands. For this reason a randomised controlled trial on the effectiveness of CBASP has started in three psychiatric hospitals in the Netherlands. CONCLUSION: CBASP is recommended as a treatment option for chronic depression in the Dutch treatment guidelines, but evidence should be further supported by additional research.

Primary isolation and detection of Helicobacter pylori from dyspeptic patients: a simple, rapid method.

The study aimed to develop a rapid and simple method for the primary isolation and detection of Helicobacter pylori from dyspeptic patients. Mucosal antral biopsy specimens were obtained from 136 consecutive dyspeptic patients diagnosed with peptic ulcer by endoscopy at Basra General Hospital, Iraq. From histopathological examination of biopsies, H. pylori was detected in 81 (59.6%) peptic ulcer patients. For bacterial culture, specimens were cultured in parallel on 2 media: the non-selective classic Columbia agar and the selective modified Columbia urea agar (MCUA). MCUA showed a higher isolation rate than classic Columbia agar (67.6% versus 44.1% of patients), and the results were obtained faster (24 hours versus 5-7 days) with more clear-cut identification.

Primary isolation and detection of Helicobacter pylori from dyspeptic patients: a simple, rapid method

The study aimed to develop a rapid and simple method for the primary isolation and detection of Helicobacter pylori from dyspeptic patients. Mucosal antral biopsy specimens were obtained from 136 consecutive dyspeptic patients diagnosed with peptic ulcer by endoscopy at Basra General Hospital, Iraq. From histopathological examination of biopsies, H. pylori was detected in 81 [59.6%] peptic ulcer patients. For bacterial culture, specimens were cultured in parallel on 2 media: the nonselective classic Columbia agar and the selective modified Columbia urea agar [MCUA]. MCUA showed a higher isolation rate than classic Columbia agar [67.6% versus 44.1% of patients], and the results were obtained faster [24 hours versus 5-7 days] with more clear-cut identification

An unbalanced submicroscopic translocation t(8;16)(q24.3;p13.3)pat associated with tuberous sclerosis complex, adult polycystic kidney disease, and hypomelanosis of Ito.

We report on a familial submicroscopic translocation involving chromosomes 8 and 16. The proband of the family had a clinical picture suggestive of a large deletion in the chromosome 16p13.3 area, as he was affected with tuberous sclerosis complex (TSC) and had alpha thalassaemia trait, and his half brother, who also had TSC, may have suffered additionally from polycystic kidney disease (PKD). FISH studies provided evidence for a familial translocation t(8;16)(q24.3;p13.3) with an unbalanced form in the proband and a balanced form in the father and in a paternal aunt. The unbalanced translocation caused the index patient to be deleted for the chromosome 16p13.3-pter region, with the most proximal breakpoint described to date for terminal 16p deletions. In addition, FISH analysis showed a duplication for the distal 8q region. Since the index patient also had hypomelanosis of Ito (HI), either of the chromosomal areas involved in the translocation may be a candidate region for an HI determining gene. Furthermore, it is noteworthy that both carriers of the balanced translocation showed a nodular goitre, while the proband has hypothyroidism.

Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosis complex patients: no evidence for genotype-phenotype correlation.

Tuberous sclerosis complex is an inherited tumour suppressor syndrome, caused by a mutation in either the TSC1 or TSC2 gene. The disease is characterised by a broad phenotypic spectrum that can include seizures, mental retardation, renal dysfunction, and dermatological abnormalities. The TSC1 gene was recently identified and has 23 exons, spanning 45 kb of genomic DNA, and encoding an 8.6 kb mRNA. After screening all 21 coding exons in our collection of 225 unrelated patients, only 29 small mutations were detected, suggesting that TSC1 mutations are under-represented among TSC patients. Almost all TSC1 mutations were small changes leading to a truncated protein, except for a splice site mutation and two in frame deletions in exon 7 and exon 15. No clear difference was observed in the clinical phenotype of patients with an in frame deletion or a frameshift or nonsense mutation. We found the disease causing mutation in 13% of our unrelated set of TSC patients, with more than half of the mutations clustered in exons 15 and 17, and no obvious under-representation of mutations among sporadic cases. In conclusion, we find no support for a genotype-phenotype correlation for the group of TSC1 patients compared to the overall population of TSC patients.