Validation of two age dependent D-dimer cut-off values for exclusion of deep vein thrombosis in suspected elderly patients in primary care: retrospective, cross sectional, diagnostic analysis

Objective To determine whether the use of age adapted D-dimer cut-off values can be translated to primary care patients who are suspected of deep vein thrombosis

Decision-making regarding antibiotic therapy duration: An observational study of multidisciplinary meetings in the intensive care unit

Purpose: Antibiotic therapy is commonly prescribed longer than recommended in intensive care patients (ICU). We aimed to provide insight into the decision-making process on antibiotic therapy duration in the ICU. Methods: A qualitative study was conducted, involving direct observations of antibiotic decision-making during multidisciplinary meetings in four Dutch ICUs. The study used an observation guide, audio recordings, and detailed field notes to gather information about the discussions on antibiotic therapy duration. We described the participants' roles in the decision-making process and focused on arguments contributing to decision-making. Results: We observed 121 discussions on antibiotic therapy duration in sixty multidisciplinary meetings. 24.8% of discussions led to a decision to stop antibiotics immediately. In 37.2%, a prospective stop date was determined. Arguments for decisions were most often brought forward by intensivists (35.5%) and clinical microbiologists (22.3%). In 28.9% of discussions, multiple healthcare professionals participated equally in the decision. We identified 13 main argument categories. While intensivists mostly used arguments based on clinical status, clinical microbiologists used diagnostic results in the discussion. Conclusions: Multidisciplinary decision-making regarding the duration of antibiotic therapy is a complex but valuable process, involving different healthcare professionals, using a variety of argument-types to determine the duration of antibiotic therapy. To optimize the decision-making process, structured discussions, involvement of relevant specialties, and clear communication and documentation of the antibiotic plan are recommended

Distinct DNA Methylation Patterns of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is a monogenic disorder caused by mutations in either the TSC1 or TSC2 gene, two key regulators of the mechanistic target of the rapamycin complex pathway. Phenotypically, this leads to growth and formation of hamartomas in several organs, including the brain. Subependymal giant cell astrocytomas (SEGAs) are low-grade brain tumors commonly associated with TSC. Recently, gene expression studies provided evidence that the immune system, the MAPK pathway and extracellular matrix organization play an important role in SEGA development. However, the precise mechanisms behind the gene expression changes in SEGA are still largely unknown, providing a potential role for DNA methylation. We investigated the methylation profile of SEGAs using the Illumina Infinium HumanMethylation450 BeadChip (SEGAs n = 42, periventricular control n = 8). The SEGA methylation profile was enriched for the adaptive immune system, T cell activation, leukocyte mediated immunity, extracellular structure organization and the ERK1 & ERK2 cascade. More interestingly, we identified two subgroups in the SEGA methylation data and show that the differentially expressed genes between the two subgroups are related to the MAPK cascade and adaptive immune response. Overall, this study shows that the immune system, the MAPK pathway and extracellular matrix organization are also affected on DNA methylation level, suggesting that therapeutic intervention on DNA level could be useful for these specific pathways in SEGA. Moreover, we identified two subgroups in SEGA that seem to be driven by changes in the adaptive immune response and MAPK pathway and could potentially hold predictive information on target treatment response

The coding and non-coding transcriptional landscape of subependymal giant cell astrocytomas

Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited neurocutaneous disorder caused by inactivating mutations in TSC1 or TSC2, key regulators of the mechanistic target of rapamycin complex 1 (mTORC1) pathway. In the CNS, TSC is characterized by cortical tubers, subependymal nodules and subependymal giant cell astrocytomas (SEGAs). SEGAs may lead to impaired circulation of CSF resulting in hydrocephalus and raised intracranial pressure in patients with TSC. Currently, surgical resection and mTORC1 inhibitors are the recommended treatment options for patients with SEGA. In the present study, high-throughput RNA-sequencing (SEGAs n = 19, periventricular control n = 8) was used in combination with computational approaches to unravel the complexity of SEGA development. We identified 9400 mRNAs and 94 microRNAs differentially expressed in SEGAs compared to control tissue. The SEGA transcriptome profile was enriched for the mitogen-activated protein kinase (MAPK) pathway, a major regulator of cell proliferation and survival. Analysis at the protein level confirmed that extracellular signal-regulated kinase (ERK) is activated in SEGAs. Subsequently, the inhibition of ERK independently of mTORC1 blockade decreased efficiently the proliferation of primary patient-derived SEGA cultures. Furthermore, we found that LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 were overexpressed at both gene and protein levels in SEGA compared to control tissue. Taken together LAMTOR1-5 can form a complex, known as the 'Ragulator' complex, which is known to activate both mTORC1 and MAPK/ERK pathways. Overall, this study shows that the MAPK/ERK pathway could be used as a target for treatment independent of, or in combination with mTORC1 inhibitors for TSC patients. Moreover, our study provides initial evidence of a possible link between the constitutive activated mTORC1 pathway and a secondary driver pathway of tumour growth

Magmatic processes in developing oceanic crust revealed in a cumulate xenolith collected at the East Pacific Rise, 9°50′N

Author Posting. © American Geophysical Union, 2006. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 7 (2006): Q12O04, doi:10.1029/2006GC001316.The petrology and geochemistry of a xenolith, a fragment of a melt-bearing cumulate, within a recently erupted mid-ocean ridge (MOR) lava flow provide information on petrogenetic processes occurring within the newly forming oceanic crust beneath the northern East Pacific Rise (NEPR). The xenolith reveals important petrologic information about MOR magmatic systems concerning (1) melt distribution in a crystal-dominated mush; (2) melt-crystal reactions within the mush; (3) the chemistry of melts that have contributed to the cumulate lithology; and (4) the chemistry of axial melts that enter the axial magma system. The xenolith was enclosed within a moderately primitive, normal mid-ocean ridge basalt (NMORB) erupted in 1991 within the neovolcanic zone of the NEPR, at approximately 9°50′N. The sample is a matrix-dominated, cumulate olivine anorthosite, composed of anorthite (An94-90) and bytownite (An89-70), intergranular olivine (Fo86±0.3), minor sulfide and spinel, and intergranular glass. Marginal corrosion of plagioclase, and possibly olivine, and internal remelting of plagioclase indicate syntexis. It is surmised that the pore volume was eviscerated several times with moderately primitive basaltic melts and reduced by intergranular crystallization of forsteritic olivine. The presence of anorthite as a cumulate phase in the xenolith and the observation of anorthite xenocrysts in NMORB lavas, and as a cumulate phase in ophiolite gabbros, indicate that Ca-rich melts that are not a part of the NMORB lineage play an important role in the construction of the oceanic crust.The Mineral Resources Program, USGS, provided support to W.I.R. for this research. Field and laboratory research was supported by NSF grants OCE-9402360, 9403773, and 0138088 to M.R.P. and NSF grants OCE-9819261 and OCE-0525863 to D.J.F

Treatment strategies and clinical outcomes in consecutive patients with locally advanced pancreatic cancer:A multicenter prospective cohort

Introduction: Since current studies on locally advanced pancreatic cancer (LAPC) mainly report from single, high-volume centers, it is unclear if outcomes can be translated to daily clinical practice. This study provides treatment strategies and clinical outcomes within a multicenter cohort of unselected patients with LAPC. Materials and methods: Consecutive patients with LAPC according to Dutch Pancreatic Cancer Group criteria, were prospectively included in 14 centers from April 2015 until December 2017. A centralized expert panel reviewed response according to RECIST v1.1 and potential surgical resectability. Primary outcome was median overall survival (mOS), stratified for primary treatment strategy. Results: Overall, 422 patients were included, of whom 77% (n = 326) received chemotherapy. The majority started with FOLFIRINOX (77%, 252/326) with a median of six cycles (IQR 4-10). Gemcitabine monotherapy was given to 13% (41/326) of patients and nab-paclitaxel/gemcitabine to 10% (33/326), with a median of two (IQR 3-5) and three (IQR 3-5) cycles respectively. The mOS of the entire cohort was 10 months (95%CI 9-11). In patients treated with FOLFIRINOX, gemcitabine monotherapy, or nab-paclitaxel/gemcitabine, mOS was 14 (95%CI 13-15), 9 (95%CI 8-10), and 9 months (95%CI 8-10), respectively. A resection was performed in 13% (32/252) of patients after FOLFIRINOX, resulting in a mOS of 23 months (95%CI 12-34). Conclusion: This multicenter unselected cohort of patients with LAPC resulted in a 14 month mOS and a 13% resection rate after FOLFIRINOX. These data put previous results in perspective, enable us to inform patients with more accurate survival numbers and will support decision-making in clinical practice. (C) 2020 The Authors. Published by Elsevier Ltd

Resectability and Ablatability Criteria for the Treatment of Liver Only Colorectal Metastases:Multidisciplinary Consensus Document from the COLLISION Trial Group

The guidelines for metastatic colorectal cancer crudely state that the best local treatment should be selected from a 'toolbox' of techniques according to patient- and treatment-related factors. We created an interdisciplinary, consensus-based algorithm with specific resectability and ablatability criteria for the treatment of colorectal liver metastases (CRLM). To pursue consensus, members of the multidisciplinary COLLISION and COLDFIRE trial expert panel employed the RAND appropriateness method (RAM). Statements regarding patient, disease, tumor and treatment characteristics were categorized as appropriate, equipoise or inappropriate. Patients with ECOG≤2, ASA≤3 and Charlson comorbidity index ≤8 should be considered fit for curative-intent local therapy. When easily resectable and/or ablatable (stage IVa), (neo)adjuvant systemic therapy is not indicated. When requiring major hepatectomy (stage IVb), neo-adjuvant systemic therapy is appropriate for early metachronous disease and to reduce procedural risk. To downstage patients (stage IVc), downsizing induction systemic therapy and/or future remnant augmentation is advised. Disease can only be deemed permanently unsuitable for local therapy if downstaging failed (stage IVd). Liver resection remains the gold standard. Thermal ablation is reserved for unresectable CRLM, deep-seated resectable CRLM and can be considered when patients are in poor health. Irreversible electroporation and stereotactic body radiotherapy can be considered for unresectable perihilar and perivascular CRLM 0-5cm. This consensus document provides per-patient and per-tumor resectability and ablatability criteria for the treatment of CRLM. These criteria are intended to aid tumor board discussions, improve consistency when designing prospective trials and advance intersociety communications. Areas where consensus is lacking warrant future comparative studies.</p

A theoretical framework to describe communication processes during medical disability assessment interviews

BACKGROUND: Research in different fields of medicine suggests that communication is important in physician-patient encounters and influences satisfaction with these encounters. It is argued that this also applies to the non-curative tasks that physicians perform, such as sickness certification and medical disability assessments. However, there is no conceptualised theoretical framework that can be used to describe intentions with regard to communication behaviour, communication behaviour itself, and satisfaction with communication behaviour in a medical disability assessment context. OBJECTIVE: The objective of this paper is to describe the conceptualization of a model for the communication behaviour of physicians performing medical disability assessments in a social insurance context and of their claimants, in face-to-face encounters during medical disability assessment interviews and the preparation thereof. CONCEPTUALIzATION: The behavioural model, based on the Theory of Planned Behaviour (TPB), is conceptualised for the communication behaviour of social insurance physicians and claimants separately, but also combined during the assessment interview. Other important concepts in the model are the evaluation of communication behaviour (satisfaction), intentions, attitudes, skills, and barriers for communication. CONCLUSION: The conceptualization of the TPB-based behavioural model will help to provide insight into the communication behaviour of social insurance physicians and claimants during disability assessment interviews. After empirical testing of the relationships in the model, it can be used in other studies to obtain more insight into communication behaviour in non-curative medicine, and it could help social insurance physicians to adapt their communication behaviour to their task when performing disability assessment