Predictors of response to intra-arterial vasodilatory therapy of non-occlusive mesenteric ischemia in patients with severe shock: results from a prospective observational study

Background: Non-occlusive mesenteric ischemia (NOMI) is a life-threatening condition occurring in patients with shock and is characterized by vasoconstriction of the mesenteric arteries leading to intestinal ischemia and multi-organ failure. Although minimal invasive local intra-arterial infusion of vasodilators into the mesenteric circulation has been suggested as a therapeutic option in NOMI, current knowledge is based on retrospective case series and it remains unclear which patients might benefit. Here, we prospectively analyzed predictors of response to intra-arterial therapy in patients with NOMI. Methods: This is a prospective single-center observational study to analyze improvement of ischemia (indicated by reduction of blood lactate > 2 mmol/l from baseline after 24 h, primary endpoint) and 28-day mortality (key secondary endpoint) in patients with NOMI undergoing intra-arterial vasodilatory therapy. Predictors of response to therapy concerning primary and key secondary endpoint were identified using a) clinical parameters as well as b) data from 2D-perfusion angiography and c) experimental biomarkers of intestinal injury. Results: A total of 42 patients were included into this study. At inclusion patients had severe shock, indicated by high doses of norepinephrine (NE) (median (interquartile range (IQR)) 0.37 (0.21-0.60) μg/kg/min), elevated lactate concentrations (9.2 (5.2-13) mmol/l) and multi-organ failure. Patients showed a continuous reduction of lactate following intra-arterial prostaglandin infusion (baseline: (9.2 (5.2-13) mmol/l vs. 24 h: 4.4 (2.5-9.1) mmol/l, p 2 mmol/l at 24 h following intervention. Initial higher lactate concentrations and lower NE doses at baseline were independent predictors of an improvement of ischemia. 28-day mortality was 59% in patients with a reduction of lactate > 2 mmol/l 24 h after inclusion, while it was 85% in all other patients (hazard ratio 0.409; 95% CI, 0.14-0.631, p = 0.005). Conclusions: A reduction of lactate concentrations was observed following implementation of intra-arterial therapy, and lactate reduction was associated with better survival. Our findings concerning outcome predictors in NOMI patients undergoing intra-arterial prostaglandin therapy might help designing a randomized controlled trial to further investigate this therapeutic approach. Trial registration Retrospectively registered on January 22, 2020, at clinicaltrials.gov (REPERFUSE, NCT04235634), https://clinicaltrials.gov/ct2/show/NCT04235634?cond=NOMI&draw=2&rank=1 . Keywords: Intestinal failure; Non-occlusive mesenteric ischemia; Sepsis; Shoc

Implementation of Novel Molecular Biomarkers for Non-small Cell Lung Cancer in the Netherlands: How to Deal With Increasing Complexity

The diagnostic landscape of non-small cell lung cancer (NSCLC) is changing rapidly with the availability of novel treatments. Despite high-level healthcare in the Netherlands, not all patients with NSCLC are tested with the currently relevant predictive tumor markers that are necessary for optimal decision-making for today's available targeted or immunotherapy. An expert workshop on the molecular diagnosis of NSCLC involving pulmonary oncologists, clinical chemists, pathologists, and clinical scientists in molecular pathology was held in the Netherlands on December 10, 2018. The aims of the workshop were to facilitate cross-disciplinary discussions regarding standards of practice, and address recent developments and associated challenges that impact future practice. This paper presents a summary of the discussions and consensus opinions of the workshop participants on the initial challenges of harmonization of the detection and clinical use of predictive markers of NSCLC. A key theme identified was the need for broader and active participation of all stakeholders involved in molecular diagnostic services for NSCLC, including healthcare professionals across all disciplines, the hospitals and clinics involved in service delivery, healthcare insurers, and industry groups involved in diagnostic and treatment innovations. Such collaboration is essential to integrate different technologies into molecular diagnostics practice, to increase nationwide patient access to novel technologies, and to ensure consensus-preferred biomarkers are tested

Intra-Organ Variation in Age-Related Mutation Accumulation in the Mouse

Using a transgenic mouse model harboring chromosomally integrated lacZ mutational target genes, we previously demonstrated that mutations accumulate with age much more rapidly in the small intestine than in the brain. Here it is shown that in the small intestine point mutations preferentially accumulate in epithelial cells of the mucosa scraped off the underlying serosa. The mucosal cells are the differentiated villus cells that have undergone multiple cell divisions. A smaller age-related increase, also involving genome rearrangements, was observed in the serosa, which consists mainly of the remaining crypts and non-dividing smooth muscle cells. In the brain we observed an accumulation of only point mutations in no other areas than hypothalamus and hippocampus. To directly test for cell division as the determining factor in the generation of point mutations we compared mutation induction between mitotically active and quiescent embryonic fibroblasts from the same lacZ mice, treated with either UV (a point mutagen) or hydrogen peroxide (a clastogen). The results indicate that while point mutations are highly replication-dependent, genome rearrangements are as easily induced in non-dividing cells as in mitotically active ones. This strongly suggests that the point mutations found to have accumulated in the mucosal part of the small intestine are the consequence of replication errors. The same is likely true for point mutations accumulating in hippocampus and hypothalamus of the brain since neurogenesis in these two areas continues throughout life. The observed intra-organ variation in mutation susceptibility as well as the variation in replication dependency of different types of mutations indicates the need to not only extend observations made on whole organs to their sub-structures but also take the type of mutations and mitotic activity of the cells into consideration. This should help elucidating the impact of genome instability and its consequences on aging and disease

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Erratum: Corrigendum: Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution

International Chicken Genome Sequencing Consortium. The Original Article was published on 09 December 2004. Nature432, 695–716 (2004). In Table 5 of this Article, the last four values listed in the ‘Copy number’ column were incorrect. These should be: LTR elements, 30,000; DNA transposons, 20,000; simple repeats, 140,000; and satellites, 4,000. These errors do not affect any of the conclusions in our paper. Additional information. The online version of the original article can be found at 10.1038/nature0315

Phantom study for comparison between computed tomography- and C-Arm computed tomography-guided puncture applied by residents in radiology

PURPOSE Comparison of puncture deviation and puncture duration between computed tomography (CT)- and C-arm CT (CACT)-guided puncture performed by residents in training (RiT). METHODS In a cohort of 25 RiTs enrolled in a research training program either CT- or CACT-guided puncture was performed on a phantom. Prior to the experiments, the RiT's level of training, experience playing a musical instrument, video games, and ball sports, and self-assessed manual skills and spatial skills were recorded. Each RiT performed two punctures. The first puncture was performed with a transaxial or single angulated needle path and the second with a single or double angulated needle path. Puncture deviation and puncture duration were compared between the procedures and were correlated with the self-assessments. RESULTS RiTs in both the CT guidance and CACT guidance groups did not differ with respect to radiologic experience (p = 1), angiographic experience (p = 0.415), and number of ultrasound-guided puncture procedures (p = 0.483), CT-guided puncture procedures (p = 0.934), and CACT-guided puncture procedures (p = 0.466). The puncture duration was significantly longer with CT guidance (without navigation tool) than with CACT guidance with navigation software (p < 0.001). There was no significant difference in the puncture duration between the first and second puncture using CT guidance (p = 0.719). However, in the case of CACT, the second puncture was significantly faster (p = 0.006). Puncture deviations were not different between CT-guided and CACT-guided puncture (p = 0.337) and between the first and second puncture of CT-guided and CACT-guided puncture (CT: p = 0.130; CACT: p = 0.391). The self-assessment of manual skills did not correlate with puncture deviation (p = 0.059) and puncture duration (p = 0.158). The self-assessed spatial skills correlated positively with puncture deviation (p = 0.011) but not with puncture duration (p = 0.541). CONCLUSION The RiTs achieved a puncture deviation that was clinically adequate with respect to their level of training and did not differ between CT-guided and CACT-guided puncture. The puncture duration was shorter when using CACT. CACT guidance with navigation software support has a potentially steeper learning curve. Spatial skills might accelerate the learning of image-guided puncture. KEY POINTS · The CT-guided and CACT-guided puncture experience of the RiTs selected as part of the program "Researchers for the Future" of the German Roentgen Society was adequate with respect to the level of training.. · Despite the lower collective experience of the RiTs with CACT-guided puncture with navigation software assistance, the learning curve regarding CACT-guided puncture may be faster compared to the CT-guided puncture technique.. · If the needle path is complex, CACT guidance with navigation software assistance might have an advantage over CT guidance.. CITATION FORMAT · Meine TC, Hinrichs JB, Werncke T et al. Phantom study for comparison between computed tomography- and C-Arm computed tomography-guided puncture applied by residents in radiology. Fortschr Röntgenstr 2022; 194: 272 - 280

Potential impact of interventions resulting in reduced exposure to ultraviolet (UV) radiation (UVA and UVB) on skin cancer incidence in four European countries, 2010-2050

Background Behavioural interventions to reduce exposure to ultraviolet radiation (UVR) can reduce risk of skin cancer. Objectives To integrate the data and to evaluate the impact of interventions to limit exposure to UVR on skin cancer incidence in four selected countries. Methods Using PREVENT, a dynamic simulation model, we modelled the potential for skin cancer prevention in four European countries under various scenarios to avoid damage by UVR. Results In general, the most effective interventions were those aimed at protecting people during outdoor work and outdoor hobbies against the harmful effects of UVR, and combinations of several interventions. These could in theory lead to reductions of up to 45% in skin cancer cases projected for the year 2050. Conclusions The scope for prevention depends on the prevalence of the risk factors in the different countries, as well as the associated risk factors and time lags modelled

The impact of the field of view (FOV) on image quality in MDCT angiography of the lower extremities

Objectives!#!To evaluate the impact of the reconstructed field-of-view (FOV) on image quality in computed-tomography angiography (CTA) of the lower extremities.!##!Methods!#!A total of 100 CTA examinations of the lower extremities were acquired on a 2 × 192-slice multidetector CT (MDCT) scanner. Three different datasets were reconstructed covering both legs (standard FOV size) as well as each leg separately (reduced FOV size). The subjective image quality was evaluated for the different vessel segments (femoral, popliteal, crural, pedal) by three readers using a semi-quantitative Likert scale. Additionally, objective image quality was assessed using an automated image quality metric on a per-slice basis.!##!Results!#!The subjective assessment of the image quality showed an almost perfect interrater agreement. The image quality of the small FOV datasets was rated significantly higher as compared to the large datasets for all patients and vessel segments (p &amp;lt; 0.05) with a tendency towards a higher effect in smaller vessels. The difference of the mean scores between the group with the large FOV and small FOV was 0.68 for the femoral level, 0.83 for the popliteal level, 1.12 for the crural level, and 1.08 for the pedal level. The objective image quality metric also demonstrated a significant improvement of image quality in the small FOV datasets.!##!Conclusions!#!Side-separated reconstruction of each leg in CTA of the lower extremities using a small reconstruction FOV significantly improves image quality as compared to a standard reconstruction with a large FOV covering both legs.!##!Key points!#!• In CT angiography of the lower legs, the side-separated reconstruction of each leg using a small field-of-views improves image quality as compared to a standard reconstruction covering both legs. • The side-separated reconstruction can be readily implemented at every commercially available CT scanner. • There is no need for additional hardware or software and no additional burden to the patient

RAS-challenge as a first-look test for detection of primary aldosteronism in patients with treatment-resistant hypertension

Purpose Primary aldosteronism (PA), characterised by low-renin hypertension, confers a high cardiovascular risk and is the most common cause of secondary hypertension, with an increased prevalence in patients with treatment-resistant hypertension. However, it is estimated that only a small percentage of affected patients are identified in routine clinical practice. Inhibitors of the renin-angiotensin system cause an increase in renin levels in patients with intact aldosterone regulation, and inadequate low renin with concurrent RAS inhibition (RASi) may therefore indicate PA, which could serve as a first look screening test for selection for formal work-up. Methods We analysed patients between 2016–2018 with treatment-resistant hypertension who had inadequate low renin in the presence of RASi (i. e. at risk for PA) and who were offered systematic work-up with adrenal vein sampling (AVS). Results A total of 26 pts were included in the study (age 54.8 ± 11, male 65%). Mean office blood pressure (BP) was 154/95 mmHg on 4.5 antihypertensive drug classes. AVS had a high technical success rate (96%) and demonstrated unilateral disease in the majority of patients (57%), most of which (77%) were undetected by cross-sectional imaging. Conclusion In patients with resistant hypertension, low renin in the presence of RASi is a strong indicator for autonomous aldosterone secretion. It may serve as an on-medication screening test for PA to select for formal PA work up