The value of post-operative chemotherapy after chemoradiotherapy in patients with high-risk locally advanced rectal cancer-results from the RAPIDO trial.

BACKGROUND: Pre-operative chemoradiotherapy (CRT) rather than radiotherapy (RT) has resulted in fewer locoregional recurrences (LRRs), but no decrease in distant metastasis (DM) rate for patients with locally advanced rectal cancer (LARC). In many countries, patients receive post-operative chemotherapy (pCT) to improve oncological outcomes. We investigated the value of pCT after pre-operative CRT in the RAPIDO trial. PATIENTS AND METHODS: Patients were randomised between experimental (short-course RT, chemotherapy and surgery) and standard-of-care treatment (CRT, surgery and pCT depending on hospital policy). In this substudy, we compared curatively resected patients from the standard-of-care group who received pCT (pCT+ group) with those who did not (pCT- group). Subsequently, patients from the pCT+ group who received at least 75% of the prescribed chemotherapy cycles (pCT ≥75% group) were compared with patients who did not receive pCT (pCT-/- group). By propensity score stratification (PSS), we adjusted for the following unbalanced confounders: age, clinical extramural vascular invasion, distance to the anal verge, ypT stage, ypN stage, residual tumour, serious adverse event (SAE) and/or readmission within 6 weeks after surgery and SAE related to pre-operative CRT. Cumulative probability of disease-free survival (DFS), DM, LRR and overall survival (OS) was analysed by Cox regression. RESULTS: In total, 396/452 patients had a curative resection. The number of patients in the pCT+, pCT >75%, pCT- and pCT-/- groups was 184, 112, 154 and 149, respectively. The PSS-adjusted analyses for all endpoints demonstrated hazard ratios between approximately 0.7 and 0.8 (pCT+ versus pCT-), and 0.5 and 0.8 (pCT ≥75% versus pCT-/-). However, all 95% confidence intervals included 1. CONCLUSIONS: These data suggest a benefit of pCT after pre-operative CRT for patients with high-risk LARC, with approximately 20%-25% improvement in DFS and OS and 20%-25% risk reductions in DM and LRR. Compliance with pCT additionally reduces or improves all endpoints by 10%-20%. However, differences are not statistically significant.

Myopathic changes in patients with long-term fatigue after COVID-19.

OBJECTIVE: To investigate the peripheral nerve and muscle function electrophysiologically in patients with persistent neuromuscular symptoms following Coronavirus disease 2019 (COVID-19). METHODS: Twenty consecutive patients from a Long-term COVID-19 Clinic referred to electrophysiological examination with the suspicion of mono- or polyneuropathy were included. Examinations were performed from 77 to 255 (median: 216) days after acute COVID-19. None of the patients had received treatment at the intensive care unit. Of these, 10 patients were not even hospitalized. Conventional nerve conduction studies (NCS) and quantitative electromyography (qEMG) findings from three muscles were compared with 20 age- and sex-matched healthy controls. RESULTS: qEMG showed myopathic changes in one or more muscles in 11 patients (55%). Motor unit potential duration was shorter in patients compared to healthy controls in biceps brachii (10.02 ± 0.28 vs 11.75 ± 0.21), vastus medialis (10.86 ± 0.37 vs 12.52 ± 0.19) and anterior tibial (11.76 ± 0.31 vs 13.26 ± 0.21) muscles. All patients with myopathic qEMG reported about physical fatigue and 8 patients about myalgia while 3 patients without myopathic changes complained about physical fatigue. CONCLUSIONS: Long-term COVID-19 does not cause large fibre neuropathy, but myopathic changes are seen. SIGNIFICANCE: Myopathy may be an important cause of physical fatigue in long-term COVID-19 even in non-hospitalized patients.

Role of regenerative therapies on erectile dysfunction after radical prostatectomy.

The present study provides a review of stem cell therapy as a treatment of erectile dysfunction from peer-reviewed human and animal trials. A literature search was conducted in PubMed-Medline, Scopus, Embase, and Cochrane databases. Tweenty-three animal studies and seven human studies in the period from 1st of January 2000 to 1st of Mai 2020 were included. The seven included human studies are primary phase one trials, and most of them treat erectile dysfunction following radical prostatectomy by injection of stem cells into the corpus cavernosum. The primary outcome measure in all human trials is safety and secondary can stem cells play a role in the recovery of erectile function. All studies conclude that it is safe to use stem cells and the majority of the studies demonstrate an improvement in erectile function. The results from both animal and human trials are promising for stem cells as a restorative treatment, but data from large randomized human phase two trials is missing before it can be concluded, that stem cells is an effective treatment for erectile dysfunction in humans.

Incidence of acute myocardial infarction-related cardiogenic shock during corona virus disease 19 (COVID-19) pandemic.

AIMS: The hospitalization of patients with MI has decreased during global lockdown due to the COVID-19 pandemic. Whether this decrease is associated with more severe MI, e.g. MI-CS, is unknown. We aimed to examine the association of Corona virus disease (COVID-19) pandemic and incidence of acute myocardial infarction with cardiogenic shock (MI-CS). METHODS: On March 11, 2020, the Danish government announced national lock-down. Using Danish nationwide registries, we identified patients hospitalized with MI-CS. Incidence rates (IR) and incidence rate ratios (IRR) were used to compare MI-CS before and after March 11 in 2015-2019 and in 2020. RESULTS: We identified 11,769 patients with MI of whom 696 (5.9%) had cardiogenic shock in 2015-2019. In 2020, 2132 MI patients were identified of whom 119 had cardiogenic shock (5.6%). The IR per 100,000 person years before March 11 in 2015-2019 was 9.2 (95% CI: 8.3-10.2) and after 8.9 (95% CI: 8.0-9.9). In 2020, the IR was 7.5 (95% CI: 5.8-9.7) before March 11 and 7.7 (95% CI: 6.0-9.9) after. The IRRs comparing the 2020-period with the 2015-2019 period before and after March 11 (lockdown) were 0.81 (95% CI: 0.59-1.12) and 0.87 (95% CI: 0.57-1.32), respectively. The IRR comparing the 2020-period during and before lockdown was 1.02 (95% CI: 0.74-1.41). No difference in 7-day mortality or in-hospital management was observed between study periods. CONCLUSION: We could not identify a significant association of the national lockdown on the incidence of MI-CS, along with similar in-hospital management and mortality in patients with MI-CS.

Infective endocarditis in patients who have undergone transcatheter aortic valve implantation: a review.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) has been approved for the treatment of severe aortic stenosis since 2008 and recent trials have shown that TAVI is at least non-inferior to surgical aortic valve replacement (SAVR) with regards to short-term efficacy and safety in patients across all surgical risk profiles. Prosthetic valve endocarditis of the transcatheter heart valve is a feared complication; data on the risk of infective endocarditis (IE) subsequent to TAVI are now gradually emerging. OBJECTIVES: We set forth to conduct a review of the incidence, diagnosis, microbial aetiologies, prevention, outcome and management of TAVI-IE. SOURCES: From the MEDLINE database we included a total of 12 observational studies and five studies of long-term results from randomized controlled trials. CONTENT: The incidence of TAVI-IE was reported to be between 0.7% and 3.0% per person-year. The most common microbes were reported to be enterococci, Staphylococcus aureus, streptococci and coagulase-negative staphylococci. International guidelines on prevention strategies of IE recommend good sanitary conditions including cutaneous care, good oral hygiene and good care of dialysis catheters. Antibiotic prophylaxis is recommended by guidelines prior to dental procedures in patients with TAVI; however, evidence is sparse. The majority of the patients included in this review with TAVI-IE had an indication for surgical intervention due to IE (50.0% or more); however, only a small subset of the patients underwent surgery (16.4% or less). The in-hospital mortality was around 25%, i.e. of the same order of magnitude as in prosthetic valve IE in general, but varied substantially between studies (from 11% to 64%). IMPLICATIONS: The US Food and Drug Administration's approval of TAVI in patients at low surgical risk may change the characteristics of patients with TAVI, which may influence the incidence, management, and outcome of patients with TAVI-IE.

Increased volumes of mildly elevated capillary transit time heterogeneity positively predict favorable outcome and negatively predict intracranial hemorrhage in acute ischemic stroke with large vessel occlusion.

OBJECTIVES: In patients with acute ischemic stroke, we aimed to investigate whether microvascular changes, as indexed by capillary transit time heterogeneity (CTH), contribute to the decline of the chance for favorable outcome over time and whether they are a predictor of an intracranial hemorrhage (ICH). METHODS: We retrospectively calculated CTH maps for 131 consecutive patients with acute ischemic stroke due to large vessel occlusion of the anterior circulation who had a relevant MRI PWI-DWI mismatch and were treated with endovascular thrombectomy (ET). Multivariable logistic regressions were conducted with favorable outcome (mRS ≤ 2 after 3 months) and occurrence of an ICH as dependent variables and the volume of mildly elevated CTH as independent variable adjusted for age, successful recanalization, hypertension, diabetes, atrial fibrillation, NIHSS score on admission, DWI lesion volume, and symptom-onset-to-treatment time (OTT). RESULTS: A larger volume of mildly elevated CTH was a positive predictor of favorable outcome (OR 1.17; 1.03-1.33; p = 0.019) and a negative predictor of ICH (OR 0.83; 0.73-0.96; p = 0.009). As expected, successful recanalization (OR 5.54; 1.8-17; p = 0.003), low NIHSS on admission (OR 0.9; 0.82-1.00; p = 0.045), short OTT (OR 0.96; 0.94-0.99; p = 0.006), and low DWI volume (OR 0.68; 0.49-0.94; p = 0.021) were also predictors of favorable outcome, whereas other negative predictors of ICH were atrial fibrillation (OR 2.69; 1.10-6.57; p = 0.030), high NIHSS score on admission (OR 1.10 (1.01-1.19); p = 0.030), and large DWI volume (OR 1.51; 1.17-1.19; p = 0.002). CONCLUSION: An increased volume of mildly elevated CTH is a positive predictor of favorable outcome and a negative predictor for ICH in patients with acute ischemic stroke and mismatch undergoing ET. KEY POINTS: • The classification of potentially salvageable tissue and infarct core based on traditional net perfusion parameters (as Tmax or CBF) does not account for the microvascular distribution of blood. • However, the microvascular distribution of blood, as indexed by the capillary transit time heterogeneity (CTH), directly affects the availability of oxygen within the hypoperfused tissue and should therefore be respected in acute ischemic stroke imaging. • In our study, mildly elevated CTH is found to be a positive predictor for a favorable clinical outcome and a negative predictor for the occurrence of an intracranial hemorrhage in patients with acute ischemic stroke and homogenous mismatch who underwent ET.

High incidence of candidaemia in a nationwide cohort: Underlying diseases, risk factors and mortality.

BACKGROUND: Denmark has a high incidence rate of candidaemia. A Nordic study suggested a higher Danish prevalence of haematological malignancies as an underlying reason. This nationwide study ascertained clinical characteristics of Danish candidaemia patients and investigated potential factors contributing to the high incidence and mortality. METHODS: Microbiological and clinical data for candidaemia patients in 2010-2011 were retrieved. 30-day mortality was estimated by hazard ratios (HR) with 95% confidence intervals (CI, Cox regression). RESULTS: Data were available for 912/973 candidaemia episodes (93.7%). Intensive care unit (ICU) held the largest share of patients (43.2%). Prevalent host factors were multi-morbidity (≥2 underlying diseases, 74.2%) and gastrointestinal disease (52.5%). Haematological disease was infrequent (7.8%). Risk factors included antibiotic exposure (90.5%), CVC (71.9%) and Candida colonisation (66.7%). 30-day mortality was 43.4%, and 53.6% in ICU. Mortality was lower for patients with recent abdominal surgery (HR 0.70, 95% CI: 0.54-0.92). CONCLUSION: A substantial prevalence of multi-morbidity and a high 30-day mortality was found. We hypothesise, that an increasing population of severely ill patients with prolonged supportive treatment and microbiological testing may in part explain the high candidaemia incidence in Denmark. Nationwide studies are warranted to clarify this issue.

The TLR9 agonist MGN1703 triggers a potent type I interferon response in the sigmoid colon.

Toll-like receptor 9 (TLR9) agonists are being developed for treatment of colorectal and other cancers, yet the impact of these drugs on human intestines remains unknown. This, together with the fact that there are additional potential indications for TLR9 agonist therapy (e.g., autoimmune and infectious diseases), led us to investigate the impact of MGN1703 (Lefitolimod) on intestinal homeostasis and viral persistence in HIV-positive individuals. Colonic sigmoid biopsies were collected (baseline and week four) from 11 HIV+ individuals on suppressive antiretroviral therapy, who received MGN1703 (60 mg s.c.) twice weekly for 4 weeks in a single-arm, phase 1b/2a study. Within sigmoid mucosa, global transcriptomic analyses revealed 248 modulated genes (false discovery rate<0.05) including many type I interferon (IFN)-stimulated genes. MGN1703 increased the frequencies of cells exhibiting MX1 (P=0.001) and ISG15 (P=0.014) protein expression. No changes were observed in neutrophil infiltration (myeloperoxidase; P=0.97). No systematic effect on fecal microbiota structure was observed (analysis of similarity Global R=-0.105; P=0.929). TLR9 expression at baseline was inversely proportional to the change in integrated HIV DNA during MGN1703 treatment (P=0.020). In conclusion, MGN1703 induced a potent type I IFN response, without a concomitant general inflammatory response, in the intestines.

Abacavir usage patterns and hypersensitivity reactions in the EuroSIDA cohort.

OBJECTIVES: Five to eight per cent of HIV-positive individuals initiating abacavir (ABC) experience potentially fatal hypersensitivity reactions (HSRs). We sought to describe the proportion of individuals initiating ABC and to describe the incidence and factors associated with HSR among those prescribed ABC. METHODS: We calculated the proportion of EuroSIDA individuals receiving ABC-based combination antiretroviral therapy (cART) among those receiving cART after 1 January 2009. Poisson regression was used to identify demographic, and current clinical and laboratory factors associated with ABC utilization and discontinuation. RESULTS: Between 2009 and 2016, of 10 076 individuals receiving cART, 3472 (34%) had ever received ABC-based cART. Temporal trends of ABC utilization were also heterogeneous, with 28% using ABC in 2009, dropping to 26% in 2010 and increasing to 31% in 2016, and varied across regions and over time. Poisson models showed lower ABC utilization in older individuals, and in those with higher CD4 cell counts, higher cART lines, and prior AIDS. Higher ABC utilization was associated with higher HIV RNA and poor renal function, and was more common in Central-East and Eastern Europe and lowest during 2014. During 779 person-years of follow-up (PYFU) in 2139 individuals starting ABC after 1 January 2009, 113 discontinued ABC within 6 weeks of initiation for any reason [incidence rate (IR) 14.5 (95% confidence interval (CI) 12.1, 17.5) per 100 PYFU], 13 because of reported HSR [IR 0.3 (95% CI 0.1, 1.0) per 100 PYFU] and 35 because of reported HSR/any toxicity [IR 4.5 (95% CI 3.2, 6.3) per 100 PYFU]. There were no factors significantly associated with ABC discontinuation because of reported HSR/any toxicity. CONCLUSIONS: ABC remains commonly used across Europe and the incidence of discontinuation because of reported HSR was low in our study population.

Impact of age on cardiovascular function, inflammation, and oxidative stress in experimental asphyxial cardiac arrest.

BACKGROUND: Advanced age is an independent predictor of poor outcome after cardiac arrest (CA). From experimental studies of regional ischemia-reperfusion injury, advanced age is associated with larger infarct size, reduced organ function, and augmented oxidative stress. The objective of this study was to investigate the effect of age on cardiovascular function, oxidative stress, inflammation, and endothelial activation after CA representing global ischemia-reperfusion. METHODS: Aged (26 months) and young (5 months) rats were subjected to 8 min of asphyxia induced CA, resuscitated and observed for 360 min. Left ventricular pressure-derived cardiac function was measured at baseline and 360 min after CA. Blood samples obtained at baseline, 120 min, and 360 min after CA were analyzed for IL-1ß, IL-6, IL-10, TNF-α, elastase, sE-selectin, sL-selectin, sI-CAM1, hemeoxygenase-1 (HO-1) and protein carbonyl. Tissue samples of brain, heart, kidney, and lung were analyzed for HO-1. RESULTS: Cardiac function, evaluated by dP/dtmax and dP/dtmin , was decreased after CA in both young and aged rats, with no group differences. Mean arterial pressure increased after CA in young, but not old rats. Aged rats showed significantly higher plasma levels of elastase and sE-selectin after CA, and there was a significant different development over time between groups for IL-6 and IL-10. Young rats showed higher levels of HO-1 in plasma and renal tissue after CA. CONCLUSION: In a rat model of asphyxial CA, advanced age is associated with an attenuated hyperdynamic blood pressure response and increased endothelial activation.

Sequential Vacc-4x and romidepsin during combination antiretroviral therapy (cART): Immune responses to Vacc-4x regions on p24 and changes in HIV reservoirs.

OBJECTIVES: The REDUC clinical study Part B investigated Vacc-4x/rhuGM-CSF therapeutic vaccination prior to HIV latency reversal using romidepsin. The main finding was a statistically significant reduction from baseline in viral reservoir measurements. Here we evaluated HIV-specific functional T-cell responses following Vacc-4x/rhuGM-CSF immunotherapy in relation to virological outcomes on the HIV reservoir. METHODS: This study, conducted in Aarhus, Denmark, enrolled participants (n = 20) with CD4>500 cells/mm3 on cART. Six Vacc-4x (1.2 mg) intradermal immunizations using rhuGM-CSF (60 µg) as adjuvant were followed by 3 weekly intravenous infusions of romidepsin (5 mg/m2). Immune responses were determined by IFN-γ ELISpot, T-cell proliferation to p24 15-mer peptides covering the Vacc-4x region, intracellular cytokine staining (ICS) to the entire HIVGag and viral inhibition. RESULTS: The frequency of participants with CD8+ T-cell proliferation assay positivity was 8/16 (50%) at baseline, 11/15 (73%) post-vaccination, 6/14 (43%) during romidepsin, and 9/15 (60%)post-romidepsin. Participants with CD8+ T-cell proliferation assay positivity post-vaccination showed reductions in total HIV DNA post-vaccination (p = 0.006; q = 0.183), post-latency reversal (p = 0.005; q = 0.183), and CA-RNA reductions post-vaccination (p = 0.015; q = 0.254). Participants (40%) were defined as proliferation 'Responders' having ≥2-fold increase in assay positivity post-baseline. Robust ELISpot baseline responses were found in 87.5% participants. No significant changes were observed in the proportion of polyfunctional CD8+ T-cells to HIVGag by ICS. There was a trend towards increased viral inhibition from baseline to post-vaccination (p = 0.08). CONCLUSIONS: In this 'shock and kill' approach supported by therapeutic vaccination, CD8+ T-cell proliferation represents a valuable means to monitor functional immune responses as part of the path towards functional HIV cure.

Tuberculosis case finding and mortality prediction: added value of the clinical TBscore and biomarker suPAR.

SETTING: A suburban area of Bissau, the capital of Guinea-Bissau; the study was conducted among presumptive pulmonary tuberculosis (prePTB) patients seeking medical care for signs and symptoms suggestive of PTB. OBJECTIVE: To determine if a clinical TB score and a biomarker suPAR (soluble urokinase plasminogen activator receptor) have separate and composite ability to predict PTB diagnosis and mortality in prePTB patients. DESIGN: Observational prospective follow-up study conducted from August 2010 to August 2012. RESULTS: We included 1011 prePTB patients (mean age 34 years, 95%CI 33-35); 55% (n = 559) were female and 161 (16%) had human immunodeficiency virus (HIV) infection. Of all included patients, 10% (n = 101) were diagnosed with PTB. Mortality during follow-up was 5% (n = 48), with a mean survival time of 158 days (95%CI 27-289) in prePTB patients diagnosed with PTB vs. 144 days (95%CI 109-178) in those not diagnosed with PTB (P = 0.774). After adjusting for HIV status and age, the best separate predictor was suPAR 5 ng/ml, with a hazard ratio (HR) of 4.6 (95%CI 2.1-9.9) for mortality and 6.7 (95%CI 4.0-11.2) for TB diagnosis. All patients who died had a TBscore II + suPAR 7; the HR of the composite score for subsequent PTB diagnosis was 33.0 (95%CI 4.6-236.6). CONCLUSION: The proposed composite score of suPAR + TBscore II 7 can improve TB case finding and clinical monitoring.

Treatment potential of the GLP-1 receptor agonists in type 2 diabetes mellitus: a review.

Over the last decade, the discovery of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) has increased the treatment options for patients with type 2 diabetes mellitus (T2DM). GLP-1 RAs mimic the effects of native GLP-1, which increases insulin secretion, inhibits glucagon secretion, increases satiety and slows gastric emptying. This review evaluates the phase III trials for all approved GLP-1 RAs and reports that all GLP-1 RAs decrease HbA1c, fasting plasma glucose, and lead to a reduction in body weight in the majority of trials. The most common adverse events are nausea and other gastrointestinal discomfort, while hypoglycaemia is rarely reported when GLP-1 RAs not are combined with sulfonylurea or insulin. Treatment options in the near future will include co-formulations of basal insulin and a GLP-1 RA.

Quantification and variability in colonic volume with a novel magnetic resonance imaging method.

BACKGROUND: Segmental distribution of colorectal volume is relevant in a number of diseases, but clinical and experimental use demands robust reliability and validity. Using a novel semi-automatic magnetic resonance imaging-based technique, the aims of this study were to describe: (i) inter-individual and intra-individual variability of segmental colorectal volumes between two observations in healthy subjects and (ii) the change in segmental colorectal volume distribution before and after defecation. METHODS: The inter-individual and intra-individual variability of four colorectal volumes (cecum/ascending colon, transverse, descending, and rectosigmoid colon) between two observations (separated by 52 ± 10) days was assessed in 25 healthy males and the effect of defecation on segmental colorectal volumes was studied in another seven healthy males. KEY RESULTS: No significant differences between the two observations were detected for any segments (All p > 0.05). Inter-individual variability varied across segments from low correlation in cecum/ascending colon (intra-class correlation coefficient [ICC] = 0.44) to moderate correlation in the descending colon (ICC = 0.61) and high correlation in the transverse (ICC = 0.78), rectosigmoid (ICC = 0.82), and total volume (ICC = 0.85). Overall intra-individual variability was low (coefficient of variance = 9%). After defecation the volume of the rectosigmoid decreased by 44% (p = 0.003). The change in rectosigmoid volume was associated with the true fecal volume (p = 0.02). CONCLUSIONS & INFERENCES: Imaging of segmental colorectal volume, morphology, and fecal accumulation is advantageous to conventional methods in its low variability, high spatial resolution, and its absence of contrast-enhancing agents and irradiation. Hence, the method is suitable for future clinical and interventional studies and for characterization of defecation physiology.

Mutations in the TLR3 signaling pathway and beyond in adult patients with herpes simplex encephalitis.

Herpes simplex encephalitis (HSE) in children has previously been linked to defects in type I interferon production downstream of Toll-like receptor (TLR)3. In the present study, we used whole-exome sequencing to investigate the genetic profile of 16 adult patients with a history of HSE. We identified novel mutations in IRF3, TYK2 and MAVS, molecules involved in generating innate antiviral immune responses, which have not previously been associated with HSE. Moreover, data revealed mutations in TLR3, TRIF, TBK1 and STAT1 known to be associated with HSE in children but not previously described in adults. All discovered mutations were heterozygous missense mutations, the majority of which were associated with significantly decreased antiviral responses to HSV-1 infection and/or the TLR3 agonist poly(I:C) in patient peripheral blood mononuclear cells compared with controls. Altogether, this study demonstrates novel mutations in the TLR3 signaling pathway in molecules previously identified in children, suggesting that impaired innate immunity to HSV-1 may also increase susceptibility to HSE in adults. Importantly, the identification of mutations in innate signaling molecules not directly involved in TLR3 signaling suggests the existence of innate immunodeficiencies predisposing to HSE beyond the TLR3 pathway.

Microcirculatory dysfunction and tissue oxygenation in critical illness.

Severe sepsis is defined by organ failure, often of the kidneys, heart, and brain. It has been proposed that inadequate delivery of oxygen, or insufficient extraction of oxygen in tissue, may explain organ failure. Despite adequate maintenance of systemic oxygen delivery in septic patients, their morbidity and mortality remain high. The assumption that tissue oxygenation can be preserved by maintaining its blood supply follows from physiological models that only apply to tissue with uniformly perfused capillaries. In sepsis, the microcirculation is profoundly disturbed, and the blood supply of individual organs may therefore no longer reflect their access to oxygen. We review how capillary flow patterns affect oxygen extraction efficacy in tissue, and how the regulation of tissue blood flow must be adjusted to meet the metabolic needs of the tissue as capillary flows become disturbed as observed in critical illness. Using the brain, heart, and kidney as examples, we discuss whether disturbed capillary flow patterns might explain the apparent mismatch between organ blood flow and organ function in sepsis. Finally, we discuss diagnostic means of detecting capillary flow disturbance in animal models and in critically ill patients, and address therapeutic strategies that might improve tissue oxygenation by modifying capillary flow patterns.

Mean Diffusional Kurtosis in Patients with Glioma: Initial Results with a Fast Imaging Method in a Clinical Setting.

BACKGROUND AND PURPOSE: Diffusional kurtosis imaging is an MR imaging technique that provides microstructural information in biologic systems. Its application in clinical studies, however, is hampered by long acquisition and postprocessing times. We evaluated a new and fast (2 minutes 46 seconds) diffusional kurtosis imaging method with regard to glioma grading, compared it with conventional diffusional kurtosis imaging, and compared the diagnostic accuracy of fast mean kurtosis (MK') to that of the widely used mean diffusivity. MATERIALS AND METHODS: MK' and mean diffusivity were measured in the contrast-enhancing tumor core, the perifocal hyperintensity (indicated on T2 FLAIR images), and the contralateral normal-appearing white and gray matter of 34 patients (22 with high-grade and 12 with low-grade gliomas). MK' and mean diffusivity in the different tumor grades were compared by using a Wilcoxon rank sum test. Receiver operating characteristic curves and the areas under the curve were calculated to determine the diagnostic accuracy of MK' and mean diffusivity. RESULTS: MK' in the tumor core, but not mean diffusivity, differentiated high-grade from low-grade gliomas, and MK' differentiated glioblastomas from the remaining gliomas with high accuracy (area under the curveMK' = 0.842; PMK' < .001). MK' and mean diffusivity identified glioblastomas in the group of high-grade gliomas with similar significance and accuracy (area under the curveMK' = 0.886; area under the curvemean diffusivity = 0.876; PMK' = .003; Pmean diffusivity = .004). The mean MK' in all tissue types was comparable to that obtained by conventional diffusional kurtosis imaging. CONCLUSIONS: The diffusional kurtosis imaging approach used here is considerably faster than conventional diffusional kurtosis imaging methods but yields comparable results. It can be accommodated in clinical protocols and enables exploration of the role of MK' as a biomarker in determining glioma subtypes or response evaluation.

Associations between bicycling and carotid arterial stiffness in adolescents: The European Youth Hearts Study.

The aim of the study was to investigate the associations between bicycling and carotid arterial stiffness, independent of objectively measured moderate-and-vigorous physical activity. This cross-sectional study included 375 adolescents (age 15.7 ± 0.4 years) from the Danish site of the European Youth Heart Study. Total frequency of bicycle usage was assessed by self-report, and carotid arterial stiffness was assessed using B-mode ultrasound. After adjusting for pubertal status, body height, and objectively measured physical activity and other personal lifestyle and demographic factors, boys using their bicycle every day of the week displayed a higher carotid arterial compliance {standard beta 0.47 [95% confidence interval (CI) 0.07-0.87]} and distension [standard beta 0.38 (95% CI -0.04 to 0.81)]. Boys using their bicycle every day of the week furthermore displayed a lower Young's elastic modulus [standard beta -0.48 (95% CI -0.91 to -0.06)]. Similar trends were observed when investigating the association between commuter bicycling and carotid arterial stiffness. These associations were not observed in girls. Our observations suggest that increasing bicycling in adolescence may be beneficial to carotid arterial health among boys.