European Concerted Action on Anticoagulation. Correction of displayed international normalized ratio on two point-of-care test whole-blood prothrombin time monitors (CoaguChek Mini and TAS PT-NC) by independent international sensitivity index calibration

The international normalized ratio (INR) on two widely used point-of-care test (POCT) prothrombin time (PT) monitors (CoaguChek Mini and TAS PT-NC) differed considerably and also differed from the 'true' INR obtained on the same samples using a manual PT and the same species thromboplastin international reference preparation. Agreement between the displayed INR and difference from 'true' INR has been reassessed following an independent international sensitivity index (ISI) calibration of the two systems. The displayed INRs taken at seven centres were compared with 'true' INRs from the same blood donations and INRs based on the resulting ISI. The overall difference between the displayed INRs on the two monitor systems was reduced from 21.0% to 3.5%. The overall difference in mean INR of system A from the 'true' INR was reduced from 19.0% to 9.5% and of system B from 6.8% to 0.3%, but individual centre's results still showed considerable mean INR variability. Differences between overall displayed INR with the two monitor systems have been reduced by an independent multicentre calibration, and agreement with 'true' INR on the same blood samples improved. However, marked variability in mean INR at individual centres remained after ISI correction, which demonstrates the need for external quality control of individual POCT whole-blood PT monitors.     

Epicardial and pericardial adipose tissues are associated with reduced diastolic and systolic function in type 2 diabetes

The aim of this study was to investigate the association of epicardial (EAT) and pericardial (PAT) adipose tissues with myocardial function in type 2 diabetes (T2D). EAT and PAT were measured by ultrasound in 770 patients with T2D and 234 age- and sex-matched non-diabetic controls. Echocardiography was performed, including tissue Doppler imaging and 2D speckle tracking. Patients with T2D versus controls had increased EAT (4.6 ± 1.8 mm vs. 3.4 ± 1.2 mm, P < 0.0001) and PAT (6.3 ± 2.8 mm vs. 5.3 ± 2.4 mm, P < 0.0001). EAT and PAT were associated with structural cardiac measures both in T2D patients and controls (all P < 0.043), but only in T2D patients with functional measures: PAT was associated with impaired global longitudinal strain [beta coefficient (SE)] [0.11% (0.04), P = 0.002], while EAT was associated with reduced diastolic function by lateral early diastolic myocardial velocity (e’_lat) [−0.31 (0.05) cm/s, P = 0.001], mitral inflow velocities: peak early (E)/peak atrial (A) ratio [−0.02 (0.01), P = 0.001] and lateral E/e’_lat [0.36 (0.10), P < 0.001]. However, no interaction was found between diabetes status and PAT (P = 0.75) or EAT (P = 0.45). Adipose tissue in intimate relation to the myocardium is higher in patients with T2D versus controls and is associated with functional myocardial measures in T2D.     

In Vivo pH Imaging with 99mTc-pHLIP

Purpose

A novel molecular imaging agent has been developed recently, which stains tissues of low extracellular pH [pH (low) insertion peptide, pHLIP^?]. A pH-dependent process of peptide folding and insertion into cell membranes has been found in vitro. Targeting of acidic solid tumours has been demonstrated in vivo using fluorescence and PET labels. Here, we present proof of feasibility studies of pHLIP with a single-photon emission computed tomography (SPECT) label, ^99mTc-AH114567, with focus on preclinical efficacy and imageability.

Procedures

Lewis lung carcinoma, lymph node carcinoma of the prostate and prostate adenocarcinoma tumour xenografts were grown in mice and characterised by the angiogenesis marker ^99mTc-NC100692 and by extracellular pH measurements with ³¹P-MRS of 3-aminopropyl phosphonate. Biodistribution was assessed and CT/SPECT imaging performed. Oral administration of bicarbonate served as control.

Results and Conclusion

Tc-AH114567 can be obtained via a robust synthesis with good radiolabelling profile and improved formulation. The tracer retains the pH-dependent ability to insert into membranes and to target tumours with similar pharmacokinetics and efficacy that had been demonstrated earlier for pHLIP with optical or ⁶⁴Cu PET labels. Despite the inherent challenges of SPECT compared to optical and PET imaging, e.g., in terms of lower sensitivity, ^99mTc-AH114567 shows adequate image quality and contrast. The main development need for transitioning SPECT labelled pHLIP into the clinic is more rapid background signal reduction, which will be the focus of a subsequent optimisation study.     

Outcomes of Follow-Up Visits to Chronic Nonmalignant Pain Patients

Follow-up visits by clinical nurse specialists are beneficial for patients with various chronic conditions. It is unknown whether patients with chronic nonmalignant pain can achieve similar benefit. The aim of this study was to assess outcomes of follow-up visits by clinical nurse specialists to chronic nonmalignant pain patients regarding health-related quality of life (HRQoL), pain, opioid treatment, quality of sleep, and depression. A total of 102 patients were enrolled in a prospective randomized controlled trial during a 2-year period after discharge from multidisciplinary pain treatment and randomized to intervention or control group. Intervention group patients (n = 52) received home visits every fourth month for 2 years. The findings showed that HRQoL improved generally more in the intervention group. Statistically significant improvements were observed for physical function and bodily pain. Whereas the intervention group maintained the pain level on a visual analog scale, the control group reported more pain. During the observation period, the control group increased dosage of opioids whereas the intervention group maintained stable dosage. No significant effect on quality of life was found. Nurses identified signs of depression in 80% of their patients scoring depression on the simultaneous depression questionnaire, and thereby could refer patients to early treatment. Follow-up visits by clinical nurse specialists appeared to offer positive benefits to patients with chronic nonmalignant pain after discharge from multidisciplinary pain treatment. The intervention improved physical functioning, reduced bodily pain and pain intensity and prevented opioid dosage increase. Most episodes of depression were identified and referred to relevant treatment.     

Imaging first impressions: distinct neural processing of verbal and nonverbal social information

First impressions profoundly influence our attitudes and behavior toward others. However, little is known about whether and to what degree the cognitive processes that underlie impression formation depend on the domain of the available information about the target person. To investigate the neural bases of the influence of verbal as compared to nonverbal information on interpersonal judgments, we identified brain regions where the BOLD signal parametrically increased with increasing strength of evaluation based on either short text vignettes or mimic and gestural behavior. While for verbal stimuli the increasing strength of subjective evaluation was correlated with increased neural activation of precuneus and posterior cingulate cortex (PC/PCC), a similar effect was observed for nonverbal stimuli in the amygdala. These findings support the assumption that qualitatively different cognitive operations underlie person evaluation depending upon the stimulus domain: while the processing of nonverbal person information may be more strongly associated with affective processing as indexed by recruitment of the amygdala, verbal person information engaged the PC/PCC that has been related to social inferential processing.     

Aneuploidy and elevated CEA indicate an increased risk for metachronous metastasis in colorectal cancer

Purpose

Presently, no markers exist to predict metachronous metastasis at the time a primary colorectal cancer is diagnosed. While aneuploidy indicates poor survival prognosis and elevated carcinoembryonic antigen (CEA) levels the presence of recurrent disease, the predictive value of both markers regarding imminent metachronous metastases is unclear.

Methods

Sixty patients with distant recurrence throughout a 5-year follow-up (TM+) were randomly chosen and 60 patients without metastasis matched to this cohort (TM?). In addition, an enlarged collective (n?=?217; n _TM+?=?85, n _TM-?=?132) with median follow-up of 79.2 months was assessed by logistic regression regarding metachronous metastases. Univariate and stepwise regression analyses included clinicopathological characteristics, preoperative CEA levels and aneuploidy assessed by DNA image cytometry.

Results

The matched-pair collective showed aneuploidy in 71.1 % (TM?) and 85.0 % (TM+; p?=?0.076), and elevated CEA in 24.5 % (TM?) and 52.2 % [TM+; odds ratio (OR), 3.414; p?=?0.007]. The enlarged collective presented aneuploidy in 71.2 % (TM?) and 83.5 % (TM+; OR 2.050, p?=?0.038), and elevated CEA in 28.6 % (TM?) and 48.9 % (TM+; OR 2.391, p?=?0.020). Elevated CEA and aneuploidy did not show any association (p?=?0.919). In contrast, logistic regression analyses demonstrated that besides increased T category (OR 1.745, p?=?0.019), both elevated CEA level (OR 2.633, p?=?0.015) and aneuploidy (OR 1.929, p?=?0.058) were independent predictive markers for metachronous metastasis.

Conclusions

Our data show that aneuploidy and elevated CEA levels besides increased T category could serve for individual risk assessment to predict metachronous metastases. The fact that still aneuploidy missed the significance level by a small margin emphasizes the need for larger validation studies.     

Effects of PTH(1-34) on Blood Pressure, Renal Function, and Hormones in Essential Hypertension: The Altered Pattern of Reactivity May Counteract Raised Blood Pressure

As it has been suggested that parathyroid hormone (PTH) is implicated in the pathophysiology of essential hypertension, the effects of PTH(1-34) were assessed during infusion over 120 min in ten men with essential hypertension and in ten healthy men. Ionized calcium was kept constant by a clamping technique. Mean arterial blood pressure fell slightly in the patients (116 mm Hg, median, before, and 108 mm Hg during the infusion, P < .01), but remained unchanged in the controls (median 87 mm Hg). The pulse rate rose to a similar extent in the two groups, but cardiac output, measured by the CO₂ rebreathing technique, was unchanged. The glomerular filtration rate (GFR) was slightly lower in the hypertensives than in the controls at baseline (92 v 109 mL/min, P < .02), but it increased similarly during PTH infusion in both groups (+13% v +9%, medians), as did the effective renal plasma flow (+50% v +38%). The urinary rate of sodium excretion, which was similar at baseline, increased more in the patients than in the controls (+191% v +46%, P < .05); this was mainly attributable to a reduction in the tubular reabsorption of sodium. Calculations based on lithium clearance indicated that mainly the proximal tubular reabsorption of sodium decreased during PTH infusion. Baseline plasma PTH(1-84) was higher in the patients than in the controls (20.5 ng/L v 16.5 ng/L, P < .05). The baseline plasma values of renin, aldosterone, atrial natriuretic peptide, endothelin, and noradrenaline were similar in the two groups. During infusion of PTH, renin increased less in the patients than in the controls (P < .02), and aldosterone increased only in the controls (P < .01). The other hormonal values remained unchanged. In conclusion, the patients with essential hypertension had increased baseline PTH values, but nevertheless PTH had more marked vasodilative and natriuretic effects than in the controls. PTH thus seems to counteract rather than aggravate elevation of blood pressure in these patients.     

New oral anticoagulants in atrial fibrillation and acute coronary syndromes: ESC Working Group on Thrombosis-Task Force on Anticoagulants in Heart Disease position paper

Until recently, vitamin K antagonists were the only available oral anticoagulants, but with numerous limitations that prompted the introduction of new oral anticoagulants targeting the single coagulation enzymes thrombin (dabigatran) or factor Xa (apixaban, rivaroxaban, and edoxaban) and given in fixed doses without coagulation monitoring. Here we review the pharmacology and the results of clinical trials with these new agents in stroke prevention in atrial fibrillation and secondary prevention after acute coronary syndromes, providing perspectives on their future incorporation into clinical practice. In phase III trials in atrial fibrillation, compared with warfarin, dabigatran etexilate 150 mg B.I.D. reduced the rates of stroke/systemic embolism without any difference in major bleeding; dabigatran etexilate 110 mg B.I.D. had similar efficacy with decreased bleeding; apixaban 5 mg B.I.D. reduced stroke, systemic embolism, and mortality as well as major bleeding; and rivaroxaban 20 mg Q.D. was noninferior to warfarin for stroke and systemic embolism without a difference in major bleeding. All these agents reduced intracranial hemorrhage. Edoxaban is currently being evaluated in a further large phase III trial. Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischemia in patients with acute coronary syndromes who were mostly receiving dual antiplatelet therapy, with conflicting results on efficacy but consistent results for increased major bleeding. Overall, the new oral anticoagulants are poised to replace vitamin K antagonists for many patients with atrial fibrillation and may have a role after acute coronary syndromes. Although convenient to administer and manage, they present challenges that need to be addressed.     

Tick cell lines for study of Crimean-Congo hemorrhagic fever virus and other arboviruses

Continuous cell lines derived from many of the vectors of tick-borne arboviruses of medical and veterinary importance are now available. Their role as tools in arbovirus research to date is reviewed and their potential application in studies of tick cell responses to virus infection is explored, by comparison with recent progress in understanding mosquito immunity to arbovirus infection. A preliminary study of propagation of the human pathogen Crimean-Congo hemorrhagic fever virus (CCHFV) in tick cell lines is reported; CCHFV replicated in seven cell lines derived from the ticks Hyalomma anatolicum (a known vector), Amblyomma variegatum, Rhipicephalus (Boophilus) decoloratus, Rhipicephalus (Boophilus) microplus, and Ixodes ricinus, but not in three cell lines derived from Rhipicephalus appendiculatus and Ornithodoros moubata. This indicates that tick cell lines can be used to study growth of CCHFV in arthropod cells and that there may be species-specific restriction in permissive CCHFV infection at the cellular level.