Improved Prognosis and Low Failure Rate with Anticoagulation as First-Line Therapy in Mesenteric Venous Thrombosis.

BACKGROUND: Monotherapy with anticoagulation has been considered as first-line therapy in patients with mesenteric venous thrombosis (MVT). The aim of this study was to evaluate outcome, prognostic factors, and failure rate of anticoagulation as monotherapy, and to identify when bowel resection was needed. METHODS: Retrospective study of consecutive patients with MVT diagnosed between 2000 and 2015. RESULTS: The overall incidence rate of MVT was 1.3/100,000 person-years. Among 120 patients, seven died due to autopsy-verified MVT without bowel resection and 15 underwent immediate bowel resection without prior anticoagulation therapy. The remaining 98 patients received anticoagulation monotherapy, whereof 83 (85%) were treated successfully. Fifteen patients failed on anticoagulation monotherapy, of whom seven underwent bowel resection and eight endovascular therapy. Endovascular therapy was followed by bowel resection in three patients. Two late bowel resections were performed due to intestinal stricture. The 30-day mortality rate was 19.0% in the former (2000-2007) and 3.2% in the latter (2008-2015) part of the study period (p = 0.006). Age ≥75 years (OR 12.4, 95% CI [2.5-60.3]), management during the former as opposed to the latter time period (OR 8.4, 95% CI [1.3-54.7]), and renal insufficiency at admission (OR 8.0, 95% CI [1.2-51.6]) were independently associated with increased mortality in multivariable analysis. CONCLUSIONS: Short-term prognosis in patients with MVT has improved. Contemporary data show that monotherapy with anticoagulation is an effective first choice in MVT patients.

Efficacy and safety of outpatient treatment with direct oral anticoagulation in pulmonary embolism.

Anticoagulant treatment of acute pulmonary embolism (PE) has traditionally been hospital-based. The lesser need for monitoring with the increasingly used direct acting oral anticoagulants (DOAC) in comparison to warfarin potentially facilitates outpatient treatment of PE with these drugs. This study aimed to evaluate efficacy and safety of outpatient treatment of PE with DOAC. We extracted data from the Swedish quality registry for patients on oral anticoagulation (AuriculA) for all 245 patients in the southernmost hospital region in Sweden (1.3 million inhabitants) selected for outpatient treatment with of PE with DOAC during 2013-2015. Comorbidites, risk factors, and simplified pulmonary embolism severity index were evaluated at baseline, and death, recurrent venous thromboembolism (VTE), and bleeding was recorded during 6 months of follow-up. Outpatient treatment was defined as discharge from the emergency department within 24 h. During 6 months of follow-up, one patient died during DOAC therapy, the cause of death was unrelated to VTE. No VTE recurrences occured, whereas, one patient experienced major bleeding, and five patients experienced minor bleedings. Outpatient treatment of PE with DOAC is efficient and safe in selected patients.

Clinical implications of CT findings in mesenteric venous thrombosis at admission.

PURPOSE: The main aim of this study was to evaluate the association of computed tomography (CT) findings at admission and bowel resection rate in patients with mesenteric venous thrombosis (MVT). It was hypothesized that abnormal intestinal findings on CT were associated with a higher bowel resection rate. METHODS: Retrospective study of MVT patients treated between 2004 and 2017. CT images at admission and at follow-up were scrutinized according to a predefined protocol. Successful recanalization was defined as partial or complete recanalization of the portomesenteric venous thrombosis at the latest CT follow-up (n = 70). RESULTS: We studied 102 patients (median age 58 years, 61 men). Lifelong anticoagulation was initiated in 64 patients, and bowel resection rate was 17%. No referral letter indicated suspicion of MVT, whereas three indicated suspected intestinal ischemia. Previous venous thromboembolism was associated with increased bowel resection rate (p = 0.049). No patient with acute pancreatitis (n = 17) underwent bowel resection (p = 0.068). The presence of mesenteric oedema (p = 0.014), small bowel wall oedema (p < 0.001), small bowel dilatation (p = 0.005), and ascites (p = 0.021) were associated with increased bowel resection rate. Small bowel wall oedema remained as an independent risk factor associated with bowel resection (OR 15.8 [95% CI 3.2-77.2]). Successful thrombus recanalization was achieved in 66% of patients. CONCLUSION: The presence of abnormal intestinal findings secondary to MVT confers an excess risk of need of bowel resection due to infarction. Responsible physicians should therefore scrutinize the CT images at diagnosis together with the radiologist to better tailor clinical surveillance.

Is it safe to withhold long-term anticoagulation therapy in patients with small pulmonary emboli diagnosed by SPECT scintigraphy?

BACKGROUND: The need for anticoagulation therapy (AC) in patients with subsegmental pulmonary embolism (SSPE) diagnosed by computed tomography of the pulmonary arteries (CTPA) has been questioned, as these patients run low risk for recurrent venous thromboembolism (VTE) during 3 months of follow-up. Whether this applies also to patients with small PE diagnosed with pulmonary scintigraphy has not yet been evaluated, however. METHODS: We therefore retrospectively evaluated 54 patients (mean age 62 ± 19 years, 36 [67 %] women) with small PE diagnosed by ventilation/perfusion singe photon emission computed tomography (V/P SPECT) who did not receive conventional long-term AC. RESULTS: More than half of our patients (36[67 %]) received less than 48 h of AC, 11 (20 %) patients were treated for 2-14 days, and 7 (13 %) for 15-30 days. The majority (28 [52 %]) of our patients had a non-low simplified pulmonary emboli severity index (S-PESI), and 7 (13 %) had malignancy. D-dimer was negative in 18 (33 %), positive in 10 (19 %), and not analyzed in 28 (52 %) patients. Phlebography of the lower extremities had been performed with negative result in one patient. During 90 days of follow up no deaths or PE occurred. Seven patients were readmitted to hospital, whereof two (2/54 [4 %]) were diagnosed with deep venous thrombosis (DVT) necessitating AC therapy. CONCLUSION: In conclusion, withholding longterm AC therapy in patients with SSPE diagnosed by V/P SPECT resulted in 4 % risk for recurrence of VTE during 90 days of follow up, and can therefore currently not be recommended.

Home treatment of patients with small to medium sized acute pulmonary embolism.

Most patients with acute pulmonary embolism (PE) are still treated as inpatients. This is a retrospective cohort study of patients with acute PE, diagnosed using V/P SPECT between 2007 and 2011. Patients were treated at home if they were hemodynamically stable, did not require oxygen or parenteral analgetics, had no contraindications to anticoagulant treatment and V/P SPECT showed an extension of the PE of less than 40%. The aim of the study was to evaluate the efficacy and safety of home treatment with our algorithm. During the study period 416 outpatients were diagnosed with acute symptomatic PE of whom in total 260 (62.5%) were discharged home from the emergency unit and another 47 (11%) within 24 h from admission. During 3 months follow-up one (0.3%) patient had a recurrent thrombotic event. Eleven (3.6%) patients had a major or clinically relevant bleed and the overall mortality was 2% (n = 6). There were no PE-related mortality. Home treatment should be considered and is safe in the majority of hemodynamically stable outpatients with small to medium size PE, quantified using V/P SPECT.

Tobacco sales and marketing within 100 yards of schools in Ahmedabad City, India.

OBJECTIVES: The Government of India passed the Cigarettes and Other Tobacco Products (Prohibition of Advertisement and Regulation of Trade and Commerce, Production, Supply and Distribution) Act, 2003 (COPTA 2003), which prohibits the sale of tobacco products within 100 yards of educational institutions and regulates tobacco advertising. The aim of this research was to monitor compliance with the section of COPTA 2003 regarding the advertisement, display and sale of tobacco products around educational institutions in Ahmedabad City, India. STUDY DESIGN: Observational study around 30 randomly selected schools. METHODS: In March 2010, an observational study was conducted to assess compliance with COPTA 2003 in Ahmedabad City, India. All vendors within a 100-yard radius of 30 randomly selected schools were identified. At locations where tobacco was sold, information was collected regarding type of product sold, sale of tobacco in single units and advertising. RESULTS: Twenty public schools and 10 private schools were sampled. Of these, 87% [n = 26, 95% confidence interval (CI) 69-95%] had tobacco sales within 100 yards of their entrance. Of the 771 vendors observed, 24% (n = 185, 95% CI 18-32%) sold tobacco products. Tobacco advertising in violation of the law was found around 57% of schools (n = 17, 95% CI 39-73%), product displays around 83% of schools (n = 25, 95% CI 65-93%) and single sales around 70% of schools (n = 21, 95% CI 51-84%). CONCLUSIONS: Violation of the sections of COPTA 2003 regarding sale of tobacco products around educational institutions and advertising in general is widespread in Ahmedabad City, India. Effective enforcement of the existing law is necessary to protect the children in India from widespread exposure to the sale and marketing of tobacco products.

Clinical probability assessment and D-dimer determination in patients with suspected deep vein thrombosis, a prospective multicenter management study.

OBJECTIVES: To investigate the reliability of a combined strategy of clinical assessment score followed by a local D-dimer test to exclude deep vein thrombosis. For comparison D-dimer was analysed post hoc and batchwise at a coagulation laboratory. DESIGN: Prospective multicenter management study. SETTING: Seven hospitals in southern Sweden. SUBJECTS: 357 patients with a suspected first episode of deep vein thrombosis (DVT) were prospectively recruited and pre-test probability score (Wells score) was estimated by the emergency physician. If categorized as low pre-test probability, D-dimer was analysed and if negative, DVT was considered to be ruled out. The primary outcome was recurrent venous thromboembolism (VTE) during 3 months of follow up. RESULTS: Prevalence of DVT was 23.5% (84/357). A low pre-test probability and a negative D-dimer result at inclusion was found in 31% (110/357) of the patients of whom one (0.9%, [95% CI 0.02-4.96]) had a VTE at follow up. Sensitivity, specificity, negative predictive value and negative likelihood ratio for our local D-dimer test in the low probability group were 85.7%, 74.5%, 98.2%, and 0,19 respectively compared to 85.6%, 67,6%, 97.9% and 0,23 using batchwise analysis at a coagulation laboratory. CONCLUSION: Pre-test probability score and D-dimer safely rule out DVT in about 30% of outpatients with a suspected first episode of DVT. One out of 110 patients was diagnosed with DVT during follow up. No significant difference in diagnostic performance was seen between local D-dimer test and the post hoc batch analysis with the same reagent in the low probability group.

Mobile phone access and comfort: implications for HIV and tuberculosis care in India and South Africa.

SETTING: India and South Africa shoulder the greatest burden of tuberculosis (TB) and human immunodeficiency virus (HIV) infection respectively, but care retention is suboptimal.OBJECTIVE: We conducted a study in Pune, India, and Matlosana, South Africa, 1) to identify the factors associated with mobile phone access and comfort of use, 2) to assess access patterns.DESIGN: A cross-sectional study assessed mobile phone access, and comfort; a longitudinal study assessed access patterns.RESULTS: We enrolled 261 participants: 136 in India and 125 in South Africa. Between 1 week and 6 months, participant contact decreased from 90% (n = 122) to 57% (n = 75) in India and from 93% (n = 116) to 70% (n = 88) in South Africa. In the latter, a reason for a clinic visit for HIV management was associated with 63% lower odds of contact than other priorities (e.g., diabetes mellitus, maternal health, TB). In India, 57% (n = 78) reported discomfort with texting; discomfort was higher in the unemployed (adjusted OR [aOR] 4.97, 95%CI 1.12-22.09) and those aged ≥35 years (aOR 1.10, 95%CI 1.04-1.16) participants, but lower in those with higher education (aOR 0.04, 95% CI 0.01-1.14). In South Africa, 91% (n = 114) reported comfort with texting.CONCLUSION: Mobile phone contact was poor at 6 months. While mHealth could transform TB-HIV care, alternative approaches may be needed for certain subpopulations.

M-CSF and GM-CSF regulation of STAT5 activation and DNA binding in myeloid cell differentiation is disrupted in nonobese diabetic mice.

Defects in macrophage colony-stimulating factor (M-CSF) signaling disrupt myeloid cell differentiation in nonobese diabetic (NOD) mice, blocking myeloid maturation into tolerogenic antigen-presenting cells (APCs). In the absence of M-CSF signaling, NOD myeloid cells have abnormally high granulocyte macrophage colony-stimulating factor (GM-CSF) expression, and as a result, persistent activation of signal transducer/activator of transcription 5 (STAT5). Persistent STAT5 phosphorylation found in NOD macrophages is not affected by inhibiting GM-CSF. However, STAT5 phosphorylation in NOD bone marrow cells is diminished if GM-CSF signaling is blocked. Moreover, if M-CSF signaling is inhibited, GM-CSF stimulation in vitro can promote STAT5 phosphorylation in nonautoimmune C57BL/6 mouse bone marrow cultures to levels seen in the NOD. These findings suggest that excessive GM-CSF production in the NOD bone marrow may interfere with the temporal sequence of GM-CSF and M-CSF signaling needed to mediate normal STAT5 function in myeloid cell differentiation gene regulation.

Testing for thrombophilia in mesenteric venous thrombosis - Retrospective original study and systematic review.

The aim was to perform a local study of risk factors and thrombophilia in mesenteric venous thrombosis (MVT), and to review the literature concerning thrombophilia testing in MVT. Patients hospitalized for surgical or medical treatment of MVT at our center 2000-2015. A systematic review of observational studies was performed. In the local study, the most frequently identified risk factor was Factor V Leiden mutation. The systematic review included 14 original studies. The highest pooled percentage of any inherited thrombophilic factor were: Factor V Leiden mutation 9% (CI 2.9-16.1), prothrombin gene mutation 7% (CI 2.7-11.8). The highest pooled percentage of acquired thrombophilic factors were JAK2 V617F mutation 14% (CI -1.9-28.1). The wide range of frequency of inherited and acquired thrombophilic factors in different populations indicates the necessity to relate these factors to background population based data in order to estimate their overrepresentation in MVT. There is a need to develop guidelines for when and how thrombophilia testing should be performed in MVT.

Household food insecurity is associated with low interferon-gamma levels in pregnant Indian women.

SETTING: Over 20% of tuberculosis (TB) cases during pregnancy occur in India. OBJECTIVE: To determine the association between household food insecurity and interferon-gamma (IFN-γ) levels in pregnancy. DESIGN: Pregnant women in India were administered the Household Food Insecurity Access Scale (HFIAS) questionnaire and underwent an IFN-γ release assay. Logistic regression was used to identify factors associated with food insecurity. RESULTS: Of 538 women, 60 (11%) had household food insecurity, 47 (78%) of which were moderate or severe food insecure. After mitogen stimulation, moderate or severe food insecure women had a median IFN-γ concentration of 4.2 IU/ml (IQR 2.2-9.8) vs. 8.4 IU/ml (IQR 3.0-10) in women with no or mild food insecurity (P = 0.03). In multivariate analysis, higher IFN-γ concentrations were associated with human immunodeficiency virus infection (OR 1.3, 95%CI 0.51-2.1, P = 0.001), and inversely associated with moderate or severe food insecurity (OR -1.6, 95%CI -2.9 to -0.27, P = 0.02) and the number of adults in the household (OR -0.08, 95%CI -0.16 to -0.01, P = 0.03). There was no association between food insecurity and IFN-γ response to Mycobacterium tuberculosis antigen. CONCLUSION: Food insecurity in pregnancy is associated with low IFN-γ levels. There was no association between food insecurity and IFN-γ response to M. tuberculosis antigen, but our study was underpowered to detect this outcome.

Comparison of repressor and transcriptional attenuator systems for control of amino acid biosynthetic operons.

In bacteria, expression from amino acid biosynthetic operons is transcriptionally controlled by two main mechanisms with principally different modes of action. When the supply of an amino acid is in excess over demand, its concentration will be high and when the supply is deficient the amino acid concentration will be low. In repressor control, such concentration variations in amino acid pools are used to regulate expression from the corresponding amino acid synthetic operon; a high concentration activates and a low concentration inactivates repressor binding to the operator site on DNA so that initiation of transcription is down or up-regulated, respectively. Excess or deficient supply of an amino acid also speeds or slows, respectively, the rate by which the ribosome translates mRNA base triplets encoding this amino acid. In attenuation of transcription, it is the rate by which the ribosome translates such "own" codons in the leader of an amino acid biosynthetic operon that decides whether the RNA polymerase will continue into the operon, or whether transcription will be aborted (attenuated). If the ribosome rate is fast (excess synthesis of amino acid), transcription will be terminated and if the rate is slow (deficient amino acid supply) transcription will continue and produce more messenger RNAs. Repressor and attenuation control systems have been modelled mathematically so that their behaviour in living cells can be predicted and their system properties compared. It is found that both types of control systems are unexpectedly sensitive when they operate in the cytoplasm of bacteria. In the repressor case, this is because amino acid concentrations are hypersensitive to imbalances between supply and demand. In the attenuation case, the reason is that the rate by which ribosomes translate own codons is hypersensitive to the rate by which the controlled amino acid is synthesised. Both repressor and attenuation mechanisms attain close to Boolean properties in vivo: gene expression is either fully on or fully off except in a small interval around the point where supply and demand of an amino acid are perfectly balanced.Our results suggest that repressors have significantly better intracellular performance than attenuator mechanisms. The reason for this is that repressor, but not attenuator, mechanisms can regulate expression from biosynthetic operons also when transfer RNAs are fully charged with amino acids so that the ribosomes work with maximal speed.

Exclusion of deep vein thrombosis using the Wells rule in clinically important subgroups: individual patient data meta-analysis.

OBJECTIVE: To assess the accuracy of the Wells rule for excluding deep vein thrombosis and whether this accuracy applies to different subgroups of patients. DESIGN: Meta-analysis of individual patient data. DATA SOURCES: Authors of 13 studies (n = 10,002) provided their datasets, and these individual patient data were merged into one dataset. ELIGIBILITY CRITERIA: Studies were eligible if they enrolled consecutive outpatients with suspected deep vein thrombosis, scored all variables of the Wells rule, and performed an appropriate reference standard. MAIN OUTCOME MEASURES: Multilevel logistic regression models, including an interaction term for each subgroup, were used to estimate differences in predicted probabilities of deep vein thrombosis by the Wells rule. In addition, D-dimer testing was added to assess differences in the ability to exclude deep vein thrombosis using an unlikely score on the Wells rule combined with a negative D-dimer test result. RESULTS: Overall, increasing scores on the Wells rule were associated with an increasing probability of having deep vein thrombosis. Estimated probabilities were almost twofold higher in patients with cancer, in patients with suspected recurrent events, and (to a lesser extent) in males. An unlikely score on the Wells rule (≤ 1) combined with a negative D-dimer test result was associated with an extremely low probability of deep vein thrombosis (1.2%, 95% confidence interval 0.7% to 1.8%). This combination occurred in 29% (95% confidence interval 20% to 40%) of patients. These findings were consistent in subgroups defined by type of D-dimer assay (quantitative or qualitative), sex, and care setting (primary or hospital care). For patients with cancer, the combination of an unlikely score on the Wells rule and a negative D-dimer test result occurred in only 9% of patients and was associated with a 2.2% probability of deep vein thrombosis being present. In patients with suspected recurrent events, only the modified Wells rule (adding one point for the previous event) is safe. CONCLUSION: Combined with a negative D-dimer test result (both quantitative and qualitative), deep vein thrombosis can be excluded in patients with an unlikely score on the Wells rule. This finding is true for both sexes, as well as for patients presenting in primary and hospital care. In patients with cancer, the combination is neither safe nor efficient. For patients with suspected recurrent disease, one extra point should be added to the rule to enable a safe exclusion.

High-throughput gene expression analysis at the level of single proteins using a microfluidic turbidostat and automated cell tracking.

We have developed a method combining microfluidics, time-lapsed single-molecule microscopy and automated image analysis allowing for the observation of an excess of 3000 complete cell cycles of exponentially growing Escherichia coli cells per experiment. The method makes it possible to analyse the rate of gene expression at the level of single proteins over the bacterial cell cycle. We also demonstrate that it is possible to count the number of non-specifically DNA binding LacI-Venus molecules using short excitation light pulses. The transcription factors are localized on the nucleoids in the cell and appear to be uniformly distributed on chromosomal DNA. An increase in the expression of LacI is observed at the beginning of the cell cycle, possibly because some gene copies are de-repressed as a result of partitioning inequalities at cell division. Finally, a size-growth rate uncertainty relation is observed where cells living in rich media vary more in the length at birth than in generation time, and the opposite is true for cells living in poorer media.

Performance of two relatively new quantitative D-dimer assays (Innovance D-dimer and AxSYM D-dimer) for the exclusion of deep vein thrombosis.

INTRODUCTION: D-dimer assays are now widely used as the first-line test in the diagnostic algorithm of suspected deep vein thrombosis (DVT). The aim of this study was to evaluate the performance of two relatively new quantitative D-Dimer assays (Innovance and AxSYM) by comparison with a clinical gold standard. PATIENTS AND METHODS: 311 samples from outpatients with clinical suspicion of DVT, included in a prospective management study, was analysed (prevalence of DVT 23%). The diagnostic workup included estimation of pre-test probability, D-dimer determination, objective imaging as well as 3 month clinical follow up of negative patients. RESULTS: No significant differences were seen in sensitivity and negative predictive values between Innovance, AxSYM and the reference assays. The area under the ROC curve was slightly lower for the AxSYM assay and the correlation to the reference assays was only moderate (r < 0.8) whereas the agreement with the Vidas assay was near excellent (kappa = 0.8). The Innovance assay reached the highest AUC, showed a strong correlation with the reference assays (r > or = 0.9) and a good agreement with the Vidas assay (kappa = 0.76). In combination with a low pre-test probability score the Innovance assay reached a NPV of 100% (95% CI, 92-100) and the AxSYM assay 98% (95% CI, 87-100). CONCLUSION: The Innovance and AxSYM assays show an overall good and comparable performance for the exclusion of DVT when compared to the established assays. Our results for the AxSYM assay indicate that the optimal cut-off value needs to be further evaluated.

Signal transduction activator of transcription 5 (STAT5) dysfunction in autoimmune monocytes and macrophages.

Autocrine granulocyte macrophage-colony stimulating factor (GM-CSF) sequentially activates intracellular components in monocyte/macrophage production of the pro-inflammatory and immunoregulatory prostanoid, prostaglandin E2 (PGE2). GM-CSF first induces STAT5 signaling protein phosphorylation, then prostaglandin synthase 2 (COX2/PGS2) gene expression, and finally IL-10 production, to downregulate the cascade. Without activation, monocytes of at-risk, type 1 diabetic (T1D), and autoimmune thyroid disease (AITD) humans, and macrophages of nonobese diabetic (NOD) mice have aberrantly high GM-CSF, PGS2, and PGE2 expression, but normal levels of IL-10. After GM-CSF stimulation, repressor STAT5A and B isoforms (80-77kDa) in autoimmune human and NOD monocytes and activator STAT5A (96-94kDa) and B (94-92kDa) isoforms in NOD macrophages stay persistently tyrosine phosphorylated. This STAT5 phosphorylation persisted despite treatment in vitro with IL-10, anti-GM-CSF antibody, or the JAK2/3 inhibitor, AG490. Phosphorylated STAT5 repressor isoforms in autoimmune monocytes had diminished DNA binding capacity on GAS sequences found in the PGS2 gene enhancer. In contrast, STAT5 activator isoforms in NOD macrophages retained their DNA binding capacity on these sites much longer than in healthy control strain macrophages. These findings suggest that STAT5 dysfunction may contribute to dysregulation of GM-CSF signaling and gene activation, including PGS2, in autoimmune monocytes and macrophages.

Spontaneous separation of bi-stable biochemical systems into spatial domains of opposite phases.

Bi-stable chemical systems are the basic building blocks for intracellular memory and cell fate decision circuits. These circuits are built from molecules, which are present at low copy numbers and are slowly diffusing in complex intracellular geometries. The stochastic reaction-diffusion kinetics of a double-negative feedback system and a MAPK phosphorylation-dephosphorylation system is analysed with Monte-Carlo simulations of the reaction-diffusion master equation. The results show the geometry of intracellular reaction compartments to be important both for the duration and the locality of biochemical memory. Rules for when the systems lose global hysteresis by spontaneous separation into spatial domains in opposite phases are formulated in terms of geometrical constraints, diffusion rates and attractor escape times. The analysis is facilitated by a new efficient algorithm for exact sampling of the Markov process corresponding to the reaction-diffusion master equation.