Summary During the past 10 years, multidrug-resistant Gram-negative Enterobacteriaceae have become a substantial challenge to infection control. It has been suggested by clinicians that the ...effectiveness of antibiotics is in such rapid decline that, depending on the pathogen concerned, their future utility can be measured in decades or even years. Unless the rise in antibiotic resistance can be reversed, we can expect to see a substantial rise in incurable infection and fatality in both developed and developing regions. Antibiotic resistance develops through complex interactions, with resistance arising by de-novo mutation under clinical antibiotic selection or frequently by acquisition of mobile genes that have evolved over time in bacteria in the environment. The reservoir of resistance genes in the environment is due to a mix of naturally occurring resistance and those present in animal and human waste and the selective effects of pollutants, which can co-select for mobile genetic elements carrying multiple resistant genes. Less attention has been given to how anthropogenic activity might be causing evolution of antibiotic resistance in the environment. Although the economics of the pharmaceutical industry continue to restrict investment in novel biomedical responses, action must be taken to avoid the conjunction of factors that promote evolution and spread of antibiotic resistance.
Variations in the blood coagulation activity, determined genetically or by medication, may alter atherosclerotic plaque progression, by influencing pleiotropic effects of coagulation proteases. ...Published experimental studies have yielded contradictory findings on the role of hypercoagulability in atherogenesis. We therefore sought to address this matter by extensively investigating the in vivo significance of genetic alterations and pharmacologic inhibition of thrombin formation for the onset and progression of atherosclerosis, and plaque phenotype determination.
We generated transgenic atherosclerosis-prone mice with diminished coagulant or hypercoagulable phenotype and employed two distinct models of atherosclerosis. Gene-targeted 50% reduction in prothrombin (FII(-/WT):ApoE(-/-)) was remarkably effective in limiting disease compared to control ApoE(-/-) mice, associated with significant qualitative benefits, including diminished leukocyte infiltration, altered collagen and vascular smooth muscle cell content. Genetically-imposed hypercoagulability in TM(Pro/Pro):ApoE(-/-) mice resulted in severe atherosclerosis, plaque vulnerability and spontaneous atherothrombosis. Hypercoagulability was associated with a pronounced neutrophilia, neutrophil hyper-reactivity, markedly increased oxidative stress, neutrophil intraplaque infiltration and apoptosis. Administration of either the synthetic specific thrombin inhibitor Dabigatran etexilate, or recombinant activated protein C (APC), counteracted the pro-inflammatory and pro-atherogenic phenotype of pro-thrombotic TM(Pro/Pro):ApoE(-/-) mice.
We provide new evidence highlighting the importance of neutrophils in the coagulation-inflammation interplay during atherogenesis. Our findings reveal that thrombin-mediated proteolysis is an unexpectedly powerful determinant of atherosclerosis in multiple distinct settings. These studies suggest that selective anticoagulants employed to prevent thrombotic events may also be remarkably effective in clinically impeding the onset and progression of cardiovascular disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Essentials
The value of compression therapy in acute phase of deep vein thrombosis is still unclear.
Patients with deep vein thrombosis received acute compression hosiery, bandaging, or none.
Acute ...compression reduces irreversible skin signs related to post thrombotic syndrome.
Compression hosiery may be the preferred choice for the acute phase
Summary
Background
The effectiveness of compression therapy in the acute phase of deep vein thrombosis (DVT) is not yet determined.
Objectives
To investigate the impact of compression therapy in the acute phase of DVT on determinants of the Villalta score, health‐related quality of life (HRQOL), and costs.
Patients/Methods
Eight hundred and sixty‐five patients with proximal DVT (substudy of the IDEAL DVT study) received, immediately after DVT diagnosis, either no compression, multilayer bandaging, or hosiery. In the acute phase and 3 months after diagnosis, HRQOL was determined by use of the EQ‐5D, SF6D, and VEINES‐QoL intrinsic method (VEINES‐QoLint). At 3 months, signs and symptoms were assessed for the total and separate items of the Villalta score, and healthcare costs were calculated.
Results
The compression groups had lower overall objective Villalta scores than the no‐compression group (1.47 standard deviation (SD) 1.570 and 1.59 SD 1.64 versus 2.21 SD 2.15). The differences were mainly attributable to irreversible skin signs (induration, hyperpigmentation, and venectasia) and pain on calf compression. Subjective and total Villalta scores were similar across groups. Differences in HRQOL were only observed at 1 month; HRQOL was better for hosiery (EQ‐5D 0.86 SD 0.18; VEINES‐QoLint 0.66 SD 0.18) than for multilayer compression bandaging (EQ‐5D 0.81 SD 0.23; VEINES‐QoLint 0.62 SD 0.19). Mean healthcare costs per patient were €417.08 (€354.10 to €489.30) for bandaging, €114.25 (€92.50 to €198.43) for hosiery, and €105.86 (€34.63 to €199.30) for no compression.
Conclusions
Initial compression reduces irreversible skin signs, edema, and pain on calf compression. Multilayer bandaging is slightly more effective than hosiery, but has substantially higher costs, without a gain in HRQOL. From a patient and economic perspective, compression hosiery would be preferred when initial compression is applied. Trial registration: IDEAL DVT study ClinicalTrials.gov number, NCT01429714.
Diagnostic and treatment response criteria for the JAK2/CALR/MPL mutation-related myeloproliferative neoplasms (MPNs) are largely based on bone marrow (BM) biopsy results. However, these biopsies ...have several limitations, such as the risk of sampling error. Also, the prognostic impact of BM abnormalities is largely unclear. Although not currently used in clinical practice, imaging techniques might offer additional information. In this review, we investigated the value of BM, liver, and spleen imaging for diagnosis, prognostication, and response monitoring of the JAK2/CALR/MPL mutation-related MPNs (i.e. essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF)).
A systematic literature search was performed via PubMed, Embase and the Cochrane Library up to 2020 March 26th. Of 5505 identified records, 55 publications met the eligibility criteria (i.e. containing original data on the imaging appearance of BM, spleen, or liver in adult ET, PV, or MF patients, published in a peer-reviewed journal, written in English).
Many explorative studies described imaging features, sometimes with comparisons to clinical characteristics. Studies reporting measures of diagnostic accuracy included 1) splenic transient elastography to predict BM fibrosis grade in MF, 2) dynamic contrast-enhanced MRI to discern MF patients from ET patients and healthy controls, and 3) 18-fluorodeoxyglucose PET to detect residual disease after stem cell transplantation in MF. The diagnostic accuracies of radiography and
Tc-colloid scintigraphy were derived from several other articles. Except for the study on 18-fluorodeoxyglucose PET, we established substantial concerns regarding risk of bias and applicability across these studies, using the QUADAS-2 tool. Three publications described a correlation between imaging results and prognosis, of which one quantified the effect.
Based on current data, MRI (T1-weighted/STIR, Dixon) seems especially promising for the evaluation of BM fat content - and indirectly cellularity/fibrosis - in MF, and possibly for estimating BM cellularity in ET/PV. 18-fluorodeoxyglucose and 18-fluorothymidine PET/CT might be useful for evaluating BM fibrosis, with good reported accuracy of the former for the diagnosis of residual disease. Further research on these and other techniques is warranted to determine their exact value. Future researchers should improve methodology and focus on evaluation of diagnostic accuracy and prognostic implications of results.
The incidence of neutropenia in metastatic castration‐resistant prostate cancer (mCRPC) patients treated with docetaxel has been reported to be lower compared to patients with other solid tumors ...treated with a similar dose. It is suggested that this is due to increased clearance of docetaxel in mCRPC patients, resulting in decreased exposure. The aims of this study were to (1) determine if exposure in mCRPC patients is lower vs patients with other solid tumors by conducting a meta‐analysis, (2) evaluate the incidence of neutropenia in patients with mCRPC vs other solid tumors in a clinical cohort, and (3) discuss potential clinical consequences. A meta‐analysis was conducted of studies which reported areas under the plasma concentration‐time curves (AUCs) of docetaxel and variability. In addition, grade 3/4 neutropenia was evaluated using logistic regression in a cohort of patients treated with docetaxel. The meta‐analysis included 36 cohorts from 26 trials (n = 1150 patients), and showed that patients with mCRPC had a significantly lower mean AUC vs patients with other solid tumors (fold change 95% confidence interval (CI): 1.8 1.5‐2.2), with corresponding AUCs of 1.82 and 3.30 mg∙h/L, respectively. Logistic regression, including 812 patient, demonstrated that patients with mCRPC had a 2.2‐fold lower odds of developing grade 3/4 neutropenia compared to patients with other solid tumors (odds ratio 95%CI: 0.46 0.31‐0.90). These findings indicate that mCRPC patients have a lower risk of experiencing severe neutropenia, possibly attributable to lower systemic exposure to docetaxel.
Patients with mCRPC have a significantly (1.8‐fold) lower docetaxel AUC compared to patients with other solid tumors, determined by our meta‐analysis. This could explain the lower incidence of neutropenia reported for this patient population, and confirmed by analysis of our clinical cohorts.
Background: Patients with a first episode of idiopathic venous thromboembolism (IVTE) have an estimated 10% incidence of cancer within 12 months after diagnosis. However, the utility of screening for ...cancer in this population is controversial. Methods: In this prospective concurrently controlled cohort study, limited and extensive cancer screening strategies were compared. All 630 patients underwent baseline screening consisting of history, physical examination, basic laboratory tests and chest X‐ray. In the extensive screening group abdominal and chest CT scan and mammography were added. Outcomes were incidence and curability of cancer, and cancer‐related and overall mortality. Results: In 12 of the 342 (3.5%) patients in the extensive screening group malignancy was diagnosed at baseline compared with 2.4% (seven of 288 patients) in the limited screening group. Extensive screening detected six additional cancers (2.0%; 95% CI, 0.74–4.3), of which three were potentially curable. During a median 2.5 years of follow‐up, cancer was diagnosed in 3.7% and 5.0% in the extensive and limited screening groups, respectively. In the extensive screening group 26 patients (7.6%) died compared with 24 (8.3%) in the limited screening group; adjusted hazard ratio 1.22 (95% CI, 0.69–2.22). Of these deaths 17 (5.0%) in the extensive screening group and 8 (2.8%) in the limited screening group were cancer related; adjusted hazard ratio 1.79 (95% CI, 0.74–4.35). Conclusions: The low yield of extensive screening and lack of survival benefit do not support routine screening for cancer with abdominal and chest CT scan and mammography in patients with a first episode of IVTE.
Analysis of myeloid-related protein 8 and 14 complex (MRP8/14) serum concentrations is a potential new tool to support the diagnosis of systemic-onset juvenile idiopathic arthritis (SJIA) in the ...presence of fever of unknown origin.
To test the ability of MRP8/14 serum concentrations to monitor disease activity in patients with SJIA and stratify patients at risk of relapse.
Serum concentrations of MRP8/14 in 52 patients with SJIA were determined by a sandwich ELISA. The monitoring of therapeutic regimens targeting interleukin 1 and tumour necrosis factor α, and methotrexate treatment was analysed and diagnostic power to predict flares was tested.
MRP8/14 levels were clearly raised in active disease and decreased significantly in response to successful treatments. Serum concentrations of MRP8/14 increased significantly (p<0.001) (mean±95% CI 12.030±3.090 ng/ml) during disease flares compared with patients with inactive disease (864±86 ng/ml). During clinical remission MRP8/14 serum levels of >740 ng/ml predicted disease flares accurately (sensitivity 92%, specificity 88%). MRP8/14 levels correlated well with clinical disease activity, as assessed by physician's global assessment of disease activity (r=0.62), Childhood Health Assessment Questionnaire (r=0.56), active joint count (r=0.46) and with C-reactive protein (r=0.71) and erythrocyte sedimentation rate (r=0.72) (for all p<0.001).
MRP8/14 serum concentrations correlate closely with response to drug treatment and disease activity and therefore might be an additional measurement for monitoring anti-inflammatory treatment of individual patients with SJIA. MRP8/14 serum concentrations are the first predictive biomarker indicating subclinical disease activity and stratifying patients at risk of relapse during times of clinically inactive disease.
Studies in cancer patients with venous thromboembolism suggested that low molecular weight heparin may prolong survival. In a double-blind study, we evaluated the effect of low molecular weight ...heparin on survival in patients with advanced malignancy without venous thromboembolism.
Patients with metastasized or locally advanced solid tumors were randomly assigned to receive a 6-week course of subcutaneous nadroparin or placebo. The primary efficacy analysis was based on time from random assignment to death. The primary safety outcome was major bleeding.
In total, 148 patients were allocated to nadroparin and 154 patients were allocated to placebo. Mean follow-up was 1 year. In the intention-to-treat analysis the overall hazard ratio of mortality was 0.75 (95% CI, 0.59 to 0.96) with a median survival of 8.0 months in the nadroparin recipients versus 6.6 months in the placebo group. After adjustment for potential confounders, the treatment effect remained statistically significant. Major bleeding occurred in five (3%) of nadroparin-treated patients and in one (1%) of the placebo recipients (P = .12). In the a priori specified subgroup of patients with a life expectancy of 6 months or more at enrollment, the hazard ratio was 0.64 (95% CI, 0.45 to 0.90) with a median survival of 15.4 and 9.4 months, respectively. For patients with a shorter life expectancy, the hazard ratio was 0.88 (95% CI, 0.62 to 1.25).
A brief course of subcutaneous low molecular weight heparin favorably influences the survival in patients with advanced malignancy and deserves additional clinical evaluation.
The impact of cardiovascular disease (CVD) risk factors, encompassing various biological determinants and unhealthy lifestyles, on the functional dynamics of circulating monocytes-a pivotal cell type ...in CVD pathophysiology remains elusive. In this study, we aimed to elucidate the influence of CVD risk factors on monocyte transcriptional responses to an infectious stimulus.
We conducted a comparative analysis of monocyte gene expression profiles from the CTMM - CIRCULATING CELLS Cohort of coronary artery disease (CAD) patients, at baseline and after lipopolysaccharide (LPS) stimulation. Gene co-expression analysis was used to identify gene modules and their correlations with CVD risk factors, while pivotal transcription factors controlling the hub genes in these modules were identified by regulatory network analyses. The identified gene module was subjected to a drug repurposing screen, utilizing the LINCS L1000 database.
Monocyte responsiveness to LPS showed a highly significant, negative correlation with blood pressure levels (ρ< -0.4; P<10
). We identified a ZNF12/ZBTB43-driven gene module closely linked to diastolic blood pressure, suggesting that monocyte responses to infectious stimuli, such as LPS, are attenuated in CAD patients with elevated diastolic blood pressure. This attenuation appears associated with a dampening of the LPS-induced suppression of oxidative phosphorylation. Finally, we identified the serine-threonine inhibitor MW-STK33-97 as a drug candidate capable of reversing this aberrant LPS response.
Monocyte responses to infectious stimuli may be hampered in CAD patients with high diastolic blood pressure and this attenuated inflammatory response may be reversed by the serine-threonine inhibitor MW-STK33-97. Whether the identified gene module is a mere indicator of, or causal factor in diastolic blood pressure and the associated dampened LPS responses remains to be determined.
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