Elevated factor XI is associated with increased risk of recurrent cerebral venous sinus thrombosis: a cohort study.

Cerebral venous sinus thrombosis (CVST) has no identified cause in 15% of cases. Elevated factors (F) VIII and FXI have been associated with thromboembolism, but data on CVST are limited. We hypothesized that elevated plasma FVIII and FXI predispose to first and recurrent CVST. In 50 CVST survivors aged < 60 years, following anticoagulant cessation and in 50 controls, we determined plasma FVIII and FXI, along with fibrin clot properties: lysis time, permeability, maximum D-dimer (D-Dmax), and maximum rate of D-dimer increase (D-Drate). We recorded CVST recurrence during a follow-up of 58.5 (55.0-60.0) months. Plasma FVIII was 22.7% higher in CVST than in controls, with elevated FVIII > 150% in 13 (26%) vs. 4 (8%) patients, respectively (p = 0.02). Median FXI tended to be higher in CVST vs. controls (110.5 [99.0-117-0]% vs. 104.5 [97.0-116.0]%, p = 0.07), while FXI > 120% was observed more commonly in the former group (12 [24%] vs. 4 [8%], respectively, p = 0.03). Patients with FVIII > 150% were less likely to achieve complete recanalization compared with the remainder (2 [15.4%] vs. 28 [75.7%], respectively; p < 0.001). Eight patients (16%) experienced CVST recurrence. They had higher baseline FXI, but not FVIII, as compared with the remainder (125.5 [114.5-140.0]% vs. 107.5 [102.0-117.0]%, respectively, p = 0.01). Patients with FXI > 120% were four times more likely to have recurrent CVST (5 [62.5%] vs. 7 [16.7%], respectively; p = 0.01). Plasma FXI > 120% could represent a novel risk factor for first and recurrent CVST. Given advances in anti-FXI agents, CVST might be another indication for this emerging treatment.

Protein Carbonylation Contributes to Prothrombotic Fibrin Clot Phenotype in Acute Ischemic Stroke: Clinical Associations.

BACKGROUND: Acute ischemic stroke (AIS) is associated with enhanced oxidative stress and unfavorably altered fibrin clot properties. We investigated determinants of plasma protein carbonylation (PC) in AIS, its impact on the prothrombotic state, and prognostic value during follow-up. METHODS: We included 98 consecutive AIS patients aged 74±12 years (male:female ratio, 50:48 [51%:49%]) at the Neurology Center in Warsaw, Poland, between January and December 2014. As many as 74 (75.5%) patients underwent thrombolysis, and 24 were unsuitable for thrombolysis. We determined plasma PC, along with thrombin generation, fibrin clot permeability, and clot lysis time on admission, at 24 hours, and 3 months. Stroke severity was assessed using the National Institutes of Health Stroke Scale and stroke outcome with the modified Rankin Scale. Hemorrhagic transformation was assessed on the computed tomography scan within 48 hours from the symptom onset, while stroke-related mortality was evaluated at 3 months. RESULTS: On admission, PC levels (median, 4.61 [3.81-5.70] nM/mg protein) were associated with the time since symptom onset (r=0.41; P<0.0001) and with the National Institutes of Health Stroke Scale score (P=0.36; P=0.0003). Higher PC levels on admission correlated with denser fibrin clot formation and prolonged clot lysis time but not with thrombin generation. In thrombolysed patients, lower PC levels were observed after 24 hours (-34%) and at 3 months (-23%; both P<0.001). PC levels at baseline and after 24 hours predicted the modified Rankin Scale score >2 at 3 months (OR, 1.90 [95% CI, 1.21-3.00]; OR, 2.19 [95% CI, 1.39-3.44], respectively). Higher PC at baseline predicted hemorrhagic transformation of stroke (OR, 1.95 [95% CI, 1.02-3.74]) and stroke-related mortality (OR, 2.02 [95% CI, 1.08-3.79]), while higher PC at 24 hours predicted solely stroke-related mortality (OR, 2.11 [95% CI, 1.28-3.46]). CONCLUSIONS: Elevated plasma PC levels in patients with AIS, related to prothrombotic fibrin clot properties, are associated with stroke severity. Thrombolysis reduces the extent of PC. The current study suggests a prognostic value of PC in AIS.

Elevated plasma factor XI predicts cardiovascular events in patients with type 2 diabetes: a long-term observational study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) patients are at high risk of cardiovascular (CV) events. Factor XI (FXI) is associated with arterial thromboembolism, including myocardial infarction (MI), stroke, and CV mortality. The role of FXI in T2DM is unknown. We investigated whether plasma FXI is associated with CV events in T2DM patients in long-term observation. METHODS: In 133 T2DM patients (aged 66 ± 8 years, 40.6% women, median T2DM duration 5 [2-10] years) we assessed plasma FXI levels, along with fibrin clot properties, thrombin generation, and fibrinolysis proteins. A composite endpoint of MI, stroke, or CV death, as well as CV mortality alone were assessed during a median follow-up of 72 months. RESULTS: Plasma FXI above the 120% upper normal limit was detected in 25 (18.8%) patients and showed positive association with LDL cholesterol and thrombin activatable fibrinolysis inhibitor, but not glycated hemoglobin, inflammatory markers or thrombin generation. The composite endpoint (n = 21, 15.8%) and CV death alone (n = 16, 12%) were more common in patients with elevated FXI (hazard ratio [HR] 10.94, 95% confidence interval [CI] 4.46-26.87, p < 0.001 and HR 7.11, 95% CI 2.61-19.31, p < 0.001, respectively). On multivariable analysis, FXI remained an independent predictor of the composite endpoint and CV death, regardless of concomitant coronary artery disease. CONCLUSIONS: To our knowledge, this study is the first to show that in T2DM patients, elevated FXI could predict major CV events, including mortality, which suggest that anti-FXI agents might be a potential novel antithrombotic option in this disease.

Risk and benefit for umbrella trials in oncology: a systematic review and meta-analysis.

BACKGROUND: Umbrella clinical trials in precision oncology are designed to tailor therapies to the specific genetic changes within a tumor. Little is known about the risk/benefit ratio for umbrella clinical trials. The aim of our systematic review with meta-analysis was to evaluate the efficacy and safety profiles in cancer umbrella trials testing targeted drugs or a combination of targeted therapy with chemotherapy. METHODS: Our study was prospectively registered in PROSPERO (CRD42020171494). We searched Embase and PubMed for cancer umbrella trials testing targeted agents or a combination of targeted therapies with chemotherapy. We included solid tumor studies published between 1 January 2006 and 7 October 2019. We measured the risk using drug-related grade 3 or higher adverse events (AEs), and the benefit by objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). When possible, data were meta-analyzed. RESULTS: Of the 6207 records identified, we included 31 sub-trials or arms of nine umbrella trials (N = 1637). The pooled overall ORR was 17.7% (95% confidence interval [CI] 9.5-25.9). The ORR for targeted therapies in the experimental arms was significantly lower than the ORR for a combination of targeted therapy drugs with chemotherapy: 13.3% vs 39.0%; p = 0.005. The median PFS was 2.4 months (95% CI 1.9-2.9), and the median OS was 7.1 months (95% CI 6.1-8.4). The overall drug-related death rate (drug-related grade 5 AEs rate) was 0.8% (95% CI 0.3-1.4), and the average drug-related grade 3/4 AE rate per person was 0.45 (95% CI 0.40-0.50). CONCLUSIONS: Our findings suggest that, on average, one in five cancer patients in umbrella trials published between 1 January 2006 and 7 October 2019 responded to a given therapy, while one in 125 died due to drug toxicity. Our findings do not support the expectation of increased patient benefit in cancer umbrella trials. Further studies should investigate whether umbrella trial design and the precision oncology approach improve patient outcomes.

Machine learning for impurity charge-state transition levels in semiconductors from elemental properties using multi-fidelity datasets.

Quantifying charge-state transition energy levels of impurities in semiconductors is critical to understanding and engineering their optoelectronic properties for applications ranging from solar photovoltaics to infrared lasers. While these transition levels can be measured and calculated accurately, such efforts are time-consuming and more rapid prediction methods would be beneficial. Here, we significantly reduce the time typically required to predict impurity transition levels using multi-fidelity datasets and a machine learning approach employing features based on elemental properties and impurity positions. We use transition levels obtained from low-fidelity (i.e., local-density approximation or generalized gradient approximation) density functional theory (DFT) calculations, corrected using a recently proposed modified band alignment scheme, which well-approximates transition levels from high-fidelity DFT (i.e., hybrid HSE06). The model fit to the large multi-fidelity database shows improved accuracy compared to the models trained on the more limited high-fidelity values. Crucially, in our approach, when using the multi-fidelity data, high-fidelity values are not required for model training, significantly reducing the computational cost required for training the model. Our machine learning model of transition levels has a root mean squared (mean absolute) error of 0.36 (0.27) eV vs high-fidelity hybrid functional values when averaged over 14 semiconductor systems from the II-VI and III-V families. As a guide for use on other systems, we assessed the model on simulated data to show the expected accuracy level as a function of bandgap for new materials of interest. Finally, we use the model to predict a complete space of impurity charge-state transition levels in all zinc blende III-V and II-VI systems.

Factors Influencing the Concentration of Exhaled Nitric Oxide (FeNO) in School Children Aged 8-9-Years-Old in Krakow, with High FeNO Values ≥ 20 ppb.

Background and Objectives: Measurement of fractional exhaled nitric oxide (FeNO) concentration is currently used as a non-invasive biomarker to assess airway inflammation. Many factors can influence the FeNO level. However, there have been no reports concerning factors attributed to FeNO levels in different age groups of children, especially those with high FeNO values. Therefore, this study aimed to assess the influence of selected factors on nitric oxide concentration in exhaled air in children aged 8-9 attending class 3 of public primary schools in Krakow with high FeNO values ≥ 20 ppb. Materials and Methods: The population-based study covered all third-grade pupils attending primary schools in the city of Krakow. Five thousand, four hundred and sixty children participated in the first screening stage, conducted from October 2017 to January 2018. Then, 792 participants with an FeNO level ≥ 20 ppb were selected. Finally, those selected pupils were invited to participate in the second stage, diagnostic, in April 2018. Four hundred and fifty-four children completed the diagnostic stage of the study, and their data was included in the presented analysis. Results and Conclusions: Significantly higher FeNO levels were observed in children diagnosed with the following diseases: asthma, allergic rhinitis, atopic dermatitis, and allergy (p < 0.05). In addition, it was observed that a higher FeNO concentration characterised children taking antihistamines compared to children not taking those medications (p = 0.008). In multivariate models, we observed that regardless of sex, age, BMI value, home smoking, and whether they were taking medications, children who had allergic rhinitis, or atopic dermatitis, or allergies had significantly higher FeNO levels. The strongest relationship was noted with allergic diseases. The results of our study may be of importance to clinicians when interpreting FeNO results, for example, when making a therapeutic decision.

Plasma fibrin clot properties and cardiovascular mortality in patients with type 2 diabetes: a long-term follow-up study.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) are at high risk of cardiovascular mortality, but the mechanisms behind this remain unclear. Prothrombotic fibrin clot properties have been shown in T2DM and cardiovascular disease. We hypothesized that formation of denser clots, which are resistant to fibrinolysis, has a negative impact on cardiovascular mortality in T2DM. METHODS: We studied 133 T2DM patients aged 43-83 years. Plasma fibrin clot turbidity, permeation, compaction, and efficiency of clot lysis using 3 assays including the determination of maximum concentration (D-Dmax) and rate of increase in D-dimer concentration (D-Drate) released during tissue plasminogen activator-induced degradation, were evaluated at the time of enrollment, along with thrombin generation and fibrinolytic proteins. During a median follow-up period of 72 months, cardiovascular mortality was recorded. RESULTS: Cardiovascular deaths (n = 16, 12%) occurred more frequently in patients with increased D-Dmax (> 4.26 mg/l, hazard ratio [HR] 5.43, 95% confidence interval [CI] 1.99-14.79), or decreased D-Drate (< 0.07 mg/l/min, HR 2.97, 95% CI 1.07-8.23), or increased peak thrombin (> 283.5 nM, HR 5.65, 95% CI 2.07-15.51). These predictors had an even more potent impact on cardiovascular mortality in patients with prior cardiovascular disease (64.7%) and with corresponding risks as follows: HR 6.18, 95% CI 2.02-18.96; HR 8.98, 95% CI 2.99-26.96; and HR 5.35, 95% CI 1.62-17.72, respectively. Other investigated fibrin variables and fibrinolytic proteins did not associate with cardiovascular mortality. In multivariable analysis, cardiovascular mortality was predicted by D-Dmax > 4.26 mg/l, age > 65 years, prior cardiovascular disease, and C-reactive protein > 3 mg/l. CONCLUSIONS: This study is the first to show that formation of denser fibrin clots resistant to fibrinolysis could be a risk factor for long-term cardiovascular mortality in T2DM.

Effectiveness of experimental and commercial pertussis vaccines in the elimination of Bordetella pertussis isolates with different genetic profiles in murine model.

The aim of this study was to compare the elimination of Bordetella pertussis clinical isolates, representing different genotypes in relation to alleles encoding virulence factors (MLST-multi-locus antigen sequence typing), MLVA type (multi-locus variable-number tandem repeat analysis) and PFGE group (pulsed-field gel electrophoresis) from the lungs of naive mice or mice were immunised with the commercial whole-cell pertussis vaccine, the acellular pertussis vaccine and the experimental whole-cell pertussis vaccine. Molecular data indicate that the resurgence of pertussis in populations with high vaccine coverage is associated with genomic adaptation of B. pertussis, to vaccine selection pressure. Pertactin-negative B. pertussis isolates were suspected to contribute to the reduced vaccine effectiveness. It was shown that one of the isolates used is PRN deficient. The mice were intranasally challenged with bacterial suspension containing approximately 5 × 10 7 CFU/ml B. pertussis. The immunogenicity of the tested vaccines against PT (pertussis toxin), PRN (pertactin), FHA (filamentous haemagglutinin) and FIM (fimbriae types 2 and 3) was examined. The commercial whole-cell and acellular pertussis vaccines induced an immunity effective at eliminating the genetically different B. pertussis isolates from the lungs. However, the elimination of the PRN-deficient isolate from the lungs of mice vaccinated with commercial vaccines was delayed as compared to the PRN ( +) isolate, suggesting phenotypic differences with the circulating isolates and vaccine strains. The most effective vaccine was the experimental vaccine with the composition identical to that of the strains used for infection.

Prognostic Factors for Nonasphyxia-Related Cardiac Arrest Patients Undergoing Extracorporeal Rewarming - HELP Registry Study.

OBJECTIVE: Extracorporeal rewarming is the treatment of choice for patients who had hypothermic cardiac arrest, allowing for best neurologic outcome. The authors' goal was to identify factors associated with survival in nonasphyxia-related hypothermic cardiac arrest patients undergoing extracorporeal rewarming. DESIGN: All 38 cardiac surgery departments in Poland were encouraged to report consecutive hypothermic cardiac arrest patients treated with extracorporeal life support. All variables collected were analyzed in order to compare survivor and nonsurvivor groups. The parameters available at the initiation of extracorporeal rewarming were considered as potential predictors of survival in a logistic regression model. The primary outcome was survival to discharge from the intensive care unit. The secondary outcome was neurologic status. SETTING: Multicenter retrospective study. PARTICIPANTS: Ninety-eight cases in the final analysis. INTERVENTIONS: All patients in nonasphyxia-related hypothermic cardiac arrest rewarmed with extracorporeal life support. MEASUREMENTS AND MAIN RESULTS: The survival rate was 53.1%, and 94.2% of survivors had favorable neurologic outcome. The lowest reported core temperature with cerebral performance category scale 1 was 11.8°C. A univariate analysis identified 3 variables associated with survival, namely: age, initial arterial pH, and lactate concentration. In a multivariate analysis, 2 independent predictors of survival were age (0.957; 95% confidence interval [CI] 0.924-0.991) and lactates (0.871; 95% CI 0.789-0.961). The area under the receiver operating characteristics curve for this fitted model was 0.71; 95% CI 0.602-0.817. CONCLUSIONS: Favorable survival with good neurologic outcome in nonasphyxiated hypothermic patients treated with extracorporeal life support was reported. Age and initial lactate level are independently associated with survival.

Elevated lipoprotein(a) as a new risk factor of cerebral venous sinus thrombosis: association with fibrin clot properties.

Elevated lipoprotein(a) [Lp(a)] has been reported to be associated with prothrombotic clot phenotype. We hypothesized that increased Lp(a) contributes to cerebral venous sinus thrombosis (CVST) and its recurrence in relation to clot features. In 80 consecutive patients (aged 39.36 ± 10.18 years, 61 women) following the first CVST after anticoagulation withdrawal, we assessed Lp(a) levels and plasma clot properties. Recurrence of CVST was recorded during follow-up (median 53, interquartile range 40-59 months). Lp(a) levels were inversely associated with clot permeability (Ks, r = - 0.58, P < 0.001) and the rate of D-dimer release from clots in the presence of tissue plasminogen activator (r = - 0.27, P = 0.017) along with increased maximum absorbance of fibrin gels (r = 0.42, P < 0.001) and maximum D-dimer levels achieved during lysis (D-Dmax, r = 0.29, P = 0.01). Recurrence of CVST was observed in 12 patients (15%) after median follow-up of 26 months. Lp(a) concentrations were higher in patients with recurrence of CVST compared to the remainder (14.15 [8.85-25.25] vs. 28.3 [18.9-35.6] mg/dL; P = 0.001). The risk of recurrent CVST was fourfold higher among 17 (21.25%) patients with Lp(a) > 30 mg/dL compared to the remainder (adjusted hazard ratio, 3.9; 95% confidence interval [CI] 1.23-12.4). Recurrence of CVST was associated with 14% lower Ks (P = 0.001) and 10% higher D-Dmax (P = 0.008), with no differences in other clot features. Multiple logistic regression model showed that CVST recurrence was independently associated with Lp(a) (odds ratio 1.09, 95% CI 1.02-1.16). Increased Lp(a) characterizes subjects at elevated risk of recurrent CVST after anticoagulation withdrawal, which could be partly explained by formation of denser fibrin clots.

Prothrombotic clot properties can predict venous ulcers in patients following deep vein thrombosis: a cohort study.

Venous ulcers are the most severe manifestation of post-thrombotic syndrome (PTS). We have previously demonstrated that formation of compact fibrin clots resistant to lysis is observed in patients following deep-vein thrombosis (DVT) who developed PTS. The current study investigated whether unfavourable fibrin clot properties can predict post-thrombotic venous ulcers. In a cohort study on 186 consecutive patients following DVT, we determined plasma fibrin clot characteristics, including clot permeability and lysability, inflammatory markers, thrombin generation, fibrinolysis proteins at 3 months since the index event. Occurrence of PTS and venous ulcers was recorded during follow-up (median, 53; range 24 to 76 months). Fifty-seven DVT patients (30.6%) developed PTS, including 12 subjects (6.45%) with a venous ulcer (4 individuals with recurrent ulcers). Patients who developed ulcers compared with the remainder had at enrolment 13.0% lower clot permeability (Ks), 17.4% longer clot lysis time (CLT), 13.1% longer lag phase of clot formation, and 5.0% higher maximum absorbance, with no difference in fibrinogen, C-reactive protein, and thrombin generation. The baseline prothrombotic fibrin clot phenotype (Ks ≤ 6.5 × 10-9 cm2 and CLT > 100 min) was associated with a higher risk of ulcers [hazard ratio (HR), 5.37; 95% confidence interval (CI), 1.3-21.5]. A multivariate model adjusted for age, sex, and fibrinogen showed that independent predictors of the ulcer occurrence were body mass index (HR 1.53; 95% CI 1.30-1.86), CLT (HR 1.43; 95% CI 1.04-2.05), and α2-antiplasmin (HR 0.95; 95% CI 0.90-0.99). This study suggests that formation of denser fibrin clots with impaired fibrinolysis predisposes to post-thrombotic venous ulcers.

Perioperative restrictive versus goal-directed fluid therapy for adults undergoing major non-cardiac surgery.

BACKGROUND: Perioperative fluid management is a crucial element of perioperative care and has been studied extensively recently; however, 'the right amount' remains uncertain. One concept in perioperative fluid handling is goal-directed fluid therapy (GDFT), wherein fluid administration targets various continuously measured haemodynamic variables with the aim of optimizing oxygen delivery. Another recently raised concept is that perioperative restrictive fluid therapy (RFT) may be beneficial and at least as effective as GDFT, with lower cost and less resource utilization. OBJECTIVES: To investigate whether RFT may be more beneficial than GDFT for adults undergoing major non-cardiac surgery. SEARCH METHODS: We searched the following electronic databases on 11 October 2019: Cochrane Central Register of Controlled Trials, in the Cochrane Libary; MEDLINE; and Embase. Additionally, we performed a targeted search in Google Scholar and searched trial registries (World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov) for ongoing and unpublished trials. We scanned the reference lists and citations of included trials and any relevant systematic reviews identified. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing perioperative RFT versus GDFT for adults (aged ≥ 18 years) undergoing major non-cardiac surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently screened references for eligibility, extracted data, and assessed risk of bias. We resolved discrepancies by discussion and consulted a third review author if necessary. When necessary, we contacted trial authors to request additional information. We presented pooled estimates for dichotomous outcomes as risk ratios (RRs) with 95% confidence intervals (CIs), and for continuous outcomes as mean differences (MDs) with standard deviations (SDs). We used Review Manager 5 software to perform the meta-analyses. We used a fixed-effect model if we considered heterogeneity as not important; otherwise, we used a random-effects model. We used Poisson regression models to compare the average number of complications per person. MAIN RESULTS: From 6396 citations, we included six studies with a total of 562 participants. Five studies were performed in participants undergoing abdominal surgery (including one study in participants undergoing cytoreductive abdominal surgery with hyperthermic intraperitoneal chemotherapy (HIPEC)), and one study was performed in participants undergoing orthopaedic surgery. In all studies, surgeries were elective. In five studies, crystalloids were used for basal infusion and colloids for boluses, and in one study, colloid was used for both basal infusion and boluses. Five studies reported the ASA (American Society of Anesthesiologists) status of participants. Most participants were ASA II (60.4%), 22.7% were ASA I, and only 16.9% were ASA III. No study participants were ASA IV. For the GDFT group, oesophageal doppler monitoring was used in three studies, uncalibrated invasive arterial pressure analysis systems in two studies, and a non-invasive arterial pressure monitoring system in one study. In all studies, GDFT optimization was conducted only intraoperatively. Only one study was at low risk of bias in all domains. The other five studies were at unclear or high risk of bias in one to three domains. RFT may have no effect on the rate of major complications compared to GDFT, but the evidence is very uncertain (RR 1.61, 95% CI 0.78 to 3.34; 484 participants; 5 studies; very low-certainty evidence). RFT may increase the risk of all-cause mortality compared to GDFT, but the evidence on this is also very uncertain (RD 0.03, 95% CI 0.00 to 0.06; 544 participants; 6 studies; very low-certainty evidence). In a post-hoc analysis using a Peto odds ratio (OR) or a Poisson regression model, the odds of all-cause mortality were 4.81 times greater with the use of RFT compared to GDFT, but the evidence again is very uncertain (Peto OR 4.81, 95% CI 1.38 to 16.84; 544 participants; 6 studies; very low-certainty evidence). Nevertheless, sensitivity analysis shows that exclusion of a study in which the final volume of fluid received intraoperatively was higher in the RFT group than in the GDFT group revealed no differences in mortality. Based on analysis of secondary outcomes, such as length of hospital stay (464 participants; 5 studies; very low-certainty evidence), surgery-related complications (364 participants; 4 studies; very low-certainty evidence), non-surgery-related complications (74 participants; 1 study; very low-certainty evidence), renal failure (410 participants; 4 studies; very low-certainty evidence), and quality of surgical recovery (74 participants; 1 study; very low-certainty evidence), GDFT may have no effect on the risk of these outcomes compared to RFT, but the evidence is very uncertain. Included studies provided no data on administration of vasopressors or inotropes to correct haemodynamic instability nor on cost of treatment. AUTHORS' CONCLUSIONS: Based on very low-certainty evidence, we are uncertain whether RFT is inferior to GDFT in selected populations of adults undergoing major non-cardiac surgery. The evidence is based mainly on data from studies on abdominal surgery in a low-risk population. The evidence does not address higher-risk populations or other surgery types. Larger, higher-quality RCTs including a wider spectrum of surgery types and a wider spectrum of patient groups, including high-risk populations, are needed to determine effects of the intervention.

Risk and surrogate benefit for pediatric Phase I trials in oncology: A systematic review with meta-analysis.

BACKGROUND: Pediatric Phase I cancer trials are critical for establishing the safety and dosing of anti-cancer treatments in children. Their implementation, however, must contend with the rarity of many pediatric cancers and limits on allowable risk in minors. The aim of this study is to describe the risk and benefit for pediatric cancer Phase I trials. METHODS AND FINDINGS: Our protocol was prospectively registered in PROSPERO (CRD42015015961). We systematically searched Embase and PubMed for solid and hematological malignancy Phase I pediatric trials published between 1 January 2004 and 1 March 2015. We included pediatric cancer Phase I studies, defined as "small sample size, non­randomized, dose escalation studies that defined the recommended dose for subsequent study of a new drug in each schedule tested." We measured risk using grade 3, 4, and 5 (fatal) drug-related adverse events (AEs) and benefit using objective response rates. When possible, data were meta-analyzed. We identified 170 studies meeting our eligibility criteria, accounting for 4,604 patients. The pooled overall objective response rate was 10.29% (95% CI 8.33% to 12.25%), and was lower in solid tumors, 3.17% (95% CI 2.62% to 3.72%), compared with hematological malignancies, 27.90% (95% CI 20.53% to 35.27%); p < 0.001. The overall fatal (grade 5) AE rate was 2.09% (95% CI 1.45% to 2.72%). Across the 4,604 evaluated patients, there were 4,675 grade 3 and 4 drug-related AEs, with an average grade 3/4 AE rate per person equal to 1.32. Our study had the following limitations: trials included in our review were heterogeneous (to minimize heterogeneity, we separated types of therapy and cancer types), and we relied on published data only and encountered challenges with the quality of reporting. CONCLUSIONS: Our meta-analysis suggests that, on the whole, AE and response rates in pediatric Phase I trials are similar to those in adult Phase I trials. Our findings provide an empirical basis for the refinement and review of pediatric Phase I trials, and for communication about their risk and benefit.

Association between tea and coffee consumption and prevalence of metabolic syndrome in Poland - results from the WOBASZ II study (2013-2014).

The study aimed to assess a relationship between tea and coffee consumption and metabolic syndrome (MetS). Cross-sectional study of a random sample of total Polish population was done (The WOBASZ II Study), and the present analysis included 5146 participants at age 20 years and above. Tea and coffee consumption was assessed by 24-h recall method. MetS was defined according to IDF/NHLBI/AHA criteria. After adjustment for covariates, coffee consumption was related to blood pressure and HDL cholesterol, and moderate drinkers had 17% lower odds of MetS compared with non-drinkers (OR = 0.83, 95%CI = 0.72-0.97). Tea consumption was related to some components but not to MetS in general. Inverse association between coffee consumption and MetS may reflect the content of the antioxidants that offer cardiovascular protection. However, weak relation of tea with components of MetS points toward the potential importance of composition of polyphenols and the types of tea consumed.

The importance of Bordetella pertussis strains which do not produce virulence factors in the epidemiology of pertussis.

Bordetella pertussis strains, which have lost the ability to produce antigens, such as pertactin - Prn, pertussis toxin - Ptx, filamentous haemagglutinin - FHA, fimbriae type 2 and 3 - Fim 2 and 3, tracheal colonization factor - TcfA, have recently been isolated in countries with a high vaccination coverage. The emergence of such isolates might have resulted from B. pertussis natural evolution course or adaptive mechanisms, allowing increased circulation of the pathogen in vaccinated populations. So far, the majority of described mutants were deficient in the Prn production. Prn deficient isolates were found in countries which use acellular pertussis vaccines (aP) in routine immunization programmes. The increase of frequency of Prn¯ strains isolation was correlated with the period of routine vaccination with aP vaccines. In most countries, the spread of these isolates has resulted from independent mutations rather than from the expansion of a single clone. Prn¯ isolates were collected from patients showing typical clinical symptoms of pertussis found for Prn+ strains. Results of in vitro and in vivo studies have shown that Prn¯, Ptx¯ and FHA¯ isolates retain cytotoxic properties, and besides Ptx¯ isolates, were lethal in intranasally infected mice. Further explanation of the impact of antigen deficiencies on virulence and transmission of B. pertussis in the context of the continuous increase of pertussis incidence is necessary to develop a new, optimized strategy of pertussis prevention.

[Susceptibility of Lactobacillus rhamnosus strains isolated from probiotic products to antimicrobial agents]. / Lekowrazliwosc szczepów Lactobacillus rhamnosus wyizolowanych z produktów probiotycznych.

INTRODUCTION: Probiotics Generally Recognized as Safe (GRAS), when given in relevant dose, are able to induce strain-specific beneficial effects for health of humans or animals. METHODS: L. rhamnosus strains originating from four medicinal products, 2 dietary foods for special medical purposes and dietary supplement, were tested for susceptibility to antibiotics and chemotherapeutics following L. rhamnosus and L.rhamnosus GG strain identity confirmation with use of PCR, rep-PCR and AFLP methods. RESULTS AND CONCLUSIONS: L. rhamnosus working seeds of medicinal products and isolates originating from dietary foods for special medical purposes or dietary supplement were found correctly classified on the levels of species or L. rhamnosus GG strain identities. Antibiotics and chemotherapeutics susceptibility profiles of L. rhamnosus strains allowed for choice of treatment options in six out of seven products under study.

Cardiovascular disease (CVD) risk factors in Kraków and in the whole Poland adult population. Results from the WOBASZ study and Polish arm of the HAPIEE project.

In Kraków, the second largest town in Poland, cardiovascular disease (CVD) mortality rate is lower than in most top largest towns in Poland and lower than the rate for total Polish population. AIM: The aim of the present analysis was to compare socioeconomic status (SES), prevalence of CVD risk factors and SCORE assessment of risk in Krakow with residents of other big towns in Poland and with general Polish population. MATERIALAND METHODS: We used data from the two large, population studies which used comparable methods for risk factors assessment: 1) Polish part of the HAPIEE Project in which 10 615 residents of Krakow at age between 45-69 years were examined, and (2) The WOBASZ Study which contributed with a sub-sample 6 888 of residents of Poland at corresponding age group. WOBASZ sample included 992 residents of big towns other than Krakow. Age-standardized proportions of persons with CVD risk factors were compared between Krakow and the other big towns in Poland and between Krakow and the whole Poland using χ2 test. RESULTS: The striking observation was that in Krakow proportions of participants with university education were substantially higher than average for the other big towns and the whole Poland. Also, the proportion of occupationally active men and women was the highest in Krakow. In both sexes, prevalence of smoking, hypercholesterolemia and hypertension in Krakow was similar to the other big towns but the prevalence of hypercholesterolemia and hypertension (in men only) was lower than average for Poland. The distribution by SCORE risk categories were similar in all three samples studied. In general, the distribution by BMI categories was less favourable but the prevalence of central obesity was lower among residents of Kraków than among residents of the other big towns and citizens of the whole Poland. Prevalence of diabetes was higher in Krakow than in the other samples studied. The differences between population of Krakow and population of other parts of Poland in the exposure to the main risk factors were found diverse and not big enough to be followed by differences in the distribution by the categories of SCORE risk assessment. The study suggested the importance of obesity and diabetes which are not used for the SCORE risk assessment and especially the importance of psychosocial and economic factors which may influence CVD risk and contribute more to the explanation of the regional differences in CVD mortality.

Consistency of Bordetella pertussis vaccine seed strains and potency of whole-cell pertussis vaccine still in use in Poland.

In Poland, where the wP vaccine has been used since 1960, pertussis rates increased in the mid-1990s. In 2012, the rate of pertussis recognised by surveillance was unexpectedly found to be two-fold higher than in the previous decade. Quality measures on potency and vaccine working seeds were introduced, to confirm the possible impact of manufacturing inconsistency or potency lowering on the observed increase in pertussis. Shewhart charts on potency values for lots released between 2001 and 2013 did not reveal any significant fluctuations. Working seeds of three vaccine strains used within last decade for wP manufacturing belong to the PFGE group III and were highly related. According to PFGE and SDS-PAGE data, all vaccine strains were found consistent according profiling on the genomic and protein levels. According to the sequencing data, they harboured ptxA2, ptxC1, prn1, fim2-1, fim3-1, tcfA2, ptxP1 and were assigned as MLST-2 type. Other factors apart from vaccine manufacturing inconsistency might be responsible for the increase in pertussis noted in 2012 in Poland.

Effectiveness of experimental whole-cell pertussis vaccines in murine model.

INTRODUCTION: Since the 1990s pertussis re-emergence has been observed in many highly immunized countries. Genetic divergence between circulating B. pertussis isolates and vaccine strains has been suggested as one of the reasons responsible for the resurgence of pertussis. This divergence was observed in some studies to affect the effectiveness of pertussis vaccine when tested in murine model. In the study, using the murine intranasal challenge model we evaluated the effectiveness of four experimental wP vaccines, prepared with B. pertussis isolates belonging to different PFGE groups, in the elimination of the bacterial infection induced with mixture of the four B. pertussis isolates. METHODS: The experimental wP vaccines were prepared with clinical isolates belonging to PFGE groups V, IVγ and C, used individually or together. The mixture of four isolates classified to PFGE groups V, IVγ, III and C was used as intranasal mice challenge. The chosen strains represent PFGE groups characteristic for isolates currently circulating in Europe (PFGE groups IV and V), specific for Poland (PFGE group C) and vaccine strains of Polish wP vaccine (PFGE group III). Additionally, to study bacterial fitness, changes in the proportions of four isolates used as the challenge within the course of infection in mice lungs were monitored. RESULTS AND CONCLUSIONS: All experimental wP vaccines were found to be equally effective in eliminating B. pertussis from mice lungs. Their effectiveness was independent on PFGE group of vaccine strain. The results on bacterial fitness during mixed infections induced in the non-immunized mice found the isolate of PFGE group IVγ dominating among the other isolates used in the mixture belonging to PFGE group III, V, and C. This data might suggest that the isolates belonging to PFGE group IV, so commonly seen in Europe, might be more fitted to explore in conditions of waning immunity.