University Hospital Dubrava

BACKGROUND: Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine added to venetoclax had promising efficacy in a previous phase 1b study. METHODS: We randomly assigned previously untreated patients with confirmed AML who were ineligible for standard induction therapy because of coexisting conditions, because they were 75 years of age or older, or both to azacitidine plus either venetoclax or placebo. All patients received a standard dose of azacitidine (75 mg per square meter of body-surface area subcutaneously or intravenously on days 1 through 7 every 28-day cycle); venetoclax (target dose, 400 mg) or matching placebo was administered orally, once daily, in 28-day cycles. The primary end point was overall survival. RESULTS: The intention-to-treat population included 431 patients (286 in the azacitidine-venetoclax group and 145 in the azacitidine-placebo [control] group). The median age was 76 years in both groups (range, 49 to 91). At a median follow-up of 20.5 months, the median overall survival was 14.7 months in the azacitidine-venetoclax group and 9.6 months in the control group (hazard ratio for death, 0.66; 95% confidence interval, 0.52 to 0.85; P<0.001). The incidence of complete remission was higher with azacitidine-venetoclax than with the control regimen (36.7% vs. 17.9%; P<0.001), as was the composite complete remission (complete remission or complete remission with incomplete hematologic recovery) (66.4% vs. 28.3%; P<0.001). Key adverse events included nausea of any grade (in 44% of the patients in the azacitidine-venetoclax group and 35% of those in the control group) and grade 3 or higher thrombocytopenia (in 45% and 38%, respectively), neutropenia (in 42% and 28%), and febrile neutropenia (in 42% and 19%). Infections of any grade occurred in 85% of the patients in the azacitidine-venetoclax group and 67% of those in the control group, and serious adverse events occurred in 83% and 73%, respectively. CONCLUSIONS: In previously untreated patients who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone. The incidence of febrile neutropenia was higher in the venetoclax-azacitidine group than in the control group. (Funded by AbbVie and Genentech; VIALE-A ClinicalTrials.gov number, NCT02993523.).

BACKGROUND: Peripheral artery disease is a major cardiovascular disease that affected 202 million people worldwide in 2010. In the past decade, new epidemiological data on peripheral artery disease have emerged, enabling us to provide updated estimates of the prevalence and risk factors for peripheral artery disease globally and regionally and, for the first time, nationally. METHODS: For this systematic review and analysis, we did a comprehensive literature search for studies reporting on the prevalence of peripheral artery disease in the general population that were published between Jan 1, 2011, and April 30, 2019, in PubMed, MEDLINE, Embase, the Global Health database, CINAHL, the Global Health Library, the Allied and Complementary Medicine Database, and ProQuest Dissertations and Theses Global. We also included the Global Peripheral Artery Disease Study of 2013 and the China Peripheral Artery Disease Study as sources. Peripheral artery disease had to be defined as an ankle-brachial index lower than or equal to 0·90. With a purpose-built data collection form, data on study characteristics, sample characteristics, prevalence, and risk factors were abstracted from all the included studies identified from the sources. Age-specific and sex-specific prevalence of peripheral artery disease was estimated in both high-income countries (HICs) and low-income and middle-income countries (LMICs). We also did random-effects meta-analyses to pool the odds ratios of 30 risk factors for peripheral artery disease in HICs and LMICs. UN population data were used to generate the number of people affected by the disease in 2015. Finally, we derived the regional and national numbers of people with peripheral artery disease on the basis of a risk factor-based model. FINDINGS: We included 118 articles for systematic review and analysis. The prevalence of peripheral artery disease increased consistently with age. At younger ages, prevalence was slightly higher in LMICs than HICs (4·32%, 95% CI 3·01-6·29, vs 3·54%, 1·17-10·24, at 40-44 years), but the increase with age was greater in HICs than LMICs, leading to a higher prevalence in HICs than LMICs at older ages (21·24%, 15·22-28·90, vs 12·04%, 8·67-16·60, at 80-84 years). In HICs, prevalence was slightly higher in women than in men up to age 75 years (eg, 7·81%, 3·97-14·77, vs 6·60%, 3·74-11·38, at 55-59 years), whereas in LMICs little difference was found between women and men (eg, 6·40%, 5·06-8·05, vs 6·37%, 4·74-8·49, at 55-59 years). Overall, the global prevalence of peripheral artery disease in people aged 25 years and older was 5·56%, 3·79-8·55, and the prevalence estimate was higher in HICs than that in LMICs (7·37%, 4·35-13·66, vs 5·09%, 3·64-7·24). Smoking, diabetes, hypertension, and hypercholesterolaemia were major risk factors for peripheral artery disease. Globally, a total of 236·62 million people aged 25 years and older were living with peripheral artery disease in 2015, among whom 72·91% were in LMICs. The Western Pacific Region had the most peripheral artery disease cases (74·08 million), whereas the Eastern Mediterranean Region had the least (14·67 million). More than two thirds of the global peripheral artery disease cases were concentrated in 15 individual countries in 2015. INTERPRETATION: Peripheral artery disease continues to become an increasingly serious public health problem, especially in LMICs. With the demographic trend towards ageing and projected rise in important risk factors, a larger burden of peripheral artery disease is to be expected in the foreseeable future. FUNDING: None.

Osteoarthritis is a common cause of disability worldwide. Although commonly referred to as a disease of the joint cartilage, osteoarthritis affects all joint tissues equally. The pathogenesis of this degenerative process is not completely understood; however, a low-grade inflammation leading to an imbalance between anabolic and katabolic processes is a well-established factor. The complex network of cytokines regulating these processes and cell communication has a central role in the development and progression of osteoarthritis. Concentrations of both proinflammatory and anti-inflammatory cytokines were found to be altered depending on the osteoarthritis stage and activity. In this review, we analyzed individual cytokines involved in the immune processes with an emphasis on their function in osteoarthritis.

BACKGROUND: The Dietary Approaches to Stop Hypertension (DASH) dietary pattern, which emphasizes fruit, vegetables, fat-free/low-fat dairy, whole grains, nuts and legumes, and limits saturated fat, cholesterol, red and processed meats, sweets, added sugars, salt and sugar-sweetened beverages, is widely recommended by international diabetes and heart association guidelines. OBJECTIVE: To summarize the available evidence for the update of the European Association of the Study of Diabetes (EASD) guidelines, we conducted an umbrella review of existing systematic reviews and meta-analyses using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach of the relation of the DASH dietary pattern with cardiovascular disease and other cardiometabolic outcomes in prospective cohort studies and its effect on blood pressure and other cardiometabolic risk factors in controlled trials in individuals with and without diabetes. METHODS: MEDLINE and EMBASE were searched through 3 January 2019. We included systematic reviews and meta-analyses assessing the relation of the DASH dietary pattern with cardiometabolic disease outcomes in prospective cohort studies and the effect on cardiometabolic risk factors in randomized and non-randomized controlled trials. Two independent reviewers extracted relevant data and assessed the risk of bias of individual studies. The primary outcome was incident cardiovascular disease (CVD) in the prospective cohort studies and systolic blood pressure in the controlled trials. Secondary outcomes included incident coronary heart disease, stroke, and diabetes in prospective cohort studies and other established cardiometabolic risk factors in controlled trials. If the search did not identify an existing systematic review and meta-analysis on a pre-specified outcome, then we conducted our own systematic review and meta-analysis. The evidence was summarized as risk ratios (RR) for disease incidence outcomes and mean differences (MDs) for risk factor outcomes with 95% confidence intervals (95% CIs). The certainty of the evidence was assessed using GRADE. RESULTS: = 65) for HbA1c. The DASH dietary pattern was associated with decreased incident cardiovascular disease (RR, 0.80 (0.76⁻0.85)), coronary heart disease (0.79 (0.71⁻0.88)), stroke (0.81 (0.72⁻0.92)), and diabetes (0.82 (0.74⁻0.92)) in prospective cohort studies and decreased systolic (MD, -5.2 mmHg (95% CI, -7.0 to -3.4)) and diastolic (-2.60 mmHg (-3.50 to -1.70)) blood pressure, Total-C (-0.20 mmol/L (-0.31 to -0.10)), LDL-C (-0.10 mmol/L (-0.20 to -0.01)), HbA1c (-0.53% (-0.62, -0.43)), fasting blood insulin (-0.15 μU/mL (-0.22 to -0.08)), and body weight (-1.42 kg (-2.03 to -0.82)) in controlled trials. There was no effect on HDL-C, triglycerides, fasting blood glucose, HOMA-IR, or CRP. The certainty of the evidence was moderate for SBP and low for CVD incidence and ranged from very low to moderate for the secondary outcomes. CONCLUSIONS: Current evidence allows for the conclusion that the DASH dietary pattern is associated with decreased incidence of cardiovascular disease and improves blood pressure with evidence of other cardiometabolic advantages in people with and without diabetes. More research is needed to improve the certainty of the estimates.

OBJECTIVE: Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (HEART2D) is a multinational, randomized, controlled trial designed to compare the effects of prandial versus fasting glycemic control on risk for cardiovascular outcomes in patients with type 2 diabetes after acute myocardial infarction (AMI). RESEARCH DESIGN AND METHODS: Patients (type 2 diabetes, aged 30-75 years) were randomly assigned within 21 days after AMI to the 1) prandial strategy (PRANDIAL) (three premeal doses of insulin lispro targeting 2-h postprandial blood glucose <7.5 mmol/l) or the 2) basal strategy (BASAL) (NPH twice daily or insulin glargine once daily targeting fasting/premeal blood glucose <6.7 mmol/l). RESULTS: A total of 1,115 patients were randomly assigned (PRANDIAL n = 557; BASAL n = 558), and the mean patient participation after randomization was 963 days (range 1-1,687 days). The trial was stopped for lack of efficacy. Risks of first combined adjudicated primary cardiovascular events in the PRANDIAL (n = 174, 31.2%) and BASAL (n = 181, 32.4%) groups were similar (hazard ratio 0.98 [95% CI 0.8-1.21]). Mean A1C did not differ between the PRANDIAL and BASAL groups (7.7 +/- 0.1 vs. 7.8 +/- 0.1%; P = 0.4) during the study. The PRANDIAL group showed a lower daily mean postprandial blood glucose (7.8 vs. 8.6 mmol/l; P < 0.01) and 2-h postprandial blood glucose excursion (0.1 vs. 1.3 mmol/l; P < 0.001) versus the BASAL group. The BASAL group showed lower mean fasting blood glucose (7.0 vs. 8.1 mmol/l; P < 0.001) and similar daily fasting/premeal blood glucose (7.7 vs. 7.3 mmol/l; P = 0.233) versus the PRANDIAL group. CONCLUSIONS: Treating diabetic survivors of AMI with prandial versus basal strategies achieved differences in fasting blood glucose, less-than-expected differences in postprandial blood glucose, similar levels of A1C, and no difference in risk for future cardiovascular event rates.

BACKGROUND: Patients with hematological malignancies (HM) are at high risk of mortality from SARS-CoV-2 disease 2019 (COVID-19). A better understanding of risk factors for adverse outcomes may improve clinical management in these patients. We therefore studied baseline characteristics of HM patients developing COVID-19 and analyzed predictors of mortality. METHODS: The survey was supported by the Scientific Working Group Infection in Hematology of the European Hematology Association (EHA). Eligible for the analysis were adult patients with HM and laboratory-confirmed COVID-19 observed between March and December 2020. RESULTS: The study sample includes 3801 cases, represented by lymphoproliferative (mainly non-Hodgkin lymphoma n = 1084, myeloma n = 684 and chronic lymphoid leukemia n = 474) and myeloproliferative malignancies (mainly acute myeloid leukemia n = 497 and myelodysplastic syndromes n = 279). Severe/critical COVID-19 was observed in 63.8% of patients (n = 2425). Overall, 2778 (73.1%) of the patients were hospitalized, 689 (18.1%) of whom were admitted to intensive care units (ICUs). Overall, 1185 patients (31.2%) died. The primary cause of death was COVID-19 in 688 patients (58.1%), HM in 173 patients (14.6%), and a combination of both COVID-19 and progressing HM in 155 patients (13.1%). Highest mortality was observed in acute myeloid leukemia (199/497, 40%) and myelodysplastic syndromes (118/279, 42.3%). The mortality rate significantly decreased between the first COVID-19 wave (March-May 2020) and the second wave (October-December 2020) (581/1427, 40.7% vs. 439/1773, 24.8%, p value < 0.0001). In the multivariable analysis, age, active malignancy, chronic cardiac disease, liver disease, renal impairment, smoking history, and ICU stay correlated with mortality. Acute myeloid leukemia was a higher mortality risk than lymphoproliferative diseases. CONCLUSIONS: This survey confirms that COVID-19 patients with HM are at high risk of lethal complications. However, improved COVID-19 prevention has reduced mortality despite an increase in the number of reported cases.

Assessing available information on the burden of sepsis: global estimates of incidence, prevalence and mortality Objective Sepsis is a complex and hard-to-define condition with many different interactions with other disorders. Presently, there are no estimates of the burden of sepsis and septicaemia at the global level and it was not included in the initial Global Burden of Disease study. Non-maternal sepsis has only recently received attention as a substantial global public health problem. The aim of this study was to assess available data on the burden of non-maternal sepsis, severe sepsis and septic shock in the community and to identify key gaps in information needed to estimate the global burden of sepsis.

Acute myeloid leukemia (AML) may follow a JAK2-positive myeloproliferative neoplasm (MPN), although the mechanisms of disease evolution, often involving loss of mutant JAK2, remain obscure. We studied 16 patients with JAK2-mutant (7 of 16) or JAK2 wild-type (9 of 16) AML after a JAK2-mutant MPN. Primary myelofibrosis or myelofibrotic transformation preceded all 7 JAK2-mutant but only 1 of 9 JAK2 wild-type AMLs (P = .001), implying that JAK2-mutant AML is preceded by mutation(s) that give rise to a "myelofibrosis" phenotype. Loss of the JAK2 mutation by mitotic recombination, gene conversion, or deletion was excluded in all wild-type AMLs. A search for additional mutations identified alterations of RUNX1, WT1, TP53, CBL, NRAS, and TET2, without significant differences between JAK2-mutant and wild-type leukemias. In 4 patients, mutations in TP53, CBL, or TET2 were present in JAK2 wild-type leukemic blasts but absent from the JAK2-mutant MPN. By contrast in a chronic-phase patient, clones harboring mutations in JAK2 or MPL represented the progeny of a shared TET2-mutant ancestral clone. These results indicate that different pathogenetic mechanisms underlie transformation to JAK2 wild-type and JAK2-mutant AML, show that TET2 mutations may be present in a clone distinct from that harboring a JAK2 mutation, and emphasize the clonal heterogeneity of the MPNs.

To update the clinical practice guidelines for nutrition therapy of the European Association for the Study of Diabetes, we conducted a systematic review and meta-analysis of prospective cohort studies and randomized clinical trials (RCTs) to evaluate the effect of the Mediterranean diet (MedDiet) on the prevention of cardiovascular disease (CVD) incidence and mortality. We searched Medline, EMBASE (through April 20, 2018) and Cochrane (through May 7, 2018) databases. Pooled relative risks (RRs) and 95% confidence interval (CI) were calculated by the generic inverse variance method. A total of 41 reports (3 RCTs and 38 cohorts) were included. Meta-analyses of RCTs revealed a beneficial effect of the MedDiet on total CVD incidence (RR: 0.62; 95% CI: 0.50, 0.78) and total myocardial infarction (MI) incidence (RR: 0.65; 95% CI: 0.49, 0.88). Meta-analyses of prospective cohort studies, which compared the highest versus lowest categories of MedDiet adherence, revealed an inverse association with total CVD mortality (RR: 0.79; 95% CI: 0.77, 0.82), coronary heart disease (CHD) incidence (RR: 0.73; 95% CI: 0.62, 0.86), CHD mortality (RR: 0.83; 95% CI: 0.75, 0.92), stroke incidence (RR: 0.80; 95% CI: 0.71, 0.90), stroke mortality (RR: 0.87; 95% CI: 0.80, 0.96) and MI incidence (RR: 0.73; 95% CI: 0.61, 0.88). The present study suggests that MedDiet has a beneficial role on CVD prevention in populations inclusive of individuals with diabetes.

Cirrhosis, highly prevalent worldwide, develops after years of hepatic inflammation triggering progressive fibrosis. Currently, the main etiologies of cirrhosis are non-alcoholic fatty liver disease and alcohol-related liver disease, although chronic hepatitis B and C infections are still major etiological factors in some areas of the world. Recent studies have shown that liver fibrosis can be assessed with relatively high accuracy noninvasively by serological tests, transient elastography, and radiological methods. These modalities may be utilized for screening for liver fibrosis in at-risk populations. Thus far, a limited number of population-based studies using noninvasive tests in different areas of the world indicate that a significant percentage of subjects without known liver disease (around 5% in general populations and a higher rate -18% to 27%-in populations with risk factors for liver disease) have significant undetected liver fibrosis or established cirrhosis. Larger international studies are required to show the harms and benefits before concluding that screening for liver fibrosis should be applied to populations at risk for chronic liver diseases. Screening for liver fibrosis has the potential for changing the current approach from diagnosing chronic liver diseases late when patients have already developed complications of cirrhosis to diagnosing liver fibrosis in asymptomatic subjects providing the opportunity of preventing disease progression.

BACKGROUND AND PURPOSE: Dural arteriovenous shunts with cortical venous reflux or drainage may cause neurological symptoms and death with or without intracranial hemorrhage. Present knowledge about the natural history of these lesions is limited, however. We investigated the incidences of intracranial hemorrhage, progressive dementia syndrome, and death in patients diagnosed in our neurovascular center. METHODS: We evaluated the records of 85 patients with dural arteriovenous shunts with cortical venous drainage or reflux hospitalized in our institution from 1978 to 2007. The annual incidences of intracranial hemorrhage, progressive dementia syndrome, and death were calculated. RESULTS: Fifty-three patients did not have an intracranial hemorrhage as the presenting event. One of these patients bled after diagnosis. Thirty-two patients had an intracranial hemorrhage as the presenting event. Three patients bled after diagnosis. One of these patients died. Apart from deficits caused by hemorrhage, no patient reported adverse neurological symptoms. In patients presenting with an intracranial hemorrhage the annual risk for hemorrhage is approximately 7.4% and in those not presenting with a hemorrhage it is approximately 1.5%. CONCLUSIONS: The risk of intracranial hemorrhage from a dural arteriovenous shunt with cortical venous drainage is most likely smaller than previously proposed. Presentation with hemorrhage is a risk factor for hemorrhage. The risks of developing neurological symptoms not related to hemorrhage are also less than previously reported.

BACKGROUND: Volatile (inhaled) anesthetic agents have cardioprotective effects, which might improve clinical outcomes in patients undergoing coronary-artery bypass grafting (CABG). METHODS: We conducted a pragmatic, multicenter, single-blind, controlled trial at 36 centers in 13 countries. Patients scheduled to undergo elective CABG were randomly assigned to an intraoperative anesthetic regimen that included a volatile anesthetic (desflurane, isoflurane, or sevoflurane) or to total intravenous anesthesia. The primary outcome was death from any cause at 1 year. RESULTS: A total of 5400 patients were randomly assigned: 2709 to the volatile anesthetics group and 2691 to the total intravenous anesthesia group. On-pump CABG was performed in 64% of patients, with a mean duration of cardiopulmonary bypass of 79 minutes. The two groups were similar with respect to demographic and clinical characteristics at baseline, the duration of cardiopulmonary bypass, and the number of grafts. At the time of the second interim analysis, the data and safety monitoring board advised that the trial should be stopped for futility. No significant difference between the groups with respect to deaths from any cause was seen at 1 year (2.8% in the volatile anesthetics group and 3.0% in the total intravenous anesthesia group; relative risk, 0.94; 95% confidence interval [CI], 0.69 to 1.29; P = 0.71), with data available for 5353 patients (99.1%), or at 30 days (1.4% and 1.3%, respectively; relative risk, 1.11; 95% CI, 0.70 to 1.76), with data available for 5398 patients (99.9%). There were no significant differences between the groups in any of the secondary outcomes or in the incidence of prespecified adverse events, including myocardial infarction. CONCLUSIONS: Among patients undergoing elective CABG, anesthesia with a volatile agent did not result in significantly fewer deaths at 1 year than total intravenous anesthesia. (Funded by the Italian Ministry of Health; MYRIAD ClinicalTrials.gov number, NCT02105610.).

BACKGROUND: This study determined the clinical safety, mechanisms, and 6-month results of excimer laser angioplasty (ELCA)+adjunct PTCA for the treatment of in-stent restenosis and (via lesion matching) compared the results of ELCA+PTCA to PTCA alone. METHODS AND RESULTS: Using quantitative angiography (QCA) and intravascular ultrasound (IVUS), we studied 107 restenotic previously stented lesions in 98 patients before and after intervention. QCA measurements included minimum lumen diameter (MLD) and diameter stenosis (DS). IVUS measurements included stent, lumen, and intimal hyperplasia (IH=stent-lumen) cross-sectional areas (CSA) and volumes. In the 54 lesions treated with ELCA+PTCA, the MLD increased from 0.73+/-0.38 mm before ELCA to 2.10+/-0.47 mm after ELCA+PTCA (P<.0001); the DS decreased from 70+/-14% to 25+/-12% (P<.0001). By IVUS, the minimum lumen CSA increased from 1.58+/-0.78 mm2 before ELCA to 6.34+/-1.75 mm2 after ELCA+PTCA (P<.0001) as a result of an increase in minimum stent CSA from 7.70+/-2.41 to 9.10+/-2.60 mm2 (P<.0001) and a decrease in IH CSA from 5.25+/-2.84 to 2.63+/-1.41 mm2 (P<.0001). Volumetric analysis showed that tissue ablation (during ELCA) contributed 29+/-15%, tissue extrusion (during adjunct PTCA) contributed 31+/-14%, and additional stent expansion (during adjunct PTCA) contributed 40+/-16% to the overall lumen gain. There were no ELCA-related complications. Matched to lesions treated with PTCA alone, ELCA+PTCA resulted in greater lumen gain, more IH ablation/extrusion, larger final lumen CSA (IVUS), and a tendency for less frequent need for subsequent target vessel revascularization (TVR, 21% versus 38%, P=.0823). CONCLUSIONS: ELCA safely and effectively ablates in-stent neointimal tissue. Adjunct PTCA extrudes neointimal tissue out of the stent and also further expands the stent. Compared with PTCA alone, ELCA+PTCA achieves better short-term and, potentially, better long-term results.

The evidence for the Portfolio dietary pattern, a plant-based dietary pattern that combines recognized cholesterol-lowering foods (nuts, plant protein, viscous fibre, plant sterols), has not been summarized. To update the European Association for the Study of Diabetes clinical practice guidelines for nutrition therapy, we conducted a systematic review and meta-analysis of controlled trials using GRADE of the effect of the Portfolio dietary pattern on the primary therapeutic lipid target for cardiovascular disease prevention, low-density lipoprotein cholesterol (LDL-C), and other established cardiometabolic risk factors. We searched MEDLINE, EMBASE, and The Cochrane Library through April 19, 2018. We included controlled trials ≥ 3-weeks assessing the effect of the Portfolio dietary pattern on cardiometabolic risk factors compared with an energy-matched control diet free of Portfolio dietary pattern components. Two independent reviewers extracted data and assessed risk of bias. The primary outcome was LDL-C. Data were pooled using the generic inverse-variance method and expressed as mean differences (MDs) with 95% confidence intervals (CIs). Heterogeneity was assessed (Cochran Q statistic) and quantified (I2-statistic). GRADE assessed the certainty of the evidence. Eligibility criteria were met by 7 trial comparisons in 439 participants with hyperlipidemia, in which the Portfolio dietary pattern was given on a background of a National Cholesterol Education Program (NCEP) Step II diet. The combination of a portfolio dietary pattern and NCEP Step II diet significantly reduced the primary outcome LDL-C by ~17% (MD, −0.73 mmol/L, [95% CI, −0.89 to −0.56 mmol/L]) as well as non-high-density lipoprotein cholesterol, apolipoprotein B, total cholesterol, triglycerides, systolic and diastolic blood pressure, C-reactive protein, and estimated 10-year coronary heart disease (CHD) risk, compared with an NCEP Step 2 diet alone (p < 0.05). There was no effect on high-density lipoprotein cholesterol or body weight. The certainty of the evidence was high for LDL-cholesterol and most lipid outcomes and moderate for all others outcomes. Current evidence demonstrates that the Portfolio dietary pattern leads to clinically meaningful improvements in LDL-C as well as other established cardiometabolic risk factors and estimated 10-year CHD risk.

STUDY DESIGN: Prospective cohort study. OBJECTIVE: We performed a prospective cohort study with standardized postoperative lumbar imaging every 3 months for a year then annually to assess the incidence and factors associated with same-level recurrent disc herniation. SUMMARY OF BACKGROUND DATA: The true incidence of same-level recurrent disc herniation after lumbar discectomy is unclear. Retrospective studies have reported widely varying incidences between 3% and 18%. Prospective controlled studies are lacking. METHODS: A total of 108 patients undergoing first-time lumbar discectomy for refractory radiculopathy were enrolled. Baseline lumbar CT and MRI and standardized clinical data were assessed before surgery, and CT and MRI scans repeated 6 weeks, 3, 6, 9, 12, and 24-months after surgery and at the time of recurrent sciatica. Age, weight, preoperative disc volume, and height, volume of disc removed, and size of anular defect were compared with postoperative disc height loss and recurrent disc herniation using regression analysis. RESULTS: One hundred patients (41 +/- 10 years old) were available for 1-year (93%) and 76 (70%) for 2-year follow-up (mean follow-up: 25 +/- 12 months). Improvement in all outcome measures was observed by 6 weeks after surgery (P < 0.005). An 18% loss of disc height was observed 3 months after surgery, progressing to 26% by 2 years. Eleven (10.2%) patients experienced recurrent disc herniation requiring revision discectomy a mean 10.5 months after surgery. Subjects with larger anular defects (P = 0.019) and with smaller percentage of disc volume removed (P = 0.028) were associated with an increased risk of recurrent disc herniation. Conversely, those from whom greater disc volumes were removed (P = 0.024) had more progressive disc height loss by 6 months after surgery. CONCLUSION: Larger anular defects and less disc removal increased the risk of reherniation. Greater volumes of disc removal were associated with accelerated disc height loss. In the setting of larger anular defects or less aggressive disc removal, concern for recurrent herniation should be increased during outpatient follow-up. In this situation effective anular repair may be helpful.

Chronic lymphocytic leukemia is marked by profound defects in T-cell function. Programmed death-1 is a receptor involved in tumor-mediated immunosuppression through binding of the PD-L1 ligand. Multiparametric flow cytometry and immunohistochemistry were used to study PD-1/PD-L1 expression. Functional assays were used to determine the involvement of the PD-1/PD-L1 axis in T-cell responses. PD-1 expression by CD4(+) and CD8(+) T lymphocytes was significantly higher in 117 chronic lymphocytic leukemia patients than in 33 donors of a comparable age. CD4(+) and CD8(+) T lymphocytes from chronic lymphocytic leukemia patients displayed increased numbers of effector memory and terminally differentiated cells, respectively, when compared to controls. The number of effector memory CD4(+) and terminally differentiated CD8(+) lymphocytes positively associated with a more advanced stage of disease, treatment requirements and unfavorable genomic aberrations. Furthermore, leukemic lymphocytes expressed higher levels of PD-L1 than circulating B lymphocytes from normal donors. PD-1 and PD-L1 surface expression spiked in proliferating T and B lymphocytes, suggesting that this interaction works efficiently in activated environments. Within chronic lymphocytic leukemia proliferation centers in the lymph node, CD4(+)/PD-1(+) T lymphocytes were found to be in close contact with PD-L1(+) chronic lymphocytic leukemia cells. Lastly, functional experiments using recombinant soluble PD-L1 and blocking antibodies indicated that this axis contributes to the inhibition of IFN-γ production by CD8(+) T cells. These observations suggest that pharmacological manipulation of the PD-1/PD-L1 axis may contribute to restoring T-cell functions in the chronic lymphocytic leukemia microenvironment.

BACKGROUND: Respiratory syncytial virus (RSV) is one of the most important viral pathogens causing acute respiratory infections in children. It results in about 3.4 million hospitalisations annually in children under five. Palivizumab is an anti-RSV monoclonal antibody, administered intramuscularly at a dose of 15 mg/kg once every 30 days. The efficacy and safety of palivizumab has been evaluated in multicentre, randomised controlled trials (RCTs) and a large number of economic evaluations (EEs) have tested its cost-effectiveness. OBJECTIVES: To assess the effectiveness and safety of palivizumab prophylaxis compared with placebo, or another type of prophylaxis, in reducing the risk of complications (hospitalisation due to RSV infection) in high-risk infants and children. To assess the cost-effectiveness (or cost-utility) of palivizumab prophylaxis compared with no prophylaxis in infants and children in different risk groups. SEARCH METHODS: We searched CENTRAL 2012, Issue 7, MEDLINE (1996 to July week 4, 2012), EMBASE (1996 to August 2012), CINAHL (1996 to August 2012) and LILACS (1996 to August 2012) for studies of effectiveness and safety. We searched the NHS Economic Evaluations Database (NHS EED 2012, Issue 4), Health Economics Evaluations Database (HEED, 9 August 2012) and Paediatric Economic Database Evaluations (PEDE, 1980 to 2009), MEDLINE (1996 to July week 4, 2012) and EMBASE (1996 to August 2012) for economic evaluations. SELECTION CRITERIA: We included RCTs comparing palivizumab prophylaxis with a placebo, no prophylaxis or another type of prophylaxis in preventing serious lower respiratory tract disease caused by RSV in paediatric patients at high risk. We included cost-effectiveness analyses and cost-utility analyses comparing palivizumab prophylaxis with no prophylaxis. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias for the included studies and extracted data for both the RCTs and EEs. We calculated risk ratios (RRs) and their associated 95% confidence intervals (CIs) for dichotomous outcomes and for adverse events (AEs). We provided a narrative summary of results for continuous outcomes, due to missing data on standard deviations. We performed fixed-effect meta-analyses for the estimation of pooled effects whenever there was no indication of heterogeneity between included RCTs. We summarised the results reported in included EEs, such as incremental costs, incremental effectiveness, and incremental cost-effectiveness and/or cost-utility ratios (ICERs), and we calculated ICER present values in 2011 Euros for all studies. MAIN RESULTS: Of the seven available RCTs, three compared palivizumab with a placebo in a total of 2831 patients, and four compared palivizumab with motavizumab in a total of 8265 patients. All RCTs were sponsored by the drug manufacturing company. The overall quality of RCTs was good, but for most of the outcomes assessed only data from two studies contributed to the analysis. Palivizumab prophylaxis was associated with a statistically significant reduction in RSV hospitalisations (RR 0.49, 95% CI 0.37 to 0.64) when compared to placebo. When compared to motavizumab, palivizumab recipients showed a non-significant increase in the risk of RSV hospitalisations (RR 1.36, 95% CI 0.97 to 1.90). In both cases, the proportion of children with any AE or any AE related to the study drug was similar between the two groups.In terms of economic evidence, we included 34 studies that reported cost-effectiveness and/or cost-utility data for palivizumab prophylaxis compared with no prophylaxis, in high-risk children with different underlying medical conditions. The overall quality of EEs was good, but the variations in modelling approaches were considerable across the studies, leading to big differences in cost-effectiveness results. The cost-effectiveness of palivizumab prophylaxis depends on the consumption of resources taken into account by the study authors; and on the cost-effectiveness threshold set by the healthcare sector in each country. AUTHORS' CONCLUSIONS: There is evidence that palivizumab prophylaxis is effective in reducing the frequency of hospitalisations due to RSV infection, i.e. in reducing the incidence of serious lower respiratory tract RSV disease in children with chronic lung disease, congenital heart disease or those born preterm.Results from economic evaluations of palivizumab prophylaxis are inconsistent, implying that economic findings must be interpreted with caution. ICER values varied considerably across studies, from highly cost-effective to not cost-effective. The availability of low-cost palivizumab would reduce its inequitable distribution, so that RSV prophylaxis would be available to the poorest countries where children are at greatest risk.

In the last year, different diseases possibly linked to Helicobacter pylori infection but localized outside of the stomach have been investigated. There are, in fact, several studies concerning cardiovascular diseases, hematologic disorders, neurologic diseases, metabolic, hepatobiliary diseases, and other conditions. Some of those studies, such as those on sideropenic anemia and idiopathic thrombocytopenic purpura, are quite large and well conducted, while in other cases there are just small or isolated studies or even case reports. Nonetheless, there is much interest among researchers all over the world for such a topic as demonstrated by the large number of studies published in the last year.

The diagnostic criteria for CLL rely on morphology and immunophenotype. Current approaches have limitations affecting reproducibility and there is no consensus on the role of new markers. The aim of this project was to identify reproducible criteria and consensus on markers recommended for the diagnosis of CLL. ERIC/ESCCA members classified 14 of 35 potential markers as "required" or "recommended" for CLL diagnosis, consensus being defined as >75% and >50% agreement, respectively. An approach to validate "required" markers using normal peripheral blood was developed. Responses were received from 150 participants with a diagnostic workload >20 CLL cases per week in 23/150 (15%), 5-20 in 82/150 (55%), and <5 cases per week in 45/150 (30%). The consensus for "required" diagnostic markers included: CD19, CD5, CD20, CD23, Kappa, and Lambda. "Recommended" markers potentially useful for differential diagnosis were: CD43, CD79b, CD81, CD200, CD10, and ROR1. Reproducible criteria for component reagents were assessed retrospectively in 14,643 cases from 13 different centers and showed >97% concordance with current approaches. A pilot study to validate staining quality was completed in 11 centers. Markers considered as "required" for the diagnosis of CLL by the participants in this study (CD19, CD5, CD20, CD23, Kappa, and Lambda) are consistent with current diagnostic criteria and practice. Importantly, a reproducible approach to validate and apply these markers in individual laboratories has been identified. Finally, a consensus "recommended" panel of markers to refine diagnosis in borderline cases (CD43, CD79b, CD81, CD200, CD10, and ROR1) has been defined and will be prospectively evaluated. © 2017 International Clinical Cytometry Society.

BACKGROUND: Plaque distribution (eccentricity) may be a determinant of the success of transcatheter therapy, and certain devices may be better suited to treating severely eccentric lesions than others. However, no study has compared methods for assessing plaque distribution or systematically studied the validity of the angiographic assessment of plaque distribution. METHODS AND RESULTS: We studied 1446 native vessel target lesions in 1349 patients by intravascular ultrasound and coronary angiography. Angiographic and intravascular ultrasound criteria for lesion eccentricity were compared. Angiography showed that 795 of 1446 (55.0%) of target lesions were eccentric. When intravascular ultrasound was used, only 219 lesions (15.1%) had an arc of normal arterial wall within the lesion (equivalent to the pathological definition of lesion eccentricity). When an eccentricity index of >/= 3.0 was used, intravascular ultrasound classified 659 lesions (45.6%) as eccentric. The concordance rates of classification were only 47.7% (versus lesions containing an arc of normal arterial wall) and 53.8% (versus lesions with an ultrasound eccentricity index of >/= 3.0). More eccentric lesions had larger lumen cross-sectional areas, smaller plaque plus media and external elastic membrane cross-sectional areas, and smaller arcs of calcium, suggesting that they may represent less advanced atherosclerotic disease. CONCLUSIONS: There was significant discordance between angiography and ultrasound in assessing plaque distribution. Angiography appeared to detect lesion eccentricity more often than intravascular ultrasound. Furthermore, markedly eccentric lesions, in which there is an arc of normal vessel wall, were uncommon.