Interferon ß-1a (IFNß-1a) in COVID-19 patients (INTERCOP): study protocol for a randomized controlled trial.

BACKGROUND: Pharmacological therapies of proven efficacy in coronavirus disease 2019 (COVID-19) are still lacking. We have identified IFNß-1a as the most promising drug to be repurposed for COVID-19. The rationale relies on the evidence of IFNß anti-viral activity in vitro against SARS-CoV-2 and animal models resembling SARS-CoV-2 infection and on a recent clinical trial where IFNß was indicated as the key component of a successful therapeutic combination. METHODS: This is a randomized, controlled, open-label, monocentric, phase II trial (INTERCOP trial). One hundred twenty-six patients with positive swab detection of SARS-CoV-2, radiological signs of pneumonia, and mild-to-moderate disease will be randomized 2:1 to IFNß-1a in addition to standard of care vs standard of care alone. No other anti-viral drugs will be used as part of the regimens, both in the control and the intervention arms. IFNß-1a will be administered subcutaneously at the dose of 44 mcg (equivalent to 12 million international units) three times per week, at least 48 h apart, for a total of 2 weeks. The primary outcome is the time to negative conversion of SARS-CoV-2 nasopharyngeal swabs. Secondary outcomes include improvement or worsening in a clinical severity score measured on a 7-point ordinal scale (including transfer to intensive care unit and death), oxygen- and ventilator-free days, mortality, changes in pulmonary computed tomography severity score, hospital stay duration, reduction of viral load measured on nasopharyngeal swabs, number of serious adverse events, and changes in biochemical markers of organ dysfunction. Exploratory outcomes include blood cell counts, cytokine and inflammatory profile, peripheral mRNA expression profiles of interferon-stimulated genes, and antibodies to SARS-CoV-2 and to IFNß-1a. INTERCOP is the first study to specifically investigate the clinical benefits of IFNß-1a in COVID-19 patients. DISCUSSION: Potential implications of this trial are multifaceted: should the primary outcome be fulfilled and the treatment be safe, one may envisage that IFNß-1a be used to reduce the infectivity of patients with mild-to moderate disease. In case IFNß-1a reduced the duration of hospital stay and/or ameliorated the clinical status, it may become a cornerstone of COVID-19 treatment. TRIAL REGISTRATION: EudraCT 2020-002458-25. Registered on May 11, 2020 ClinicalTrials.gov Identifier: NCT04449380.

Validation of a new score for outcome prediction in patients with heart failure with reduced ejection fraction.

BACKGROUND: Most models for outcome prediction in heart failure are under-utilized because complex or including non-routine clinical use variables. We aimed to develop a prognostic score for patients with stable heart failure, including only easily obtainable parameters. METHODS: In 376 outpatients with heart failure (ejection fraction ≤40%), twelve variables were individually correlated with 5-year mortality. Those resulted significant predictors of cardiac and overall mortality were used to obtain a risk score. It was validated on a different sample of 325 patients previously enrolled in other clinical studies, according to tertiles of score. RESULTS: Previous acute decompensated heart failure, atrial fibrillation, ejection fraction <30%, not-taking beta-blockers, chronic renal failure were the variables included in the final model. There was a significant difference in 5-year cardiac (P=0.004) and all-cause (P=0.003) mortality risk. Compared to the first tertile of the score, the second tertile and the third tertile had an increasing risk for cardiac cause admission (respectively, HR: 2.7; 95% CI: 1.5-4.9 and HR: 3.2; 95% CI: 1.7-6.1) and for heart failure worsening hospitalization (HR:4.3; 95% CI: 1.3-14.5 and HR: 3.8; 95% CI: 1.03-14.1) as well as the third tertile (respectively, HR:3.2; 95% CI: 1.7-6.1 and HR:3.8; 95% CI: 1.03-14.1.). CONCLUSIONS: Our prognostic model, named OSR HF Risk Score, is a simple, quick, inexpensive tool for predicting patient outcome in 5 years. It might be used as an adjunctive tool in outpatients evaluation alongside more complex scores.

Gamma glutamyltransferase, alanine aminotransferase and risk of cancer: systematic review and meta-analysis.

The prospective evidence for the associations of gamma glutamyltransferase (GGT) and alanine aminotransferase (ALT) with risk of cancer in the general population is uncertain. We conducted a systematic review and meta-analysis of published prospective observational studies evaluating the associations of baseline levels of GGT and ALT with risk of overall (incidence and/or mortality) and site-specific cancers. Relevant studies were identified in a literature search of MEDLINE, EMBASE, Web of Science, reference lists of relevant studies to April 2014 and email contact with investigators. Study specific relative risks (RRs) were meta-analyzed using random effects models. Fourteen cohort studies with data on 1.79 million participants and 57,534 cancer outcomes were included. Comparing top versus bottom thirds of baseline circulating GGT levels, pooled RRs (95% confidence intervals) were 1.32 (1.15-1.52) for overall cancer, 1.09 (0.95-1.24) for cancers of the breast and female genital organs, 1.09 (1.02-1.16) for cancers of male genital organs, 1.94 (1.35-2.79) for cancers of digestive organs and 1.33 (0.94-1.89) for cancers of respiratory and intrathoracic organs. For ALT, corresponding RRs for overall cancer were 0.96 (0.94-0.99) and 1.65 (1.52-1.79) in European and Asian populations, respectively. There was an increased risk of cancers of the digestive organs 2.44 (1.23-4.84). The pooled RR for overall cancer per 5 U/L increment in GGT levels was 1.04 (1.03-1.05). Available observational data indicate a positive log-linear association of GGT levels with overall cancer risk. The positive association was generally evident for site-specific cancers. There are geographical variations in the association of ALT and overall cancer.

Macular dysfunction is common in both type 1 and type 2 diabetic patients without macular edema.

PURPOSE: To study retinal function in asymptomatic Type 1 and Type 2 diabetic patients with nonproliferative diabetic retinopathy (NPDR) and no clinical signs of diabetic macular edema. METHODS: Thirty-six consecutive Type 1 and Type 2 diabetic patients with nonproliferative diabetic retinopathy and no diabetic macular edema and 28 healthy controls underwent a complete ophthalmologic examination, including spectral domain optical coherence tomography and microperimetry. RESULTS: Seventy-one eyes (17 patients with Type 1 and 19 with Type 2 diabetes) were tested, and data from 36 (17 Type 1 and 19 Type 2) eyes were analyzed. Mean best-corrected visual acuity was 0.00 ± 0.01 logMAR and 0.00 ± 0.02 logMAR for Type 1 and Type 2 diabetic patients, respectively (P = 0.075). Mean central foveal thickness was 234.5 ± 13.7 µm and 256.3 ± 12.7 µm for Type 1 and Type 2 diabetic patients, respectively (P = 0.04); the central foveal thickness was statistically different compared with the control groups (P = 0.04 and P = 0.01, respectively). Mean retinal sensitivity was 18.9 ± 0.5 dB and 17.7 ± 0.4 dB for Type 1 and Type 2 diabetic patients, respectively; it was statistically different compared with control groups (P < 0.0001 and P < 0.0001, respectively). CONCLUSION: We demonstrated a significantly reduced sensitivity in both nonproliferative diabetic retinopathy groups without diabetic macular edema compared with healthy controls; this reduction was greater in Type 2 diabetic patients. Central foveal thickness was increased in all diabetic patients compared with healthy controls, despite the absence of diabetic macular edema.

Prognostic role of stress/rest myocardial perfusion scintigraphy in patients with cardiac syndrome x.

AIM: The prognostic utility of myocardial perfusion scintigraphy (MPS) in patients with angiographically normal coronary arteries has not been evaluated yet. Our aim was to determine the prognostic role of positive MPS in patients with angina, positive exercise test and smooth coronary arteries (syndrome X). METHODS: A total of 156 patients with angina, positive exercise test, positive MPS and normal coronary arteries and 172 patients with angina and positive exercise test who had negative MPS were selected for study. The primary endpoint was combined all-cause mortality and hospitalizations for cardiac causes. The secondary endpoint was hospitalization for cardiac causes. RESULTS: Kaplan-Meier analysis showed a greater (p=0.001) incidence of the primary endpoint in patients with positive MPS, compared to those with negative MPS. Additionally, Kaplan-Meier analysis for cardiovascular hospitalization showed a significant difference (p=0.003) between the two groups. Cox regression analysis, adjusted for age, sex, BMI and antianginal therapy confirmed a significant risk increase for patients with positive MPS, with a hazard ratio (HR)=3.20 (CI 95%: 1.14-9.02; p=0.028). Cox analysis for cardiovascular hospitalization also showed a significant risk increase for patients with positive MPS (HR=3.19; CI 95%: 1.13-9.00; p=0.03). Finally, Cox analysis showed that patients with positive MPS tend to have a higher risk to remain symptomatic in the follow-up period (HR=1.614; CI 95%: 0.999-2.607; p=0.51). CONCLUSIONS: This study shows that inducible myocardial hypoperfusion at MPS in patients with syndrome X could discriminate patients with a more severe prognosis, especially in terms of further hospitalization and symptomatic burden.

Association of LOXIN, a new functional splicing isoform of the OLR1 gene, with severity and prognostic localization of critical coronary artery stenoses.

AIMS: To evaluate the association between LOXIN, a new functional protective splicing isoform of the oxidized LDL receptor 1 (OLR1) gene, and the severity of coronary artery stenoses. METHODS: We analyzed 100 consecutive patients with coronary artery disease (CAD) and 100 controls, all evaluated by a new molecular biology test using highly specific allele primers able to identify the single nucleotide variation (IVS4-14 A>G) in the OLR1 gene (Loxin Test - Technogenetics). All the patients and the controls underwent coronary angiography and, for quantitative evaluation, we used both vessel and stenosis score, and SYNTAX score to evaluate the severity of CAD. Moreover, we defined the prognostic localization of CAD as a critical stenosis (>50%) of the left main and/or proximal segment of left anterior descending artery (LAD). Finally, we evaluated a correlation with the presence of diabetes mellitus, dyslipidemia, hypertension, smoking and family history of CAD. RESULTS: In this selected population, even though the 'AA nonrisk haplotype' is more frequent in the controls, we did not find any statistically significant correlation between the severity of CAD or the prognostic localization of critical stenosis and the difference of IVS4-14 A>G OLR1 genotype (P > 0.05). CAD patients showed significantly higher frequencies of dyslipidemia and smoking (P < 0.05) than controls, but no significant association was found between overall risk factors and the OLR1 polymorphism. CONCLUSION: In this selected population, we did not find any correlation of LOXIN with the severity or prognostic localization of CAD on left main and/or proximal LAD.

Informed consent as an ethical requirement in clinical trials: an old, but still unresolved issue. An observational study to evaluate patient's informed consent comprehension.

We explored the comprehension of the informed consent in 77 cancer patients previously enrolled in randomised phase II or phase III clinical trials, between March and July 2011, at the San Raffaele Scientific Institute in Milano. We asked participants to complete an ad hoc questionnaire and analysed their answers. Sixty-two per cent of the patients understood the purpose and nature of the trial they were participating in; 44% understood the study procedures and 40% correctly listed at least one of the major risks or complications related to their participation in the trial. We identified three factors associated with comprehension of the informed consent: age, education and type of tumour/investigator team. We suggest several possible improvements of how to obtain informed consent that will increase patient awareness, as well as the validity and effectiveness of the clinical trials.

Improved survival in patients with chronic mild/moderate systolic heart failure followed up in a specialist clinic.

OBJECTIVE: To relate therapeutic issues, comorbidities and functional parameters to mortality/morbidity of mild/moderate heart failure patients. METHODS: From our heart failure clinic, 372 heart failure patients (269 men, aged 66 ± 11 years), with stable heart failure and ejection fraction 45% or less were recruited. Survival curves were estimated according to the Kaplan-Meier method. Associations of protective/risk factors with cardiovascular mortality/morbidity were also evaluated. RESULTS: One hundred and two patients (27%) died (aged 70 ± 10 years at diagnosis, 76 ± 10 at death) during follow-up (overall mortality at 60 months: 19.2%; mean follow-up period: 67 ± 44 months). Cardiovascular deaths were 64 (63% of total deaths, 44 men, age at diagnosis 70 ± 9). Cardiovascular mortality at 60 months was 12%; standardized mortality ratio was 5.9 for women and 6.8 for men. The remaining 38 patients (37% of total deaths, 30 men, age at diagnosis 70 ± 10) died of noncardiovascular causes. Overall, noncardiovascular mortality at 60 months was 7.2%; mean survival time from diagnosis to death was 63 ± 69 months (median 42, Q1 = 27.5, Q3 = 77.7). Average cardiovascular admission rate was 1.63 ± 1.84 admissions/patient. At multivariate analysis, only previous history of myocardial infarction [hazard ratio: 3.62 (1.70-7.73)], class of ejection fraction at diagnosis [hazard ratio: 0.36 (0.32-0.60)], acute cardiac decompensation at any time [hazard ratio: 1.55 (1.32-1.84)], implanted defibrillator [hazard ratio: 0.11 (0.01-0.83)] and use of statins [hazard ratio: 0.08 (0.007-0.42)] were independently associated with cardiovascular mortality. Factors associated to higher annual cardiovascular morbidity were age at diagnosis, chronic renal failure, diabetes, cardiac decompensation at any time, female sex and diuretic therapy. Angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin-receptor-blockers reduced annual cardiovascular morbidity. CONCLUSION: Survival in mild/moderate heart failure patients has consistently improved. Further improvements are warranted in terms of morbidity reduction.

Increased low-grade inflammation is associated with lack of functional response to carvedilol in patients with systolic heart failure.

BACKGROUND: The aim of this study was to evaluate, according to functional response, the neuroendocrine and inflammatory status in patients with chronic heart failure before and after therapy with carvedilol. METHODS AND RESULTS: Serum tumor necrosis factor-α (TNF-α) soluble receptors (sTNF-R1 and sTNF-R2), interleukin (IL)-10 and IL-18, chromogranin A (CgA) and brain natriuretic peptide (pro-BNP) were measured in 37 New York Heart Association class II to IV heart failure patients, at baseline and after 6 months of therapy with carvedilol. Patients were divided in two groups according to whether, following carvedilol, left-ventricular ejection fraction (LVEF) had increased by at least 5% (17 patients) or not (20 patients). Baseline LVEF was higher in nonresponders (38 ± 5 vs. 31 ± 7%, P = 0.002). In responders, LVEF increased from 31 ± 7 to 51 ± 7% (P < 0.0001), whereas in nonresponders it decreased from 38 ± 5 to 33 ± 7%, (P = 0.02). sTNF-R1 (P = 0.019) and sTNF-R2 (P = 0.025) increased in nonresponders, whereas they did not change in responders. After carvedilol, IL-10 was significantly higher in responders (P = 0.03). Conversely, no significant IL-18 and CgA changes were observed in either group. CgA was not significantly different between groups at baseline and after carvedilol in either group, whereas pro-BNP significantly increased in nonresponders (from 438 ± 582 to 1324 ± 1664 pg/ml, P = 0.04) and decreased in responders (from 848 ± 1221 to 420 ± 530 pg/ml, P = 0.08). CONCLUSION: Increased inflammatory activation observed only in heart failure patients not improving left-ventricular function after carvedilol may indicate that inflammation, either as a direct cause or as a consequence, is associated with progressive ventricular dysfunction.

Effect of partial fatty acid oxidation inhibition with trimetazidine on mortality and morbidity in heart failure: results from an international multicentre retrospective cohort study.

OBJECTIVES: The aim of this cohort study was to retrospectively evaluate, in patients with chronic heart failure (CHF), the long term effect of trimetazidine (TMZ) on morbidity and mortality. BACKGROUND: Previous small studies in patients with CHF have shown that TMZ can improve left ventricular function, exercise capacity and NYHA class compared to placebo. However, no data on the effects of TMZ on survival in patients with CHF have ever been produced. METHODS: In this international multicentre retrospective cohort study data from 669 patients were analyzed. 362 patients were on TMZ due to symptom persistence despite up-titration of optimal CHF therapy, while the remaining patients continued conventional CHF therapy alone. Propensity score analysis was performed in order to minimize selection bias between the two groups. RESULTS: Kaplan-Meier analysis for global mortality showed 11.3% improved global survival (p=0.015) and 8.5% improved survival for cardiovascular (CVD) death (p=0.050) in the TMZ group. Cox regression analysis for global mortality showed a significant risk reduction for TMZ treated patients with a hazard ratio (HR)=0.189 (confidence interval - CI 95%: 0.017-0.454; p=0.0002). TMZ also showed a good risk reduction profile for CVD death causes (HR=0.072, CI 95%: 0.019-0.268, p=0.0001). The rate of hospitalization for cardiovascular causes was reduced by 10.4% at 5 years (p<0.0005) with increased hospitalization-free survival of 7.8 months. CONCLUSION: TMZ is effective in reducing mortality and event-free survival in patients with CHF. The addition of TMZ on top of optimal medical therapy improves long term survival in CHF patients.

Beneficial effects of beta-blockers on left ventricular function and cellular energy reserve in patients with heart failure.

Beta-blockers have been shown to improve left ventricular (LV) function in patients with heart failure. The aim of this study is to non-invasively assess, by means of in vivo 31P-magnetic resonance spectroscopy (31P-MRS), the effects of beta-blockers on LV cardiac phosphocreatine and adenosine triphosphate (PCr/ATP) ratio in patients with heart failure. Ten heart failure patients on full medical therapy were beta-blocked by either carvedilol or bisoprolol. Before and after 3 months of treatment, exercise testing, 2D echocardiography, MRS, New York Heart Association (NYHA) class, ejection fraction (EF), maximal rate-pressure product and exercise metabolic equivalent system (METS) were evaluated. Relative concentrations of PCr and ATP were determined by cardiac 31P-MRS. After beta-blockade, NYHA class decreased (from 2.2 ± 0.54 to 1.9 ± 0.52, P = 0.05), whereas EF (from 33 ± 7 to 44 ± 6%, P = 0.0009) and METS (from 6.74 ± 2.12 to 8.03 ± 2.39, P = 0.01) increased. Accordingly, the mean cardiac PCr/ATP ratio increased by 33% (from 1.48 ± 0.22 to 1.81 ± 0.48, P = 0.03). Beta-blockade-induced symptomatic and functional improvement in patients with heart failure is associated to increased PCr/ATP ratio, indicating preservation of myocardial high-energy phosphate levels.

Severity and prognostic localization of critical coronary artery stenoses: correlation with clinical control of major traditional risk factors.

PURPOSE: To evaluate the association between the severity and angiographic localization of coronary artery stenoses and clinical control of major traditional risk factors (RF). METHODS: We analyzed 500 patients without known cardiovascular disease, undergoing coronary angiography for the diagnosis of coronary artery disease (CAD), with one or more major traditional RF, all in optimal clinical control. For the quantitative evaluation of CAD, we used a vessel and stenosis score to evaluate the severity of CAD. Moreover, we defined the prognostic localization of CAD as a critical stenosis (≥50%) of the left main (LM) and/or the proximal segment of the left anterior descending coronary artery (LAD). RESULTS: The presence of RF was as follows: one in 14.2%, two in 40.6%, three in 35%, and more than three in 10.2% of the patients. Prognostic localization of critical stenosis on the proximal segment of LAD and/or LM was found in 174 patients (34.8%). The severity of CAD and prognostic localization of critical stenosis was not correlated with all of the conventional RF evaluated or their association (P>0.05). CONCLUSION: In this population with optimally controlled traditional RF, the severity of CAD or prognostic localization on LM and/or proximal LAD was not correlated with the major RF analyzed.

Insulin resistance/hyperinsulinemia and cancer mortality: the Cremona study at the 15th year of follow-up.

Type 2 diabetes is associated with risk of cancer. Hyperinsulinemia and insulin resistance may be the link with cancer, but whether this is independent of the diabetes status, obesity/visceral obesity and metabolic syndrome is uncertain and the present study wanted to address this issue. Fifteen-year all-cause, CVD and cancer mortality data were obtained through the Regional Health Registry in 2,011 out of 2,074 Caucasian middle-aged individuals of the Cremona Study, a population study on the prevalence of diabetes mellitus in Italy in which anthropometric and metabolic characteristics were collected. During the 15-year observation period, 495 deaths were registered: 221 CVD related and 180 cancer related. Age and sex were independently associated with all-cause, cancer and CVD mortality rates. Age- and sex-adjusted analysis showed that HOMA-IR, cigarette smoking and diabetes were independently associated with all-cause mortality; HOMA-IR, systolic blood pressure and fibrinogen were independently associated with CVD mortality; HOMA-IR and smoking habit were independently associated with cancer mortality. Individuals in the highest quintile of serum insulin had a 62% higher risk of cancer mortality (HR = 1.62 95% CI: 1.19-2.20; P < 0.0022) and 161% higher risk of gastrointestinal cancer mortality (HR = 2.61 95% CI: 1.73-3.94; P < 0.0001). Age- and sex-adjusted analysis showed that hyperinsulinemia/insulin resistance is associated with cancer mortality independently of diabetes, obesity/visceral obesity and the metabolic syndrome.

High-sensitivity C-reactive protein is within normal levels at the very onset of first ST-segment elevation acute myocardial infarction in 41% of cases: a multiethnic case-control study.

OBJECTIVES: This study sought to assess the prevalence of normal levels of high sensitivity C-reactive protein (hsCRP) at the very onset of ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Levels of hsCRP ≥2 mg/l identify individuals who benefit from lipid lowering and possibly anti-inflammatory agents, but how many patients develop infarction in spite of hsCRP levels <2 mg/l and thus would be ineligible for these treatments? METHODS: We studied 887 patients with unequivocally documented STEMI as the first manifestation of coronary disease and 887 matched control subjects from urban areas of Italy, Scotland, and China. Blood samples were obtained before reperfusion strategies <6 h from symptoms onset in order to limit acute event-related increases. RESULTS: hsCRP values were similar in samples obtained <2 h, 2 to 4 h, and 4 to 6 h from symptoms onset in all ethnic groups, consistent with the delayed hsCRP elevation after myocardial necrosis and thus indicative of pre-infarction levels. Median hsCRP values were significantly higher in patients than in control subjects: 2.49 (interquartile range [IQR]: 1.18 to 5.55) mg/l versus 1.32 (IQR: 0.58 to 3.10) mg/l (p < 0.0001), which is consistent with previous findings. However, 41% of patients had hsCRP levels <2 mg/l and conversely, 37% of control subjects had values ≥2 mg/l. CONCLUSIONS: The measurement of hsCRP, with a 2 mg/l cutoff, would not have predicted 41% of unequivocally documented STEMIs in 3 ethnic groups without evidence of previous coronary disease, thus indicating both its limitations as an individual prognostic marker and as an indicator of a generalized inflammatory pathogenetic component of STEMI. New specific prognostic and therapeutic approaches should be found for such a large fraction of patients at risk.

Resting cardiac energy metabolism is inversely associated with heart rate in healthy young adult men.

BACKGROUND: 31-Phosphorus-magnetic resonance spectroscopy may provide pathophysiological insights into the high-energy phosphate metabolism of the myocardium as measured by phosphocreatine to adenosine triphosphate (PCr/ATP) ratio. Aim of the present study was to determine in vivo the relation between cardiac PCr/ATP ratio and heart rate in normal male subjects. METHODS: One hundred twelve apparently healthy, young male individuals (age 34 ± 10 years) were prospectively evaluated. They underwent cardiac cine magnetic resonance imaging to assess left ventricular (LV) function and morphology and 3D-ISIS (31)P-magnetic resonance spectroscopy of the LV to assess the PCr/ATP ratio (a recognized in vivo marker of myocardial energy metabolism). Data were analyzed after segregation by tertiles of the resting PCr/ATP ratio. RESULTS: A significant inverse association between PCr/ATP ratios and resting heart rate was observed (Spearman ρ: r=-0.37; P < .0001). PCr/ATP ratios were also inversely associated with body mass index, diastolic blood pressure, wall mass and with insulin resistance, but in multiple regression analysis heart rate was found to be independently related to PCr/ATP. CONCLUSIONS: The present study shows that resting heart rate is proportionally lower across tertiles of increasing PCr/ATP ratio of the LV in apparently healthy young male individuals, supporting the hypothesis that heart rate is a major determinant of cardiac energy stores. These findings may explain the prognostic role of heart rate in the general population as evidenced by previous large epidemiological studies.

Efficacy of trunk balance exercises for individuals with chronic low back pain: a randomized clinical trial.

STUDY DESIGN: Randomized clinical trial. OBJECTIVES: To determine the efficacy of trunk balance exercises for individuals with chronic low back pain. BACKGROUND: The majority of exercises focusing on restoring lumbopelvic stability propose targeting the feedforward control of the lumbopelvic region. Less attention has been paid to feedback control during balance adjustments. METHODS: Seventy-nine patients were randomly allocated to 2 different groups. The experimental group performed trunk balance exercises in addition to standard trunk flexibility exercises. The control group performed strengthening exercises in addition to the same standard trunk flexibility exercises. The primary outcome measures were pain intensity (visual analogue scale), disability (Roland-Morris Questionnaire), and quality of life (12-Item Short-Form Health Survey). Secondary outcomes were painful positions, use of analgesic drugs, and referred pain. Analysis of variance and relative risk were used to analyze the data for the primary and secondary outcome measures, respectively. The number of participants reaching the minimal clinically important difference in the 2 groups for each outcome measure was compared using relative risk. RESULTS: A significant difference in scores on the Roland-Morris Questionnaire (P = .011) and the physical component of the 12-Item Short-Form Health Survey (P = .048), and in the number of participants reaching the minimal clinically important difference for the Roland-Morris Questionnaire (relative risk, 1.79; 95% confidence interval [CI]: 1.05, 3.04) and the secondary outcome of painful positions (relative risk, 1.37; 95% CI: 1.03, 1.83) were found in favor of the experimental treatment. CONCLUSIONS: Trunk balance exercises combined with flexibility exercises were found to be more effective than a combination of strength and flexibility exercises in reducing disability and improving the physical component of quality of life in patients with chronic low back pain.

Effect of partial inhibition of fatty acid oxidation by trimetazidine on whole body energy metabolism in patients with chronic heart failure.

OBJECTIVE: Trimetazidine may have beneficial effects on left ventricular (LV) function in patients with systolic heart failure. The authors assessed whether long-term addition of trimetazidine to conventional treatment could improve, along with LV function, resting whole body energy metabolism in patients with chronic systolic heart failure. DESIGN: Single blind randomised study. SETTING: University Hospital. PATIENTS: 44 patients with systolic heart failure receiving full medical treatment. INTERVENTIONS: Indirect calorimetry and two-dimensional echocardiography at baseline and after 3 months. MAIN OUTCOME MEASURES: Whole body resting energy expenditure (REE), percentage of predicted REE, LV ejection fraction (EF), NYHA class, quality of life. RESULTS: Trimetazidine increased EF compared with conventional therapy alone (from 35±8% to 42±11% vs from 35±7% to 36±6%; p=0.02, analysis of variance for repeated measures). NYHA class and quality of life also improved compared with conventional therapy (p<0.0001). REE (from 1677±264 to 1580±263 kcal/day) and percentage of predicted REE (based on the Harris-Benedict equation: from 114±10% to 108±9%) decreased in the trimetazidine group, but not in the control group (REE from 1679±304 to 1690±337 kcal/day and percentage of predicted REE from 113±12% to 115±14%). The variation was different between groups (p=0.03 and 0.023, respectively). CONCLUSIONS: In patients with systolic heart failure, improvement in functional class and LV function induced by middle-term trimetazidine therapy is paralleled by a reduction in whole body REE. The beneficial cardiac effects of trimetazidine may be also mediated by a peripheral metabolic effect.

Fatty liver index and mortality: the Cremona study in the 15th year of follow-up.

UNLABELLED: A fatty liver, which is a common feature in insulin-resistant states, can lead to chronic liver disease. It has been hypothesized that a fatty liver can also increase the rates of non-hepatic-related morbidity and mortality. Therefore, we wanted to determine whether the fatty liver index (FLI), a surrogate marker and a validated algorithm derived from the serum triglyceride level, body mass index, waist circumference, and γ-glutamyltransferase level, was associated with the prognosis in a population study. The 15-year all-cause, hepatic-related, cardiovascular disease (CVD), and cancer mortality rates were obtained through the Regional Health Registry in 2011 for 2074 Caucasian middle-aged individuals in the Cremona study, a population study examining the prevalence of diabetes mellitus in Italy. During the 15-year observation period, 495 deaths were registered: 34 were hepatic-related, 221 were CVD-related, 180 were cancer-related, and 60 were attributed to other causes. FLI was independently associated with the hepatic-related deaths (hazard ratio = 1.04, 95% confidence interval = 1.02-1.05, P < 0.0001). Age, sex, FLI, cigarette smoking, and diabetes were independently associated with all-cause mortality. Age, sex, FLI, systolic blood pressure, and fibrinogen were independently associated with CVD mortality; meanwhile, age, sex, FLI, and smoking were independently associated with cancer mortality. FLI correlated with the homeostasis model assessment of insulin resistance (HOMA-IR), a surrogate marker of insulin resistance (Spearman's ρ = 0.57, P < 0.0001), and when HOMA-IR was included in the multivariate analyses, FLI retained its association with hepatic-related mortality but not with all-cause, CVD, and cancer-related mortality. CONCLUSION: FLI is independently associated with hepatic-related mortality. It is also associated with all-cause, CVD, and cancer mortality rates, but these associations appear to be tightly interconnected with the risk conferred by the correlated insulin-resistant state.

Macular micropseudocysts in early stages of diabetic retinopathy.

PURPOSE: To identify by noninvasive means early retinal abnormalities that may predict diabetic macular edema. METHODS: The authors analyzed retrospectively data from consecutive patients with Type 1 (n = 16) or Type 2 (n = 23) diabetes who presented for routine follow-up of early retinopathy, had no clinical signs or symptoms of diabetic macular edema, and were evaluated with spectral-domain optical coherence tomography. Age- and gender-matched nondiabetic subjects provided normative data. RESULTS: Spectral-domain optical coherence tomography revealed in the macular region of diabetic patients small hyporeflective areas (median diameter, 55 µm) contained within discrete retinal layers that we named micropseudocysts (MPCs). Micropseudocysts are associated with vascular leakage. The patients showing MPCs had more frequently systemic hypertension and increased central foveal thickness than those without MPCs. The association with increased central foveal thickness was only in the patients with Type 2 diabetes. CONCLUSION: Macular MPCs in patients with mild diabetic retinopathy appear to reflect leakage and can precede macular thickening. The association of MPCs with increased central foveal thickness in patients with Type 2 diabetes, but not in patients with Type 1 diabetes, points to a greater tendency to retinal fluid accumulation in patients with Type 2 diabetes. Studies in larger cohorts will determine the usefulness of MPCs in strategies to abort diabetic macular edema.