Abstract Background Filamin C (encoded by the FLNC gene) is essential for sarcomere attachment to the plasmatic membrane. FLNC mutations have been associated with myofibrillar myopathies, and cardiac ...involvement has been reported in some carriers. Accordingly, since 2012, the authors have included FLNC in the genetic screening of patients with inherited cardiomyopathies and sudden death. Objectives The aim of this study was to demonstrate the association between truncating mutations in FLNC and the development of high-risk dilated and arrhythmogenic cardiomyopathies. Methods FLNC was studied using next-generation sequencing in 2,877 patients with inherited cardiovascular diseases. A characteristic phenotype was identified in probands with truncating mutations in FLNC . Clinical and genetic evaluation of 28 affected families was performed. Localization of filamin C in cardiac tissue was analyzed in patients with truncating FLNC mutations using immunohistochemistry. Results Twenty-three truncating mutations were identified in 28 probands previously diagnosed with dilated, arrhythmogenic, or restrictive cardiomyopathies. Truncating FLNC mutations were absent in patients with other phenotypes, including 1,078 patients with hypertrophic cardiomyopathy. Fifty-four mutation carriers were identified among 121 screened relatives. The phenotype consisted of left ventricular dilation (68%), systolic dysfunction (46%), and myocardial fibrosis (67%); inferolateral negative T waves and low QRS voltages on electrocardiography (33%); ventricular arrhythmias (82%); and frequent sudden cardiac death (40 cases in 21 of 28 families). Clinical skeletal myopathy was not observed. Penetrance was >97% in carriers older than 40 years. Truncating mutations in FLNC cosegregated with this phenotype with a dominant inheritance pattern (combined logarithm of the odds score: 9.5). Immunohistochemical staining of myocardial tissue showed no abnormal filamin C aggregates in patients with truncating FLNC mutations. Conclusions Truncating mutations in FLNC caused an overlapping phenotype of dilated and left-dominant arrhythmogenic cardiomyopathies complicated by frequent premature sudden death. Prompt implantation of a cardiac defibrillator should be considered in affected patients harboring truncating mutations in FLNC.
Background Data on the clinical effectiveness of oseltamivir in patients with pandemic 2009 influenza A(H1N1) (AH1N1) virus infection are scarce. We aimed to determine the effect of timing of ...oseltamivir administration on outcomes in hospitalized adults with A(H1N1). Methods Observational analysis of a prospective cohort of adults hospitalized with laboratory-confirmed A(H1N1) was performed at 13 Spanish hospitals. Time from onset of symptoms to oseltamivir administration was the independent variable. Outcomes were duration of fever, hospital length of stay (LOS), need for mechanical ventilation, and mortality during hospitalization. Multivariate logistic regression was used to describe the association between the independent variable and the outcomes. Results Five hundred thirty-eight hospitalized patients with A(H1N1) were studied. The median time from onset of symptoms to oseltamivir administration was 3 days (interquartile range IQR, 2-5 days). With regard to outcomes, the median duration of fever was 2 days (IQR, 1-3 days), the median LOS was 5 days (IQR, 3-8 days), 49 patients (9.1%) underwent mechanical ventilation, and 11 patients (2%) died during hospitalization. In univariate analysis, prolonged duration of fever (above the median), prolonged LOS (above the median), need for mechanical ventilation, and mortality all increased with time to oseltamivir administration (χ2 test for trend P = .001, P ≤ .001, P = .008, and P = .001, respectively). After adjustment for confounding factors, time from onset of symptoms to oseltamivir administration (+ 1-day increase) was associated with a prolonged duration of fever (OR, 1.10; 95% CI, 1.02-1.19), prolonged LOS (OR, 1.07; 95% CI, 1.00-1.15), and higher mortality (OR, 1.20; 95% CI, 1.06-1.35). Conclusions Timely oseltamivir administration has a beneficial effect on outcomes in hospitalized adults with A(H1N1), even in those who are admitted beyond 48 h after onset of symptoms.
Background To date, antidepressant drugs show limited efficacy, leaving a large number of patients experiencing severe and persistent symptoms of major depression. Previous open-label clinical trials ...have reported significant sustained improvements with deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) in patients with severe, chronic treatment-resistant depression (TRD). This study aimed to confirm the efficacy and measure the impact of discontinuation of the electrical stimulation. Methods We conducted a 6-month double-blind, randomized, sham-controlled crossover study in implanted patients with previous severe TRD who experienced full remission after chronic stimulation. After more than 3 months of stable remission, patients were randomly assigned to 2 treatment arms: the ON–OFF arm, which involved active electrode stimulation for 3 months followed by sham stimulation for 3 months, and the OFF–ON arm, which involved sham stimulation for 3 months followed by active stimulation for 3 months. The primary outcome measure was the difference in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score between sham and active stimulation. Results We enrolled 5 patients in our trial. A Friedman repeated-measures analysis of variance revealed a significant effect of treatment (χ21 = 5.0, p = 0.025) in patients with higher depression scores during sham stimulation. At the end of active stimulation, depression was remitted in 4 of 5 patients and none of them had experienced a relapse, whereas at the end of sham stimulation, 2 patients remained in remission, 2 relapsed and 1 showed a progressive worsening without reaching relapse criteria. Limitations The small sample size limited the statistical power and external validity. Conclusion These preliminary findings indicate that DBS of the SCG is an effective and safe treatment for severe forms of TRD and that continuous electrical stimulation is required to maintain therapeutic effects. Trialregistration NCT01268137 ( ClinicalTrials.gov ).
Objective To produce a comprehensive anatomical and hemodynamic ultrasound scan mapping of the whole limb in patients with primary varicose veins (VVs). Design An analysis of venous duplex scans ...performed on patients referred for treatment of primary VVs. Methods A total of 2036 limbs were evaluated, looking for the origin of VVs in the saphenous systems and in the perforating vein (PV) systems, as well as for the presence of non-saphenous reflux. Results The sapheno-femoral junction (SFJ) of the great saphenous vein (GSV) was involved in 1330 limbs (65.3%). We have noted that finding reflux in the groin does not imply that it originates at that point necessarily, as reflux from the pelvis or abdominal wall can also cause primary VVs (SFJ reflux, 41.9% and competent SFJ with reflux from proximal veins, 35.4%). We also noted that analyzing only the presence of reflux in the SFJ of the GSV would miss 10.9% of limbs of reflux in the SFJ of the anterior accessory GSV. In 237 limbs (11.6%), reflux was observed in the popliteal fossa. In the PV system, we distinguished those PVs with retrograde flow that acted as an origin of the VVs, and other PVs that acted as re-entry points. Based on this difference, the location identified as the most frequent origin of VVs in the PV system was the thigh, specifically in the group of PVs of the medial thigh of the femoral canal, with 85 PVs with a total of 238 incompetent PVs identified. Pure non-saphenous reflux was observed in 162 limbs (8%). Conclusion The assumption that the origin of VVs would be exclusively in the sapheno-femoral or sapheno-popliteal junction, is a mistaken attitude and a comprehensive duplex scan mapping is recommended.
Although numerous existing studies have analyzed the prognostic factors of patients who have had surgical intervention for lung metastases of colorectal carcinoma (CRC), many of the results obtained ...until now have been contradictory. As a consequence, there is no established consensus about which group of prognostic factors could have a greater value when considered together.
This was a multicenter prospective cohort study that included all patients who underwent a first pulmonary metastasectomy of CRC, with radical intent, during a 2-year period (March 2008 to February 2010). The follow-up continued until March 2013, and an analysis of disease-specific survival (DSS), determined from the first pulmonary metastasectomy, was implemented. The selection of the best submodel was taken based on their coefficient of determination (R(2)) and how parsimonious they were depending on the number of variables included.
The series, consisting of 522 patients, presented the following survival rates: median, 54.9 months; 3-year DSS, 69.4% (95% confidence interval CI, 65% to 73.8%); and 5-year DSS, 46.1% (95% CI, 38.5% to 53.7%). The resulting survival model consisted of disease-free interval of 12 months or less (hazard ratio HR, 1.76; 95% CI, 1.21 to 2.54; p = 0.003), carcinoembryonic antigen level exceeding 5 ng/mL (HR, 1.50; 95% CI, 1.04 to 2.17; p = 0.028), bilateral lung disease (HR, 1.81; 95% CI, 1.20 to 2.75; p = 0.005), and thoracic lymph node involvement (HR, 2.71; 95% CI, 1.44 to 5.12; p = 0.002).
According to these results from the Spanish Group of Lung Metastases of Colo-Rectal Cancer, the combination of these four variables-disease-free interval, carcinoembryonic antigen level, laterality, and thoracic lymph node involvement-constitutes the first-choice survival causal model based on the clinical and pathologic factors most frequently referenced in literature.
Chronic renal failure has been described as a risk factor for the development of atrial fibrillation (AF). The aim of this study was to examine the association between contrast-induced nephropathy ...(CIN) and new-onset AF in patients with acute coronary syndromes. A total of 1,520 consecutive patients (mean age 67.1 ± 12.7 years) with acute coronary syndromes (34.4% with ST-segment elevation myocardial infarctions) who underwent coronary angiography were studied. CIN was defined as an increase in serum creatinine of 0.5 mg/dl within 72 hours of contrast exposure. The independent effect of AF history (chronic or paroxysmal AF before catheterization) on the development of CIN, as well as the independent effect of CIN on the development of new-onset AF (after catheterization, during the in-hospital phase), were tested by using different logistic regression models. One hundred thirty-nine patients (9.1%) had histories of AF before catheterization (60 with paroxysmal and 79 with chronic AF), and 56 (4.1%) developed new-onset AF after catheterization. Eighty-seven patients (5.7%) had CIN. AF history was a predictor of CIN in univariate analysis (odds ratio 2.19, 95% confidence interval 1.22 to 3.95, p = 0.007) but not in multivariate analysis, after adjusting for confounding variables (odds ratio 1.69, 95% confidence interval 0.89 to 3.22, p = 0.111). In contrast, those with CIN had an increased prevalence of new-onset AF (15.3% vs 3.4%, p <0.001). After adjusting for those variables associated with new-onset AF in the univariate analysis, CIN continued to show a significant association with new-onset AF, with a twofold increased risk (odds ratio 2.45, 95% confidence interval 1.07 to 5.64, p = 0.035). In conclusion, the development of CIN is an independent predictor of new-onset AF in the context of acute coronary syndromes.
Objective To compare the incidence and epidemiology of bacteremic community-acquired pneumonia (CAP) in the setting of changes in 13-valent pneumococcal conjugate vaccine (PCV13) coverage. Study ...design In the region of Madrid, universal immunization with the PCV13 started in May 2010. In July 2012, public funding ceased. Vaccination coverage decreased from >95% to 82% in 2013 and to 67% in 2014. We performed a multicenter surveillance and case-control study from 2009-2014. Cases were hospitalized children with bacteremic CAP. Controls were children selected 1:1 from next-admitted with negative blood cultures and typical, presumed bacterial CAP. Results Annual incidence of bacteremic CAP declined from 7.9/100 000 children (95% CI 5.1-11.1) in 2009 to 2.1/100 000 children (95% CI 1.1-4.1) in 2012. In 2014, 2 years after PCV13 was withdrawn from the universal vaccination program, the incidence of bacteremic CAP increased to 5.4/100 000 children (95% CI 3.5-8.4). We enrolled 113 cases and 113 controls. Streptococcus pneumoniae caused most of bloodstream infections (78%). Empyema was associated with bacteremia ( P = .003, OR 3.6; 95% CI 1.4-8.9). Simple parapneumonic effusion was not associated with bacteremia. Incomplete PCV immunization was not a risk factor for bacteremic pneumonia. Conclusions High rate of PCV13 immunization was associated with decreased incidence of bacteremic CAP; this incidence increased when rate of immunization fell. Empyema (but not parapneumonic pleural effusion) was associated with bacteremia.
Aim Right ventricular (RV) pump function is of essential clinical and prognostic importance in a variety of heart and lung diseases. While the evaluation of RV performance at rest has been ...implemented in the clinical setting, it is unknown whether this assessment during exercise may provide additional benefit. With this aim, we evaluated the exercise-induced pulmonary arterial systolic pressure (PASP) increase during exercise in patients with severe chronic obstructive pulmonary disease (COPD) as an expression of RV contractile reserve. Method Cardiopulmonary exercise testing (CPET) with synchronic echocardiography was performed in 81 patients. Patients were classified into two groups according to an exercise-induced PASP increase above 30 mmHg (High PSAP) or below 30 mmHg (Low PSAP) during maximal exercise. Patients were then followed for three years. Results Sixteen patients (20%) had low PSAP and 65 (80%) showed high PSAP. These were not significant clinical and functional differences. Low PSAP was associated with a significantly lower peak VO2 (mean (SD), 35 (2) % predicted) compared to high PSAP response (peak VO2 45 (3) % predicted), p=0.045. Factors associated with mortality were age and exercise-induced PASP. Seventeen patients died during the three years of follow-up (7 (39%) in the low PSAP group and only 10 (1%) in the high PSAP group, p=0.041). Conclusion Cardiopulmonary exercise testing with a synchronic echocardiography may be a useful tool for the assessment of RV contractile reserve in severe COPD patients. Exercise-induced PSAP emerges as a possible prognostic factor in these patients.
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