Abstract Background In EVEREST II (Endovascular Valve Edge-to-Edge Repair Study), treatment of mitral regurgitation (MR) with a novel percutaneous device showed superior safety compared with surgery, ...but less effective reduction in MR at 1 year. Objectives This study sought to evaluate the final 5-year clinical outcomes and durability of percutaneous mitral valve (MV) repair with the MitraClip device compared with conventional MV surgery. Methods Patients with grade 3+ or 4+ MR were randomly assigned to percutaneous repair with the device or conventional MV surgery in a 2:1 ratio (178:80). Patients prospectively consented to 5 years of follow-up. Results At 5 years, the rate of the composite endpoint of freedom from death, surgery, or 3+ or 4+ MR in the as-treated population was 44.2% versus 64.3% in the percutaneous repair and surgical groups, respectively (p = 0.01). The difference was driven by increased rates of 3+ to 4+ MR (12.3% vs. 1.8%; p = 0.02) and surgery (27.9% vs. 8.9%; p = 0.003) with percutaneous repair. After percutaneous repair, 78% of surgeries occurred within the first 6 months. Beyond 6 months, rates of surgery and moderate-to-severe MR were comparable between groups. Five-year mortality rates were 20.8% and 26.8% (p = 0.4) for percutaneous repair and surgery, respectively. In multivariable analysis, treatment strategy was not associated with survival. Conclusions Patients treated with percutaneous repair more commonly required surgery for residual MR during the first year after treatment, but between 1- and 5-year follow-up, comparably low rates of surgery for MV dysfunction with either percutaneous or surgical therapy endorse the durability of MR reduction with both repair techniques. (EVEREST II Pivotal Study High Risk Registry; NCT00209274 )
Abstract Objective Patient-reported distress (PRD) has not been well assessed in association with survival after radiation therapy (RT). The aims of this study were to evaluate the association ...between PRD level and survival after definitive RT and to identify the main causes of distress in definitive RT patients. Methods and materials A total of 678 consecutive patients receiving definitive RT at our institution from April 2012 through May 2015 were included. All patients answered a PRD questionnaire that contained 30 items related to possible causes of distress, which could be rated from 1 (no distress) to 5 (high distress). Additionally, patients were asked to rate their overall distress level from 0 (no distress) to 10 (extreme distress). This overall distress level was our primary patient-reported distress measure and was examined as a continuous variable and as a categorical variable with 3 PRD levels (low, 0-3 n = 295; moderate, 4-6 n = 222; and high, 7-10 n = 161). Results As a continuous variable in multivariable Cox regression analysis, a higher overall PRD level was associated with poorer survival after RT (hazard ratio HR, 1.39; P = .004). As a categorical variable, compared with patients with low distress, survival was poorer for patients with moderate distress (HR, 1.62; P = .038) or high distress (HR, 1.49; P = .12), but the latter difference was not significant. When the moderate and high distress levels were combined, survival was significantly poorer compared with the low distress level (HR, 1.57; P = .034). The top 5 specific causes of distress that patients mentioned were “How I feel during treatment,” “Fatigue,” “Out-of-pocket medical costs,” “Pain that affects my daily functioning,” and “Sleep difficulties.” Conclusions PRD before or during RT is a prognostic factor associated with decreased survival. Distress screening guidelines and interventions should be implemented for patients receiving definitive RT.
Background Follicular helper T (TFH ) cells underpin T cell–dependent humoral immunity and the success of most vaccines. TFH cells also contribute to human immune disorders, such as autoimmunity, ...immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of TFH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities. Objective We sought to determine the signaling pathways and cellular interactions required for the development and function of TFH cells in human subjects. Methods Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cTFH ) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3 , STAT1 , TYK2 , IL21 , IL21R , IL10R , IFNGR1/2 , IL12RB1 , CD40LG , NEMO , ICOS , or BTK. Results Loss-of-function (LOF) mutations in STAT3 , IL10R , CD40LG , NEMO , ICOS , or BTK reduced cTFH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cTFH cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cTFH cell function in vitro and in vivo , as corroborated by hypergammaglobulinemia in patients with IFNGR1/2 , STAT1 , and IL12RB1 LOF mutations. Conclusion Specific mutations affect the quantity and quality of cTFH cells, highlighting the need to assess TFH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions in vivo to restrain TFH cell–induced B-cell differentiation. These findings shed new light on TFH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs.
Abstract Background Symptomatic mitral regurgitation (MR) is associated with high morbidity and mortality that can be ameliorated by surgical valve repair or replacement. Despite this, many patients ...with MR do not undergo surgery. Transcatheter mitral valve replacement (TMVR) may be an option for selected patients with severe MR. Objectives This study aimed to examine the effectiveness and safety of TMVR in a cohort of patients with native valve MR who were at high risk for cardiac surgery. Methods Patients underwent transcatheter, transapical delivery of a self-expanding mitral valve prosthesis and were examined in a prospective registry for short-term and 30-day outcomes. Results Thirty patients (age 75.6 ± 9.2 years; 25 men) with grade 3 or 4 MR underwent TMVR. The MR etiology was secondary (n = 23), primary (n = 3), or mixed pathology (n = 4). The Society of Thoracic Surgeons Predicted Risk of Mortality was 7.3 ± 5.7%. Successful device implantation was achieved in 28 patients (93.3%). There were no acute deaths, strokes, or myocardial infarctions. One patient died 13 days after TMVR from hospital-acquired pneumonia. Prosthetic leaflet thrombosis was detected in 1 patient at follow-up and resolved after increased oral anticoagulation with warfarin. At 30 days, transthoracic echocardiography showed mild (1+) central MR in 1 patient, and no residual MR in the remaining 26 patients with valves in situ. The left ventricular end-diastolic volume index decreased (90.1 ± 28.2 ml/m2 at baseline vs. 72.1 ± 19.3 ml/m2 at follow-up; p = 0.0012), as did the left ventricular end-systolic volume index (48.4 ± 19.7 ml/m2 vs. 43.1 ± 16.2 ml/m2 ; p = 0.18). Seventy-five percent of the patients reported mild or no symptoms at follow-up (New York Heart Association functional class I or II). Successful device implantation free of cardiovascular mortality, stroke, and device malfunction at 30 days was 86.6%. Conclusions TMVR is an effective and safe therapy for selected patients with symptomatic native MR. Further evaluation of TMVR using prostheses specifically designed for the mitral valve is warranted. This intervention may help address an unmet need in patients at high risk for surgery. (Early Feasibility Study of the Tendyne Mitral Valve System Global Feasibility Study; NCT02321514 )
Objective To examine the extent to which weight gain and weight status in the first 2 years of life relate to the risk of neurodevelopmental impairment in extremely preterm infants. Study design In a ...cohort of 1070 infants born between 23 and 27 weeks' gestation, we examined weight gain from 7-28 days of life (in quartiles) and weight z -score at 12 and 24 months corrected age (in 4 categories: <−2; ≥−2, <−1; ≥1, <1; and ≥1) in relation to these adverse neurodevelopmental outcomes: Bayley-II mental development index <55, Bayley-II psychomotor development index <55, cerebral palsy, Gross Motor Function Classification System ≥1 (cannot walk without assistance), microcephaly. We adjusted for confounders in logistic regression, stratified by sex, and performed separate analyses including the entire sample, and excluding children unable to walk without assistance (motor impairment). Results Weight gain in the lowest quartile from 7-28 days was not associated with higher risk of adverse outcomes. Children with a 12-month weight z-score <−2 were at increased risk for all adverse outcomes in girls, and for microcephaly and Gross Motor Function Classification System ≥1 in boys. However, excluding children with motor impairment attenuated all associations except that of weight z-score <−2 with microcephaly in girls. Similarly, most associations of low weight z-score at 24 months with adverse outcomes were attenuated with exclusion of children with motor impairment. Conclusion Excluding children who have gross motor impairment appears to eliminate the association of low weight status with neurodevelopmental impairments at 2 years in extremely preterm infants.
Objectives Pre-clinical experiments demonstrated that intravenous99m Tc labelled DI-DD-3B6/22-80B3 humanised anti-fibrin-D-dimer Fab′ fragments (99m Tc-DI-80B3) allowed scintigraphic imaging of acute ...pulmonary emboli (PE). The aims of this clinical study were to determine the safety of99m Tc-DI-80B3 in patients with PE and evaluate the resulting scintigraphic images for the localisation of acute PE. Materials/patients and methods99m Tc-DI-80B3 (0.5 mg, 710–850 MBq) was administered intravenously to subjects ( n = 14) with segmental or larger PE on recent contrast-enhanced helical CT scans. Thoracic SPECT scans were acquired 15 minutes, 2 hours and 4 hours afterwards. Subjects were followed for 90 days subsequently. Results There were no serious adverse events or antibody responses associated with99m Tc-DI-80B3 administration. Focal accumulations of99m Tc-DI-80B3 on the SPECT images of the thorax acquired at four hours corresponded to pulmonary emboli detected by CT. Two independent “blinded” SPECT readers identified 79% and 71% (respectively) of the right lung and 79% and 64% (respectively) of the left lung in which CT scans disclosed PE. Conclusions99m Tc-DI-80B3 is well-tolerated in patients with acute PE and does not induce an immune response.99m Tc-DI-80B3 may offer a novel approach to imaging PE in a clinically acceptable timeframe without exposure to potentially nephrotoxic radiographic contrast agents.
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