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Purpose: The shoulder is the most common site for upper extremity tumors. The aim of the study was to analyze the outcomes and the complications of modular reverse shoulder arthroplasty (RSA) after proximal humerus resection., Methods: We retrospectively included 15 consecutive patients who underwent a modular MUTARS™ RSA reconstruction after proximal humerus tumour resection between 2017 and 2020. The mean age was 52 years. Their clinical outcomes were assessed using the Constant-Murley score and the MSTS shoulder. Radiological outcomes were assessed based on the presence of loosening, osteolysis, and scapular notching. Complications such as dislocation, oncological recurrence, and infection were assessed. Mean follow-up time was 32.9 months (24 to 45)., Results: The mean adjusted Constant score was 50.7% (min 22, max 81), and the mean MSTS score was 15.6 (min 4, max 26). We had no loosening, osteolysis, or scapular notching on the radiographs at last follow-up. We had a high complication rate of 53%: one infection, one oncological recurrence, and six dislocations (40%), of which five were re-operated., Conclusion: In our experience, the MUTARS™ Implantcast™ modular RSA has poor functional results and a high rate of dislocation in the case of large proximal humerus resections below the distal insertion of the deltoid., (© 2024. The Author(s) under exclusive licence to SICOT aisbl.)

Background: While modular reconstruction implants can be used to replace the bone lost after bone tumor resection, tumor excision from the neighboring soft tissues can lead to loss of strength and joint range of motion (ROM), which results in worse knee function. Functional recovery after total knee arthroplasty for osteoarthritis has been extensively documented. But few studies have evaluated the recovery after total knee reconstruction following tumor excision despite the fact that most of these patients are young and have high functional demands. We did a prospective cross-sectional study to: 1) compare muscle strength recovery around the knee with an isokinetic dynamometer after tumor excision and reconstruction with a modular implant to the healthy contralateral knee; 2) determine if the differences in peak torque (PT) in the knee extensors and flexors had a clinical impact., Hypothesis: Resection of soft tissues during tumor excision around the knee causes strength loss that cannot be fully recovered., Methods: The 36 patients who underwent extra- or intra-articular resection of a primary or secondary bone tumor in the knee area followed by reconstruction with a rotating hinge knee system between 2009 and 2021 were eligible for this study. The primary outcome was the ability to actively lock the operated knee. The secondary outcomes were the concentric PT during isokinetic testing at slow (90°/sec) and fast (180°/sec) speeds, flexion-extension ROM, Musculoskeletal Tumor Society (MSTS) score, the IKS, Oxford Knee Score (OKS) and KOOS., Results: Nine patients agreed to participate in the study, all of whom had regained the ability to lock their knee postoperatively. PT in flexion and extension on the operated knee was less than the healthy knee. The PT ratio for the operated/healthy knee at 60°/sec and 180°/sec in flexion was 56.3%±16.2 [23.2-80.1] and 57.8%±12.3 [37.7-77.4], respectively, which corresponded to a slow-speed strength deficit of 43.7% in the knee flexors. The PT ratio for the operated/healthy knee at 60°/sec and 180°/sec in extension was 34.3%±24.6 [8.6-76.5] and 43%±27.2 [13.1-93.4], respectively, which corresponded to a slow-speed strength deficit of 65.7% in the knee extensors. The mean MSTS was 70%±20 [63-86]. The OKS was 29.9/48±11 [15-45], the mean IKS knee was 149.6±36 [80-178] and the mean KOOS was 67.43±18.5 [35-88.7]., Discussion: Despite all patients having the ability to lock out their knee, there was an imbalance in the strength between opposite muscle groups: 43.7% strength deficit at slow-speed and 42.2% at fast speed for the hamstring muscles, and 65.7% at slow-speed and 57% at fast speed for the quadriceps muscles. This difference is considered pathological with an increased risk of knee injury. Despite this strength deficit, this joint replacement technique, which is free of complications, can preserve good knee function with acceptable knee joint ROM and satisfactory quality of life., Level of Evidence: III; prospective cross-sectional case-control study., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Introduction: The Latarjet procedure provides satisfactory functional results, with low rates of recurrence. It is, however, sometimes claimed to induce osteoarthritis due to the positioning of the bone-block and hardware. The aims of the present study were to assess the long-term prevalence of osteoarthritis following the procedure, to determine risk factors and assess clinical impact. The study hypothesis was that osteoarthritis risk can be reduced by good bone-block positioning. The secondary objective was to assess long-term recurrence of instability., Materials and Methods: Out of a cohort of 102 patients (106 shoulders) operated on between 1984 and 1998, 77 had complete radiology files for analysis in a previous study published in 2003. Forty-four of these patients were seen again for clinical and radiological assessment at a mean 22 years' follow-up, to be compared to results previously reported at 8 years. Clinical assessment comprised range of motion and Constant and Walch-Duplay scores. X-rays were taken systematically to determine Samilson osteoarthritis stage; 31 patients also underwent CT., Results: In the 44 patients, the rate of osteoarthritis was 34.1%. 90.9% of patients were satisfied. Mean Constant score was 83.5±14 and mean Walch-Duplay score was 71.6±23.4. Advanced age at surgery and at assessment, length of follow-up and age >30 years at first episode of instability were the main factors for onset of osteoarthritis, independently of surgery. Lateral bone-block overhang correlated with onset of osteoarthritis: 71.4%, versus 16.7% in medial or flush bone-block (p=0.0004). Humeral notch, glenoid bone defect and number of preoperative episodes of instability were unrelated to onset of osteoarthritis. Lateral bone-block overhang was the only risk factor related to surgery. The clinical impact of the osteoarthritis was significant only in advanced stages (Samilson 3 and 4)., Conclusion: Lateral bone-block overhang was the only surgical risk factor for osteoarthritis in the long-term. Strict coracoid positioning is therefore essential, and could be facilitated by specific instrumentation and by arthroscopy., Level of Evidence: IV; retrospective study., (Copyright © 2021. Published by Elsevier Masson SAS.)

Background. We assessed the usefulness of a longitudinal strain adjusted to regional thickness in hypertrophic cardiomyopathy (HCM). Indeed, with conventional software, the width of the region of interest (ROI) is the same over the entire myocardial wall, wherein the software analyzes only partially the left ventricular (LV) hypertrophic segments. Methods. We included 110 patients: 55 patients with HCM (HCM group) and 55 healthy subjects (age- and sex-matched control group). The global longitudinal strain (GLS) and regional strain for each of the 17 segments was calculated with standard software (for two groups) and with software adjusted to the myocardial wall thickness (for the HCM group). Results. GLS was significantly decreased in the HCM group compared to the control group (−15.1 ± 4.8% versus −20.5 ± 4.3%, p < 0.0001). In the HCM group, GLS (standard method versus adjusted to thickness) measurements were not significantly different (p = 0.34). Interestingly, the regional strain adjusted to thickness was significantly lower than the standard strain in the hypertrophic segments, especially in the basal inferoseptal segment (p = 0.0002), median inferoseptal segment (p < 0.001) and median anteroseptal segment (p = 0.02). The strain adjusted to thickness was still significantly lower in the most hypertrophic segments (≥20 mm) (−3.7 ± 3%, versus −5.9 ± 4.4%, p = 0.049 in the basal inferoseptal segment and −5.7 ± 3.5% versus −8.3 ± 4.5%, p = 0.0007 in the median inferoseptal segment). In the segments with significant myocardial fibrosis, the longitudinal strain adjusted to thickness was significantly lower than the conventional strain (−8.3 ± 3.3% versus −11.4 ± 4.5%, p = 0.002). The analysis of the strain adjusted to thickness had a better feasibility (97.5% versus 99%, p = 0.01). Conclusions. The analysis of a longitudinal strain adjusted to regional thickness is feasible in HCM and allows a better evaluation of myocardial deformation, especially in the most LV hypertrophic segments.

Intranasal corticosteroid drugs are widely used in chronic rhinosinusitis with nasal polyps (CRSwNP). In contrast to classical delivery with nasal pump sprays, pulsating aerosols can deliver significant doses into superior and posterior sinonasal spaces. A case-control study was designed to assess the efficacy of corticosteroid transnasal nebulization on short-term mucosal recovery and quality of life (QoL) following endoscopic sinus surgery in CRSwNP. Thirty patients were prospectively enrolled to receive either 1-month budesonide nasal pump spray or 1-month budesonide 100-Hz acoustic pulsating nebulization at the first postoperative visit (day 8). Patients were evaluated with Lund-Kennedy endoscopic score at day 8 (D8) and 1 month later (M1). CRS-related QoL questionnaires (SNOT22 and RhinoQOL) were fulfilled at M1. The Lund-Kennedy endoscopic scores compared between D8 and M1 were suggestively improved in the group treated with budesonide nebulization (mean difference between groups, - 18.28 units; 95%CI, - 31.29 to - 5.28 units, p = 0.014). QoL measurements were comparable at M1 between the groups of patients. No unexpected adverse event was described with both budesonide delivery protocols. In the early postoperative period, patients with CRswNP may benefit from pulsating nebulization. Large studies should be conducted to confirm the results. Safety profile related to systemic steroid absorption and bioavailability in chronic respiratory diseases also need to be addressed for further use., (© 2021. Controlled Release Society.)

Background: The authors assessed the performance of pocket-sized transthoracic echocardiography (pTTE) compared with standard transthoracic echocardiography (sTTE) and auscultation for early screening of valvular heart disease (VHD). Early diagnosis of significant VHD is a challenge, but it enables appropriate follow-up and implementation of the best therapeutic strategy., Methods: sTTE, pTTE, and auscultation were performed by three different experienced physicians on 284 unselected patients. All cases of VHD detected by each of these three techniques were noted. sTTE was the gold standard. Each physician performed one examination and was blinded to the results of other examinations., Results: We diagnosed a total of 301 cases of VHD, with a large predominance of regurgitant lesions: 269 cases (89.3%) of regurgitant VHD and 32 (10.7%) of stenotic VHD. pTTE was highly sensitive (85.7%) and specific (97.9%) for screening for VHD, while auscultation detected only 54.1%. All significant cases of VHD (at least mild severity) were detected on pTTE. The weighted κ coefficient between pTTE and sTTE for the assessment of mitral regurgitation was 0.71 (95% CI, 0.70-0.72), indicating good agreement. The weighted κ coefficients between pTTE and sTTE for the assessment of aortic regurgitation and aortic stenosis were 0.97 (95% CI, 0.96-0.98) and 0.98 (95% CI, 0.97-0.99), respectively, indicating excellent agreement., Conclusions: pTTE performed by physicians with level III competency in echocardiography is reliable for identifying significant VHD and should be proposed as a new screening tool., (Copyright © 2021 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Background The development of carcinoid heart disease (CaHD) is still relatively unclear. It is difficult to define an optimal follow-up for patients without any cardiac involvement at baseline. The aim of this study was to assess the prevalence and natural history of CaHD by annual echocardiographic examinations. Methods and Results We studied 137 consecutive patients (61±12 years, 53% men) with proven digestive endocrine tumor and carcinoid syndrome between 1997 and 2017. All patients underwent serial conventional transthoracic echocardiographic studies. Right-sided and left-sided CaHD were systematically assessed. We used a previous validated echocardiographic scoring system of severity for the assessment of CaHD. An increase of 25% of the score was considered to be significant. Mean follow-up was 54±45 months. Prevalence of CaHD was 27% at baseline and 32% at 5-year follow-up. Disease progression was reported in 28% of patients with initial CaHD followed up for >2 years (n=25). In patients without any cardiac involvement at baseline, occurrence of disease was 21%. CaHD occurred >5 years from the initial echocardiographic examination in 42% of our cases, especially in patients presenting with new recurrence of a digestive endocrine tumor. An increase of urinary 5-hydroxyindoleacetic acid by 25% during follow-up was identified as an independent predictor of CaHD occurrence during follow-up (hazard ratio [HR], 5.81; 95% CI, 1.19-28.38; P =0.03), as well as a maximum value of urinary 5-hydroxyindoleacetic acid >205 mg/24 h during follow-up (HR, 8.41; 95% CI, 1.64-43.07; P =0.01). Conclusions Our study demonstrates that in patients without initial CaHD, cardiac involvement may occur late and is related to serotonin. Our data emphasize the need for cardiologic follow-up in patients with recurrence of the tumor process.

Introduction: The teres minor (TM) participates in active external rotation (ER) after reverse shoulder arthroplasty (RSA). The TM index of trophicity (T2/G) measured on CT scan is a predictor of poor results in patients who have irreparable rotator cuff tears. The aim of this study was to evaluate how T2/G impacts the functional outcomes of RSA in the context of massive rotator cuff tears. We hypothesized that a T2/G less than 0.75 is a predictor of worse functional outcomes., Materials and Methods: This study involved 32 shoulders in 26 patients (mean age 71 years) who underwent RSA for cuff tear arthropathy and had a minimum follow-up of 1 year (mean 3 years). T2/G is the ratio between T2 (TM thickness) and G (maximum glenoid cavity thickness) on preoperative axial CT slices. Clinical examination at the final assessment involved determining the Constant score, the shoulder joint's range of motion and the Subjective Shoulder Value (SSV)., Results: Eight shoulders had a T2/G of less than 0.75 (group 1) while 24 shoulders had an index above 0.75 (group 2). These two groups were similar preoperatively. The Constant-Murley score in group 1 was significantly lower than in group 2 (50.2 points versus 59.7 points, p<0.05). Group 1 had a postoperative improvement of 1̊ in their ER with elbow at side while group 2 had a 16.5̊ improvement (p=0.002). Group 1 had a postoperative loss of 6.3̊ in their ER in 90̊ abduction while group 2 had a 21.7̊ improvement (p=0.001). The SSV at the final assessment was 69% in group 1 versus 79% in group 2 (p=0.094)., Conclusion: Having a TM index of trophicity below 0.75 is a negative predictor of clinical outcomes due to lack of ER after RSA., Level of Evidence: IV., (Copyright © 2021. Published by Elsevier Masson SAS.)

Background: The risk of recurrence after the first episode of anterior shoulder dislocation is high with nonoperative treatment in younger patients., Purpose/hypothesis: The aim of this study was to compare the results of arthroscopic Bankart repair and nonoperative treatment for shoulder dislocation in patients younger than 25 years, with a minimum of 2 years of follow-up. The hypothesis was that surgery would decrease the risk of recurrence., Study Design: Randomized controlled trial; Level of evidence, 1., Methods: We included patients aged between 18 and 25 years after a first episode of anterior shoulder dislocation and divided them into 2 groups. The first group was treated surgically with an arthroscopic Bankart repair within 2 weeks after the dislocation; the second group was treated nonoperatively. Both groups were immobilized for 3 weeks in internal rotation and followed the same physical therapy protocol. Standard radiography and computed tomography were performed immediately after reduction of the dislocation, and follow-up was performed at 3, 6, 12, and 24 months. The primary outcome measure was instability recurrence, defined as another anterior shoulder dislocation requiring closed reduction by another person (the patient was unable to reduce the dislocated joint themselves), a subluxation, or a positive apprehension test. Secondary outcome measures included range of motion, return to sport, and functional scores such as the short version of the Disabilities of the Arm, Shoulder and Hand score the Walch-Duplay score, and the Western Ontario Shoulder Instability Index (WOSI)., Results: A total of 20 patients were included in each group. The mean ± SD age was 21 ± 1.8 years, and there were 33 men (82.5%) and 7 women (17.5%) in the total sample. Recurrence of instability was significantly decreased in the surgical treatment group compared with the nonoperative group (2 [10%] vs 14 [70%], respectively; P = .0001). Fewer patients in the surgical treatment group versus the nonoperative group had another episode of dislocation (0 vs 6 [30%], respectively), subluxation (2 [10%] vs 13 [65%], respectively; P = .003), or a positive apprehension test (1 [5%] vs 11 [58%], respectively; P = .0005). The Walch-Duplay score (88.4 vs 70.3 points; P = .046) and WOSI (11.5 vs 17.7 points; P = .035) were significantly better in the surgical group versus the nonoperative group after a 2-year follow-up. Level of sport was the same or better in 89% of the surgical treatment group vs 53% of the nonoperative treatment group ( P = .012). No surgical complication was recorded. We did not find any significant difference in range of motion., Conclusion: In patients with first-time shoulder dislocations, arthroscopic labral repair (Bankart procedure) reduced the risk of secondary shoulder dislocation and improved functional outcome versus nonoperative treatment after a 2-year follow-up. Surgical treatment after a first episode of shoulder dislocation could be offered as a primary treatment option in a younger population if these results are confirmed by larger studies with a longer follow-up., Registration: NCT03315819 (ClinicalTrials.gov identifier).

Background: Diastolic dysfunction in hypertrophic cardiomyopathy (HCM) is common, but its assessment is difficult using conventional echocardiography., Aims: To assess left atrial (LA) function in HCM by longitudinal strain and determine its role in understanding of symptoms., Methods: We studied 144 patients divided into 3 age- and sex-matched groups: 48 consecutive patients with HCM, 48 control subjects, and 48 athlete subjects. We assessed LA function by conventional echocardiographic parameters and by longitudinal atrial strain (early-diastolic left atrial strain during reservoir phase [LASr]; end-diastolic left atrial strain during conduit phase; end-systolic peak of the left atrial strain during contraction phase)., Results: NYHA classification was as follows in HCM group: I in 46%, II in 31%, III in 19%, and IV in 4%. Conventional echocardiographic parameters of diastolic function were depressed in the HCM group as compared to the control and athlete groups, but not related to symptoms. All longitudinal atrial strain parameters were significantly reduced in HCM group as compared to two groups (P < .0001). LASr was significantly correlated to peak VO2 (r = 0.44, P = .01) and was the best parameter for detecting symptomatic patients presenting with HCM, with a cutoff value of 15%: Sensitivity was 71%, specificity was 79%, PPV was 77%, and NPV was 73%., Conclusion: Assessment of LA function in HCM is feasible using longitudinal strain, and this technique is more reliable than conventional echocardiographic parameters for the understanding of determinants of symptoms., (© 2021 Wiley Periodicals LLC.)

The pathogenesis of atherosclerosis is complex, evolves, and involves many cell types. Macrophages and vascular smooth muscle cells (VSMCs) are critically involved in atherosclerosis development and progression. Several studies have shown that WNT5A protein is abundantly expressed in human atherosclerotic lesions; however, the mechanism and role of WNT signaling pathway activation is not clearly known. Using THP-1 derived macrophages, and human aortic VSMC cells, we evaluated in vitro how oxidized low-density lipoprotein (oxLDL) and WNT5A signaling interact in these two cell lines. We used western blot, scratch assay, metabolic proliferation assay, as well as immunostaining to analyze the effect of Wnt signaling activation. The results demonstrated that oxLDL, as well as WNT5A (control), induced Disheveled-2 (DVL2) activation and Kif26b degradation, indicating activation of non-canonical Wnt signaling. We found that oxLDL and WNT5A induced FZD5-ROR2 co-localization at the cellular membrane in vitro in THP-1 derived macrophages. Box5 (FZD5 receptor antagonist) inhibited oxLDL-induced DVL2/JNK activation secondary to newly secreted WNT protein from THP-1 derived macrophages. We found that WNT3A (canonical Wnt) and WNT5A showed different roles in this VSMC cell line. These findings indicate that WNT5A is upregulated by oxLDL, promotes foam cell formation, and affects VSMC phenotype and migration in these two cell lines. Also, in these cell lines FZD5 signaling seems to be necessary for lipid accumulation and, through this mechanism, WNT5A could modulate foam cell formation. Thus, our results suggest that WNT5A may contribute to the pathogenesis of vascular disease through modulating macrophage and VSMC behavior., (Copyright © 2020 Ackers, Szymanski, Silver and Malgor.)

Introduction: Peripheral skeletal metastasis (PSM) has a negative impact on quality of life. New treatments for the primary tumor or the osteolysis hold out hope of improved survival. The few published French series were small, and we therefore undertook a multicenter retrospective analysis of PSM surgery between 2005 and December 2016, with the aim of assessing: 1) rate and type of complications, 2) functional results, and 3) overall survival and corresponding risk factors., Hypothesis: The French data for clinical results, survival and complications are in agreement with the international literature., Materials and Method: The series comprised 391 patients with 434 metastatic locations. There was female predominance: 247 women (63%). Two sites were treated in 46 patients (12%), and three in 5. The main etiologies were breast cancer (151/391: 39%), lung cancer (103/391: 26%) and kidney cancer (52/391: 13%). There was synchronous visceral metastasis in 166 patients (42.5%), other peripheral locations in 137 (35%) and spinal location in 142 (39%). One hundred (27%) had ASA score>3; 61 (16%) had WHO score>3. The reason for surgery was pathologic fracture (n=137: 35%). Locations were femoral (274: 70%), acetabular (58: 15%), humeral (40: 0%), tibial (12: 3%) or other (7: 2%)., Results: There were surgery site complications in 41 patients (9.4%), including 13 surgery site infections, and general complications in 47 patients (11%), including 11 cases of thromboembolism, 6 of blood loss, 9 pulmonary complications and 6 perioperative deaths. Overall survival, taking all etiologies and sites together, was 10 months (range, 5 days to 9 years; 95% CI, 8-13 months), and significantly better in females (14 versus 6 months; p=0.01), under-65 year-olds (p=0.001), and in preventive surgery versus fractured PSM (p=0.001). Median survival was 22 months (95% CI, 17-28 months) after breast cancer, 3 months (95% CI, 2-5 months) after lung cancer, and 17 months (95% CI, 8-58 months) after kidney cancer. Preoperatively, walking was impossible for 143 patients (38%), versus 23 (6.5%) postoperatively; 229 patients (63.5%) could walk normally or nearly normally after surgery, versus 110 (28%) before. After surgery, 3 patients (6%) were not using their operated upper limb, versus 27 (45%) before; 30 patients (54%) had normal upper limb use after surgery, versus 8 (5%) before., Conclusion: The study hypothesis was on the whole confirmed in terms of survival according to type of primary and whether surgery was indicated preventively or for fracture., Level of Evidence: IV, retrospective study without control group., (Copyright © 2019. Published by Elsevier Masson SAS.)

Introduction: The proximal femur is the most frequent operative site for metastasis, but there is no consensus between internal fixation and hip replacement. The present multicenter retrospective observational study sought: (1) to compare early clinical results between internal fixation and hip replacement for proximal femoral metastasis (PFM), and (2) to assess events affecting survival., Hypothesis: The study hypothesis was that internal fixation and hip replacement give comparable clinical results, operative site complications rates and survival., Material and Methods: The series comprised 309 cases, 10 of which were bilateral, in 182 females and 117 males, with a mean age of 67.2±11.5 years and 62.5±13.2 years, respectively. Primaries were mainly breast (118; 38.2%), lung (85; 25.5%) or kidney (40; 12.9%). PFM was revelatory in 114 cases (36.9%). There was visceral involvement in 142 patients (46%), multiple peripheral bone involvement in 212 (68.6%), and spinal involvement in 134 (43.4%). There were 124 pathologic fractures (40%), 51 of which were revelatory. Metastases were cervicocephalic in 135 cases (43.7%), metaphyseal in 166 (53.7%) and both in 8 (2.6%). PFM was osteolytic in 90% of cases, managed by hip replacement in 161 cases and internal fixation in 148 (12 screwed plates, 136 nails). Seventy-seven patients had postoperative radiation therapy., Results: After hip replacement (n=144), walking was normal in 35 cases (24.3%), impaired but unassisted in 53 (36.8%), with 1 forearm crutch in 24 (16.6%), 2 crutches or a frame in 26 (18%), and impossible in 6 (4.1%). After nailing (n=125), results were respectively 38 (30.4%), 47 (37.6%), 15 (12%), 18 (14.4) and 7 (5.6%). Recovery of normal walking capacity did not significantly differ according to technique (p=0.162); nor did pain or function. Recovery of normal walking capacity was better after preventive surgery (p<0.001). Perioperative complications comprised: 10 cases of severe blood loss, 7 pulmonary embolisms, 6 digestive hemorrhages, and 5 lung infections. Secondarily, there were 11 infections (7 after hip replacement, 2 after nailing, 2 after plate fixation), 7 progressive osteolyses and 5 fractures. Complications rates were significantly higher with plate fixation, with no difference between nailing and hip replacement. Survival did not significantly differ between hip replacement (12 months [95% CI: 7-19]), nailing (7 months [95% CI: 6-11]) and plate fixation (16 months [95% CI: 6-not calculable])., Conclusions: Clinical results and survival were comparable between hip replacement and nailing, confirming the study hypothesis, in agreement with the literature. Each technique has its indications. Patients with severely impaired walking capacity benefited greatly from surgery. The importance of preventive surgery was highlighted., Level of Evidence: IV, retrospective study., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background: Despite maximum medical treatment and endoscopic sinus surgery (ESS), chronic rhinosinusitis with nasal polyps (CRSwNP) can require revision surgery. With a growing literature on the diversity of cytokine inflammation patterns in CRSwNP, an endotype-driven approach could lead to the identification of cytokine profiles that predict recurrence., Methods: A monocentric longitudinal study was carried out until June 2019 following CRSwNP patients who underwent surgery for the first time between December 2010 and January 2012. The biomarker profiles were established on blood and nasal secretions at the time of the first surgery (Interleukin (IL)-5, IgE, IgA, eosinophilic cationic protein (ECP) and eosinophilic- derived neurotoxin (EDN)). Profiles were compared between the patients still controlled by medical treatment and the patients requiring revision surgery during the course of the follow-up period., Results: Among the 48 patients initially enrolled in our study, 8 required revision surgery (16,7%). Clinical features (asthma, allergy, aspirin intolerance, active smoking) and levels of blood markers measured at the time of the first surgery were comparable between the 2 groups of patients. Levels of IL-5, IgE and ECP in nasal secretions were significantly increased in the group of patients needing revision surgery., Conclusions: Based on simple approach of nasal secretions sampling, we showed that a predominant T helper 2 proteins expression profile can be associated with recurrent CRSwNP after ESS. Initial immunoprofiling in CRSwNP disease may contribute to better predict the therapeutic response to optimal medical and surgical treatment, and help define the role of innovative targeted treatment, beside corticosteroids and ESS.

Cilia and flagella are evolutionarily conserved organelles whose motility relies on the outer and inner dynein arm complexes (ODAs and IDAs). Defects in ODAs and IDAs result in primary ciliary dyskinesia (PCD), a disease characterized by recurrent airway infections and male infertility. PCD mutations in assembly factors have been shown to cause a combined ODA-IDA defect, affecting both cilia and flagella. We identified four loss-of-function mutations in TTC12, which encodes a cytoplasmic protein, in four independent families in which affected individuals displayed a peculiar PCD phenotype characterized by the absence of ODAs and IDAs in sperm flagella, contrasting with the absence of only IDAs in respiratory cilia. Analyses of both primary cells from individuals carrying TTC12 mutations and human differentiated airway cells invalidated for TTC12 by a CRISPR-Cas9 approach revealed an IDA defect restricted to a subset of single-headed IDAs that are different in flagella and cilia, whereas TTC12 depletion in the ciliate Paramecium tetraurelia recapitulated the sperm phenotype. Overall, our study, which identifies TTC12 as a gene involved in PCD, unveils distinct dynein assembly mechanisms in human motile cilia versus flagella., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Introduction: Despite the good outcomes with shoulder resurfacing procedures reported by some authors, our team has documented several failures caused by glenoid erosion and rotator cuff rupture, likely due to implant overstuffing. The aim of this study was to evaluate the clinical and radiological outcomes of reverse shoulder arthroplasty (RSA) performed after failed humeral head resurfacing (HHR)., Material and Methods: This was a retrospective, single-center study of 17 patients who underwent RSA after failed HHR between January 2011 and February 2016. The mean patient age was 69.4 years and the mean time between HHR and surgical revision was 41 months (14.7-73.5±18.8). Preoperative ultrasonography and CT were used to evaluate the condition of the rotator cuff, extent of glenoid erosion and to look for signs of humeral cup loosening. The clinical outcomes were evaluated pre- and postoperatively using the simple shoulder test (SST), DASH (Disabilities of the Arm, Shoulder and Hand) and the Constant-Murley score. Pain was estimated using a visual analog scale (VAS). The range of motion (ROM) was determined pre- and postoperatively. All patients had standard AP and lateral X-ray views of the shoulder taken as part of their postoperative follow-up protocol to look for implant loosening., Results: The mean follow-up was 35.9 months (24-59±10.7). There were no intraoperative or postoperative complications. All the functional scores were improved after RSA. The median weighted Constant score preoperatively was 46% (36; 62) while it was 92% postoperatively (78; 100) (p<0.0001). The active ROM improved by 65° in forward flexion (p=0.0003) and by 30° in external rotation (p=0.002). On X-rays, we identified one patient with Sirveaux stage 4 glenoid notching and one patient with a humeral periprosthetic radiolucent line less than 2mm thick in zone 6, with no clinical consequences., Conclusion: The excellent outcomes after RSA for failed HHR in our study are similar to the ones reported when RSA is performed for cuff tear arthropathy., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Dobutamine stress echocardiography (DSE) is a widely used examination for assessment of coronary ischemia, but several complications have been reported. The aim of this study was to assess the incidence of atrial fibrillation (AF) during DSE, and a systematic review and meta-analysis were also performed to determine an accurate estimate of the AF incidence. Over a 16-year period, we reviewed all patients referred for DSE. We systematically analyzed all ECG performed during DSE to detect AF during the examination. DSE was completely performed in 4,818 patients (mean age: 62.1 ± 11.7 years). AF was observed in 40 patients (31 men, mean age: 79.7 ± 8.9 years). Incidence of AF during DSE was 0.83%. Regarding the meta-analysis, the combined AF incidence was 0.86%. In our study, patients with AF occurrence had more frequent previous history of paroxysmal AF (p = 0.02) were also older (p < 0.0001) and incidence of AF during DSE increased with age: 0% below 60 years, 0.45% in patients 60 to 69 years, 1.3% in patients 70 to 79 years, and 4% in patients >80 years (p < 0.0001). In multivariate analysis, the factors significantly associated with an increased risk of AF were age (adjusted odds ratio (aOR) = 2.4, 95% confidence interval: 1.5 to 3.3, p = 0.003) and previous history of paroxysmal AF (aOR = 1.5, 95% confidence interval: 1.1 to 1.9; p = 0.04). In conclusion, AF is uncommon during DSE, and elderly patients and patients with previous history of paroxysmal AF are at risk of AF during DSE., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Scientific guidelines consider atrial fibrillation (AF) complicating degenerative mitral regurgitation (DMR) a debated indication for surgery., Objectives: This study analyzed the prognostic/therapeutic implications of AF at DMR diagnosis and long-term., Methods: Patients were enrolled in the MIDA (Mitral Regurgitation International Database) registry, which reported the consecutive, multicenter, international experience with DMR due to flail leaflets echocardiographically diagnosed., Results: Among 2,425 patients (age 67 ± 13 years; 71% male, 67% asymptomatic, ejection fraction 64 ± 10%), 1,646 presented at diagnosis with sinus rhythm (SR), 317 with paroxysmal AD, and 462 with persistent AF. Underlying clinical/instrumental characteristics progressively worsened from SR to paroxysmal to persistent AF. During follow-up, paroxysmal and persistent AF were associated with excess mortality (10-year survival in SR and in paroxysmal and persistent AF was 74 ± 1%, 59 ± 3%, and 46 ± 2%, respectively; p < 0.0001), that persisted 20 years post-diagnosis and independently of all baseline characteristics (p values <0.0001). Surgery (n = 1,889, repair 88%) was associated with better survival versus medical management, regardless of all baseline characteristics and rhythm (adjusted hazard ratio: 0.26; 95% confidence interval: 0.23 to 0.30; p < 0.0001) but post-surgical outcome remained affected by AF (10-year post-surgical survival in SR and in paroxysmal and persistent AF was 82 ± 1%, 70 ± 4%, and 57 ± 3%, respectively; p < 0.0001)., Conclusions: AF is a frequent occurrence at DMR diagnosis. Although AF is associated with older age and more severe presentation of DMR, it is independently associated with excess mortality long-term after diagnosis. Surgery is followed by improved survival in each cardiac rhythm subset, but persistence of excess risk is observed for each type of AF. Our study indicates that detection of AF, even paroxysmal, should trigger prompt consideration for surgery., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Left atrial (LA) enlargement has been previously identified as a predictor of mortality in patients with medically managed mitral regurgitation (MR) due to mitral valve prolapse (MVP). No study has specifically assessed the prognostic value of LA size in patients undergoing mitral valve repair (MVRp)., Objective: We aimed to investigate the relationship between LA area and mortality in patients in sinus rhythm (SR) undergoing MVRp for MVP., Methods: We included 305 patients in SR who underwent MVRp for MVP. Median follow-up time was 7.9 years. Patients were divided into 3 groups: LA area ≤25 cm2 (reference group), LA 26-30 cm2, and LA >30 cm2., Results: Compared with patients with an LA area ≤25 cm2, those with an LA area >30 cm2 had a lower 10-year survival (98 ± 2 vs. 86 ± 4%; p = 0.037). In multivariate analysis, after adjustment for established outcome predictors including age, symptoms, EuroSCORE, and left ventricular size and function, LA enlargement >30 cm2 was associated with increased mortality (adjusted HR = 2.20, 95% CI 1.03-4.90; p = 0.042), whereas LA enlargement between 26 and 30 cm2 was not (adjusted HR = 1.37, 95% CI 0.56-3.56; p = 0.52)., Conclusion: LA enlargement is independently predictive of long-term mortality after MVRp in patients in SR with severe MR due to MVP. Our findings suggest that MVRp should be considered before the LA area exceeds 30 cm2., (© 2019 S. Karger AG, Basel.)

The natural specificity of bacteriophages toward their hosts represents great potential for the development of platforms for the capture and detection of bacterial pathogens. Whole phage can carry reporter genes to alter the phenotype of the target pathogen. Phage can also act as staining agents or the progeny of the infection process can be detected. Alternatively, using phage components as probes offer advantages over whole phage particles, including smaller probe size and resilience to desiccation. Phage structures can be engineered for improved affinity, specificity, and binding properties. However, such concepts require the ability to anchor phage and phage-components onto mechanical supports such as beads or flat surfaces. The ability to orient the anchoring is desired in order to optimize binding efficiency. This chapter presents various methods that have been employed for the attachment of phage and phage components onto support structures such as beads, filters, and sensor surfaces.

Aims: To evaluate the prognostic value of apical four-chamber (A4-C) longitudinal strain (LS) in patients with aortic stenosis (AS)., Methods and Results: In a multicentre cohort, 582 patients (74.3 ± 10.9 years) with moderate or severe AS and preserved left ventricular (LV) ejection fraction (≥50%) were included in this retrospective study. Patients with severe AS were classified in four subgroups according to flow and gradient: low flow (LF) was defined as a stroke volume index <35 mL/m2 compared with normal flow (NF); low-gradient (LG) as a mean gradient <40 mmHg compared with high gradient (HG). The end point was all-cause of mortality. A4-C LS was measured by two-dimensional speckle tracking and was feasible in all patients. The degree of A4-C LV longitudinal dysfunction increased according to the severity and subgroups of severe AS: from the least to the most impaired: moderate AS, NF/HG, NF/LG, LF/HG, and LF/LG AS (P < 0.001). During a mean follow-up of 2.6 ± 0.2 years, 58(10%) patients died. The 2-year survival was 76.8% in patients with LF/LG vs. 89.3% in patients with other groups. The best threshold of A4-C LS associated with overall mortality was an absolute cut-off value of |13.75%|. According to this cut-off, the 2-year survival was higher both in patients with moderate AS (96.3 vs. 70%, P = 0.02) and those with severe AS (92.9 vs. 80.9%, P = 0.005). However when dichotomized according to flow/gradient patterns, the association was only statistically significant in the subgroup of patients with NF/HG. By multivariable cox regression analysis, A4-C LS <|13.75| remained independently associated with overall mortality (hazard ratio: 1.8; P = 0.045)., Conclusion: A4-C LS is independently associated with death in patients with AS and preserved LVEF, however the flow/gradient pattern should also be considered as an important parameter. The management of these patients may use A4-C LS as a new parameter of evaluation of LV function and prognosis.

Introduction: Peroneal tendinopathy is an under-diagnosed pathology, mainly triggered by ankle sprain. Failure of medical treatment often leads to surgery, with modalities adapted to the lesion type. The present study aimed to assess clinical and functional results of tendon repair and to analyze the influence of hindfoot alignment on quality of outcome. The study hypothesis was that hindfoot varus impairs medium-term results., Materials and Methods: A retrospective series of 30 patients undergoing peroneal tendon repair or tenodesis was analyzed at a mean 20 months' follow-up. All patients had preoperative ultrasound scan or NMRI. Clinical assessment was based on AOFAS and FAAM scores. Hindfoot alignment was assessed on Méary view; 2 groups were distinguished: valgus (n=11) and varus (n=17)., Results: Mean AOFAS score improved, from 74.5±11.2 preoperatively to 86.7±9.4 at follow-up. There was a significant intergroup difference (p=0.0003) in AOFAS at follow-up: valgus, 93/100; varus, 82/100. There was no significant intergroup difference in FAAM score. Time to surgery, lesion type and surgical technique did not influence clinical results., Discussion/conclusion: Clinical results for surgical repair of peroneal tendons were satisfactory and in line with literature reports. However, hindfoot varus was associated with poorer results, raising the possibility of correction by opening wedge calcaneal osteotomy., Level of Evidence: IV, retrospective case series., (Copyright © 2018. Published by Elsevier Masson SAS.)

Background and Aims: Wnt5a is a highly studied member of the Wnt family and recently has been implicated in the pathogenesis of atherosclerosis, but its precise role is unknown. Foam cell development is a critical process to atherosclerotic plaque formation. In the present study, we investigated the role of noncanonical Wnt5a signaling in the development of foam cells., Methods: Human carotid atherosclerotic tissue and THP-1-derived macrophages were used to investigate the contribution of Wnt5a signaling in the formation of foam cells. Immunohistochemistry was used to evaluate protein expression of scavenger receptors and noncanonical Wnt5a receptors [frizzled 5 (Fz5) and receptor tyrosine kinase-like orphan receptor 2 (Ror2)] in human atherosclerotic macrophages/foam cells. Changes in protein expression in response to Wnt5a stimulation/inhibition were determined by Western blot, and lipid accumulation was evaluated by fluorescent lipid droplet staining., Results: Wnt5a (P<.05), Fz5 (P<.01), and Ror2 (P<.01) were significantly expressed in advanced atherosclerotic lesions compared to less advanced lesions (N=10). Wnt5a, Fz5, and Ror2 were expressed in macrophages/foam cells within the plaque. In vitro studies revealed that Wnt5a significantly increased the expression of the lipid uptake receptor CD36 (P<.05) but not the lipid efflux receptor ATP-binding cassette transporter (P>.05). rWnt5a also significantly increased lipid accumulation in THP-1 macrophages (P<.05). Furthermore, inhibition of Wnt5a signaling with Box5 prevented lipid accumulation (P<.01) and prevented CD36 up-regulation (P<.01)., Conclusions: These results suggest a direct role for Wnt5a signaling in the pathogenesis of atherosclerosis, specifically the accumulation of lipid in macrophages and the formation of foam cells., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aims: In degenerative mitral regurgitation (DMR), lack of mortality scores predicting death favours misperception of individual patients' risk and inappropriate decision-making., Methods and Results: The Mitral Regurgitation International Database (MIDA) registries include 3666 patients (age 66 ± 14 years; 70% males; follow-up 7.8 ± 5.0 years) with pure, isolated, DMR consecutively diagnosed by echocardiography at tertiary (European/North/South-American) centres. The MIDA Score was derived from the MIDA-Flail-Registry (2472 patients with DMR and flail leaflet-Derivation Cohort) by weighting all guideline-provided prognostic markers, and externally validated in the MIDA-BNP-Registry (1194 patients with DMR and flail leaflet/prolapse-Validation Cohort). The MIDA Score ranged from 0 to 12 depending on accumulating risk factors. In predicting total mortality post-diagnosis, the MIDA Score showed excellent concordance both in Derivation Cohort (c = 0.78) and Validation Cohort (c = 0.81). In the whole MIDA population (n = 3666 patients), 1-year mortality with Scores 0, 7-8, and 11-12 was 0.4, 17, and 48% under medical management and 1, 7, and 14% after surgery, respectively (P < 0.001). Five-year survival with Scores 0, 7-8, and 11-12 was 98 ± 1, 57 ± 4, and 21 ± 10% under medical management and 99 ± 1, 82 ± 2, and 57 ± 9% after surgery (P < 0.001). In models including all guideline-provided prognostic markers and the EuroScoreII, the MIDA Score provided incremental prognostic information (P ≤ 0.002)., Conclusion: The MIDA Score may represent an innovative tool for DMR management, being able to position a given patient within a continuous spectrum of short- and long-term mortality risk, either under medical or surgical management. This innovative prognostic indicator may provide a specific framework for future clinical trials aiming to compare new technologies for DMR treatment in homogeneous risk categories of patients.

Aggressive giant cell tumors are rare at the distal ulna. We report the results of two patients who were treated surgically using a distal ulna prosthesis stabilized by ligament reconstruction with the brachioradialis tendon. At the maximum follow-up of 18months, the two patients were satisfied. Joint range of motion and functional scores were improved. X-rays showed no recurrence or subluxation; however gradual impingement of the ulnar notch of radius by the prosthesis was visible. Our technique seems to be a viable alternative when compared with the treatments described in other published case reports., (Copyright © 2017 SFCM. Published by Elsevier Masson SAS. All rights reserved.)

We walk together, we watch together, we win together: Interpersonally coordinated actions are omnipresent in everyday life, yet the associated neural mechanisms are not well understood. Available evidence suggests that the synchronization of oscillatory activity across brains may provide a mechanism for the temporal alignment of actions between two or more individuals. In an attempt to provide a direct test of this hypothesis, we applied transcranial alternating current stimulation simultaneously to two individuals (hyper-tACS) who were asked to drum in synchrony at a set pace. Thirty-eight female-female dyads performed the dyadic drumming in the course of 3 weeks under three different hyper-tACS stimulation conditions: same-phase-same-frequency; different-phase-different-frequency; sham. Based on available evidence and theoretical considerations, stimulation was applied over right frontal and parietal sites in the theta frequency range. We predicted that same-phase-same-frequency stimulation would improve interpersonal action coordination, expressed as the degree of synchrony in dyadic drumming, relative to the other two conditions. Contrary to expectations, both the same-phase-same-frequency and the different-phase-different-frequency conditions were associated with greater dyadic drumming asynchrony relative to the sham condition. No influence of hyper-tACS on behavioral performance was seen when participants were asked to drum separately in synchrony to a metronome. Individual and dyad preferred drumming tempo was also unaffected by hyper-tACS. We discuss limitations of the present version of the hyper-tACS paradigm, and suggest avenues for future research.

Background: Left atrial (LA) enlargement is frequent in patients with aortic stenosis (AS), yet its determinants and prognostic implications are poorly understood., Aims: To identify the echocardiographic variables associated with increased LA volume index (LAVI), and test the prognostic value of LAVI in AS., Methods: We prospectively included 715 patients with AS in sinus rhythm at enrolment. Echocardiography was performed at baseline. Median follow-up was 22.0 (9-34) months. Patients were divided into two groups according to the best cut-off for event prediction during follow-up (45mL/m 2 )., Results: Compared with LAVI<45mL/m 2 , patients with LAVI≥45mL/m 2 had a lower stroke volume, cardiac output and left ventricular (LV) ejection fraction, greater LV volumes and mass and higher filling pressures. By linear regression, LAVI was best correlated with E wave mitral velocity (r=0.34), E/A ratio (r=0.34), E/e' ratio (r=0.28), indexed LV mass (r=0.29), systolic pulmonary artery pressure (r=0.34) and LV longitudinal strain (r=-0.28). Multivariable analysis confirmed the independent association of LAVI with age (P<0.001), indexed aortic valve area (P=0.04), indexed LV mass (P<0.001), LV ejection fraction (P=0.007), LV end-diastolic volume (P=0.001), E/A ratio (P<0.001) and E/e' ratio (P<0.001). LAVI≥45mL/m 2 was independently predictive of the combined endpoint of cardiovascular death or hospitalization for heart failure (adjusted hazard ratio 1.69, 95% confidence interval 1.04-2.73)., Conclusion: LA enlargement is correlated with AS severity, but also with variables reflecting LV systolic and diastolic dysfunction. Further studies are needed to investigate the outcome implication of LA enlargement in patients with AS., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: After myocardial infarction (MI), mitral valve (MV) tethering stimulates adaptive leaflet growth, but counterproductive leaflet thickening and fibrosis augment mitral regurgitation (MR), doubling heart failure and mortality. MV fibrosis post-MI is associated with excessive endothelial-to-mesenchymal transition (EMT), driven by transforming growth factor (TGF)-β overexpression. In vitro, losartan-mediated TGF-β inhibition reduces EMT of MV endothelial cells., Objectives: This study tested the hypothesis that profibrotic MV changes post-MI are therapeutically accessible, specifically by losartan-mediated TGF-β inhibition., Methods: The study assessed 17 sheep, including 6 sham-operated control animals and 11 with apical MI and papillary muscle retraction short of producing MR; 6 of the 11 were treated with daily losartan, and 5 were untreated, with flexible epicardial mesh comparably limiting left ventricular (LV) remodeling. LV volumes, tethering, and MV area were quantified by using three-dimensional echocardiography at baseline and at 60 ± 6 days, and excised leaflets were analyzed by histopathology and flow cytometry., Results: Post-MI LV dilation and tethering were comparable in the losartan-treated and untreated LV constraint sheep. Telemetered sensors (n = 6) showed no significant losartan-induced changes in arterial pressure. Losartan strongly reduced leaflet thickness (0.9 ± 0.2 mm vs. 1.6 ± 0.2 mm; p < 0.05; 0.4 ± 0.1 mm sham animals), TGF-β, and downstream phosphorylated extracellular-signal-regulated kinase and EMT (27.2 ± 12.0% vs. 51.6 ± 11.7% α-smooth muscle actin-positive endothelial cells, p < 0.05; 7.2 ± 3.5% sham animals), cellular proliferation, collagen deposition, endothelial cell activation (vascular cell adhesion molecule-1 expression), neovascularization, and cells positive for cluster of differentiation (CD) 45, a hematopoietic marker associated with post-MI valve fibrosis. Leaflet area increased comparably (17%) in constrained and losartan-treated sheep., Conclusions: Profibrotic changes of tethered MV leaflets post-MI can be modulated by losartan without eliminating adaptive growth. Understanding the cellular and molecular mechanisms could provide new opportunities to reduce ischemic MR., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

A key component of California's cap-and-trade program is the use of carbon offsets as compliance instruments for reducing statewide GHG emissions. Under this program, offsets are tradable credits representing real, verifiable, quantifiable, enforceable, permanent, and additional reductions or removals of GHG emissions. This paper focuses on the permanence and additionality standards for offset credits as defined and operationalized in California's Compliance Offset Protocol for U.S. Forest Projects. Drawing on a review of the protocol, interviews, current offset projects, and existing literature, we discuss how additionality and permanence standards relate to project participation and overall program effectiveness. Specifically, we provide an overview of offset credits as compliance instruments in California's cap-and-trade program, the timeline for a forest offset project, and the factors shaping participation in offset projects. We then discuss the implications of permanence and additionality at both the project and program levels. Largely consistent with previous work, we find that stringent standards for permanent and additional project activities can present barriers to participation, but also, that there may be a trade-off between project quality and quantity (i.e. levels of participation) when considering overall program effectiveness. We summarize what this implies for California's forest offset program and provide suggestions for improvements in light of potential program diffusion and policy learning., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Working memory (WM) is crucial for intelligent cognitive functioning, and synchronization phenomena in the fronto-parietal network have been suggested as an underlying neural mechanism. In an attempt to provide causal evidence for this assumption, we applied transcranial alternating current stimulation (tACS) at theta frequency over fronto-parietal sites during a visuospatial match-to-sample (MtS) task. Depending on the stimulation protocol, i.e., in-phase, anti-phase or sham, we anticipated a differential impact of tACS on behavioral WM performance as well as on the EEG (electroencephalography) during resting state before and after stimulation. We hypothesized that in-phase tACS of the fronto-parietal theta network (stimulation frequency: 5 Hz; intensity: 1 mA peak-to-peak) would result in performance enhancement, whereas anti-phase tACS would cause performance impairment. Eighteen participants (nine female) received in-phase, anti-phase, and sham stimulation in balanced order. While being stimulated, subjects performed the MtS task, which varied in executive demand (two levels: low and high). EEG analysis of power peaks within the delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), and beta (12-30 Hz) frequency bands was carried out. No significant differences were observed between in-phase and anti-phase stimulation regarding both behavioral and EEG measurements. Yet, with regard to the alpha frequency band, we observed a statistically significant drop of peak power from pre to post in the sham condition, whereas alpha power remained on a similar level in the actively stimulated conditions. Our results indicate a frequency-unspecific modulation of neuronal oscillations by tACS. However, the closer participants' individual theta peak frequencies were to the stimulation frequency of 5 Hz after anti-phase tACS, the faster they responded in the MtS task. This effect did not reach statistical significance during in-phase tACS and was not present during sham. A lack of statistically significant behavioral results in the MtS task and frequency-unspecific effects on the electrophysiological level question the effectiveness of tACS in modulating cortical oscillations in a frequency-specific manner.

Aims: In patients with atrial fibrillation (AF) pharmacological or electrical cardioversion may be performed to restore sinus rhythm. The procedure is associated with an increased risk of thromboembolic events, which can be significantly reduced by adequate anticoagulation (OAC). Our aim was to create a partly prospective, partly retrospective cardioversion registry, particularly focusing on OAC strategies in different European countries, and on emerging choice of OAC over time., Methods: From September 2014 to October 2015, cardioversions due to AF performed in six European city hospitals in five European countries (Hungary: Budapest-1 and -2; Italy: Bari and Pisa; France: Amiens; Spain: Madrid; and Lithuania: Kaunas) were recorded in the registry., Results: A total of 1101 patients (retrospective/prospective: 679/422, male/female: 742/359, mean age: 67.3 years ± 11.2) were registered. Most of the cardioversions were electrical (97%). Oral anticoagulants were administered in 87% of the patient, the usage of non-VKA oral anticoagulants (NOACs) vs Vitamin K antagonists (VKA) was 31.5% vs 68.5%, respectively. Seventy seven percent of the patients were given oral anticoagulants more than 3 weeks prior to the procedure, and 86% more than 4 weeks after the procedure. When using VKA, international normalized ratio (INR) at cardioversion was above 2.0 in 76% of the cases. A decline in VKA usage (P = 0.033) in elective cardioversion over approximately 1 year was observed. During the observation period, there was an increase in apixaban (P < 0.001), a slight increase in rivaroxaban (P = 0.028) and no changes in dabigatran (P = 0.34) usage for elective cardioversion. There were differences in use of OAC between the countries: Spain used most VKA (89%), while France used least VKA (39%, P < 0.001)., Conclusion: According to current AF guidelines, NOACs are adequate alternatives to VKA for thromboembolic prevention in AF patients undergoing elective cardioversion. Our results indicate that NOAC use is increasing and there is a significant decrease in VKA use., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Working together feels easier with some people than with others. We asked participants to perform a visual search task either alone or with a partner while simultaneously measuring each participant's EEG. Local phase synchronization and inter-brain phase synchronization were generally higher when subjects jointly attended to a visual search task than when they attended to the same task individually. Some participants searched the visual display more efficiently and made faster decisions when working as a team, whereas other dyads did not benefit from working together. These inter-team differences in behavioral performance gain in the visual search task were reliably associated with inter-team differences in local and inter-brain phase synchronization. Our results suggest that phase synchronization constitutes a neural correlate of social facilitation, and may help to explain why some teams perform better than others., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Cavovarus deformity can be classified by the severity of malalignment ranging from a subtle and flexible to a severe and fixed cavovarus deformity of the foot.In the mild cavovarus foot, careful clinical assessment is required to identify the deformity.Weight-bearing radiographs are necessary to indicate the apex of the deformity and quantify the correction required.Surgery is performed when conservative measures fail and various surgical procedures have been described, including a combination of soft-tissue releases, tendon transfers and osteotomies, all with the aim of achieving a plantigrade and balanced foot.Joint-sparing surgery is the best option in flexible cavovarus foot even in Charcot-Marie-Tooth (CMT) disease (peroneal muscular atrophy).Arthrodesis is indicated in severe rigid cavus foot or in degenerative cases. Cite this article: EFORT Open Rev 2017;2. DOI: 10.1302/2058-5241.2.160077. Originally published online at www.efortopenreviews.org., Competing Interests: ICMJE Conflict of Interest Statement: None.

Background: The objective of this study was to assess clinical and computed-tomography (CT) outcomes at least 2 years after humeral head resurfacing to treat concentric gleno-humeral osteoarthritis., Hypothesis: Humeral head resurfacing provides similar outcomes to those achieved with stemmed humeral head implants., Materials and Methods: This single-centre retrospective study included 40 Copeland™ and 65 Aequalis™ humeral resurfacing heads implanted between 2004 and 2012. Mean patient age at diagnosis was 64 years. The diagnoses were osteoarthritis with an intact (68%) or torn (21%) rotator cuff, avascular necrosis (5%), osteoarthritis complicating chronic instability (3%), post-traumatic osteoarthritis (2%), and chronic inflammatory joint disease (1%). Validated clinical scores, radiographs, and CT before surgery and at last follow-up were compared., Results: During the mean follow-up of 56 months, complications occurred in 24 implants. Revision surgery with reverse shoulder replacement was required in 18 cases, after a mean of 43.6 months, to treat glenoid wear or a rotator cuff tear. At last follow-up, for the implants that did not require revision surgery, the mean Constant score was 64/100. The implants had a mean varus of 5° and mean retroversion of -13.3°. The mean increase in glenoid cavity depth was 2.4mm. Mean increases in medial and lateral humeral offset were 1.9mm and 2.7mm, respectively. Pre-operative factors significantly associated with failure were rotator cuff tear (P=0.017) and glenoid erosion (P=0.001)., Discussion: We found a high failure rate related to glenoid wear or progressive rotator-cuff impairment, although CT showed no evidence of implant malposition or overstuffing. Previous studies of stemmed humeral head implants showed better outcomes. Given the low medium-term prosthesis survival rate, we now reserve humeral head resurfacing for concentric osteoarthritis without glenoid erosions or rotator cuff damage., Level of Evidence: IV, retrospective study., (Copyright © 2017. Published by Elsevier Masson SAS.)

Background: Mitral valve (MV) repair is preferred over replacement in clinical guidelines and is an important determinant of the indication for surgery in degenerative mitral regurgitation. However, the level of evidence supporting current recommendations is low, and recent data cast doubts on its validity in the current era. Accordingly, the aim of the present study was to analyze very long-term outcome after MV repair and replacement for degenerative mitral regurgitation with a flail leaflet., Methods: MIDA (Mitral Regurgitation International Database) is a multicenter registry enrolling patients with degenerative mitral regurgitation with a flail leaflet in 6 tertiary European and US centers. We analyzed the outcome after MV repair (n=1709) and replacement (n=213) overall, by propensity score matching, and by inverse probability-of-treatment weighting., Results: At baseline, patients undergoing MV repair were younger, had more comorbidities, and were more likely to present with a posterior leaflet prolapse than those undergoing MV replacement. After propensity score matching and inverse probability-of-treatment weighting, the 2 treatments groups were balanced, and absolute standardized differences were usually <10%, indicating adequate match. Operative mortality (defined as a death occurring within 30 days from surgery or during the same hospitalization) was lower after MV repair than after replacement in both the entire population (1.3% versus 4.7%; P<0.001) and the propensity-matched population (0.2% versus 4.4%; P<0.001). During a mean follow-up of 9.2 years, 552 deaths were observed, of which 207 were of cardiovascular origin. Twenty-year survival was better after MV repair than after MV replacement in both the entire population (46% versus 23%; P<0.001) and the matched population (41% versus 24%; P<0.001). Similar superiority of MV repair was obtained in patient subsets on the basis of age, sex, or any stratification criteria (all P<0.001). MV repair was also associated with reduced incidence of reoperations and valve-related complications., Conclusions: Among patients with degenerative mitral regurgitation with a flail leaflet referred to mitral surgery, MV repair was associated with lower operative mortality, better long-term survival, and fewer valve-related complications compared with MV replacement., (© 2016 American Heart Association, Inc.)

Molecular mapping of live biofilms at submicrometer resolution presents a grand challenge. Here, we present the first chemical mapping results of biofilm extracellular polymeric substance (EPS) in biofilms using correlative imaging between super resolution fluorescence microscopy and liquid time-of-flight secondary ion mass spectrometry (TOF-SIMS). Shewanella oneidensis is used as a model organism. Heavy metal chromate (Cr 2 O 7 2- ) anions consisting of chromium Cr(VI) was used as a model environmental stressor to treat the biofilms. Of particular interest, biologically relevant water clusters have been first observed in the biofilms. Characteristic fragments of biofilm matrix components such as proteins, polysaccharides, and lipids can be spatially imaged. Furthermore, characteristic fatty acids (e.g., palmitic acid), quinolone signal, and riboflavin fragments were found to respond after the biofilm is treated with Cr(VI), leading to biofilm dispersal. Significant changes in water clusters and quorum sensing signals indicative of intercellular communication in the aqueous environment were observed, suggesting that they might result in fatty acid synthesis and inhibition of riboflavin production. The Cr(VI) reduction seems to follow the Mtr pathway leading to Cr(III) formation. Our approach potentially opens a new avenue for mechanistic insight of microbial community processes and communications using in situ imaging mass spectrometry and super resolution optical microscopy.

Purpose: The goal of this study was to identify rotational abnormalities of the lower limb in adult patients with primary symptomatic flatfoot., Materials and Methods: From September 2009 to May 2012, 24 patients (12 women, 12 men; mean age: 40 years) were prospectively included in the study. Each patient underwent radiographs of the flat foot and weight-bearing upright EOS ® examination. Three-dimensional reconstructions of the lower extremities were performed with derived measurements (length, hip and knee parameters, rotations). A total of 31 symptomatic primary flat feet (bilateral flat foot, n=7 patients; unilateral flat foot, n=17 patients) were studied and compared to 30 control subjects matched for age and gender. A comparison between the two groups was made with the Student t-test., Results: No significant differences were found between patients and control subjects on the coronal and sagittal planes. Similarly, no significant differences were observed between the 2 groups for rotation of the lower limbs (femoral torsion, tibial torsion, tibiofemoral rotation)., Conclusion: There are no rotational abnormalities of the lower extremities in adult patients with primary symptomatic flat foot., (Copyright © 2016. Published by Elsevier Masson SAS.)

Background: Studies suggesting that B-type natriuretic peptide (BNP) may predict outcomes of mitral regurgitation (MR) are plagued by small size, inconsistent etiologies, and lack of accounting for shifting normal BNP ranges with age and sex., Objectives: This study assessed the effect of BNP activation on mortality in a large, multicenter cohort of patients with degenerative MR., Methods: In 1,331 patients with degenerative MR, BNP was prospectively measured at diagnosis and expressed as BNPratio (ratio to upper limit of normal for age, sex, and assay). Initial surgical management was performed within 3 months of diagnosis in 561 patents., Results: The cohort had a mean age of 64 ± 15 years, was 66% male, and had a mean ejection fraction 64 ± 9%, mean regurgitant volume 67 ± 31 ml, and low mean Charlson comorbidity index of 1.09 ± 1.76. Median BNPratio was 1.01 (25th and 75th percentiles: 0.42 to 2.36). Overall, BNPratio was a powerful, independent predictor of mortality (hazard ratio: 1.33 [95% confidence interval: 1.15 to 1.54]; p < 0.0001), whereas absolute BNP was not (p = 0.43). In patients who were initially treated medically (n = 770; 58%), BNPratio was a powerful, independent, and incremental predictor of mortality after diagnosis (hazard ratio: 1.61 [95% confidence interval: 1.34 to 1.93]; p < 0.0001). Higher BNP activation was associated with higher mortality (p < 0.0001). All subgroups, particularly severe MR, incurred similar excess mortality with BNP activation. After initial surgical treatment (n = 561, 42%) BNP activation did not impose excess long-term mortality (p = 0.23)., Conclusions: In patients with degenerative MR, BNPratio is a powerful, independent, and incremental predictor of long-term mortality under medical management. BNPratio should be incorporated into the routine clinical assessment of patients with degenerative MR., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: Foot and ankle injuries (FAI) are very common, with about 6000 cases per day in France. Unlike lateral ankle sprain (LAS), the diagnosis of midtarsal joint sprain (MJS, also known as Chopart's joint sprain) is not widely known. This prospective study aims to detail the epidemiology of MJS and compare it to LAS., Patients and Method: The study was conducted within our institution over a period of 16 months. Patients with clinical signs predictive of MJS without radiographic bone lesion underwent ultrasound assessment. MJS was diagnosed in case of at least 1 lesion of the dorsal midtarsal joint ligaments., Results: A total of 2412 patients consulted for FAI; 188 had clinical and radiographic criteria for ultrasound examination. Eighty-two cases of MJS were diagnosed (3.4% of FAIs). Sports injuries were more frequent in MJS (P=0.04), and mechanisms more varied than in LAS, with inversion injury in 75% of cases and plantar hyperflexion in 22%. Sprain was severe in 70% of cases, with complete ligament tear. Clinical and ultrasound analyses correlated in only 40% of cases of MJS, versus 98% for LAS., Conclusion: MJS is frequent, difficult to diagnose clinically, and often severe. Clinical presentation and injury mechanisms differ from ankle sprain. Ultrasound seems to be an indispensable tool in diagnosis., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Chemical imaging of single cells at the molecular level is important in capturing biological dynamics. Single cell correlative imaging is realized between super-resolution microscopy, namely, structured illumination microscopy (SIM), and time-of-flight secondary ion mass spectrometry (ToF-SIMS) using a multimodal microreactor (i.e., System for Analysis at the Liquid Vacuum Interface, SALVI). SIM characterized cells and guided subsequent ToF-SIMS analysis. Lipid fragments were identified in the cell membrane via dynamic ToF-SIMS depth profiling. Positive SIMS spectra show intracellular potassium and sodium ion transport due to exposure to nanoparticles. Spectral principal component analysis elucidates differences in chemical composition among healthy alveolar epithelial mouse lung C10 cells, cells that uptake zinc oxide nanoparticles, and various wet and dry control samples. The observation of Zn(+) gives the first direct evidence of ZnO NP uptake and dissolution by the cell membrane. Our results provide submicron chemical mapping for investigating cell dynamics at the molecular level.

Objectives: The St Jude Medical Trifecta bioprosthesis incorporates a single pericardial sheet externally mounted on a titanium stent that provides excellent haemodynamic results. The purpose of this multicentre study was to report on the haemodynamic performance and the expected lower risk of prosthesis-patient mismatch in patient with small aortic annulus diameters., Methods: The 19- and 21-mm Trifecta valves were implanted in 88 and 266 eligible patients, respectively between 2011 and 2013 at three centres in France (Angers, Rennes and Amiens). The mean age of the population was 78 ± 7 and 76 ± 6 years for 19- and 21-mm valve sizes of which 96.6 and 68% were female, respectively. The aortic valve replacement was associated with another surgery in 18.2 and 21.8% in each group, respectively., Results: The mean follow-up was 20.3 ± 11.9 and 24 ± 11.4 months for 19- and 21-mm valves, respectively. Early all-cause mortality was 2.5% and late mortality occurred in 5.8% of patients. The mean pressure gradient and the effective orifice area at discharge and at 1 year were respectively 12.4 ± 4.6 and 14.7 ± 5.8 mmHg (P = 0.003), 1.5 ± 0.3 and 1.4 ± 0.9 cm(2) (P = 0.06) in the 19-mm valve group; 10.4 ± 3.8 and 11.7 ± 4.5 mmHg (P = 0.001), 1.8 ± 0.3 and 1.5 ± 0.4 cm(2) (P = 0.1) in the 21-mm valve group. At 1 year, only 38 (11%) and 28 (8.1%) patients presented a moderate or severe prosthesis-patient mismatch for the two groups. After univariate analysis, no risk factor of mismatch was found., Conclusions: The 19- and 21-mm St Jude Medical Trifecta provide excellent haemodynamic performance and the rate of moderate and severe prosthesis-patient mismatch is low., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: In patients with myocardial infarction (MI), leaflet tethering by displaced papillary muscles induces mitral regurgitation (MR), which doubles mortality. Mitral valves (MVs) are larger in such patients but fibrosis sets in counterproductively. The investigators previously reported that experimental tethering alone increases mitral valve area in association with endothelial-to-mesenchymal transition., Objectives: The aim of this study was to explore the clinically relevant situation of tethering and MI, testing the hypothesis that ischemic milieu modifies mitral valve adaptation., Methods: Twenty-three adult sheep were examined. Under cardiopulmonary bypass, the papillary muscle tips in 6 sheep were retracted apically to replicate tethering, short of producing MR (tethered alone). Papillary muscle retraction was combined with apical MI created by coronary ligation in another 6 sheep (tethered plus MI), and left ventricular remodeling was limited by external constraint in 5 additional sheep (left ventricular constraint). Six sham-operated sheep were control subjects. Diastolic mitral valve surface area was quantified by 3-dimensional echocardiography at baseline and after 58 ± 5 days, followed by histopathology and flow cytometry of excised leaflets., Results: Tethered plus MI leaflets were markedly thicker than tethered-alone valves and sham control subjects. Leaflet area also increased significantly. Endothelial-to-mesenchymal transition, detected as α-smooth muscle actin-positive endothelial cells, significantly exceeded that in tethered-alone and control valves. Transforming growth factor-β, matrix metalloproteinase expression, and cellular proliferation were markedly increased. Uniquely, tethering plus MI showed endothelial activation with vascular adhesion molecule expression, neovascularization, and cells positive for CD45, considered a hematopoietic cell marker. Tethered plus MI findings were comparable with external ventricular constraint., Conclusions: MI altered leaflet adaptation, including a profibrotic increase in valvular cell activation, CD45-positive cells, and matrix turnover. Understanding cellular and molecular mechanisms underlying leaflet adaptation and fibrosis could yield new therapeutic opportunities for reducing ischemic MR., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

In the general concept of self-disturbances in schizophrenia and schizophrenia spectrum disorders, somatopsychic depersonalization (SPD) occupies a special place as it constitutes a syndrome that comprises feelings of detachment from one's own body and mental processes. However, apart from clinical descriptions, to date the pathophysiology of SPD is not fully understood due to the rareness of the syndrome and a lack of experimental studies. In a case study of one patient with schizotypal disorder, we applied a multimodal approach to understanding the SPD phenomena. The patient's clinical profile was identified as disruption of implicit bodily function, accompanied by depressive symptoms. On a neuropsychological level, the patient exhibited impairment in executive functioning, intact tactile perception and kinesthetic praxis. Behavioral tests revealed an altered sense of time but unimpaired self-agency. Furthermore, the patient exhibited a lack of empathy and he had autistic traits, although with a sufficient ability to verbalize his feelings. On the neurobiological level using an active and passive touch paradigm during functional magnetic resonance imaging (fMRI), we found a hyperconnectivity of the default-mode network and salience network and a hypoconnectivity of the central executive brain networks in the performance of the touch task as well as intact perceptual touch processing emerging from the direct comparisons of the touch conditions. Our data provide evidence for the important role of altered large-brain network functioning in SPD that corresponds to the specific behavioral and neurocognitive phenomena., (© 2015 The Institute of Psychology, Chinese Academy of Sciences and Wiley Publishing Asia Pty Ltd.)

Malignant transformation of fibrous dysplasia (FD) in long bones is rare (less than 1% of cases) and occurs in the form of osteosarcomas. They can occur on FD associated with multiple myxomas, which corresponds to Mazabraud syndrome. To our knowledge, only six cases of FD malignant transformation into osteosarcoma in the context of Mazabraud syndrome have been described. Here, we describe the first case of malignant transformation of femur FD into chondrosarcoma in a 51-year-old female patient. The patient had significant changes in the size and number of myxomas around the femur before the malignant transformation into chondrosarcoma. She underwent complete femur replacement with a favourable result after 4 years' follow-up. Close surveillance is strongly recommended in this syndrome, particularly when the number and size of myxomas increase., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Background: To prevent left ventricular dysfunction (LVD), surgery is recommended in patients with severe primary mitral regurgitation as soon as ejection fraction (EF) ≤60% or LV end-systolic diameter ≥40 mm. However, LVD may be concealed behind preoperative normal LVEF and LV end-systolic diameter. We sought to identify whether a new composite echocardiographic Doppler marker of the LV ejection according to the LV dilatation may predict postoperative LVD and outcome after mitral valve repair in patients with primary mitral regurgitation., Methods and Results: Between 1991 and 2010, patients who underwent mitral valve repair for primary mitral regurgitation were studied. From preoperative echocardiography, we calculated LV ejection index (LVEI) using following formula: LVEI=indexed LV end-systolic diameter/LV outflow tract time-velocity integral. In the 278 patients included, the best correlation with postoperative LVEF was found with LVEI (r=-0.40; P<0.0001), even in patients with preoperative LVEF≥60% (r=-0.46; P<0.0001). In multivariable analysis, LCEI>1.13 was an independent predictor of postoperative LVD (P<0.0001). During a mean follow-up of 10±4.6 years, 67 (29%) deaths occurred. When compared with patients with preserved LVEI, those with LVEI>1.13 had significantly lower both survival and cardiac death-free survival (P=0.017 and P=0.008, respectively). Similar results were found in patients with preoperative LVEF≥60% (P=0.049 and P=0.016, respectively). In Cox proportional hazard model, after meticulous adjustment for cofactors, LVEI>1.13 remains independently associated with death (hazard ratio, 1.64; P=0.039) and cardiac-related death (hazard ratio, 3.27; P=0.026)., Conclusions: After mitral valve repair for primary mitral regurgitation, the preoperative LVEI is a new and simple composite parameter of both LV dilatation and LV forward flow able to accurately predict postoperative LVD and outcome., (© 2015 American Heart Association, Inc.)

The aim of the study was to assess the impact of atrial fibrillation (AF) on outcome in patients who underwent mitral valve repair (MVRp) for mitral valve prolapse (MVP). Four hundred and forty-three consecutive patients underwent MVRp for organic mitral regurgitation due to MVP. Echocardiography was performed preoperatively and after surgery. Postoperative left ventricular dysfunction (LVD) was defined as left ventricular ejection fraction (LVEF) <50%. Before surgery, 187 patients (42%) had preoperative AF. After surgery, LVEF significantly decreased from 67 ± 9% to 56 ± 10% (p <0.0001). Compared with patients in sinus rhythm (SR), those in AF were significantly older (p <0.0001), had more severe symptoms (p = 0.004), had lower LVEF (p = 0.002), and higher EuroSCORE (p = 0.05). Compared with patients in SR, patients with AF had significantly lower 10-year survival (64 ± 4% vs 83 ± 3%, p = 0.001). On multivariate analysis, preoperative AF was identified as an independent predictor of overall mortality (hazard ratio 1.67; 95% confidence interval 1.15 to 2.42; p = 0.007). At 10 years, patients with paroxysmal AF had lower survival and higher heart failure rate than patients in SR (78 ± 3% vs 66 ± 6%) but had a better outcome compared with those with permanent AF (66 ± 6% vs 53 ± 6%, p = 0.022). Patients with AF had a significantly higher rate of postoperative LVD (23.3% vs 13.4%, p = 0.007). In conclusion, preoperative AF is a predictor of long-term mortality and postoperative LVD after MVRp for MVP. To improve postoperative outcome, surgery in these patients should be performed before onset of AF., (Copyright © 2015 Elsevier Inc. All rights reserved.)

During non-rapid eye movement (NREM) sleep (stage N3), when consciousness fades, cortico-cortical interactions are impaired while neurons are still active and reactive. Why is this? We compared cortico-cortical evoked-potentials recorded during wakefulness and NREM by means of time-frequency analysis and phase-locking measures in 8 epileptic patients undergoing intra-cerebral stimulations/recordings for clinical evaluation. We observed that, while during wakefulness electrical stimulation triggers a chain of deterministic phase-locked activations in its cortical targets, during NREM the same input induces a slow wave associated with an OFF-period (suppression of power>20Hz), possibly reflecting a neuronal down-state. Crucially, after the OFF-period, cortical activity resumes to wakefulness-like levels, but the deterministic effects of the initial input are lost, as indicated by a sharp drop of phase-locked activity. These findings suggest that the intrinsic tendency of cortical neurons to fall into a down-state after a transient activation (i.e. bistability) prevents the emergence of stable patterns of causal interactions among cortical areas during NREM. Besides sleep, the same basic neurophysiological dynamics may play a role in pathological conditions in which thalamo-cortical information integration and consciousness are impaired in spite of preserved neuronal activity., (Copyright © 2015. Published by Elsevier Inc.)