Comparing pulsed field electroporation and radiofrequency ablation for the treatment of paroxysmal atrial fibrillation: design and rationale of the BEAT PAROX-AF randomized clinical trial.

AIMS: Using thermal-based energy sources [radiofrequency (RF) energy/cryo energy] for catheter ablation is considered effective and safe when performing pulmonary vein isolation (PVI) in patients with paroxysmal atrial fibrillation (AF). However, treatment success remains limited and complications can occur due to the propagation of thermal energy into non-target tissues. We aim to compare pulsed field ablation (PFA) with RF ablation in terms of efficacy and safety for patients with drug-resistant paroxysmal AF. METHODS AND RESULTS: The BEAT PAROX-AF trial is a European multicentre, superiority, open-label randomized clinical trial in two parallel groups. A total of 292 participants were recruited in 9 high-volume European clinical centres in 5 countries. Patients with paroxysmal AF were randomized to PFA (FARAPULSE Endocardial Ablation System©, Boston Scientific) or RF using the CLOSE protocol with contact force sensing catheter (SmartTouch© catheter and CARTO© Biosense Webster). The primary endpoint will be the 1-year recurrence of atrial arrhythmia, and the major secondary safety endpoint will be the occurrence of acute (<7 days) procedure-related serious adverse events, or pulmonary vein stenosis, or atrio-oesophageal fistula up to 12 months. Additionally, five sub-studies investigate the effect of PFA on oesophageal safety, cerebral lesions, cardiac autonomic nervous system, durability of PVI as assessed during redo ablation procedures, and atrial and ventricular function. The study began on 27 December 2021 and concluded recruitment on 17 January 2024. Results will be available in mid-2025. CONCLUSION: The BEAT PAROX-AF trial aims to provide critical insights into the optimal treatment approach for patients with paroxysmal AF.

Development and external validation of a prediction model for the transition from mild to moderate or severe form of COVID-19.

OBJECTIVES: COVID-19 pandemic seems to be under control. However, despite the vaccines, 5 to 10% of the patients with mild disease develop moderate to critical forms with potential lethal evolution. In addition to assess lung infection spread, chest CT helps to detect complications. Developing a prediction model to identify at-risk patients of worsening from mild COVID-19 combining simple clinical and biological parameters with qualitative or quantitative data using CT would be relevant to organizing optimal patient management. METHODS: Four French hospitals were used for model training and internal validation. External validation was conducted in two independent hospitals. We used easy-to-obtain clinical (age, gender, smoking, symptoms' onset, cardiovascular comorbidities, diabetes, chronic respiratory diseases, immunosuppression) and biological parameters (lymphocytes, CRP) with qualitative or quantitative data (including radiomics) from the initial CT in mild COVID-19 patients. RESULTS: Qualitative CT scan with clinical and biological parameters can predict which patients with an initial mild presentation would develop a moderate to critical form of COVID-19, with a c-index of 0.70 (95% CI 0.63; 0.77). CT scan quantification improved the performance of the prediction up to 0.73 (95% CI 0.67; 0.79) and radiomics up to 0.77 (95% CI 0.71; 0.83). Results were similar in both validation cohorts, considering CT scans with or without injection. CONCLUSION: Adding CT scan quantification or radiomics to simple clinical and biological parameters can better predict which patients with an initial mild COVID-19 would worsen than qualitative analyses alone. This tool could help to the fair use of healthcare resources and to screen patients for potential new drugs to prevent a pejorative evolution of COVID-19. CLINICAL TRIAL REGISTRATION: NCT04481620. CLINICAL RELEVANCE STATEMENT: CT scan quantification or radiomics analysis is superior to qualitative analysis, when used with simple clinical and biological parameters, to determine which patients with an initial mild presentation of COVID-19 would worsen to a moderate to critical form. KEY POINTS: • Qualitative CT scan analyses with simple clinical and biological parameters can predict which patients with an initial mild COVID-19 and respiratory symptoms would worsen with a c-index of 0.70. • Adding CT scan quantification improves the performance of the clinical prediction model to an AUC of 0.73. • Radiomics analyses slightly improve the performance of the model to a c-index of 0.77.

Correlation of nailfold capillaroscopy findings with history of digital ulcer on same finger: Results of SCLEROCAP study.

Systemic sclerosis may be complicated by digital ulcers. Nailfold capillaroscopy on one finger might reflect an increased risk of digital ulcer (DU). In the present study we studied the correlations between a history of ulcer and capillary findings on the finger. METHOD: This study is part of Sclerocap, a multicenter study aiming at validating prospectively the prognostic value of Maricq's and Cutolo's capillaroscopic classifications during a three-year longitudinal follow-up. A history of past or present digital ulcer was recorded at inclusion and nailfold capillaroscopy was performed. Elementary findings as well as Cutolo and Maricq's classifications were assessed. RESULTS: 387 patients were included in Sclerocap (327 females, 60 males) and 3096 fingers were examined by capillaroscopy at inclusion: 316 fingers (10%) belonging to 113 patients had a history of DU. Late Cutolo's stage was statistically correlated with a history of DU, both by univariate: OR 2.08 [1.09-3.96] and multivariate analysis: OR 1.97 [1.06-3.63]. Among the elemental abnormalities, only edema and decreased capillary density were correlated with a history of DU by multivariate analysis: respectively OR 1.92 [1.17-3.16] and 0.65 [0.49-0.85]. CONCLUSION: This cross-sectional study in a large cohort of patients with systemic sclerosis shows a correlation between a history of digital ulcer and edema, a decrease in capillary density and the late stage in Cutolo's classification. The extent of capillary abnormalities on one finger is associated with a history of local digital ulcer. Capillaroscopy might be used to predict the risk of DU but these results need first to be confirmed by prospective studies.

Brain 5-HT1A Receptor Binding in Multiple System Atrophy: An [18 F]-MPPF PET Study.

BACKGROUND: Loss of medullary serotonin (5-hydroxytryptamine) neurons has been linked to respiratory disturbances in multiple system atrophy (MSA). Broader 5-hydroxytryptamine dysfunction may contribute to additional motor/nonmotor symptoms in MSA. The objective of this study was to compare brain 5-hydroxytryptamine1A receptor binding between MSA and healthy controls. Secondary objectives were to compare 5-hydroxytryptamine1A receptor binding between MSA and Parkinson's disease (PD) and to assess potential associations with motor/nonmotor symptoms in MSA. METHODS: 2'-Methoxyphenyl-(N-2'-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine positron emission tomography was performed in matched MSA patients (n = 16), PD patients (n = 15), and healthy controls (n = 18). RESULTS: 2'-Methoxyphenyl-(N-2'-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine distribution volume ratios were lower in MSA patients versus healthy controls in several brain regions including the caudate, raphe nuclei, thalamus, and brain stem. Distribution volume ratios were also lower in brain stem and amygdala in MSA versus PD. Moderate associations were found between 2'-methoxyphenyl-(N-2'-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine distribution volume ratios and fatigue, pain, and apathy in MSA. CONCLUSION: Our results demonstrate 5-hydroxytryptamine dysfunction in several brain regions in MSA, which may contribute to fatigue, pain, and apathy. © 2020 International Parkinson and Movement Disorder Society.

Effects of a Mindfulness-Based Intervention versus Health Self-Management on Subclinical Anxiety in Older Adults with Subjective Cognitive Decline: The SCD-Well Randomized Superiority Trial.

INTRODUCTION: Older adults experiencing subjective cognitive decline (SCD) have a heightened risk of developing dementia and frequently experience subclinical anxiety, which is itself associated with dementia risk. OBJECTIVE: To understand whether subclinical anxiety symptoms in SCD can be reduced through behavioral interventions. METHODS: SCD-Well is a randomized controlled trial designed to determine whether an 8-week mindfulness-based intervention (caring mindfulness-based approach for seniors; CMBAS) is superior to a structurally matched health self-management program (HSMP) in reducing subclinical anxiety. Participants were recruited from memory clinics at 4 European sites. The primary outcome was change in anxiety symptoms (trait subscale of the State-Trait Anxiety Inventory; trait-STAI) from pre- to postintervention. Secondary outcomes included a change in state anxiety and depression symptoms postintervention and 6 months postrandomization (follow-up). RESULTS: One hundred forty-seven participants (mean [SD] age: 72.7 [6.9] years; 64.6% women; CMBAS, n = 73; HSMP, n = 74) were included in the intention-to-treat analysis. There was no difference in trait-STAI between groups postintervention (adjusted change difference: -1.25 points; 95% CI -4.76 to 2.25) or at follow-up (adjusted change difference: -0.43 points; 95% CI -2.92 to 2.07). Trait-STAI decreased postintervention in both groups (CMBAS: -3.43 points; 95% CI -5.27 to -1.59; HSMP: -2.29 points; 95% CI -4.14 to -0.44) and reductions were maintained at follow-up. No between-group differences were observed for change in state anxiety or depression symptoms. CONCLUSIONS: A time-limited mindfulness intervention is not superior to health self-management in reducing subclinical anxiety symptoms in SCD. The sustained reduction observed across both groups suggests that subclinical anxiety symptoms in SCD are modifiable. ClinicalTrials.gov identifier: NCT03005652.

Neurodegeneration of the Substantia Nigra after Ipsilateral Infarct: MRI R2* Mapping and Relationship to Clinical Outcome.

Background The substantia nigra (SN) is suspected to be affected after remote infarction, in view of its large array of connections with the supratentorial brain. Whether secondary involvement of SN worsens overall clinical outcome after a supratentorial stroke has not previously been studied. Purpose To assess longitudinal changes in SN R2* by using MRI in the setting of ipsilesional supratentorial infarct and the relationship of SN signal change to clinical outcome. Materials and Methods Participants prospectively included from 2012 to 2015 were evaluated at 24-72 hours (baseline visit) and at 1 year with MRI to quantify R2*. The SN was segmented bilaterally to calculate an R2* asymmetry index (SN-AI); greater SN-AI indicated greater relative R2* in the ipsilateral compared with contralateral SN. The 95th percentile of R2* (hereafter, SN-AI95) was compared according to infarct location with mixed linear regression models. We also conducted voxel-based comparisons of R2* and identified individual infarcted voxels associated with high SN-AI95 through voxel-based lesion-symptom mapping. Multivariable regression models tested the association between SN-AI95 and clinical scores. Results A total of 181 participants were evaluated (127 men, 54 women; mean age ± standard deviation, 64.2 years ± 13.1; 75 striatum infarcts, 106 other locations). Visual inspection, SN-AI95, and average maps consistently showed higher SN R2* at 1 year if ipsilateral striatum was infarcted than if it was not (SN-AI95, 4.25 vs -0.88; P < .001), but this was not observed at baseline. The striatal location of the infarct was associated with higher SN-AI95 at 1 year independently from infarct volume, SN-AI95 at baseline, microbleeds, age, and sex (ß = 4.99; P < .001). Voxel-based lesion-symptom mapping confirmed that striatum but also insula, internal capsule, and external capsule were associated with higher SN-AI95 at 1 year. SN-AI95 was an independent contributor of poor motor outcome (Box and Block Test, ß = -.62 points; P = .01). Conclusion In patients with stroke, greater substantia nigra R2*, likely reflective of greater iron content, can be observed at 1 year ipsilateral from remote infarcts of specific location, which is associated with worse motor function. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Vernooij in this issue.

Organ preservation for rectal cancer (GRECCAR 2): a prospective, randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: Organ preservation is a concept proposed for patients with rectal cancer after a good clinical response to neoadjuvant chemotherapy, to potentially avoid morbidity and side-effects of rectal excision. The objective of this study was to compare local excision and total mesorectal excision in patients with a good response after chemoradiotherapy for lower rectal cancer. METHODS: We did a prospective, randomised, open-label, multicentre, phase 3 trial at 15 tertiary centres in France that were experts in the treatment of rectal cancer. Patients aged 18 years and older with stage T2T3 lower rectal carcinoma, of maximum size 4 cm, who had a good clinical response to neoadjuvant chemoradiotherapy (residual tumour ≤2 cm) were centrally randomly assigned by the surgeon before surgery to either local excision or total mesorectal excision surgery. Randomisation, which was done via the internet, was not stratified and used permuted blocks of size eight. In the local excision group, a completion total mesorectal excision was required if tumour stage was ypT2-3. The primary endpoint was a composite outcome of death, recurrence, morbidity, and side-effects at 2 years after surgery, to show superiority of local excision over total mesorectal excision in the modified intention-to-treat (ITT) population (expected proportions of patients having at least one event were 25% vs 60% for superiority). This trial was registered with ClinicalTrials.gov, number NCT00427375. FINDINGS: From March 1, 2007, to Sept 24, 2012, 186 patients received chemoradiotherapy and were enrolled in the study. 148 good clinical responders were randomly assigned to treatment, three were excluded (because they had metastatic disease, tumour >8 cm from anal verge, and withdrew consent), and 145 were analysed: 74 in the local excision group and 71 in the total mesorectal excision group. In the local excision group, 26 patients had a completion total mesorectal excision. At 2 years in the modified ITT population, one or more events from the composite primary outcome occurred in 41 (56%) of 73 patients in the local excision group and 33 (48%) of 69 in the total mesorectal excision group (odds ratio 1·33, 95% CI 0·62-2·86; p=0·43). In the modified ITT analysis, there was no difference between the groups in all components of the composite outcome, and superiority was not shown for local excision over total mesorectal excision. INTERPRETATION: We failed to show superiority of local excision over total mesorectal excision, because many patients in the local excision group received a completion total mesorectal excision that probably increased morbidity and side-effects, and compromised the potential advantages of local excision. Better patient selection to avoid unnecessary completion total mesorectal excision could improve the strategy. FUNDING: National Cancer Institute of France, Sanofi, Roche Pharma.

Evaluation of the Diagnostic Accuracy of Two Immunochromatographic Tests Detecting Campylobacter in Stools and Their Role in Campylobacter Infection Diagnosis.

The detection of campylobacters in stools is performed essentially by culture, but this technique has a low sensitivity. New detection methods are now available. Among them, immunochromatography tests (ICTs) are very attractive in that they offer a result within 15 min. However, previous studies suggest that these tests have a relatively low specificity. The objective of this study was to evaluate the performance of these tests. During the study period, all patients who consulted the emergency units and had a stool culture were included. Their stool samples were tested with two ICTs, Ridaquick Campylobacter and ImmunoCard STAT! Campy. Stools were also tested by a home-made PCR and two commercially available enzyme-linked immunosorbent assays (ELISAs) when one of the ICTs was positive. The composite reference standard (CRS) was defined as positive if the culture was positive or, in case of a negative culture, if the PCR and one of the ELISAs were positive simultaneously. Three hundred and five patients were included. Among the 50 positive specimens with Ridaquick Campylobacter, 47 were considered true positives by the CRS, corresponding to a positive predictive value (PPV) of 94.0%. Among the 52 positive specimens with ImmunoCard STAT! Campy, 44 were considered true positives by the CRS, corresponding to a PPV of 84.6%. The negative predictive values were estimated at 94.9 and 92.4% for the Ridaquick Campylobacter and ImmunoCard STAT! Campy tests, respectively. ICTs appear to be very efficient and allow a very rapid detection of campylobacters, which is important for treating early campylobacter infections with an adapted antibiotherapy.

Stroke Location Is an Independent Predictor of Cognitive Outcome.

BACKGROUND AND PURPOSE: On top of functional outcome, accurate prediction of cognitive outcome for stroke patients is an unmet need with major implications for clinical management. We investigated whether stroke location may contribute independent prognostic value to multifactorial predictive models of functional and cognitive outcomes. METHODS: Four hundred twenty-eight consecutive patients with ischemic stroke were prospectively assessed with magnetic resonance imaging at 24 to 72 hours and at 3 months for functional outcome using the modified Rankin Scale and cognitive outcome using the Montreal Cognitive Assessment (MoCA). Statistical maps of functional and cognitive eloquent regions were derived from the first 215 patients (development sample) using voxel-based lesion-symptom mapping. We used multivariate logistic regression models to study the influence of stroke location (number of eloquent voxels from voxel-based lesion-symptom mapping maps), age, initial National Institutes of Health Stroke Scale and stroke volume on modified Rankin Scale and MoCA. The second part of our cohort was used as an independent replication sample. RESULTS: In univariate analyses, stroke location, age, initial National Institutes of Health Stroke Scale, and stroke volume were all predictive of poor modified Rankin Scale and MoCA. In multivariable analyses, stroke location remained the strongest independent predictor of MoCA and significantly improved the prediction compared with using only age, initial National Institutes of Health Stroke Scale, and stroke volume (area under the curve increased from 0.697-0.771; difference=0.073; 95% confidence interval, 0.008-0.155). In contrast, stroke location did not persist as independent predictor of modified Rankin Scale that was mainly driven by initial National Institutes of Health Stroke Scale (area under the curve going from 0.840 to 0.835). Similar results were obtained in the replication sample. CONCLUSIONS: Stroke location is an independent predictor of cognitive outcome (MoCA) at 3 months post stroke.

Accuracy of repeated measurements of late-night salivary cortisol to screen for early-stage recurrence of Cushing's disease following pituitary surgery.

OBJECTIVE: The performance of late-night salivary cortisol (LNSC) to accurately screen for postoperative recurrence of Cushing's disease (CD) at an early stage is unknown. The aim of this study was to compare the accuracy of multiple sampling strategies to suggest the optimal number of LNSC samples needed for diagnosing post-surgical recurrences of CD at an early stage. DESIGN: Retrospective analysis in a single centre. PATIENTS AND MEASUREMENTS: Thirty-six patients in surgical remission of CD had successive measurements of LNSC, defined as 'sequences', using a locally modified RIA assay as part of long-term follow-up (69·2 ± 10·6 months). Patients underwent an extensive biochemical evaluation within 3 months before or after a sequence of saliva sampling and were classified as being in remission or in early-stage recurrence. The accuracy of three diagnostic strategies combining two, three or four LNSC results from a sequence was estimated using areas under the ROC curves (AUC), sensitivity, specificity and predictive values. RESULTS: Forty-four sequences of LNSC measurements were available. Fifty-two percent of sequences were performed during early-stage recurrence. The intrasequence variability of LNSC was higher during recurrence than during remission (medians of SDs: 2·1 vs 0·5 nm; P < 0·0001). AUCs from ROC curves ranged from 0·93 to 0·96 depending on the strategy. For 90% sensitivities, the best specificities (92·9% and 90·9%) were achieved by strategies taking into account three or four measurements summarized either by their mean or their maximum value. CONCLUSIONS: Increase in LNSC concentration is an early abnormality during post-surgical recurrence of CD. However, due to a major within-patient variability of LNSC from 1 day to another, a screening strategy using three or four samples collected on successive days may be recommended to detect early-stage recurrence of CD with a high accuracy.

Acoustic Radiation Force Impulse (ARFI) and Transient Elastography (TE) for evaluation of liver fibrosis in HIV-HCV co-infected patients.

BACKGROUND: Transient elastography (TE) is widely used for non-invasive assessment of liver fibrosis in HIV-HCV co-infected patients. TE, however, cannot determine liver morphology. Acoustic radiation force impulse (ARFI) imaging is a novel procedure enabling assessment of liver fibrosis during a conventional ultrasonographic examination. This study evaluated the correlation between liver fibrosis measurements by TE and ARFI. METHODS: Each of 46 HIV-HCV patients underwent both ARFI and TE within 6 months. Patients were evaluated by the "equivalent METAVIR" scoring system, using previously established cut-off values. Agreements between the ARFI and TE scores were estimated by Kappa coefficients, with Kappa values ≥0.40, ≥0.60, and ≥0.80 defined as moderate, good and very good agreement, respectively. RESULTS: ARFI and TE yielded "Equivalent Metavir" fibrosis scores of F1 in 26 and 31 patients, respectively; F2 in nine and seven, respectively; F3 in three and two, respectively; and F4 in eight and six, respectively. The two methods showed very good agreement in predicting overall stages [Kappa = 0.82] and for F ≥3 [Kappa = 0.80] and moderate agreement in predicting significant fibrosis F ≥2 [Kappa = 0.50]. Morphologic ultrasound analysis concomitant to ARFI detected two hepatocarcinomas. CONCLUSIONS: ARFI showed promising results in the non-invasive assessment of liver fibrosis in HIV-HCV patients, with liver fibrosis staging similar to that of TE. Moreover, ARFI can assess morphology and fibrosis during the same session.

Comparison of 68Ga-PSMA-617 PET/CT and 68Ga-RM2 PET/CT in Patients with Localized Prostate Cancer Who Are Candidates for Radical Prostatectomy: A Prospective, Single-Arm, Single-Center, Phase II Study.

Considering the wide range of therapeutic options for localized prostate cancer (e.g., active surveillance, radiation-beam therapy, focal therapy, and radical prostatectomy), accurate assessment of the aggressiveness and localization of primary prostate cancer lesions is essential for treatment decision making. National Comprehensive Cancer Network guidelines recognize prostate-specific membrane antigen (PSMA) PET/CT for use in initial staging of high-risk primary prostate cancer. The gastrin-releasing peptide receptor (GRP-R) is a neuropeptide receptor overexpressed by low-risk prostate cancer cells. We aimed to perform the first (to our knowledge) prospective head-to-head comparison of PSMA- and GRP-R-targeted imaging at initial staging to understand how PSMA PET and GRP-R PET can be used or combined in clinical practice. Methods: This was a prospective, single-center, diagnostic cross-sectional imaging study using anonymized, masked, and independent interpretations of paired PET/CT studies in 22 patients with 68Ga-PSMA-617 (a radiolabeled PSMA inhibitor) and 68Ga-RM2 (68Ga-DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, a radiolabeled GRP-R antagonist). We enrolled patients with newly diagnosed, biopsy-proven prostate cancer. None had received neoadjuvant hormone therapy or chemotherapy, and all underwent extended pelvic lymph node dissection. Histologic findings served as a reference. Results: On a lesion-based analysis (including lesions < 0.1 cm3), 68Ga-PSMA-617 PET/CT detected 74.3% (26/35) of all tumor lesions and 68Ga-RM2 PET/CT detected 78.1% (25/32; 1 patient could not be offered 68Ga-RM2 PET/CT). Paired examinations showed positive uptake of the 2 tracers in 21 of 32 lesions (65.6%), negative uptake in 5 of 32 lesions (15.6%), and discordant uptake in 6 of 32 lesions (18.8%). Uptake of 68Ga-PSMA-617 was higher when the International Society of Urological Pathology (ISUP) score was at least 4 versus at least 1 (P < 0.0001) or 2 (P = 0.0002). There were no significant differences in uptake between ISUP scores for 68Ga-RM2. Median 68Ga-RM2 SUVmax was significantly higher than median 68Ga-PSMA-617 SUVmax in the ISUP-2 subgroup (P = 0.01). Conclusion: 68Ga-PSMA-617 PET/CT is useful to depict higher, more clinically significant ISUP score lesions, and 68Ga-RM2 PET/CT has a higher detection rate for low-ISUP tumors. Combining PSMA PET and GRP-R PET allows for better classification of intraprostatic lesions.

Tuberculosis Diagnosis in HIV-Infected Children: Comparison of the 2012 and 2015 Clinical Case Definitions for Classification of Intrathoracic Tuberculosis Disease.

BACKGROUND: There is no gold standard for tuberculosis diagnosis in children. Clinical Case Definitions for Classification of Intrathoracic Tuberculosis in Children were proposed by international experts in 2012 and updated in 2015. We aimed to compare the 2012 and 2015 Clinical Case Definitions in HIV-infected children with suspected tuberculosis. METHODS: We enrolled HIV-infected children with suspected tuberculosis in Burkina Faso, Cambodia, Cameroon, and Vietnam (ANRS [Agence Nationale de Recherches sur le SIDA et les hépatites virales] 12229 PAANTHER [Pediatric Asian African Network for Tuberculosis and HIV Research] 01 Study). We classified children using the 2012 and 2015 Case Definitions considering as tuberculosis cases those with confirmed tuberculosis and those with probable and unconfirmed tuberculosis in the 2012 and the 2015 classifications, respectively. We assessed agreement between both classifications. RESULTS: Of 438 children enrolled, 197 (45.0%) children were classified as tuberculosis (45 confirmed, 152 probable) using the 2012 Case Definition and 251 (57.3%) were classified as tuberculosis (55 confirmed, 196 unconfirmed) using the 2015 classification. Inter-classification agreement for tuberculosis diagnosis was 364/438, 83.1%, with a kappa statistic of 0.667 (95% confidence interval 0.598-0.736). Of 152 children with probable tuberculosis (2012), 142 (93.4%) were considered as tuberculosis by the 2015 version and 10 (6.6%) as unlikely tuberculosis including 9 with spontaneous clinical improvement. Of 132 possible tuberculosis (2012), 58 (43.9%) were reclassified as tuberculosis (2015). CONCLUSIONS: Agreement between the 2 versions of the Case Definition was substantial but more children were considered as tuberculosis using the 2015 version. Spontaneous symptom resolution reinforces both confidence in the "unlikely" category as being children without tuberculosis and the importance of the clinician's treatment decision in the study.

Effect of an 18-Month Meditation Training on Regional Brain Volume and Perfusion in Older Adults: The Age-Well Randomized Clinical Trial.

Importance: No lifestyle-based randomized clinical trial directly targets psychoaffective risk factors of dementia. Meditation practices recently emerged as a promising mental training exercise to foster brain health and reduce dementia risk. Objective: To investigate the effects of meditation training on brain integrity in older adults. Design, Setting, and Participants: Age-Well was a randomized, controlled superiority trial with blinded end point assessment. Community-dwelling cognitively unimpaired adults 65 years and older were enrolled between November 24, 2016, and March 5, 2018, in France. Participants were randomly assigned (1:1:1) to (1) an 18-month meditation-based training, (2) a structurally matched non-native language (English) training, or (3) no intervention arm. Analysis took place between December 2020 and October 2021. Interventions: Meditation and non-native language training included 2-hour weekly group sessions, practice of 20 minutes or longer daily at home, and 1-day intensive practices. Main Outcomes and Measures: Primary outcomes included volume and perfusion of anterior cingulate cortex (ACC) and insula. Main secondary outcomes included a global composite score capturing metacognitive, prosocial, and self-regulatory capacities and constituent subscores. Results: Among 137 participants (mean [SD] age, 69.4 [3.8] years; 83 [60.6%] female; 54 [39.4%] male) assigned to the meditation (n = 45), non-native language training (n = 46), or no intervention (n = 46) groups, all but 1 completed the trial. There were no differences in volume changes of ACC (0.01 [98.75% CI, -0.02 to 0.05]; P = .36) or insula (0.01 [98.75% CI, -0.02 to 0.03]; P = .58) between meditation and no intervention or non-native language training groups, respectively. Differences in perfusion changes did not reach statistical significance for meditation compared with no intervention in ACC (0.02 [98.75% CI, -0.01 to 0.05]; P = .06) or compared with non-native language training in insula (0.02 [98.75% CI, -0.01 to 0.05]; P = .09). Meditation was superior to non-native language training on 18-month changes in a global composite score capturing attention regulation, socioemotional, and self-knowledge capacities (Cohen d, 0.52 [95% CI, 0.19-0.85]; P = .002). Conclusions and Relevance: The study findings confirm the feasibility of meditation and non-native language training in elderly individuals, with high adherence and very low attrition. Findings also show positive behavioral effects of meditation that were not reflected on volume, and not significantly on perfusion, of target brain areas. Trial Registration: ClinicalTrials.gov Identifier: NCT02977819.

Cerebral Small Vessel Disease MRI Features Do Not Improve the Prediction of Stroke Outcome.

OBJECTIVE: To determine whether the total small vessel disease (SVD) score adds information to the prediction of stroke outcome compared to validated predictors, we tested different predictive models of outcome in patients with stroke. METHODS: White matter hyperintensity, lacunes, perivascular spaces, microbleeds, and atrophy were quantified in 2 prospective datasets of 428 and 197 patients with first-ever stroke, using MRI collected 24 to 72 hours after stroke onset. Functional, cognitive, and psychological status were assessed at the 3- to 6-month follow-up. The predictive accuracy (in terms of calibration and discrimination) of age, baseline NIH Stroke Scale score (NIHSS), and infarct volume was quantified (model 1) on dataset 1, the total SVD score was added (model 2), and the improvement in predictive accuracy was evaluated. These 2 models were also developed in dataset 2 for replication. Finally, in model 3, the MRI features of cerebral SVD were included rather than the total SVD score. RESULTS: Model 1 showed excellent performance for discriminating poor vs good functional outcomes (area under the curve [AUC] 0.915), and fair performance for identifying cognitively impaired and depressed patients (AUCs 0.750 and 0.688, respectively). A higher SVD score was associated with a poorer outcome (odds ratio 1.30 [1.07-1.58], p = 0.0090 at best for functional outcome). However, adding the total SVD score (model 2) or individual MRI features (model 3) did not improve the prediction over model 1. Results for dataset 2 were similar. CONCLUSIONS: Cerebral SVD was independently associated with functional, cognitive, and psychological outcomes, but had no clinically relevant added value to predict the individual outcomes of patients when compared to the usual predictors, such as age and baseline NIHSS.

Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study).

BACKGROUND & AIMS: The diagnostic accuracy of non-invasive liver fibrosis tests that may replace liver biopsy in patients with chronic hepatitis remains controversial. We assessed and compared the accuracy of FibroScan® and that of the main biomarkers used for predicting cirrhosis and significant fibrosis (METAVIR ≥ F2) in patients with chronic viral hepatitis. METHODS: A multicenter prospective cross-sectional diagnostic accuracy study was conducted in the Hepatology departments of 23 French university hospitals. Index tests and reference standard (METAVIR fibrosis score on liver biopsy) were measured on the same day and interpreted blindly. Consecutive patients with chronic viral hepatitis (hepatitis B or C virus, including possible Human Immunodeficiency Virus co-infection) requiring liver biopsy were recruited in the study. RESULTS: The analysis was first conducted on the total population (1839 patients), and after excluding 532 protocol deviations, on 1307 patients (non-compliant FibroScan® examinations). The overall accuracy of FibroScan® was high (AUROC 0.89 and 0.90, respectively) and significantly higher than that of biomarkers in predicting cirrhosis (AUROC 0.77-0.86). All non-invasive methods had a moderate accuracy in predicting significant fibrosis (AUROC 0.72-0.78). Based on multilevel likelihood ratios, non-invasive tests provided a relevant gain in the likelihood of diagnosis in 0-60% of patients (cirrhosis) and 9-30% of patients (significant fibrosis). CONCLUSIONS: The diagnostic accuracy of non-invasive tests was high for cirrhosis, but poor for significant fibrosis. A clinically relevant gain in the likelihood of diagnosis was achieved in a low proportion of patients. Although the diagnosis of cirrhosis may rely on non-invasive tests, liver biopsy is warranted to diagnose intermediate stages of fibrosis.

Prospective Comparison of 18F-Choline Positron Emission Tomography/Computed Tomography (PET/CT) and 18F-Fluorodeoxyglucose (FDG) PET/CT in the Initial Workup of Multiple Myeloma: Study Protocol of a Prospective Imaging Trial.

BACKGROUND: The International Myeloma Working Group recommends the use of 18-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for treatment response evaluation, as it is superior to magnetic resonance imaging (MRI). However, at initial staging, the sensitivity of FDG-PET remains inferior to that of MRI. Therefore, there is a need for an imaging technique that could have a sensitivity equal to that of MRI at diagnosis and could serve to evaluate therapy. 18F-choline has shown increased sensitivity when compared with 18-FDG, with about 75% more lesions detected in patients with relapsed or progressive multiple myeloma (MM). OBJECTIVE: Our primary objective is to prospectively compare the detection rate of bone lesions by 18F-choline PET/CT (FCH-PET) and FDG-PET in newly diagnosed MM. Our secondary objectives are to assess the accuracy of both PET modalities for the detection of bone lesions and the diagnosis of diffuse disease, to assess the detection rate of extramedullary lesions. METHODS: We will prospectively include 30 patients in a paired comparative accuracy study. Patients with de novo MM will undergo FCH-PET, FDG-PET, and whole-body MRI (WB-MRI) within a 3-week period. WB-MRI will be composed of conventional sequences on the spine and pelvis and of whole-body diffusion axial sequences. The following 6 skeletal areas will be defined: skull, sternum/costal grid, spine, pelvis, superior limbs, and inferior limbs. The number of focal lesions, their respective localization, and intensity of uptake will be retrieved for each skeletal area. Readings will be performed blinded from other imaging techniques. The reference standard will be WB-MRI. Focal lesions present on PET/CT but not on WB-MRI will require a decision made with a consensus of experts based on clinical and imaging data. The number of bone lesions and number of extramedullary lesions will be compared using the Wilcoxon test. The accuracy of FCH-PET and FDG-PET will be compared using the McNemar test. RESULTS: The study started in September 2019, and enrollment is ongoing. As of June 2020, 8 participants have been included. Data collection is expected to be completed in June 2021, and the results are expected to be available in December 2021. CONCLUSIONS: This study will assess if FCH-PET is superior to FDG-PET for the evaluation of MM tumor burden. This will pave the way for future prospective evaluations of the prognostic value of 18-FCH for treatment response evaluation in MM patients. Additionally, this work may provide new perspectives for better assessment of the risk of smoldering MM progressing to MM. TRIAL REGISTRATION: ClinicalTrials.gov NCT03891914; https://clinicaltrials.gov/ct2/show/NCT03891914. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/17850.

Organ preservation with chemoradiotherapy plus local excision for rectal cancer: 5-year results of the GRECCAR 2 randomised trial.

BACKGROUND: GRECCAR 2 was the first multicentre, randomised trial to compare local excision with total mesorectal excision in downstaged low rectal cancer. Encouraging oncological results were noted at 3 years' follow-up but needed to be corroborated with longer follow-up. In this study, we aimed to report the 5-year oncological outcomes, including local recurrence, metastatic disease, and survival. METHODS: Patients age 18 years and older with T2T3 low rectal cancer, of maximum size 4 cm, who were clinically good responders after chemoradiotherapy (residual tumour ≤2 cm) were randomly assigned before surgery to either local excision or total mesorectal excision. Randomisation was centralised and not stratified and used permuted blocks of size eight. In the local excision group, a completion total mesorectal excision was performed if pathological tumour stage was ypT2-3. The primary objective of this study was to assess the 5-year oncological outcomes of local recurrence, metastatic disease, disease-free survival, overall survival, and cancer-specific mortality, which were the secondary endpoints of GRECCAR 2. We used Kaplan-Meier estimates and Cox modelling to estimate and compare recurrence and survival in modified intention-to-treat and as-treated populations. This trial was registered with ClinicalTrials.gov, number NCT00427375. FINDINGS: Between March 1, 2007, and Sept 24, 2012, 148 patients who were good clinical responders were randomly assigned to treatment, three patients were excluded after randomisation (because they had metastatic disease, tumour >8 cm from anal verge, or withdrew consent), leaving 145 for analysis: 74 in the local excision group and 71 in the total mesorectal excision group. Median follow-up was 60 months (IQR 58-60) in the local excision group and 60 months (57-60) in the total mesorectal excision group. 23 patients died and five were lost to follow-up. In the local excision group, 26 had a completion total mesorectal excision for ypT2-3 tumour. In the modified intention-to-treat analysis, there was no difference between the local excision and total mesorectal excision groups in 5-year local recurrence (7% [95% CI 3-16] vs 7% [3-16]; adjusted hazard ratio [HR] 0·71 [95% CI 0·19-2·58]; p=0·60), metastatic disease (18% [CI 11-30] vs 19% [11-31]; 0·86 [0·36-2·06]; p=0·73), overall survival (84% [73-91] vs 82% [71-90]; 0·92 [0·38-2·22]; p=0·85), disease-free survival (70% [58-79] vs 72% [60-82]; 0·87 [0·44-1·72]; p=0·68), or cancer-specific mortality (7% [3-17] vs 10% [5-20]; 0·65 [0·17-2·49]; p=0·53). INTERPRETATION: The 5-year results of this multicentre randomised trial corroborate the 3-year results, providing no evidence of difference in oncological outcomes between local excision and total mesorectal excision. Local excision can be proposed in selected patients having a small T2T3 low rectal cancer with a good clinical response after chemoradiotherapy. FUNDING: National Cancer Institute of France.

Influence of ethnic origin (Asian v. Caucasian) and background diet on the bioavailability of dietary isoflavones.

Soya isoflavones: genistein and daidzein are increasingly consumed in Western countries. Their beneficial effects are discussed considering nutrition and health in Asia. The present study aimed to check whether chronic ingestions, ethnic origin and dietary context can influence soya phyto-oestrogen bioavailability. Two prospective trials were carried out to blindly assess the pharmacokinetics after acute and chronic intake of soya-based cheese (45.97 (sd1.57) mg isoflavones) taken once a day for 10 d. Twelve healthy young Asians immersed for 2 months in France were randomised in a cross-over design to compare the influence of a Western v. Asian dietary context. The second trial partly nested in the first one, compared Asians under the Western diet to twelve healthy young male Caucasians under the same diet. All volunteers were non-equol producers. After an acute intake of soya in Western diet, Asians exhibited higher maximum concentration measured in plasma (Cmax) and area under the plasma concentration-time curve (AUC) for genistein and daidzein than Caucasians (P = 0.005, 0.006, 0.032 and 0.008, respectively). In Caucasians under Western diet, AUC and Cmax values significantly increased after chronic intake. This was not the case for daidzein in Asians whatever the dietary context. For the first time, it is evidenced that on acute intake of soya cheese, Asians absorb soya phyto-oestrogens better than Caucasians, regardless of whether the background diet is Western or Asian. On chronic ingestions, AUC and Cmax values were increased for daidzein and genistein in Caucasians but not in Asians. There are ethnic differences in isoflavone pharmacokinetic and bioavailability. This may influence health outcomes.