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Aims: Epicardial adipose tissue (EAT) volume and attenuation on computed tomography (CT) have been associated with atrial fibrillation. Beyond these conventional CT measures, radiomics allows extraction of high-dimensional data and deep quantitative adipose tissue phenotyping, which may capture its underlying biology. We aimed to explore the EAT proteomic and CT-radiomic signatures associated with impaired left atrial (LA) remodelling and post-operative atrial fibrillation (POAF)., Methods and Results: We prospectively included 132 patients with severe aortic stenosis with no prior atrial fibrillation referred for aortic valve replacement. Pre-operative non-contrast CT images were obtained for extraction of EAT volume and other radiomic features describing EAT texture. The LA function was assessed by 2D-speckle-tracking echocardiography peak atrial longitudinal strain and peak atrial contraction strain. The EAT biopsies were performed during surgery for proteomic analysis by sequential windowed acquisition of all theoretical fragment ion mass spectra (SWATH-MS). The POAF incidence was monitored from surgery until discharge. Impaired LA function and incident POAF were associated with EAT up-regulation of inflammatory and thrombotic proteins, and down-regulation of cardioprotective proteins with anti-inflammatory and anti-lipotoxic properties. The EAT volume was independently associated with LA enlargement, impaired function, and POAF risk. On CT images, EAT texture of patients with POAF was heterogeneous and exhibited higher maximum grey-level values than sinus rhythm patients, which correlated with up-regulation of inflammatory and down-regulation of lipid droplet-formation EAT proteins. The CT radiomics of EAT provided an area under the curve of 0.80 (95% confidence interval: 0.68-0.92) for discrimination between patients with POAF and sinus rhythm., Conclusion: Pre-operative CT-radiomic profile of EAT detected adverse EAT proteomics and identified patients at risk of developing POAF., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

During the XXVIII Brazilian Congress of SBFa, 24 specialists met and, from a leading position on scientific research as a tool for connecting laboratory and clinic, five fronts of knowledge of the voice specialty were discussed as following: Perceptual-auditory judgment of vocal quality; 2. Acoustic analysis of the vocal signal; 3. Voice self-assessment; 4. Traditional techniques of therapy; 5. Modern techniques of electrostimulation and photobiomodulation (PBMT) in voice. Part "a" of this publication was associated with the consolidation of the analyses of the first three aspects. The trend in the perceptual-auditory judgment of vocal quality was related to the use of standard protocols. The acoustic evaluation of the vocal signal is accessible and can be done descriptively or by extraction of parameters, thus preferring multiparametric measures. Finally, the analysis of the individual himself closes this triad of voice documentation, which will be the basis for the conclusion of the evaluation, reference for monitoring progress, and evaluation of treatment results.

Introduction: The MONALEESA-7 trial compared ribociclib plus endocrine therapy (ET) with placebo as first-line treatment of advanced luminal/HER2-negative breast cancer (ABC) in premenopausal and perimenopausal women (age <50 years) and showed significant benefits to progression-free survival and overall survival. This study aimed to compare the cost-effectiveness of ribociclib + ET versus ET alone in patients with ABC from the perspective of the Brazilian public national health system., Methods: We calculated the incremental cost-effectiveness ratio (ICER) using a Markov model with progression-free survival, post-progression survival, and death states. We expressed ICER as incremental costs per progression-free life-year (PFLY) and quality-adjusted life-year (QALY) gained in a 10-year time horizon. We used parametric survival distributions fit to MONALEESA-7 data to generate survival distributions for progression-free and post-progression survival. The largest British preference study in breast cancer served as the basis to estimate health-state utilities. We estimated direct costs (ABC treatment, follow-up, monitoring, and adverse events) using Brazilian-specific values from public sources. An expert consensus panel determined the resource patterns required. We applied annual discounts of 5% to costs and QALYs., Results: Ribociclib + ET resulted in an incremental gain of 1.03 PFLYs and 0.80 QALYs at a cost of $37,319.31. The ICER of ribociclib + ET versus ET was $36,379.41 per PFLY gained and $46,590.79 per QALY gained. In deterministic sensitivity analysis, results were primarily affected by the annual discount rate, followed by the cost of ribociclib. In probabilistic sensitivity analysis, simulations agreed with the base-case., Conclusion: Ribociclib increased PFLYs and QALYs in patients with HR+/HER2- ABC when added to ET. Because Brazil does not have a formally defined cost-effectiveness threshold, other domains need to be considered for incorporation decisions, such as disease burden and humanistic impact on this young, economically active population. These findings may be useful in discussions for incorporation of ribociclib into the Brazilian public health system., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.M.B. and M.S. are employers of Novartis Biociências S.A. The other authors received fees for the composite of the consensus panel., (© The Author(s), 2022.)

Introduction: Mentor Mothers (MM) provide peer support to pregnant and postpartum women living with HIV (PPWH) and their infants with perinatal HIV exposure (IPE) throughout the cascade of prevention of vertical transmission (PVT) services. MM were implemented in Zambézia Province, Mozambique starting in August 2017. This evaluation aimed to determine the effect of MM on PVT outcomes., Methods: A retrospective interrupted time series analysis was done using routinely collected aggregate data from 85 public health facilities providing HIV services in nine districts of Zambézia. All PPWH (and their IPE) who initiated antiretroviral therapy (ART) from August 2016 through April 2019 were included. Outcomes included the proportion per month per district of: PPWH retained in care 12 months after ART initiation, PPWH with viral suppression and IPE with HIV DNA PCR test positivity by 9 months of age. The effect of MM on outcomes was assessed using logistic regression., Results: The odds of 12-month retention increased 1.5% per month in the pre-MM period, compared to a monthly increase of 7.6% with-MM (35-61% pre-MM, 56-72% with-MM; p < 0.001). The odds of being virally suppressed decreased by 0.9% per month in the pre-MM period, compared to a monthly increase of 3.9% with-MM (49-85% pre-MM, 59-80% with-MM; p < 0.001). The odds of DNA PCR positivity by 9 months of age decreased 8.9% per month in the pre-MM period, compared to a monthly decrease of 0.4% with-MM (0-14% pre-MM, 4-10% with-MM; p < 0.001). The odds of DNA PCR uptake (the proportion of IPE who received DNA PCR testing) by 9 months of age were significantly higher in the with-MM period compared to the pre-MM period (48-100% pre-MM, 87-100% with-MM; p < 0.001)., Conclusions: MM services were associated with improved retention in PVT services and higher viral suppression rates among PPWH. While there was ongoing but diminishing improvement in DNA PCR positivity rates among IPE following MM implementation, this might be explained by increased uptake of HIV testing among high-risk IPE who were previously not getting tested. Additional efforts are needed to further optimize PVT outcomes, and MM should be one part of a comprehensive strategy to address this critical need., (© 2022 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Purpose: An expert panel on breast cancer and COVID-19 disease was convened to address the impact of the COVID-19 pandemic for early breast cancer (eBC) management., Methods: To ensure that the most clinically relevant information was addressed, essential information was drawn from several of the latest national and international guidelines and another technical document. The expert panel met in five virtual closed sessions from November 2020 to May 2021 to consult on the relevant data from evidence-based results. The data gathered were discussed on an online platform., Results: This article reports the expert panel's highlights of these meetings' discussions. In addition, it provides practical recommendations covering topics regarding diagnosis, treatment, and management of patients with eBC in clinical settings routinely encountered by health care professionals amid the COVID-19 pandemic., Conclusion: This article provided guidance on several topics regarding eBC management amid the COVID-19 pandemics to inform safer care practices., Competing Interests: Francisco Pimentel CavalcanteConsulting or Advisory Role: Pfizer, Roche, MSD OncologySpeakers' Bureau: Roche, Pfizer, Gencell Pharma, LibbsTravel, Accommodations, Expenses: Roche, Gencell Pharma Carlos Eduardo dos Santos FerreiraSpeakers' Bureau: Roche Diagnostica Brasil, Beckman Coulter, Abbott Diagnostics Gilberto AmorimStock and Other Ownership Interests: Pfizer, AstraZenecaHonoraria: Roche, Novartis, Lilly, Sanofi/Aventis, Pfizer, MSD OncologyConsulting or Advisory Role: Novartis, Roche, MSD OncologyTravel, Accommodations, Expenses: Roche, Novartis Luciana LandeiroConsulting or Advisory Role: GlaxoSmithKline Álvaro Pulchinelli JrConsulting or Advisory Role: Roche, Thermo Fisher Scientific, bioMerieux, BD Biosciences Daniela Dornelles RosaConsulting or Advisory Role: Roche, Novartis, AstraZeneca, Lilly, GlaxoSmithKline, Sanofi, Libbs, Pfizer, Amgen, Zodiac PharmaSpeakers' Bureau: Novartis, Lilly, PfizerTravel, Accommodations, Expenses: RocheNo other potential conflicts of interest were reported.

Background: Historically, antiretroviral therapy (ART) initiation was based on CD4 criteria, but this has been replaced with "Test and Start" wherein all people living with HIV are offered ART. We describe the baseline immunologic status among children relative to evolving ART policies in Mozambique., Methods: This retrospective evaluation was performed using routinely collected data. Children living with HIV (CL aged 5-14 years) with CD4 data in the period of 2012-2018 were included. ART initiation "policy periods" corresponded to implementation of evolving guidelines: in period 1 (2012-2016), ART was recommended for CD4 <350 cells/mm3; during period 2 (2016-2017), the CD4 threshold increased to <500 cells/mm3; Test and Start was implemented in period 3 (2017-2018). We described temporal trends in the proportion of children with severe immunodeficiency (CD4 <200 cells/mm3) at enrollment and at ART initiation. Multivariable regression models were used to estimate associations with severe immunodeficiency., Results: The cohort included 1815 children with CD4 data at enrollment and 1922 at ART initiation. The proportion of children with severe immunodeficiency decreased over time: 20% at enrollment into care in period 1 vs. 16% in period 3 (P = 0.113) and 21% at ART initiation in period 1 vs. 15% in period 3 (P = 0.004). Children initiating ART in period 3 had lower odds of severe immunodeficiency at ART initiation compared with those in period 1 [adjusted odds ratio (aOR) = 0.67; 95% CI: 0.51 to 0.88]. Older age was associated with severe immunodeficiency at enrollment (aOR = 1.13; 95% CI: 1.06 to 1.20) and at ART initiation (aOR = 1.14; 95% CI: 1.08 to 1.21)., Conclusions: The proportion of children with severe immunodeficiency at ART initiation decreased alongside more inclusive ART initiation guidelines. Earlier treatment of children living with HIV is imperative., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Aims: Altered left atrial (LA) blood flow characteristics account for an increase in cardioembolic stroke risk in atrial fibrillation (AF). Here, we aimed to assess whether exposure to stroke risk factors is sufficient to alter LA blood flow even in the presence of sinus rhythm (SR)., Methods and Results: We investigated 95 individuals: 37 patients with persistent AF, who were studied before and after cardioversion [Group 1; median CHA2DS2-VASc = 2.0 (1.5-3.5)]; 35 individuals with no history of AF but similar stroke risk to Group 1 [Group 2; median CHA2DS2-VASc = 3.0 (2.0-4.0)]; and 23 low-risk individuals in SR [Group 3; median CHA2DS2-VASc = 0.0 (0.0-0.0)]. Cardiac function and LA flow characteristics were evaluated using cardiac magnetic resonance. Before cardioversion, Group 1 displayed impaired left ventricular (LV) and LA function, reduced LA flow velocities and vorticity, and a higher normalized vortex volume (all P < 0.001 vs. Groups 2 and 3). After restoration of SR at ≥4-week post-cardioversion, LV systolic function and LA flow parameters improved significantly (all P < 0.001 vs. pre-cardioversion) and were no longer different from those in Group 2. However, in the presence of SR, LA flow peak and mean velocity, and vorticity were lower in Groups 1 and 2 vs. Group 3 (all P < 0.01), and were associated with impaired LA emptying fraction (LAEF) and LV diastolic dysfunction., Conclusion: Patients at moderate-to-high stroke risk display altered LA flow characteristics in SR in association with an LA myopathic phenotype and LV diastolic dysfunction, regardless of a history of AF., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Measurement errors are present in many data collection procedures and can harm analyses by biasing estimates. To correct for measurement error, researchers often validate a subsample of records and then incorporate the information learned from this validation sample into estimation. In practice, the validation sample is often selected using simple random sampling (SRS). However, SRS leads to inefficient estimates because it ignores information on the error-prone variables, which can be highly correlated to the unknown truth. Applying and extending ideas from the two-phase sampling literature, we propose optimal and nearly-optimal designs for selecting the validation sample in the classical measurement-error framework. We target designs to improve the efficiency of model-based and design-based estimators, and show how the resulting designs compare to each other. Our results suggest that sampling schemes that extract more information from the error-prone data are substantially more efficient than SRS, for both design- and model-based estimators. The optimal procedure, however, depends on the analysis method, and can differ substantially. This is supported by theory and simulations. We illustrate the various designs using data from an HIV cohort study.

Introduction: Factors associated with losses in the latent tuberculosis infection (LTBI) cascade of care in contacts of patients with tuberculosis (TB) were investigated in a multicentre prospective cohort from highly endemic regions in Brazil., Methods: Close contacts of 1187 patients with culture-confirmed pulmonary TB were prospectively studied between 2015 and 2019, with follow-up of 6-24 months. Data on TB screening by clinical investigation, radiographic examination and interferon-gamma release assay (IGRA) were collected. Multivariable regressions were used to identify determinants of losses in the LTBI cascade., Results: Among 4145 TB contacts initially identified, 1901 were examined (54% loss). Among those examined, 933 were people living with HIV, ≤5 years old and/or had positive IGRA results, and therefore had a recommendation to start TB preventive treatment (TPT). Of those, 454 (23%) initiated treatment, and 247 (54% of those initiating; 26% of those in whom treatment was recommended) completed TPT. Multivariable regression analysis revealed that living with HIV, illiteracy and black/ pardo (brown) race were independently associated with losses in the cascade., Conclusion: There were losses at all LTBI cascade stages, but particularly at the initial screening and examination steps. Close contacts of low socioeconomic status and living with HIV were at heightened risk of not completing the LTBI cascade of care in Brazil., Competing Interests: Competing interests: The funders of the study had no role in study design, data analysis, data interpretation, or writing of the report. All authors had access to all the data in the study and had final responsibility for the decision to submit for publication., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Preventing unintended pregnancies is paramount for women living with HIV (WLHIV). Previous studies have suggested that efavirenz-containing antiretroviral therapy (ART) reduces contraceptive effectiveness of implants, but there are uncertainties regarding the quality of the electronic medical record (EMR) data used in these prior studies., Methods: We conducted a retrospective, cohort study of EMR data from 2011 to 2015 among WLHIV of reproductive age accessing HIV care in public facilities in western Kenya. We validated a large subsample of records with manual chart review and telephone interviews. We estimated adjusted incidence rate ratios (aIRRs) with Poisson regression accounting for the validation sampling using inverse probability weighting and generalized raking., Results: A total of 85,324 women contributed a total of 170,845 women-years (w-y) of observation time; a subset of 5080 women had their charts reviewed, and 1285 underwent interviews. Among implant users, the aIRR of pregnancy for efavirenz- vs. nevirapine-containing ART was 1.9 (95% CI 1.6, 2.4) using EMR data only and 3.2 (95% CI 1.8, 5.7) when additionally using both chart review and interview validated data. Among efavirenz users, the aIRR of pregnancy for depomedroxyprogesterone acetate (DMPA) vs. implant use was 1.8 (95% CI 1.5, 2.1) in EMR only and 2.4 (95% CI 1.0, 6.1) using validated data., Conclusion: Pregnancy rates are higher when contraceptive implants are concomitantly used with efavirenz-containing ART, though rates were similar to leading alternative contraceptive methods such as DMPA. Our data provides policymakers, program staff, and WLHIV greater confidence in guiding their decision-making around contraceptive and ART options. Our novel, 3-phase validation sampling provides an innovative tool for using routine EMR data to improve the robustness of data quality., (© 2021. The Author(s).)

Introduction: From the outset of the COVID-19 pandemic, guidance from WHO has promoted social distancing, wearing face masks, frequent hand washing, and staying-at-home as measures to prevent the spread of COVID-19. For many across Africa, compliance can be difficult. The aim of this study was to 1) understand the impact of student's household's ability to comply with COVID-19 mitigation strategies, 2) identify predictors of mitigation strategy compliance, and 3) describe the impact of COVID-19 on household economics, food-security, and mental well-being., Materials and Methods: We conducted an email-based survey among current medical and pharmacy students of the University of Liberia College of Health Sciences between July and October 2020. The questionnaire was designed to explore their household's ability to comply with current mitigation strategies, as well as the pandemic´s impact on the student's household's finances and food security. Descriptive statistics were used to delineate demographic characteristics. Logistic regression was used to model factors associated with ability to comply with COVID-19 mitigation strategies, as well as participant's food security., Results: 113 persons responded to the questionnaire. Seventy-six (67∙3%) reported income losses as a result of the pandemic, with 93 (82∙3%) reporting being "somewhat" or "very worried" about their households' finances. Seventy-seven (68∙1%) participants reported food stocks that were sufficient for one-week or less. Forty (35%) participants reported eating less preferred foods or skipping meals in the past week. Overall, 20 participants (19∙4%) had a positive depression screen., Conclusions: Study participants showed mixed results in being able to adhere to national COVID-19 mitigation strategies, with household level stressors experienced around finances and food security. Until Liberia has access to vaccinations for most of its citizens, COVID-19 response measures need to provide social protections that address basic needs (shelter, clothing and food), and which specifically targets food insecurity. Preventative interventions for mental health problems must be incorporated into Liberia's response to the pandemic., Competing Interests: The authors have declared that no competing interests exist.

Background: Neutrophils have been associated with lung tissue damage in many diseases, including tuberculosis (TB). Whether neutrophil count can serve as a predictor of adverse treatment outcomes is unknown., Methods: We prospectively assessed 936 patients (172 HIV-seropositive) with culture-confirmed pulmonary TB, enrolled in a multicenter prospective cohort study from different regions in Brazil, from June 2015 to June 2019, and were followed up to two years. TB patients had a baseline visit before treatment (month 0) and visits at month 2 and 6 (or at the end of TB treatment). Smear microscopy, and culture for Mycobacterium tuberculosis (MTB) were performed at TB diagnosis and during follow-up. Complete blood counts were measured at baseline. Treatment outcome was defined as either unfavorable (death, treatment failure or TB recurrence) or favorable (cure or treatment completion). We performed multivariable logistic regression, with propensity score regression adjustment, to estimate the association between neutrophil count with MTB culture result at month 2 and unfavorable treatment outcome. We used a propensity score adjustment instead of a fully adjusted regression model due to the relatively low number of outcomes., Results: Among 682 patients who had MTB culture results at month 2, 40 (5.9%) had a positive result. After regression with propensity score adjustment, no significant association between baseline neutrophil count (10 3 /mm 3 ) and positive MTB culture at month 2 was found among either HIV-seronegative (OR = 1.06, 95% CI = [0.95;1.19] or HIV-seropositive patients (OR = 0.77, 95% CI = [0.51; 1.20]). Of 691 TB patients followed up for at least 18 months and up to 24 months, 635 (91.9%) were either cured or completed treatment, and 56 (8.1%) had an unfavorable treatment outcome. A multivariable regression with propensity score adjustment found an association between higher neutrophil count (10 3 /mm 3 ) at baseline and unfavorable outcome among HIV-seronegative patients [OR= 1.17 (95% CI= [1.06;1.30]). In addition, adjusted Cox regression found that higher baseline neutrophil count (10 3 /mm 3 ) was associated with unfavorable treatment outcomes overall and among HIV-seronegative patients (HR= 1.16 (95% CI = [1.05;1.27])., Conclusion: Increased neutrophil count prior to anti-TB treatment initiation was associated with unfavorable treatment outcomes, particularly among HIV-seronegative patients. Further prospective studies evaluating neutrophil count in response to drug treatment and association with TB treatment outcomes are warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Carvalho, Amorim, Melo, Silveira, Vargas, Moreira, Rocha, Souza, Arriaga, Araújo-Pereira, Figueiredo, Durovni, Lapa-e-Silva, Cavalcante, Rolla, Sterling, Cordeiro-Santos, Andrade, Silva, Kritski and the RePORT Brazil consortium.)

When COVID-19 hit the UK in early 2020, there were no known treatments for a condition that results in the death of around one in four patients hospitalised with this disease. Around the world, possible treatments were administered to huge numbers of patients, without any reliable assessments of safety and efficacy. The rapid generation of high-quality evidence was vital. RECOVERY is a streamlined, pragmatic, randomised controlled trial, which was set up in response to this challenge. As of April 2021, over 39,000 patients have been enrolled from 178 hospital sites in the UK. Within 100 days of its initiation, RECOVERY demonstrated that dexamethasone improves survival for patients with severe disease; a result that was rapidly implemented in the UK and internationally saving hundreds of thousands of lives. Importantly, it also showed that other widely used treatments (such as hydroxychloroquine and azithromycin) have no meaningful benefit for hospitalised patients. This was only possible through randomisation of large numbers of patients and the adoption of streamlined and pragmatic procedures focused on quality, together with widespread collaboration focused on a single goal. RECOVERY illustrates how clinical trials and healthcare can be integrated, even in a pandemic. This approach provides new opportunities to generate the evidence needed for high-quality healthcare not only for a pandemic but for the many other conditions that place a burden on patients and the healthcare system., (© Royal College of Physicians 2021. All rights reserved.)

Background: Four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) allows sophisticated quantification of left atrial (LA) blood flow, and could yield novel biomarkers of propensity for intra-cardiac thrombus formation and embolic stroke. As reproducibility is critically important to diagnostic performance, we systematically investigated technical and temporal variation of LA 4D flow in atrial fibrillation (AF) and sinus rhythm (SR)., Methods: Eighty-six subjects (SR, n = 64; AF, n = 22) with wide-ranging stroke risk (CHA 2 DS 2 VASc 0-6) underwent LA 4D flow assessment of peak and mean velocity, vorticity, vortex volume, and stasis. Eighty-five (99%) underwent a second acquisition within the same session, and 74 (86%) also returned at 30 (27-35) days for an interval scan. We assessed variability attributable to manual contouring (intra- and inter-observer), and subject repositioning and reacquisition of data, both within the same session (same-day scan-rescan), and over time (interval scan). Within-subject coefficients of variation (CV) and bootstrapped 95% CIs were calculated and compared., Results: Same-day scan-rescan CVs were 6% for peak velocity, 5% for mean velocity, 7% for vorticity, 9% for vortex volume, and 10% for stasis, and were similar between SR and AF subjects (all p > 0.05). Interval-scan variability was similar to same-day scan-rescan variability for peak velocity, vorticity, and vortex volume (all p > 0.05), and higher for stasis and mean velocity (interval scan CVs of 14% and 8%, respectively, both p < 0.05). Longitudinal changes in heart rate and blood pressure at the interval scan in the same subjects were associated with significantly higher variability for LA stasis (p = 0.024), but not for the remaining flow parameters (all p > 0.05). SR subjects showed significantly greater interval-scan variability than AF patients for mean velocity, vortex volume, and stasis (all p < 0.05), but not peak velocity or vorticity (both p > 0.05)., Conclusions: LA peak velocity and vorticity are the most reproducible and temporally stable novel LA 4D flow biomarkers, and are robust to changes in heart rate, blood pressure, and differences in heart rhythm.

Introduction and Objectives: In severe aortic stenosis (AS), the impact of aortic valve replacement (AVR) on left ventricular (LV) systolic function assessed by strain and measured by echocardiography or cardiac magnetic resonance (CMR) has been controversial. We aimed to investigate LV systolic myocardial function changes six months after AVR using global longitudinal (GLS), circumferential (GCS) and radial (GRS) strain derived from CMR imaging., Methods: We included 39 severe AS patients (69.3±7.8 years; 61.5% male) with preserved LV ejection fraction (LVEF) who were recruited as part of the EPICHEART study and underwent successful AVR (aortic valvular area: 0.8 cm 2 (IQR: 0.2) pre- to 1.8 cm 2 (IQR:0.5) post-AVR). Structural and functional parameters were assessed at baseline and six months after AVR, including LV GRS, GCS and GLS analysis by CMR, using cine short-axial and two-, three-, and four-chamber long-axial view. Comparison between baseline and postoperative LV remodeling was performed using Student t-test and Wilcoxon test., Results: At six-month follow-up, LV mass, end-diastolic and end-systolic volumes, stroke volume, cardiac output, lateral E/e', tricuspid annular plane systolic excursion, right ventricular (RV) S wave velocity, GLS [-15.6% (IQR: 4.39) to -13.7% (IQR: 4.62)] and GCS [-17.8±3.58% to -16.1±2.94%] reduced significantly, while LVEF and GRS remained unchanged and lateral e' velocity increased., Conclusions: Despite favorable reverse LV structural and diastolic functional remodeling six months following AVR, GLS and GCS assessed by CMR reduced compared to baseline, LVEF remained unchanged. The clinical utility and timing of assessment of postoperative strain changes as a marker of systolic function progression needs further research., (Copyright © 2021 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

In modern observational studies using electronic health records or other routinely collected data, both the outcome and covariates of interest can be error-prone and their errors often correlated. A cost-effective solution is the two-phase design, under which the error-prone outcome and covariates are observed for all subjects during the first phase and that information is used to select a validation subsample for accurate measurements of these variables in the second phase. Previous research on two-phase measurement error problems largely focused on scenarios where there are errors in covariates only or the validation sample is a simple random sample of study subjects. Herein, we propose a semiparametric approach to general two-phase measurement error problems with a quantitative outcome, allowing for correlated errors in the outcome and covariates and arbitrary second-phase selection. We devise a computationally efficient and numerically stable expectation-maximization algorithm to maximize the nonparametric likelihood function. The resulting estimators possess desired statistical properties. We demonstrate the superiority of the proposed methods over existing approaches through extensive simulation studies, and we illustrate their use in an observational HIV study., (© 2020 John Wiley & Sons Ltd.)

Background: A major goal of tuberculosis (TB) epidemiological studies is to obtain results that can be generalized to the larger population with TB. The ability to extrapolate findings on the determinants of TB treatment outcomes is also important., Methods: We compared baseline clinical and demographic characteristics and determinants of anti-TB treatment outcomes between persons enrolled in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort between June 2015 and June 2019, and the registry of TB cases reported to the Brazilian National TB Program (Information System for Notifiable Diseases [SINAN]) during the same time period. Multivariable regression models adjusted for the study site were performed using second-generation p-values, a novel statistical approach. Associations with unfavorable treatment outcomes were tested for both RePORT-Brazil and SINAN cohorts., Findings: A total of 1,060 culture-confirmed TB patients were enrolled in RePORT-Brazil and 455,873 TB cases were reported to SINAN. Second-generation p-value analyses revealed that the cohorts were strikingly similar with regard to sex, age, use of antiretroviral therapy and positive initial smear sputum microscopy. However, diabetes, HIV infection, and smoking were more frequently documented in RePORT-Brazil. Illicit drug use, the presence of diabetes, and history of prior TB were associated with unfavorable TB treatment outcomes; illicit drug use was associated with such outcomes in both cohorts., Conclusions: There were important similarities in demographic characteristics and determinants of clinical outcomes between the RePORT-Brazil cohort and the Brazilian National registry of TB cases., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Accumulation of epicardial adipose tissue (EAT) is associated with coronary artery disease (CAD) and increased risk of coronary events in asymptomatic subjects and low-risk patients, suggesting that EAT promotes atherosclerosis in its early stage. Recent studies have shown that the presence of CAD affects the properties of adjacent EAT, leading to dynamic changes in the molecular players involved in the interplay between EAT and the coronary arteries over the history of the disease. The role of EAT in late-stage CAD has not been investigated., Objectives: In a comparative analysis with mediastinal and subcutaneous adipose tissue, we aim to investigate whether the volume of EAT assessed by computed tomography and its proteome assessed by SWATH-MS mass spectrometry are associated with late stages of CAD in an elderly cohort of severe aortic stenosis patients., Methods: The EPICHEART study (NCT03280433) is a prospective study enrolling patients with severe degenerative aortic stenosis referred for elective aortic valve replacement, whose protocol includes preoperative clinical, nutritional, echocardiographic, cardiac computed tomography and invasive coronary angiographic assessments. During cardiac surgery, samples of EAT and mediastinal and subcutaneous thoracic adipose tissue are collected for proteomics analysis by SWATH-MS. In addition, pericardial fluid and peripheral and coronary sinus blood samples are collected to identify circulating and local adipose tissue-derived biomarkers of CAD., Conclusion: We designed a translational study to explore the association of EAT quantity and quality with advanced CAD. We expect to identify new biochemical factors and biomarkers in the crosstalk between EAT and the coronary arteries that are involved in the pathogenesis of late coronary atherosclerosis, especially coronary calcification, which might be translated into new therapeutic targets and imaging tools by biomedical engineering., (Copyright © 2020. Publicado por Elsevier España, S.L.U.)

Aims: The COVID-19 pandemic required a significant redeployment of worldwide healthcare resources. Fear of infection, national lockdowns and altered healthcare priorities have the potential to impact utilisation of healthcare resources for non-communicable diseases. To survey health professionals' views of the impact of the COVID-19 pandemic on the rate and timing of admission of patients with ST-elevation myocardial infarction (STEMI), the European Society of Cardiology (ESC) administered an internet-based questionnaire to cardiologists and cardiovascular nurses across 6 continents., Methods and Results: 3101 responses were received from 141 countries across 6 continents. 88.3% responded that their country was in "total lockdown" and 7.1% in partial lockdown. 78.8% responded that the number of patients presenting with STEMI was reduced since the coronavirus outbreak and 65.2% indicated that the reduction in STEMI presentations was >40%. Approximately 60% of all respondents reported that STEMI patients presented later than usual and 58.5% that >40% of STEMI patients admitted to hospital presented beyond the optimal window for primary percutaneous intervention (PCI) or thrombolysis. Independent predictors of the reported higher rate of delayed STEMI presentation were a country in total lockdown, >100 COVID-19 cases admitted locally, and the complete restructuring of the local cardiology service., Conclusion: The survey indicates that the impact of COVID-19 on STEMI presentations is likely to be substantial, with both lower presentations and a higher rate of delayed presentations occurring. This has potentially important ramifications for future healthcare and policy planning in the event of further waves of this pandemic., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background & Aims: The role of epicardial adipose tissue (EAT) in the pathophysiology of late stage-coronary artery disease (CAD) has not been investigated. We explored the association of EAT volume and its proteome with advanced coronary atherosclerosis., Methods: The EPICHEART Study prospectively enrolled 574 severe aortic stenosis patients referred to cardiac surgery. Before surgery, EAT volume was quantified by computed tomography (CT). During surgery, epicardial, mediastinal (MAT) and subcutaneous (SAT) adipose tissue samples were collected to explore fat phenotype by analyzing the proteomic profile using SWATH-mass spectrometry; pericardial fluid and peripheral venous blood were also collected. CAD presence was defined as coronary artery stenosis ≥50% in invasive angiography and by CT-derived Agatston coronary calcium score (CCS)., Results: EAT volume adjusted for body fat was associated with higher CCS, but not with the presence of coronary stenosis. In comparison with mediastinal and subcutaneous fat depots, EAT exhibited a pro-calcifying proteomic profile in patients with CAD characterized by upregulation of annexin-A2 and downregulation of fetuin-A; annexin-A2 protein levels in EAT samples were also positively correlated with CCS. We confirmed that the annexin-A2 gene was overexpressed in EAT samples of CAD patients and positively correlated with CCS. Fetuin-A gene was not detected in EAT samples, but systemic fetuin-A was higher in CAD than in non-CAD patients, suggesting that fetuin-A was locally downregulated., Conclusions: In an elderly cohort of stable patients, CCS was associated with EAT volume and annexin-A2/fetuin-A signaling, suggesting that EAT might orchestrate pro-calcifying conditions in the late phases of CAD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Characterized by fluvio-alluvial sedimentation processes, the heterogeneity in the Pantanal Basin allows its division in several sub-regions, which present natural characteristics of their own. It is possible to find in the literature different proposals to subdivide the Pantanal plain, which vary in total area and number of sub-regions. Each author uses specific criteria - mainly vegetation, soil and humidity - in his delimitation, but does not consider the tectonic aspects of the basin. In this sense, we intend to analyze three Pantanal delimitations from the literature and to relate them to the neotectonic context of the Pantanal plain by comparing the boundaries proposed in the delimitations to structural lineaments present in the basin. As a result, we observe that the comparison of the Pantanal boundaries with the lineaments shows a high compatibility between them, suggesting the influence of these structures in the development of the sub-regions.

Glomeruloid hemangiomas were first described by Chan in 1990 as a cutaneous marker of POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal proteinemia, and Skin changes). POEMS syndrome is a multisystem disease with a significant cutaneous involvement. Among its manifestations, hemangiomas are common, observed in up to one third of the patients, and, although specific, the glomeruloid subtype is very rare. The vascular endothelium growth factor (VEGF) is an angiogenic stimulation factor, which also induces increased systemic vascular permeability. Thus, a scenario of overexpression of VEGF can credibly lead to the assumption of an association between cutaneous hemangiomas and systemic manifestations, implying prognostic and therapeutic considerations and reinforcing the importance of dermatological periodical consultations for these patients. We report the case of a patient in whom glomeruloid hemangiomas marked the recurrence of POEMS syndrome, occurring before the systemic symptoms.

Introduction and Objectives: Left atrial dysfunction in aortic stenosis may precede atrial enlargement and predict the occurrence of atrial fibrillation (AF). To test this hypothesis, we assessed left atrial function and determined its impact on the incidence of AF after aortic valve replacement., Methods: A total of 149 severe aortic stenosis patients (74±8.6 years, 51% men) with no prior AF were assessed using speckle-tracking echocardiography. Left atrial function was evaluated using peak atrial longitudinal strain (PALS), peak atrial contraction strain (PACS), and phasic left atrial volumes. The occurrence of AF was monitored in 114 patients from surgery until hospital discharge., Results: In multiple linear regression, PALS and PACS were inversely correlated with left atrial dilation, left ventricular hypertrophy, and diastolic function. Atrial fibrillation occurred in 36 patients within a median time of 3 days [interquartile range, 1-4] after aortic valve replacement. In multiple Cox regression, PALS and PACS were independently associated with the incidence of AF (HR, 0.946; 95%CI, 0.910-0.983; P=.005 and HR, 0.932; 95%CI, 0.883-0.984; P=.011, respectively), even after further adjustment for left atrial dimensions. Both reduced PALS and PACS were associated with the incidence of AF in patients with nondilated left atria (P value for the interaction of PALS with left atrial dimensions=.013)., Conclusions: In severe aortic stenosis, left atrial dysfunction predicted the incidence of postoperative AF independently of left atrial dilation, suggesting that speckle-tracking echocardiography before surgery may help in risk stratification, particularly in patients with nondilated left atria., (Copyright © 2017 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: Evaluation of patient characteristics inducing toxicity in breast radiotherapy, using simultaneous modeling of multiple endpoints., Methods and Materials: In 269 early-stage breast cancer patients treated with whole-breast irradiation (WBI) after breast-conserving surgery, toxicity was scored, based on five dichotomized endpoints. Five logistic regression models were fitted, one for each endpoint and the effect sizes of all variables were estimated using maximum likelihood (MLE). The MLEs are improved with James-Stein estimates (JSEs). The method combines all the MLEs, obtained for the same variable but from different endpoints. Misclassification errors were computed using MLE- and JSE-based prediction models. For associations, p-values from the sum of squares of MLEs were compared with p-values from the Standardized Total Average Toxicity (STAT) Score., Results: With JSEs, 19 highest ranked variables were predictive of the five different endpoints. Important variables increasing radiation-induced toxicity were chemotherapy, age, SATB2 rs2881208 SNP and nodal irradiation. Treatment position (prone position) was most protective and ranked eighth. Overall, the misclassification errors were 45% and 34% for the MLE- and JSE-based models, respectively. p-Values from the sum of squares of MLEs and p-values from STAT score led to very similar conclusions, except for the variables nodal irradiation and treatment position, for which STAT p-values suggested an association with radiosensitivity, whereas p-values from the sum of squares indicated no association. Breast volume was ranked as the most significant variable in both strategies., Discussion: The James-Stein estimator was used for selecting variables that are predictive for multiple toxicity endpoints. With this estimator, 19 variables were predictive for all toxicities of which four were significantly associated with overall radiosensitivity. JSEs led to almost 25% reduction in the misclassification error rate compared to conventional MLEs. Finally, patient characteristics that are associated with radiosensitivity were identified without explicitly quantifying radiosensitivity.

We report a healthy, 44-year-old woman presenting with an at least a 20-year history of hardened papules in the forehead region, extending to the scalp. The biopsy and histopathologic exam confirmed a diagnosis of osteoma cutis. We review the literature review and discuss the classification of the cutaneous ossification process presented, along with the results of the surgical treatment.

Purpose: Patients with human epidermal growth factor receptor 2 (HER2) -positive metastatic tumors treated in the public health system in Brazil do not have access to trastuzumab. This study aimed to estimate the impact of the lack of access to anti-HER2 therapies on the mortality of these patients., Methods: On the basis of published data, the number of patients with HER2-positive advanced breast cancer in 2016 who should receive anti-HER2 targeted therapy was estimated. Three different treatment groups were considered for this hypothetical cohort: chemotherapy alone, chemotherapy plus trastuzumab, and chemotherapy plus trastuzumab and pertuzumab. The number of patients alive after 2 years of follow-up was estimated on the basis of the efficacy results of the pivotal trials considering these interventions., Results: It was calculated that 2,008 women will be diagnosed with advanced HER2-positive breast cancer in Brazil in 2016. It was estimated that only 808 women would be alive in 2018 if they receive only chemotherapy (which is the treatment offered by the public health system). On the other hand, the bar rises to 1,408 women alive in 2018 if they receive chemotherapy plus trastuzumab and 1,576 women alive in 2018 if they receive the gold standard of chemotherapy plus trastuzumab and pertuzumab., Conclusion: Trastuzumab is included in the WHO's list of essential medications, but the Brazilian public health system does not yet provide this treatment to its population with advanced disease. The introduction of trastuzumab and pertuzumab would have a positive effect, preventing premature deaths in women with metastatic HER2-positive breast cancer in Brazil., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.Márcio DebiasiNo relationship to discloseTomás ReinertNo relationship to discloseRafael KaliksConsulting or Advisory Role: Roche, AstraZeneca Speakers' Bureau: Pfizer, Janssen, Roche Travel, Accommodations, Expenses: AstraZeneca, Novartis, Roche, JanssenGilberto AmorimConsulting or Advisory Role: Roche Speakers' Bureau: Roche, NovartisMaira CaleffiNo relationship to discloseCarlos SampaioNo relationship to discloseGustavo dos Santos FernandesConsulting or Advisory Role: Roche Speakers' Bureau: Roche Expert Testimony: Novartis Travel, Accommodations, Expenses: RocheCarlos H. BarriosHonoraria: Novartis, Genentech, Pfizer, GlaxoSmithKline, Sanofi, Boehringer Ingelheim, Eisai Consulting or Advisory Role: Boehringer Ingelheim, Genentech, Novartis, Astellas Pharma, GlaxoSmithKline, Eisai, Pfizer Research Funding: Pfizer, Novartis, Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Genentech, Eli Lilly, Sanofi, Taiho Pharmaceutical, Mylan, Merrimack, Merck, AbbVie, Astellas Pharma, Biomarin, Bristol-Myers Squibb, Daiichi Sankyo, Abraxis BioScience, AB Science, Asana Biosciences, Medivation, Exelixis, ImClone Systems, LEO Pharma, Millennium

Standard analyses of data from case-control studies that are nested in a large cohort ignore information available for cohort members not sampled for the sub-study. This paper reviews several methods designed to increase estimation efficiency by using more of the data, treating the case-control sample as a two or three phase stratified sample. When applied to a study of coronary heart disease among women in the hormone trials of the Women's Health Initiative, modest but increasing gains in precision of regression coefficients were observed depending on the amount of cohort information used in the analysis. The gains were particularly evident for pseudo- or maximum likelihood estimates whose validity depends on the assumed model being correct. Larger standard errors were obtained for coefficients estimated by inverse probability weighted methods that are more robust to model misspecification. Such misspecification may have been responsible for an important difference in one key regression coefficient estimated using the weighted compared with the more efficient methods.

TonB-dependent transporters (TBDTs) are bacterial outer membrane proteins that internalize nutrients such as vitamin B12, metal complexes, heme, some carbohydrates, etc. In addition to their transport activity, several TBDTs are also involved in a signalling cascade from the cell surface into the cytoplasm, via their periplasmic signalling domain. Here we report the backbone and side chain resonance assignments of the signalling domain of HasR, a TonB-dependent outer membrane heme transporter from Serratia marcescens as a first step towards its structural study.

Objective: According to data from Brazil's National Cancer Institute nearly 30% of the new patients who present with breast cancer have locally advanced disease. These patients are inoperable and tumor reduction is usually attempted with chemotherapy. First-line anthracyclin-based neoadjuvant chemotherapy is often effective; however, about 30% of the patients fail and to date there is no established second-line treatment. We have studied the concomitant use of radiation therapy and capecitabine in this setting, to determine the toxicity and efficacy of this regimen as a second-line neoadjuvant treatment., Patients and Methods: Twenty-eight patients with inoperable locally advanced breast cancer refractory to first-line anthracycline based treatment were enrolled between January 2003 and May 2004. Patients received radiation therapy (total dose 5000 cGy) and concomitant capecitabine (850 mg/m2) twice daily for 14 days every 3 weeks., Results: This treatment rendered 23 of the 28 patients (82%) operable. The 5 remaining patients did not undergo surgery because of disease progression. The median clinical tumor size decreased from 80 cm2 to 49 cm2. Microscopic residual disease was observed in 3 patients (13%) and another patient achieved a complete pathologic response. The median number of involved lymph nodes was 2 and treatment was well tolerated with no grade 3 or 4 events., Conclusion: Our data indicate that second-line neoadjuvant treatment with radiation therapy and capecitabine is feasible, well tolerated, and effective in patients with locally advanced breast cancer refractory to primary anthracycline-based treatment. These results suggest that a randomized study should be done to compare radiotherapy alone to capecitabine combined with radiotherapy.

Background: Rett syndrome (RTT) is a severe neurodevelopmental disorder of girls, caused by mutations in the X-linked MECP2 gene. Worldwide recognition of the RTT clinical phenotype in the early 1980's allowed many cases to be diagnosed, and established RTT as one of the most common mental retardation syndromes in females. The years since then led to a refinement of the phenotype and the recent elaboration of Revised Diagnostic Criteria (RDC). Here, we study the impact of the presence versus the absence of the use of diagnostic criteria from the RDC to make a diagnosis of RTT on MECP2 mutation detection in Canadian patients diagnosed and suspected of having RTT., Methods: Using dHPLC followed by sequencing in all exons of the MECP2 gene, we compared mutation detection in a historic cohort of 35 patients diagnosed with RTT without the use of specific diagnostic criteria to a separate more recent group of 101 patients included on the basis of strict fulfillment of the RDC., Results: The MECP2 mutation detection rate was much higher in subjects diagnosed using a strict adherence to the RDC (20% vs. 72%)., Conclusions: These results suggest that clinical diagnostic procedures significantly influence the rate of mutation detection in RTT, and more generally emphasize the importance of diagnostic tools in the assessment of neurobehavioral syndromes.

Aerial applications of Foray 48B, which contains Bacillus thuringiensis strain HD1, were carried out on 9 to 10 May, 19 to 21 May, and 8 to 9 June 1999 to control European gypsy moth (Lymantria dispar) populations in Victoria, British Columbia, Canada. A major assessment of the health impact of B. thuringiensis subsp. kurstaki was conducted by the Office of the Medical Health Officer of the Capital Health Region during this period. Environmental (air and water) and human (nasal swab) samples, collected before and after aerial applications of Foray 48B, both in the spray zone and outside of the spray zone, were analyzed for the presence of strain HD1-like bacteria. Random amplified polymorphic DNA analysis, cry gene-specific PCR, and dot blot DNA hybridization techniques were used to screen over 11,000 isolates of bacteria. We identified bacteria with genetic patterns consistent with those of B. thuringiensis subsp. kurstaki HD1 in 9,102 of 10,659 (85.4%) isolates obtained from the air samples, 13 of 440 (2.9%) isolates obtained from the water samples, and 131 of 171 (76.6%) isolates from the nasal swab samples. These analyses suggest that B. thuringiensis subsp. kurstaki HD1-like bacteria were present both in the environment and in the human population of Victoria prior to aerial applications of Foray 48B. The presence of B. thuringiensis subsp. kurstaki HD1-like bacteria in human nasal passages increased significantly after the application of Foray 48B, both inside and outside the spray zone.

Nuclear magnetic resonance is an important tool for high-resolution structural studies of proteins. It demands high protein concentration and high purity; however, the expression of proteins at high levels often leads to protein aggregation and the protein purification step can correspond to a high percentage of the overall time in the structural determination process. In the present article we show that the step of sample optimization can be simplified by selective labeling the heterologous protein expressed in Escherichia coli by the use of rifampicin. Yeast thioredoxin and a coix transcription factor Opaque 2 leucine zipper (LZ) were used to show the effectiveness of the protocol. The (1)H/(15)N heteronuclear correlation two-dimensional NMR spectrum (HMQC) of the selective (15)N-labeled thioredoxin without any purification is remarkably similar to the spectrum of the purified protein. The method has high yields and a good (1)H/(15)N HMQC spectrum can be obtained with 50 ml of M9 growth medium. Opaque 2 LZ, a difficult protein due to the lower expression level and high hydrophobicity, was also probed. The (15)N-edited spectrum of Opaque 2 LZ showed only the resonances of the protein of heterologous expression (Opaque 2 LZ) while the (1)H spectrum shows several other resonances from other proteins of the cell lysate. The demand for a fast methodology for structural determination is increasing with the advent of genome/proteome projects. Selective labeling the heterologous protein can speed up NMR structural studies as well as NMR-based drug screening. This methodology is especially effective for difficult proteins such as hydrophobic transcription factors, membrane proteins, and others., (Copyright 2001 Academic Press.)

We have examined melanocytic cells derived directly from fresh biopsy tissue for the presence of p53 mutations. Using selective media that permits growth of melanocytes and inhibits growth of fibroblasts and keratinocytes, we established short-term, primary cultures of melanocytes from skin biopsies of common acquired nevi, dysplastic nevi, and from metastatic melanoma. Using PCR-single-stranded conformational polymorphism analysis, we have detected p53 mutations in 2 of 11 benign compound nevi and 2 of 5 dysplastic nevi. All nevi positive for p53 mutations were derived from patients who previously had cutaneous moles and three of the four had a family and/or personal history of melanoma.