A Multi-institutional Analysis of Factors Influencing the Rate of Positive MRI Biopsy Among Women with Early-Stage Breast Cancer.

BACKGROUND: The use of preoperative magnetic resonance imaging (MRI) for early-stage breast cancer (ESBC) is increasing, but its utility in detecting additional malignancy is unclear and delays surgical management (Jatoi and Benson in Future Oncol 9:347-353, 2013. https://doi.org/10.2217/fon.12.186 , Bleicher et al. J Am Coll Surg 209:180-187, 2009. https://doi.org/10.1016/j.jamcollsurg.2009.04.010 , Borowsky et al. J Surg Res 280:114-122, 2022. https://doi.org/10.1016/j.jss.2022.06.066 ). The present study sought to identify ESBC patients most likely to benefit from preoperative MRI by assessing the positive predictive values (PPVs) of ipsilateral and contralateral biopsies. METHODS: A retrospective cohort study included patients with cTis-T2N0-N1 breast cancer from two institutions during 2016-2021. A "positive" biopsy result was defined as additional cancer (PositiveCancer) or cancer with histology often excised (PositiveSurg). The PPV of MRI biopsies was calculated with respect to age, family history, breast density, and histology. Uni- and multivariate logistic regression determined whether combinations of age younger than 50 years, dense breasts, family history, and pure ductal carcinoma in situ (DCIS) histology led to higher biopsy yield. RESULTS: Of the included patients, 447 received preoperative MRI and 131 underwent 149 MRI-guided biopsies (96 ipsilateral, 53 contralateral [18 bilateral]). PositiveCancer for ipsilateral biopsy was 54.2%, and PositiveCancer for contralateral biopsy was 17.0%. PositiveSurg for ipsilateral biopsy was 62.5%, and PositiveSurg for contralateral biopsy was 24.5%. Among the contralateral MRI biopsies, patients younger than 50 years were less likely to have PositiveSurg (odds ratio, 0.02; 95% confidence interval, 0.00-0.84; p = 0.041). The combinations of age, density, family history, and histology did not lead to a higher biopsy yield. CONCLUSION: Historically accepted factors for recommending preoperative MRI did not appear to confer a higher MRI biopsy yield. To prevent delays to surgical management, MRI should be carefully selected for individual patients most likely to benefit from additional imaging.

Microbial communities from weathered outcrops of a sulfide-rich ultramafic intrusion, and implications for mine waste management.

The Duluth Complex (DC) contains sulfide-rich magmatic intrusions that represent one of the largest known economic deposits of copper, nickel, and platinum group elements. Previous work showed that microbial communities associated with experimentally-weathered DC waste rock and tailings were dominated by uncultivated taxa and organisms not typically associated with mine waste. However, those experiments were designed for kinetic testing and do not necessarily represent the conditions expected for long-term environmental weathering. We used 16S rRNA gene methods to characterize the microbial communities present on the surfaces of naturally-weathered and historically disturbed outcrops of DC material. Rock surfaces were dominated by diverse uncultured Ktedonobacteria, Acetobacteria, and Actinobacteria, with abundant algae and other phototrophs. These communities were distinct from microbial assemblages from experimentally-weathered DC rocks, suggesting different energy and nutrient resources in environmental samples. Sulfide mineral incubations performed with and without algae showed that photosynthetic microorganisms could have an inhibitory effect on autotrophic populations, resulting in slightly lower sulfate release and differences in dominant microorganisms. The microbial assemblages from these weathered outcrops show how communities develop during weathering of sulfide-rich DC rocks and represent baseline data that could evaluate the effectiveness of future reclamation of waste produced by large-scale mining operations.

Lack of Racial Diversity in Surgery and Pathology Textbooks Depicting Diseases of the Breast.

INTRODUCTION: The lack of racial diversity depicted in medical education texts may contribute to an implicit racial bias among clinicians. This bias influences outcomes, as familiarity with the various cutaneous manifestations of disease is essential to making an accurate diagnosis. To better understand the racial disparities in breast surgery, we sought to determine the extent of skin tone representation depicted in images of breast surgery and pathology textbooks. METHODS: Textbooks were screened for color images of conditions with sufficient skin tissue present to assign the Fitzpatrick skin phototype (FSP). Figures were independently assigned an FP score (range: 1-6), and subdivided into "light skin" (FP 1-3) and "dark skin" (FP 4-6). Number of figures in each category and percentage of patients with each skin tone were calculated. RESULTS: 557 figures were included. Among 12 textbooks reviewed, seven textbooks were from the discipline of surgery, while five were pathology-related. Textbook year of publication spanned from 1996 to 2018. Overall, 533 (95.7%) figures depicted patients with light skin color versus 24 (4.3%) with dark skin color. There was no association between FP score and year of textbook publication (P = 0.69). CONCLUSIONS: Patient images in breast textbooks are overwhelmingly of light skin tones, excluding patients with darker skin tones. The dearth of images depicting dark skinned individuals did not improve over time. Inclusion of patients of color in future textbooks may help reduce racial disparities within breast cancer care.

Sex Differences in Atrial Fibrillation and Associated Complications in Hypertensive Patients with Left Ventricular Hypertrophy: The LIFE Study.

BACKGROUND: There is no consensus on whether biological differences account for the higher risk of stroke seen in females compared to males with atrial fibrillation (AF). METHODS: Capitalizing on The Losartan Intervention for Endpoint study, a multicenter randomized clinical trial randomizing 9,193 patients and followed for at least four years, we aimed to identify sex differences in the risk of stroke in the presence of AF in patients with hypertension and left ventricular hypertrophy (LVH). RESULTS: 342 Patients had a history of AF, and 669 developed new-onset AF. History of AF and new-onset AF were more prevalent among males (5.0% vs. 2.9% and 3.0% vs. 0.9%) in patients aged 55-63 years, but the relative difference decreased with age. Females with new-onset AF tended to have a higher risk of stroke than males (HR 1.52 [95% CI 0.95-2.43]). However, females with a history of AF did not have a higher risk than males (HR 0.88 [95% CI 0.5-1.6]). In patients with new-onset AF, the relative higher stroke risk in females increased with age. Among patients with a history of AF, stroke risk was comparable and increased with age in both sexes. CONCLUSIONS: Among patients with hypertension and LVH, females with new-onset AF had a higher risk of stroke than males, especially in patients above 64 years. However, the risk did not differ between the sexes among patients with a history of AF.

Drug interventions for prevention of COVID-19 progression to severe disease in outpatients: a systematic review with meta-analyses and trial sequential analyses (The LIVING Project).

OBJECTIVES: To assess the effects of interventions authorised by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA) for prevention of COVID-19 progression to severe disease in outpatients. SETTING: Outpatient treatment. PARTICIPANTS: Participants with a diagnosis of COVID-19 and the associated SARS-CoV-2 virus irrespective of age, sex and comorbidities. INTERVENTIONS: Drug interventions authorised by EMA or FDA. PRIMARY OUTCOME MEASURES: Primary outcomes were all-cause mortality and serious adverse events. RESULTS: We included 17 clinical trials randomising 16 257 participants to 8 different interventions authorised by EMA or FDA. 15/17 of the included trials (88.2%) were assessed at high risk of bias. Only molnupiravir and ritonavir-boosted nirmatrelvir seemed to improve both our primary outcomes. Meta-analyses showed that molnupiravir reduced the risk of death (relative risk (RR) 0.11, 95% CI 0.02 to 0.64; p=0.0145, 2 trials; very low certainty of evidence) and serious adverse events (RR 0.63, 95% CI 0.47 to 0.84; p=0.0018, 5 trials; very low certainty of evidence). Fisher's exact test showed that ritonavir-boosted nirmatrelvir reduced the risk of death (p=0.0002, 1 trial; very low certainty of evidence) and serious adverse events (p<0.0001, 1 trial; very low certainty of evidence) in 1 trial including 2246 patients, while another trial including 1140 patients reported 0 deaths in both groups. CONCLUSIONS: The certainty of the evidence was very low, but, from the results of this study, molnupiravir showed the most consistent benefit and ranked highest among the approved interventions for prevention of COVID-19 progression to severe disease in outpatients. The lack of certain evidence should be considered when treating patients with COVID-19 for prevention of disease progression. PROSPERO REGISTRATION NUMBER: CRD42020178787.

Lenient rate control versus strict rate control for atrial fibrillation: a statistical analysis plan for the Danish Atrial Fibrillation (DanAF) randomized clinical trial.

BACKGROUND: A key decision in the treatment of atrial fibrillation is choosing between a rhythm control strategy or a rate control strategy as the main strategy. When choosing rate control, the optimal heart rate target is uncertain. The Danish Atrial Fibrillation trial is a randomized, multicenter, two-group, superiority trial comparing strict rate control versus lenient rate control in patients with either persistent or permanent atrial fibrillation at inclusion. To prevent bias arising from selective reporting and data-driven analyses, we developed a predefined description of the statistical analysis. METHODS: The primary outcome of this trial is the physical component score of the SF-36 questionnaire. A total of 350 participants will be enrolled based on a minimal important difference of 3 points on the physical component score of the SF-36 questionnaire, a standard deviation of 10 points, a statistical power of 80% (beta of 20%), and an acceptable risk of type I error of 5%. All secondary, exploratory, and echocardiographic outcomes will be hypothesis-generating. The analyses of all outcomes will be based on the intention-to-treat principle. We will analyze continuous outcomes using linear regression adjusting for "site," type of atrial fibrillation at inclusion (persistent/ permanent), left ventricular ejection fraction (≥ 40% or < 40%), and the baseline value of the outcome (all as fixed effects). We define our threshold for statistical significance as a p-value of 0.05 and assessments of clinical significance will be based on the anticipated intervention effects defined in the sample size and power estimations. Thresholds for both statistical and clinical significance will be assessed according to the 5-step procedure proposed by Jakobsen and colleagues. DISCUSSION: This statistical analysis plan will be published prior to enrolment completion and before any data are available and is sought to increase the validity of the DANish Atrial Fibrillation trial. TRIAL REGISTRATION: Clinicaltrials.gov NCT04542785. Registered on Sept 09, 2020.

The Whiteboard Time Out: A Novel Tool to Improve Resident Learning in the Operating Room.

OBJECTIVE: "Flipping the classroom" is a strategy that has been implemented in various educational environments to create a student-centered learning environment. Within this model of teaching, "first exposure" occurs prior to the classroom in a lower form of cognitive demand, allowing students to employ higher forms of cognition within the classroom. Surgical education has evolved over recent years to incorporate different modalities of learning; however, optimal educational approaches within the operating room (OR) have not been clearly defined. The Whiteboard Time Out (WBTO) utilizes the idea of "flipping the classroom" to make learning within the OR more resident centered. Residents complete most of the preoperative work prior to the case with a focus on the indications, steps of the procedure, and potential complications associated with the procedure. Residents then utilize a whiteboard located in the OR to outline, diagram, and discuss this information with the attending. Aims of the study are to enhance higher level intraoperative resident learning and attending teaching and improve resident knowledge and the ability to communicate surgical steps. DESIGN: Faculty and residents completed a preimplementation questionnaire aligned to the Student Evaluation of Educational Quality (SEEQ) in July 2021. Participants were assigned 3 digit codes to ensure anonymity. The questionnaire was composed of 6 questions with a 5-point Likert scale. Whiteboards were mounted in every operating room, 19 total, in both the general OR and an ambulatory surgical center. The residents were expected to go to the OR, prior to scrubbing the case, and use the whiteboard to outline the indications, key steps and potential complications. After the resident completed the white board, the resident and attending reviewed the white board together prior to the start of the case. After the procedure, residents uploaded a picture of the whiteboard with a self-evaluation and faculty provided resident feedback via an online Wufoo Survey link. The start of the utilization of the whiteboards occurred after the initial survey in July 2021. The SEEQ questionnaire was again administered in October 2021, 3 months post-WBTO implementation, to assess resident and attending satisfaction. SEEQ questionnaire results were compared using a t-test. PARTICIPANTS: Participants included surgical residents and attendings at Maimonides Medical Center (MMC). MMC is a 700-bed university-affiliated, academic, tertiary medical center in Brooklyn, New York. The General Surgery Residency is approved for up to 5 graduates annually. RESULTS: A total of 17 attendings and 17 residents filled out the questionnaire. The average number of whiteboards completed was highest amongst the PGY1 class with an average of 18 whiteboards per resident. However, the average number of whiteboards completed declined amongst more senior residents. There was a statistically significant increase in overall SEEQ survey score amongst residents and attendings after implementation of the WBTO suggesting that whiteboards were useful (p < 0.03 and p < 0.02, respectively). Residents found that the whiteboard was an effective means of teaching surgical education compared to the current curriculum (p < 0.04). CONCLUSIONS: The whiteboard timeout is a tool created to enhance resident education in the OR. This idea is centered on a "flipped classroom," an educational strategy to increase student engagement. Our data demonstrates that the whiteboard timeout is an effective method of intraoperative teaching.

Cannabinoids versus placebo for pain: A systematic review with meta-analysis and Trial Sequential Analysis.

OBJECTIVES: To assess the benefits and harms of cannabinoids in participants with pain. DESIGN: Systematic review of randomised clinical trials with meta-analysis, Trial Sequential Analysis, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. DATA SOURCES: The Cochrane Library, MEDLINE, Embase, Science Citation Index, and BIOSIS. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Published and unpublished randomised clinical trials comparing cannabinoids versus placebo in participants with any type of pain. MAIN OUTCOME MEASURES: All-cause mortality, pain, adverse events, quality of life, cannabinoid dependence, psychosis, and quality of sleep. RESULTS: We included 65 randomised placebo-controlled clinical trials enrolling 7017 participants. Fifty-nine of the trials and all outcome results were at high risk of bias. Meta-analysis and Trial Sequential Analysis showed no evidence of a difference between cannabinoids versus placebo on all-cause mortality (RR 1.20; 98% CI 0.85 to 1.67; P = 0.22). Meta-analyses and Trial Sequential Analysis showed that cannabinoids neither reduced acute pain (mean difference numerical rating scale (NRS) 0.52; 98% CI -0.40 to 1.43; P = 0.19) or cancer pain (mean difference NRS -0.13; 98% CI -0.33 to 0.06; P = 0.1) nor improved quality of life (mean difference -1.38; 98% CI -11.81 to 9.04; P = 0.33). Meta-analyses and Trial Sequential Analysis showed that cannabinoids reduced chronic pain (mean difference NRS -0.43; 98% CI -0.72 to -0.15; P = 0.0004) and improved quality of sleep (mean difference -0.42; 95% CI -0.65 to -0.20; P = 0.0003). However, both effect sizes were below our predefined minimal important differences. Meta-analysis and Trial Sequential Analysis indicated that cannabinoids increased the risk of non-serious adverse events (RR 1.20; 95% CI 1.15 to 1.25; P < 0.001) but not serious adverse events (RR 1.18; 98% CI 0.95 to 1.45; P = 0.07). None of the included trials reported on cannabinoid dependence or psychosis. CONCLUSIONS: Cannabinoids reduced chronic pain and improved quality of sleep, but the effect sizes are of questionable importance. Cannabinoids had no effects on acute pain or cancer pain and increased the risks of non-serious adverse events. The harmful effects of cannabinoids for pain seem to outweigh the potential benefits.

Radar reflector guided axillary surgery in node positive breast cancer patients.

INTRODUCTION: In patients with non-palpable breast cancer, the availability of wireless localization techniques facilitates removal of the target lesion. One such technique uses a radar reflector for localization (RRL). This study evaluates the feasibility and effectiveness of RRL to guide excision of axillary lymph nodes in patients with node-positive breast cancer. METHODS: Our Breast Cancer Database was queried for patients diagnosed with breast cancer, between 5/2017 and 10/2021, who underwent preoperative placement of a radar reflector into a biopsy proven axillary lymph node. Clinicopathologic data were reported using descriptive statistics. RESULTS: Twenty patients underwent preoperative placement of a radar reflector into the axilla. Intraoperatively, the clip and radar reflector were successfully removed in all patients. Among the 10 patients treated with NAC, 5 patients achieved an axillary pathologic complete response (pCR) and were spared a complete axillary lymph node dissection (cALND). Among the entire cohort, RRL resulted in a 53% reduction in the number of lymph nodes removed. CONCLUSIONS: Wireless localization of axillary lymph nodes is safe and feasible. The technique ensures excision of biopsy proven positive axillary lymph nodes and enables a targeted approach to assessing the axilla, both in the setting of NAC and upfront surgery.

The Association of Preoperative Magnetic Resonance Imaging (MRI) With Surgical Management in Patients With Early-Stage Breast Cancer.

INTRODUCTION: The rate of mastectomy in lumpectomy-eligible patients with unilateral breast cancer is increasing. We sought to investigate the association between magnetic resonance imaging (MRI) and surgical management of patients with early-stage breast cancer by comparing the rate of mastectomy as first surgery in patients with and without preoperative MRI. METHODS: A bi-institutional retrospective study included patients diagnosed between 2016 and 2020. Lumpectomy-eligible patients with in situ and invasive cancer were included. Those receiving preoperative therapy, MRI before diagnosis, or with known bilateral cancer were excluded. The risk factors for bilateral and multicentric disease were accounted for. Fisher's exact and chi-square tests compared categorical variables, Wilcoxon two-sample test analyzed continuous variables, and multivariate analyses were performed with Poisson regression. RESULTS: Four hundred twenty-eight participants met inclusion criteria. Patients who received MRI were younger (58 versus 67 y; P < 0.001) and had denser breasts (group 3 or 4; 61% versus 25%; P < 0.001). Mastectomy rate was twice as high in patients undergoing MRI (32% versus 15%, rate ratio 2.16; P < 0.001), which remained significant in multivariate analysis (rate ratio 2.0; P < 0.001). Contralateral mastectomy (12% versus 4%; P = 0.466) and reexcision (13% versus 12%; P = 0.519) rates were similar. Time to surgery was greater in those receiving MRI alone and MRI biopsy (34 [no MRI] versus 45 [MRI] versus 62 [MRI biopsy]; P < 0.001 for both). CONCLUSIONS: MRI receipt is associated with a doubled rate of mastectomy in lumpectomy-eligible patients. Future work is needed to standardize patient selection for MRI to those with the highest likelihood of having additional undiagnosed disease.

Physical activity paradox: could inflammation be a key factor?

OBJECTIVE: The aim of this study was to test the extent to which physical activity performed during work and leisure is associated with systemic inflammation. METHODS: Data regarding job history and high-sensitivity C reactive protein (hs-CRP) levels, as well as potential confounders, came from the Copenhagen Aging and Midlife Biobank. The participants' self-reported job history was combined with a job exposure matrix to give a more valid assessment of cumulated occupational physical activity compared with conventional self-reported activity. Occupational physical activity was measured as cumulative ton-years (lifting 1000 kg each day for a year). Current leisure time physical activity was self-reported into four different categories. We analysed the association between occupational physical activity, current leisure time physical activity and hs-CRP level in a multivariable linear regression model with adjustment for age, sex, smoking history, number of chronic diseases, body mass index and alcohol. RESULTS: In unadjusted analysis, higher occupational physical activity was associated with increased hs-CRP levels, while higher leisure time physical activity was associated with lower hs-CRP levels. In adjusted analysis, lower leisure time physical activity resulted in 12% higher hs-CRP levels while higher occupational physical activities showed a 6% increase in hs-CRP. When we analysed occupational and leisure time physical activity as continuous variables, only leisure time physical activity affected hs-CRP. CONCLUSION: This study indicates that the relationship between physical activity and hs-CRP depends on the setting of physical activity, with lower hs-CRP related to leisure time physical activity and higher hs-CRP related to occupational physical activity. The results suggest that systemic inflammation may explain the physical activity paradox.

Documentation and Prediction of Increasing Groundwater Chloride in the Twin Cities, Minnesota.

We provide a comprehensive overview of historic chloride concentrations in the groundwater of the Twin Cities metropolitan area (TCMA) in Minnesota, in order to define the extent of chloride contamination, due primarily to the seasonal application of deicing salt to roadways. Data collected from 1278 wells between 1965 and 2020 are representative of the major aquifers underlying the TCMA and establish a regional natural background chloride concentration of less than 10 mg/L. However, 55% of all measurements (1616 of 2943) are above 10 mg/L, with the highest concentrations found within the uppermost Quaternary aquifers. Chloride concentrations in underlying bedrock aquifers are negatively correlated with the thickness and clay composition of overlying materials. Most chloride measurements (92%) remain below chronic exposure limits set by state and federal authorities. Historical trends indicate that, if the current imbalance between chloride inputs and outflows persists, chloride concentrations in TCMA aquifers will surpass regulatory thresholds by midcentury as surface waters and Quaternary aquifer waters migrate into underlying bedrock aquifers. Most wells in this study are monitored annually, making it impossible to detect important sub-annual fluctuations of chloride concentration that can exceed 40%.

Stalagmite paleomagnetic record of a quiet mid-to-late Holocene field activity in central South America.

Speleothems can provide high-quality continuous records of the direction and relative paleointensity of the geomagnetic field, combining high precision dating (with U-Th method) and rapid lock-in of their detrital magnetic particles during calcite precipitation. Paleomagnetic results for a mid-to-late Holocene stalagmite from Dona Benedita Cave in central Brazil encompass ~1900 years (3410 BP to 5310 BP, constrained by 12 U-Th ages) of paleomagnetic record from 58 samples (resolution of ~33 years). This dataset reveals angular variations of less than 0.06° yr-1 and a relatively steady paleointensity record (after calibration with geomagnetic field model) contrasting with the fast variations observed in younger speleothems from the same region under influence of the South Atlantic Anomaly. These results point to a quiescent period of the geomagnetic field during the mid-to-late Holocene in the area now comprised by the South Atlantic Anomaly, suggesting an intermittent or an absent behavior at the multi-millennial timescale.

Vaccines to prevent COVID-19: A living systematic review with Trial Sequential Analysis and network meta-analysis of randomized clinical trials.

BACKGROUND: COVID-19 is rapidly spreading causing extensive burdens across the world. Effective vaccines to prevent COVID-19 are urgently needed. METHODS AND FINDINGS: Our objective was to assess the effectiveness and safety of COVID-19 vaccines through analyses of all currently available randomized clinical trials. We searched the databases CENTRAL, MEDLINE, Embase, and other sources from inception to June 17, 2021 for randomized clinical trials assessing vaccines for COVID-19. At least two independent reviewers screened studies, extracted data, and assessed risks of bias. We conducted meta-analyses, network meta-analyses, and Trial Sequential Analyses (TSA). Our primary outcomes included all-cause mortality, vaccine efficacy, and serious adverse events. We assessed the certainty of evidence with GRADE. We identified 46 trials; 35 trials randomizing 219 864 participants could be included in our analyses. Our meta-analyses showed that mRNA vaccines (efficacy, 95% [95% confidence interval (CI), 92% to 97%]; 71 514 participants; 3 trials; moderate certainty); inactivated vaccines (efficacy, 61% [95% CI, 52% to 68%]; 48 029 participants; 3 trials; moderate certainty); protein subunit vaccines (efficacy, 77% [95% CI, -5% to 95%]; 17 737 participants; 2 trials; low certainty); and viral vector vaccines (efficacy 68% [95% CI, 61% to 74%]; 71 401 participants; 5 trials; low certainty) prevented COVID-19. Viral vector vaccines decreased mortality (risk ratio, 0.25 [95% CI 0.09 to 0.67]; 67 563 participants; 3 trials, low certainty), but comparable data on inactivated, mRNA, and protein subunit vaccines were imprecise. None of the vaccines showed evidence of a difference on serious adverse events, but observational evidence suggested rare serious adverse events. All the vaccines increased the risk of non-serious adverse events. CONCLUSIONS: The evidence suggests that all the included vaccines are effective in preventing COVID-19. The mRNA vaccines seem most effective in preventing COVID-19, but viral vector vaccines seem most effective in reducing mortality. Further trials and longer follow-up are necessary to provide better insight into the safety profile of these vaccines.

Beta-blockers in patients without heart failure after myocardial infarction.

BACKGROUND: Cardiovascular disease is the number one cause of death globally. According to the World Health Organization (WHO), 7.4 million people died from ischaemic heart disease in 2012, constituting 15% of all deaths. Beta-blockers are recommended and are often used in patients with heart failure after acute myocardial infarction. However, it is currently unclear whether beta-blockers should be used in patients without heart failure after acute myocardial infarction. Previous meta-analyses on the topic have shown conflicting results. No previous systematic review using Cochrane methods has assessed the effects of beta-blockers in patients without heart failure after acute myocardial infarction. OBJECTIVES: To assess the benefits and harms of beta-blockers compared with placebo or no treatment in patients without heart failure and with left ventricular ejection fraction (LVEF) greater than 40% in the non-acute phase after myocardial infarction. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index - Expanded, BIOSIS Citation Index, the WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, European Medicines Agency, Food and Drug Administration, Turning Research Into Practice, Google Scholar, and SciSearch from their inception to February 2021. SELECTION CRITERIA: We included all randomised clinical trials assessing effects of beta-blockers versus control (placebo or no treatment) in patients without heart failure after myocardial infarction, irrespective of publication type and status, date, and language. We excluded trials randomising participants with diagnosed heart failure at the time of randomisation. DATA COLLECTION AND ANALYSIS: We followed our published protocol, with a few changes made, and methodological recommendations provided by Cochrane and Jakobsen and colleagues. Two review authors independently extracted data. Our primary outcomes were all-cause mortality, serious adverse events, and major cardiovascular events (composite of cardiovascular mortality and non-fatal myocardial reinfarction). Our secondary outcomes were quality of life, angina, cardiovascular mortality, and myocardial infarction during follow-up. We assessed all outcomes at maximum follow-up. We systematically assessed risks of bias using seven bias domains and we assessed the certainty of evidence using the GRADE approach. MAIN RESULTS: We included 25 trials randomising a total of 22,423 participants (mean age 56.9 years). All trials and outcomes were at high risk of bias. In all, 24 of 25 trials included a mixed group of participants with ST-elevation myocardial infarction and non-ST myocardial infarction, and no trials provided separate results for each type of infarction. One trial included participants with only ST-elevation myocardial infarction. All trials except one included participants younger than 75 years of age. Methods used to exclude heart failure were various and were likely insufficient. A total of 21 trials used placebo, and four trials used no intervention, as the comparator. All patients received usual care; 24 of 25 trials were from the pre-reperfusion era (published from 1974 to 1999), and only one trial was from the reperfusion era (published in 2018). The certainty of evidence was moderate to low for all outcomes. Our meta-analyses show that beta-blockers compared with placebo or no intervention probably reduce the risks of all-cause mortality (risk ratio (RR) 0.81, 97.5% confidence interval (CI) 0.73 to 0.90; I² = 15%; 22,085 participants, 21 trials; moderate-certainty evidence) and myocardial reinfarction (RR 0.76, 98% CI 0.69 to 0.88; I² = 0%; 19,606 participants, 19 trials; moderate-certainty evidence). Our meta-analyses show that beta-blockers compared with placebo or no intervention may reduce the risks of major cardiovascular events (RR 0.72, 97.5% CI 0.69 to 0.84; 14,994 participants, 15 trials; low-certainty evidence) and cardiovascular mortality (RR 0.73, 98% CI 0.68 to 0.85; I² = 47%; 21,763 participants, 19 trials; low-certainty evidence). Hence, evidence seems to suggest that beta-blockers versus placebo or no treatment may result in a minimum reduction of 10% in RR for risks of all-cause mortality, major cardiovascular events, cardiovascular mortality, and myocardial infarction. However, beta-blockers compared with placebo or no intervention may not affect the risk of angina (RR 1.04, 98% CI 0.93 to 1.13; I² = 0%; 7115 participants, 5 trials; low-certainty evidence). No trials provided data on serious adverse events according to good clinical practice from the International Committee for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH-GCP), nor on quality of life. AUTHORS' CONCLUSIONS: Beta-blockers probably reduce the risks of all-cause mortality and myocardial reinfarction in patients younger than 75 years of age without heart failure following acute myocardial infarction. Beta-blockers may further reduce the risks of major cardiovascular events and cardiovascular mortality compared with placebo or no intervention in patients younger than 75 years of age without heart failure following acute myocardial infarction. These effects could, however, be driven by patients with unrecognised heart failure. The effects of beta-blockers on serious adverse events, angina, and quality of life are unclear due to sparse data or no data at all. All trials and outcomes were at high risk of bias, and incomplete outcome data bias alone could account for the effect seen when major cardiovascular events, angina, and myocardial infarction are assessed. The evidence in this review is of moderate to low certainty, and the true result may depart substantially from the results presented here. Future trials should particularly focus on patients 75 years of age and older, and on assessment of serious adverse events according to ICH-GCP and quality of life. Newer randomised clinical trials at low risk of bias and at low risk of random errors are needed if the benefits and harms of beta-blockers in contemporary patients without heart failure following acute myocardial infarction are to be assessed properly. Such trials ought to be designed according to the SPIRIT statement and reported according to the CONSORT statement.

Enhanced avionic sensing based on Wigner's cusp anomalies.

Typical sensors detect small perturbations by measuring their effects on a physical observable, using a linear response principle (LRP). It turns out that once LRP is abandoned, new opportunities emerge. A prominent example is resonant systems operating near Nth-order exceptional point degeneracies (EPDs) where a small perturbation ε ≪ 1 activates an inherent sublinear response [Formula: see text] in resonant splitting. Here, we propose an alternative sublinear optomechanical sensing scheme that is rooted in Wigner's cusp anomalies (WCAs), first discussed in the framework of nuclear reactions: a frequency-dependent square-root singularity of the differential scattering cross section around the energy threshold of a newly opened channel, which we use to amplify small perturbations. WCA hypersensitivity can be applied in a variety of sensing applications, besides optomechanical accelerometry discussed in this paper. Our WCA platforms are compact, do not require a judicious arrangement of active elements (unlike EPD platforms), and, if chosen, can be cavity free.

Linear and nonlinear hydromagnetic stability in laminar and turbulent flows.

We consider the evolution of arbitrarily large perturbations of a prescribed pure hydrodynamical flow of an electrically conducting fluid. We study whether the flow perturbations as well as the generated magnetic fields decay or grow with time and constitute a dynamo process. For that purpose we derive a generalized Reynolds-Orr equation for the sum of the kinetic energy of the hydrodynamic perturbation and the magnetic energy. The flow is confined in a finite volume so the normal component of the velocity at the boundary is zero. The tangential component is left arbitrary in contrast with previous works. For the magnetic field we mostly employ the classical boundary conditions where the field extends in the whole space. We establish critical values of hydrodynamic and magnetic Reynolds numbers below which arbitrarily large initial perturbations of the hydrodynamic flow decay. This involves generalization of the Rayleigh-Faber-Krahn inequality for the smallest eigenvalue of an elliptic operator. For high Reynolds number turbulence we provide an estimate of critical magnetic Reynolds number below which arbitrarily large fluctuations of the magnetic field decay.

Lenient rate control versus strict rate control for atrial fibrillation: a protocol for the Danish Atrial Fibrillation (DanAF) randomised clinical trial.

INTRODUCTION: Atrial fibrillation is the most common heart arrhythmia with a prevalence of approximately 2% in the western world. Atrial fibrillation is associated with an increased risk of death and morbidity. In many patients, a rate control strategy is recommended. The optimal heart rate target is disputed despite the results of the the RAte Control Efficacy in permanent atrial fibrillation: a comparison between lenient vs strict rate control II (RACE II) trial.Our primary objective will be to investigate the effect of lenient rate control strategy (<110 beats per minute (bpm) at rest) compared with strict rate control strategy (<80 bpm at rest) on quality of life in patients with persistent or permanent atrial fibrillation. METHODS AND ANALYSIS: We plan a two-group, superiority randomised clinical trial. 350 outpatients with persistent or permanent atrial fibrillation will be recruited from four hospitals, across three regions in Denmark. Participants will be randomised 1:1 to a lenient medical rate control strategy (<110 bpm at rest) or a strict medical rate control strategy (<80 bpm at rest). The recruitment phase is planned to be 2 years with 3 years of follow-up. Recruitment is expected to start in January 2021. The primary outcome will be quality of life using the Short Form-36 (SF-36) questionnaire (physical component score). Secondary outcomes will be days alive outside hospital, symptom control using the Atrial Fibrillation Effect on Quality of Life, quality of life using the SF-36 questionnaire (mental component score) and serious adverse events. The primary assessment time point for all outcomes will be 1 year after randomisation. ETHICS AND DISSEMINATION: Ethics approval was obtained through the ethics committee in Region Zealand. The design and findings will be published in peer-reviewed journals as well as be made available on ClinicalTrials.gov. TRIAL REGISTRATION NUMBER: NCT04542785.

Reynolds number dependence of Lyapunov exponents of turbulence and fluid particles.

The Navier-Stokes equations generate an infinite set of generalized Lyapunov exponents defined by different ways of measuring the distance between exponentially diverging perturbed and unperturbed solutions. This set is demonstrated to be similar, yet different, from the generalized Lyapunov exponent that provides moments of distance between two fluid particles below the Kolmogorov scale. We derive rigorous upper bounds on dimensionless Lyapunov exponent of the fluid particles that demonstrate the exponent's decay with Reynolds number Re in accord with previous studies. In contrast, terms of cumulant series for exponents of the moments have power-law growth with Re. We demonstrate as an application that the growth of small fluctuations of magnetic field in ideal conducting turbulence is hyperintermittent, being exponential in both time and Reynolds number. We resolve the existing contradiction between the theory, that predicts slow decrease of dimensionless Lyapunov exponent of turbulence with Re, and observations exhibiting quite fast growth. We demonstrate that it is highly plausible that a pointwise limit for the growth of small perturbations of the Navier-Stokes equations exists.

The effects of adding quinolones to beta-lactam antibiotics for sepsis.

BACKGROUND: Sepsis is common, deadly, and a major challenge to treat. Quinolones added to beta-lactam antibiotics are currently recommended as a second-line empiric regimen in sepsis, but the evidence regarding their benefits and harms is unclear. OBJECTIVE: To assess the benefits and harms of adding quinolones to standard care for sepsis. DATA SOURCES: We conducted a systematic review of randomized clinical trials with meta-analysis and Trial Sequential Analysis. We searched CENTRAL, MEDLINE, Embase, LILACS, SCI-Expanded, and BIOSIS. STUDY SELECTION: Randomized clinical trials assessing the effects of adding any quinolone to standard care for children and adults with sepsis. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers screened studies and extracted data. The certainty of the evidence was assessed by GRADE. RESULTS: We included three trials randomizing 995 adults. All trials were at overall "high risk of bias." All trials compared a quinolone (moxifloxacin, levofloxacin, or ciprofloxacin) and a beta-lactam antibiotic versus the same beta-lactam antibiotic. We found no evidence of an effect of adding quinolones to beta-lactam antibiotics when assessing all-cause mortality (RR 1.07, 95% CI 0.86 to 1.33; 2 trials; 915 participants; very low certainty of evidence) and serious adverse events (RR 1.00, 95% CI 0.67 to 1.50; 977 participants; two trials; very low certainty of evidence). No trials reported on quality of life. CONCLUSIONS: The effects of adding quinolones to beta-lactam antibiotics for the treatment of sepsis were unclear for all outcomes. Additional trial data are warranted to support the recommendation of empirical use of quinolones for sepsis.