Exploring Aerosols near Clouds with High-Spatial-Resolution Aircraft Remote Sensing During SEAC4RS

Since aerosols are important to our climate system, we seek to observe the variability of aerosol properties within cloud systems. When applied to the satelliteborne Moderateresolution Imaging Spectroradiometer (MODIS), the Dark Target retrieval algorithm provides global aerosol optical depth (AOD; at 0.55 m) in cloudfree scenes. Since MODIS' resolution (500m pixels, 3 or 10km product) is too coarse for studying nearcloud aerosol, we ported the Dark Target algorithm to the highresolution (~50m pixels) enhancedMODIS Airborne Simulator (eMAS), which flew on the highaltitude ER2 during the Studies of Emissions, Atmospheric Composition, Clouds, and Climate Coupling by Regional Surveys Airborne Science Campaign over the United States in 2013. We find that even with aggressive cloud screening, the ~0.5km eMAS retrievals show enhanced AOD, especially within 6 km of a detected cloud. To determine the cause of the enhanced AOD, we analyze additional eMAS products (cloud retrievals and degradedresolution AOD), coregistered Cloud Physics Lidar profiles, MODIS aerosol retrievals, and groundbased Aerosol Robotic Network observations. We also define spatial metrics to indicate local cloud distributions near each retrieval and then separate into nearcloud and farfromcloud environments. The comparisons show that low cloud masking is robust, and unscreened thin cirrus would have only a small impact on retrieved AOD. Some of the enhancement is consistent with clearcloud transition zone microphysics such as aerosol swelling. However, 3D radiation interaction between clouds and the surrounding clear air appears to be the primary cause of the high AOD near clouds

The Winter Strategy – a Multifaceted Integrated Care Intervention to Support People with Chronic and Complex Care Needs during the Australian Winter Period

Introduction: Health care demands increase over the winter period, especially for people with chronic diseases. Hospital avoidance programs have potential to address seasonal surges. Methods: An integrated care intervention was provided to patients at high risk of hospitalisation during the 2017 and 2018 winters in Northern New South Wales, Australia. Patients received increased support including general practice sick day action plans, automated admission notifications to the general practitioner, and care coordination services. Outcomes were provider and patient experience and preventable hospitalisation rates. Results: The program enrolled 1244 participating patients from 37 general practices with at least 12 months follow-up. It was associated with marked improvements in provider and patient experience. However, when compared to a propensity score matched control group there was no difference in hospital utilisation or emergency presentation rates. Discussion and Conclusion: An integrated care strategy to address chronic care needs of patients in winter was well received by practitioners and patients, but did not translate to changes in hospital utilisation or emergency presentation rates. Areas for improvement include: strengthening inter-professional engagement between hospital, specialists and primary care providers, more tailored support services for patients with complex health needs, and a more expansive set of process measures beyond hospital and emergency utilisation to assess impact

Using a conceptual framework during learning attenuates the loss of expert-type knowledge structure

BACKGROUND: During evolution from novice to expert, knowledge structure develops into an abridged network organized around pathophysiological concepts. The objectives of this study were to examine the change in knowledge structure in medical students in one year and to investigate the association between the use of a conceptual framework (diagnostic scheme) and long-term knowledge structure. METHODS: Medical students' knowledge structure of metabolic alkalosis was studied after instruction and one year later using concept-sorting. Knowledge structure was labeled 'expert-type' if students shared ≥ 2 concepts with experts and 'novice-type' if they shared < 2 concepts. Conditional logistic regression was used to study the association between short-term knowledge structure, the use of a diagnostic scheme and long-term knowledge structure. RESULTS: Thirty-four medical students completed the concept-sorting task on both occasions. Twenty-four used a diagnostic scheme for metabolic alkalosis. Short-term knowledge structure was not a correlate of long-term knowledge structure, whereas use of a diagnostic scheme was associated with increased odds of expert-type long-term knowledge structure (odds ratio 12.6 [1.4, 116.0], p = 0.02). There was an interaction between short-term knowledge structure and the use of a diagnostic scheme. In the group who did not use a diagnostic scheme the number of students changing from expert-type to novice-type was greater than vice versa (p = 0.046). There was no significant change in the group that used the diagnostic scheme (p = 0.6). CONCLUSION: The use of a diagnostic scheme by students may attenuate the loss of expert-type knowledge structure

SER-109: An Oral Investigational Microbiome Therapeutic for Patients with Recurrent Clostridioides difficile Infection (rCDI)

Clostridioides difficile infection (CDI) is classified as an urgent health threat by the Centers for Disease Control and Prevention (CDC), and affects nearly 500,000 Americans annually. Approximately 20–25% of patients with a primary infection experience a recurrence, and the risk of recurrence increases with subsequent episodes to greater than 40%. The leading risk factor for CDI is broad-spectrum antibiotics, which leads to a loss of microbial diversity and impaired colonization resistance. Current FDA-approved CDI treatment strategies target toxin or toxin-producing bacteria, but do not address microbiome disruption, which is key to the pathogenesis of recurrent CDI. Fecal microbiota transplantation (FMT) reduces the risk of recurrent CDI through the restoration of microbial diversity. However, FDA safety alerts describing hospitalizations and deaths related to pathogen transmission have raised safety concerns with the use of unregulated and unstandardized donor-derived products. SER-109 is an investigational oral microbiome therapeutic composed of purified spore-forming Firmicutes. SER-109 was superior to a placebo in reducing CDI recurrence at Week 8 (12% vs. 40%, respectively; p \u3c 0.001) in adults with a history of recurrent CDI with a favorable observed safety profile. Here, we discuss the role of the microbiome in CDI pathogenesis and the clinical development of SER-109, including its rigorous manufacturing process, which mitigates the risk of pathogen transmission. Additionally, we discuss compositional and functional changes in the gastrointestinal microbiome in patients with recurrent CDI following treatment with SER-109 that are critical to a sustained clinical response

Six versus 12 months' adjuvant trastuzumab in patients with HER2-positive early breast cancer: the PERSEPHONE non-inferiority RCT

Background The addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes in human epidermal growth factor receptor 2 (HER2) positive early, potentially curable breast cancer. Twelve months’ trastuzumab tested in the registration trials was adopted for standard adjuvant treatment in 2006. Subsequently similar outcomes were demonstrated using 9 weeks trastuzumab. Shorter durations were therefore tested for non-inferiority. Objectives To establish whether 6 months’ adjuvant trastuzumab is non-inferior to 12 months in HER2-positive early breast cancer using a primary endpoint of 4-year disease-free-survival (DFS). Design Phase III randomised, controlled, non-inferiority trial. Setting 152 NHS Hospitals. Participants 4088 patients with HER2-positive early breast cancer planned to receive both chemotherapy and trastuzumab. Intervention Randomisation (1:1) between six months’ or twelve months’ trastuzumab. Main outcomes Primary endpoint was DFS four years after diagnosis. Secondary endpoints were overall survival (OS), cost effectiveness, and cardiac function during trastuzumab. Assuming a 4-year DFS rate of 80% with 12 months, 4000 patients were required to demonstrate non-inferiority of 6-months (5% 1-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life years (QALYs) were estimated by within-trial analysis and a lifetime decision-analytic model. Results Between 4th October 2007 and 31st July 2015, 2045 patients were randomised to 12-months’ trastuzumab and 2043 to 6-months. Sixty-nine percent had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% had trastuzumab sequentially after chemotherapy; 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years median follow-up with 389 (10%) deaths, and 566 (14%) DFS events, 4-year DFS rates for the 4088 patients were 89.5% (95% CI, 88.1-90.8) in the 6-month group and 90.3% (95% CI 88.9- 91.5) in the 12-month group (Hazard Ratio 1.10; 90% CI 0.96–1.26, non-inferiority p=0.01), demonstrating non-inferiority of 6-months’ trastuzumab. Congruent results were found for OS (non-inferiority p=0.0003), and landmark analyses 6 months from starting trastuzumab (non-inferiority p=0.03 (DFS) and p=0.006 (OS)). 6-months’ trastuzumab resulted in fewer patients reporting adverse events of severe grade (365/1929 (19%) versus 460/1935 (24%) 12-month patients, p=0.0003) or stopping early because of cardiotoxicity (61/1977 (3%) versus 146/1941 (8%) 12-month patients, p<0.0001). Health economic analysis showed significantly lower lifetime costs and similar lifetime QALYs, and thus a high probability that 6 months is cost-effective compared to 12 months. Patient reported experiences on the trial highlighted fatigue, and aches and pains most frequently. Limitations The type of chemotherapy and timing of trastuzumab changed through the recruitment phase of the study as standard practice altered. Conclusions PERSEPHONE demonstrated that in HER2-positive early breast cancer 6 months’ adjuvant trastuzumab was non-inferior to 12 months. There was significantly less cardiac toxicity and fewer severe adverse events with 6 months’ treatment. Future work On-going translational work investigates patient and tumour genetic determinants of toxicity, and trastuzumab efficacy. An individual patient data meta-analysis with PHARE and other trastuzumab duration trials is planned. Trial registration ISRCTN 52968807 Funding National Institute for Health Research, Health Technology Assessment Programme (HTA Project: 06/303/98).National Institute for Health Research, Health Technology Assessment Programme (HTA Project: 06/303/98)

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Identifying Optimal Restoration Sites to Connect Prairie Remnants in Southwest Wisconsin

Includes Photograph, Maps, Tables, Graphs, Appendices and Bibliography.Wisconsin prairies are significantly reduced from their original pre-settlement range. Remaining remnants are often small, fragmented and isolated making them vulnerable to environmental threats and prairie-dependent species more susceptible to edge effects and genetic bottlenecks. We will identify optimal sites for prairie restoration that will create natural corridors connecting existing prairie fragments in southwest Wisconsin. We will assess restoration potential and identify sites by intersecting historic prairie boundaries, current land cover, and the habitat needs of a prairie-dependent species

Living every day with my heart failure

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