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Clinical research networks conduct important studies that would not otherwise be performed by other entities. In the case of the Antibacterial Resistance Leadership Group (ARLG), such studies include diagnostic studies using master protocols, controlled phage intervention trials, and studies that evaluate treatment strategies or dynamic interventions, such as sequences of empiric and definitive therapies. However, the value of a clinical research network lies not only in the results from these important studies but in the creation of new approaches derived from collaborative thinking, carefully examining and defining the most important research questions for clinical practice, recognizing and addressing common but suboptimal approaches, and anticipating that the standard approaches of today may be insufficient for tomorrow. This results in the development and implementation of new methodologies and tools for the design, conduct, analyses, and reporting of research studies. These new methodologies directly impact the studies conducted within the network and have a broad and long-lasting impact on the field, enhancing the scientific value and efficiency of generations of research studies. This article describes innovations from the ARLG in diagnostic studies, observational studies, and clinical trials evaluating interventions for the prevention and treatment of antibiotic-resistant bacterial infections. [ABSTRACT FROM AUTHOR]

An iconic member of the Ediacara Biota, Dickinsonia Sprigg is one of few such taxa with multiple species. Here we use Gaussian finite mixture models to assess the validity of species distinctions for this genus. Our results indicate that the five described species of Dickinsonia from the Ediacara Member, South Australia are better classified as two based on multiple approaches. Two different methods for dimension reduction both provide strong support for two groups, with overlapping but distinct mixture models. The variable selection method produces the most biologically realistic clusters, indicating that the two species can be primarily differentiated based on the greater relative size of the anterior most unit of Dickinsonia costata Sprigg compared with Dickinsonia tenuis Glaessner & Wade. Despite differences in aspect ratio and number of modules, both species regulated growth to maintain overall shape. The greater likelihood of preservation of a midline and an irregular outer margin in D. tenuis highlights differential structural integrity and flexibility. Co-occurrence in the Ediacara Member indicates that both species occupied the same environments and temporal distribution. Smaller maximum and average size for D. costata, combined with higher abundance, may suggest a comparatively shorter lifespan and increased rates of reproduction. [ABSTRACT FROM AUTHOR]

Objective(s): The coronavirus pandemic caused by SARS-CoV-2 commenced in late 2019, and global wide vaccination appears to be the only reasonable solution to fight this dreadful virus. There are two main types of COVID-19 immunization using viral vector and mRNA-based vaccines. However, the impact of each of type on 18FFDG PET/CT needs to be accurately assessed. This study aimed to compare the 18FFDG PET/CT features of these two types of COVID-19 vaccines. Methods: A total of 188 patients referred for 18F-FDG PET/CT with a recent history of either BioNTech/Pfizer or AstraZeneca COVID-19 vaccination, and a control group of 40 patients with no history of any type of recent vaccination, were included in the study. 18F-FDG PET/CT studies of vaccinated patients assessed for injection site uptake and regional nodal and systemic reactions post vaccination. The data were compared to the control group and to the contralateral side for each patient. The findings were compared between patients who received Pfizer and AstraZeneca vaccines. Results: 18F-FDG PET/CT was semiquantitatively positive in 50.5% of the studied population for vaccine-related features. The ipsilateral axillary and infra- and supraclavicular lymph nodes were significantly larger in size and exhibited higher metabolic activity compared to the contralateral lymph nodes after both types of vaccination. The prevalence of regional nodal reactions post Pfizer and AstraZeneca vaccination was 39% and 17.9% on visual, and 61% and 47.6% on semiquantitative assessments, respectively. Patients receiving the Pfizer vaccine exhibited higher metabolic activity in the ipsilateral regional lymph nodes (p<0.05). No significant difference in the intensity of regional nodal reaction post vaccination was noted between the first four weeks. Conclusion: Significant local and regional nodal reactions are observed after both viral vector and mRNA COVID-19 vaccination with a tendency to extend toward the infra- and supraclavicular nodal stations but not to the pulmonary hilum. The greater intensity and extension of the nodal reaction after Pfizer vaccination suggests a higher possibility of false-positive results on 18F-FDG PET/CT studies using mRNA vaccination technology. [ABSTRACT FROM AUTHOR]

The Ediacara Biota--the oldest communities of complex, macroscopic fossils--consists of three temporally distinct assemblages: the Avalon (ca. 575-560 Ma), White Sea (ca. 560-550 Ma), and Nama (ca. 550-539 Ma). Generic diversity varies among assemblages, with a notable decline at the transition from White Sea to Nama. Preservation and sampling biases, biotic replacement, and environmental perturbation have been proposed as potential mechanisms for this drop in diversity. Here, we compile a global database of the Ediacara Biota, specifically targeting taphonomic and paleoecological characters, to test these hypotheses. Major ecological shifts in feeding mode, life habit, and tiering level accompany an increase in generic richness between the Avalon and White Sea assemblages. We find that ~80% of White Sea taxa are absent from the Nama interval, comparable to loss during Phanerozoic mass extinctions. The paleolatitudes, depositional environments, and preservational modes that characterize the White Sea assemblage are well represented in the Nama, indicating that this decline is not the result of sampling bias. Counter to expectations of the biotic replacement model, there are minimal ecological differences between these two assemblages. However, taxa that disappear exhibit a variety of morphological and behavioral characters consistent with an environmentally driven extinction event. The preferential survival of taxa with high surface area relative to volume may suggest that this was related to reduced global oceanic oxygen availability. Thus, our data support a link between Ediacaran biotic turnover and environmental change, similar to other major mass extinctions in the geologic record. [ABSTRACT FROM AUTHOR]

It is healthy to periodically question things that we have long taken for granted. Randomized clinical trials are the gold standard for evaluating the benefits and harms of interventions, though often fails to provide the practical evidence to inform medical decision-making. A primary reason is failure to recognize the most important questions for treating patients in clinical practice, and using this as the motivation for the design, monitoring, analysis, and reporting of clinical trials. Our most promising opportunity is placing increased interest on questions of a pragmatic origin to match their clinical importance. Improvements to traditional approaches are needed. Standard approaches synthesizing information obtained from separate marginal analysis of each outcome, fail to incorporate associations between outcomes and recognize the cumulative nature of outcomes in individual patients, suffer from competing risk complexities during interpretation of individual outcomes, and since efficacy and safety analyses are often conducted on different populations, generalizability is unclear. The utility of clinical trials can be enhanced by: (i) using outcomes to analyze patients rather than patients to analyze the outcomes, and (ii) incorporating benefit:risk evaluation into standard trial design and conduct, rather than conducted as a post-hoc exercise. Benefit: risk outcomes such as the desirability of outcome ranking (DOOR), can become a standard, prespecified along with efficacy and safety outcomes. Inclusion and analyses of such endpoints provide important information regarding the effects on patients, unable to be obtained by marginal analyses of efficacy and safety. Prespecified procedures to identify subgroups of patients with a positive benefit:risk profile will further advance clinical trial science. [ABSTRACT FROM AUTHOR]

The oldest evidence of motile complex benthic multicellular organisms is found in Ediacaran aged rocks. At Nilpena Ediacara National Park (NENP), South Australia, one of the most iconic of such organisms, Dickinsonia, are found in abundance, with over 500 individuals preserved across the site's 33 in situ, fossiliferous beds. These beds vary in mat type and maturity, community diversity and population size. Here, we investigate six beds using spatial point pattern analysis (SPPA) to compare Dickinsonia spatial distributions between populations. Five populations were best-fit to a completely spatially random pattern, with a single outlier (TC-MM3) exhibiting signs of environmental heterogeneity. When distributions were examined in relation to other taxa, no indication of spatial competition was detected. Univariate and bivariate spatial distributions imply that Dickinsonia was generally not impacted by competition with other taxa, meter-scale environmental heterogeneity, or other external factors. These patterns hold when analyses were split between populations of large and small individuals, and these two size cohorts had no measurable effect on each other's spatial distributions. Additionally, we find no indication of intraspecific competition for Dickinsonia or any change in the preferred resources or habitats with growth. These results suggest that the anactualistic environmental conditions produced by ubiquitous organic mats present across Ediacaran seafloors at NENP provided such abundant nutrients that Dickinsonia did not have to compete for resources at the meter scale. These results further inform community-scale dynamics of Earth's earliest complex ecosystem. • Dickinsonia • Abundant resources in the Ediacaran promoted random and independent distributions. • Ongoing research at Nilpena Ediacara National Park, South Australia. • Applied spatial point pattern analysis. • Motile organisms' interactions with Ediacaran ecosystems. [ABSTRACT FROM AUTHOR]

• Joint op(miza(on of energy and learning has poten(al to reduce carbon 30 %. • Entropy economy op(mized where, when, and how AI/ML models are created . • Less-Energy-Usage network (LEAN) minimizes deep network energy costs. • Kolmogorov structure func(on to achieve energy efficient, generalizable AI/ML models. • Kolmogorov learning cycle to explain the thermodynamic of machine learning. We augment the Kolmogorov Structure Function with energy cost and drive the concept of "Additive AI" where Machine Learning Models are created by traversing the Kolmogorov Structure function from low model complexity to high while seeking models achieving the Kolmogorov Minimum Sufficient Statistic with least energy cost. In this way, the intersection of Algorithmic Information Theory (AIT) with Machine Learning (ML) can enable optimization of the "Entropy Economy," where the precious resource of entropy flow is managed to jointly optimize computation, energy, and learning. In this paper we lay out the Kolmogorov Learning Cycle as a framework for this joint optimization and demonstrate the energy efficient machine learning algorithm Least Energy Usage Network (LEAN) as an example of how restraining complexity can reduce learning energy cost while maintaining performance. We motivate further directions for optimizing how AI models can be optimally learned and discuss additional opportunities to optimize where and when AI and machine learning models can be created to maximize learning while minimizing energy (and subsequently carbon costs) through the intersection of AIT and ML. [ABSTRACT FROM AUTHOR]

Aim: Cardiac transthyretin amyloidosis (ATTR) patients have high rates of atrial arrhythmias. We evaluated echocardiographic structural and functional left atrial (LA) parameters and correlated these with technetium-99m 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) bone scintigraphy tracer uptake within the LA in ATTR patients.Methods: ATTR patients (wild-type, hereditary and asymptomatic transthyretin [TTR] variant carriers) who had undergone 99mTc-DPD and transthoracic echocardiogram (TTE) were selected. Quantitative 99mTc-DPD uptake analysis and echocardiographic evaluation of LA structural and functional parameters was performed.Results: Forty (40) ATTR patients (wild-type n=17; hereditary ATTR and TTR variant carriers n=23; median age 68.8±22 years) were included. TTE parameters including indexed LA minimum (LAVmin) (r=0.66), and LA maximum volumes (LAVmax) (r=0.64), LA emptying fraction (LAEF) (r=-0.68), LA function index (LAFI) (r=-0.70) and reservoir strain (ƐR) (r=-0.70) (p<0.001 for all) demonstrated good correlation to LA tracer uptake. Normal LA volume (LAVmin and LAVmax) and function (LAEF, LAFI and ƐR) was observed in hereditary ATTR and TTR variant carriers without cardiac tracer uptake. The subgroup of ATTR patients with atrial fibrillation/flutter demonstrated increased LAVmin and LAVmax with further reduction in LA function (LAEF, LAFI and ƐR). Receiver operating characteristic curves demonstrated strong diagnostic accuracies for LA structural (LAVmin and LAVmax; area under the curve [AUC] of 0.83 and 0.84 respectively) and functional (LAEF, LAFI and ƐR; AUC 0.81, 0.88 and 0.85, respectively) parameters.Conclusion: Left atrial structural and functional parameters demonstrated good correlations with quantitative 99mTc-DPD tracer LA uptake. Echocardiography and 99mTc-DPD scintigraphy may have significant roles in identification and surveillance of ATTR patients likely to develop atrial arrhythmias. [ABSTRACT FROM AUTHOR]

There is an innate desire to conduct research faster and cheaper. The desire is magnified by todays' business and political pressures. Though understandable, such desires can be dangerous threatening our objectivity and ability to reason, resulting in studies with lower integrity, replicability, and applicability. Modern ideas include: conducting observational rather than randomized studies rationalized by the increasing access to real world data and the belief that modeling can replace randomization, using surrogate rather than clinical outcomes, using surrogate rather than clinical diseases, using PP (Per Protocol) analyses instead of ITT (Intention-to-Treat), using assumptions regarding treatment effects in place of data to estimate those effects, and using adaptive designs that promise efficiencies. These trends are often labeled as "innovation." But is this progress...or regress...a fancy way of lowering the usual evidentiary standard and introducing greater uncertainty? Is it time for a market correction for these "products" that are often presented with a degree of commercialism rather than scientific objectivity? Indeed, our traditional approaches are in need in improvements. Rather than compromising on scientific rigor, can we redirect our motivation to find BETTER answers to the most important questions for patients and clinicians? Though often misunderstood, one such movement is pragmatism, the concept of truly getting closer to understanding the effects of interventions as they are experienced by patients and the value of diagnostics in real world practice. I propose that we place increased interest on questions of a pragmatic origin to match their clinical importance and utility. I present ideas for more pragmatic assessments of the effects of interventions and the yield of diagnostics. [ABSTRACT FROM AUTHOR]

Many new cancer therapies target specific molecular subtypes. Methods for addressing the bias induced from augmenting the control-arm data in a randomized clinical trial with nonconcurrent data from patients that have received the control treatment outside the randomized trial have been proposed ([9]). There are obvious scenarios where the significance level could be relaxed, for example, in exploratory settings where confirmatory evidence is expected to come via future studies or in the context of serious diseases for which there is no proven effective treatment. Brown et al. ([10]) implemented an alternative strategy relaxing the statistical significance level to.15 in a trial evaluating treatments for newly diagnosed KMT2A-rearranged infant acute lymphoblastic leukemia. [Extracted from the article]

In December 2019, the Antibacterial Resistance Leadership Group (ARLG) was awarded funding for another 7-year cycle to support a clinical research network on antibacterial resistance. ARLG 2.0 has 3 overarching research priorities: infections caused by antibiotic-resistant (AR) gram-negative bacteria, infections caused by AR gram-positive bacteria, and diagnostic tests to optimize use of antibiotics. To support the next generation of AR researchers, the ARLG offers 3 mentoring opportunities: the ARLG Fellowship, Early Stage Investigator seed grants, and the Trialists in Training Program. The purpose of this article is to update the scientific community on the progress made in the original funding period and to encourage submission of clinical research that addresses 1 or more of the research priority areas of ARLG 2.0. [ABSTRACT FROM AUTHOR]

The Ediacara Biota preserves the oldest fossil evidence of abundant, complex metazoans. Despite their significance, assigning individual taxa to specific phylogenetic groups has proved problematic. To better understand these forms, we identify developmentally controlled characters in representative taxa from the Ediacaran White Sea assemblage and compare them with the regulatory tools underlying similar traits in modern organisms. This analysis demonstrates that the genetic pathways for multicellularity, axial polarity, musculature, and a nervous system were likely present in some of these early animals. Equally meaningful is the absence of evidence for major differentiation of macroscopic body units, including distinct organs, localized sensory machinery or appendages. Together these traits help to better constrain the phylogenetic position of several key Ediacara taxa and inform our views of early metazoan evolution. An apparent lack of heads with concentrated sensory machinery or ventral nerve cords in such taxa supports the hypothesis that these evolved independently in disparate bilaterian clades. [ABSTRACT FROM AUTHOR]

The article focuses on the updated Duke criteria for diagnosing infective endocarditis, comparing the 2000 and 2023 versions in terms of sensitivity, specificity and clinical decision-making regarding possible endocarditis cases. Topics include the criteria's evolution; validation studies comparing their performance; and strategies for optimizing clinical decisions based on sensitivity-specificity tradeoffs and prevalence of endocarditis pathogens.

Analysis of modern animals and Ediacaran trace fossils predicts that the oldest bilaterians were simple and small. Such organisms would be difficult to recognize in the fossil record, but should have been part of the Ediacara Biota, the earliest preserved macroscopic, complex animal communities. Here, we describe Ikaria wariootia gen. et sp. nov. from the Ediacara Member, South Australia, a small, simple organism with anterior/posterior differentiation. We find that the size and morphology of Ikaria match predictions for the progenitor of the trace fossil Helminthoidichnites—indicative of mobility and sediment displacement. In the Ediacara Member, Helminthoidichnites occurs stratigraphically below classic Ediacara body fossils. Together, these suggest that Ikaria represents one of the oldest total group bilaterians identified from South Australia, with little deviation from the characters predicted for their last common ancestor. Further, these trace fossils persist into the Phanerozoic, providing a critical link between Ediacaran and Cambrian animals. [ABSTRACT FROM AUTHOR]

We discuss using prediction as a flexible and practical approach for monitoring futility in clinical trials with two co-primary endpoints (CPE). This approach is appealing in that it provides quantitative evaluation of potential effect sizes and associated precision, and can be combined with flexible error-spending strategies. We extend prediction of effect size estimates and the construction of predicted intervals to the two CPE case, and illustrate interim futility monitoring of treatment effects using prediction with an example. We also discuss alternative approaches based on the conditional and predictive powers, compare these methods and provide some guidance on the use of prediction for better decision in clinical trials with CPE. [ABSTRACT FROM AUTHOR]

Data monitoring committees (DMCs), or data and safety monitoring boards, protect clinical trial participants by conducting benefit-risk assessments during the course of a clinical trial. These evaluations may be improved by broader access to data and more effective analyses and presentation. Data monitoring committees should have access to all data, including efficacy data, at each interim review. The DMC reports should include graphical presentations that summarize benefits and harms in efficient ways. Benefit-risk assessments should include summaries that are consistent with the intention-to-treat principle and have a pragmatic focus. This article provides examples of graphical summaries that integrate benefits and harms, and proposes that such summaries become standard in DMC reports. [ABSTRACT FROM AUTHOR]

Background: We attempted to resect peripheral chondrosarcoma of the pelvis with clear margins. Because of the proximity of vessels or organs, there is still concern that narrow surgical margins may have an adverse effect on disease outcomes. Although current guidelines recommend resection of histologic Grade II or Grade III chondrosarcomas with a "wide" margin, there are no specific recommendations for the adequate width of a surgical margin.Questions/purposes: (1) What is the disease-specific and local recurrence-free survival of patients with peripheral chondrosarcoma of the pelvis treated with resection or amputation? (2) Is the width of a surgical margin associated with the outcome of disease in patients with peripheral chondrosarcoma of the pelvis? (3) Does the histologic grade as determined with a preoperative biopsy correlate with the final grade after resection? (4) What are surgical complications in these patients?Methods: We retrospectively reviewed records from three international collaborating hospitals. Between 1983 and 2017, we resected 262 pelvic chondrosarcomas of all types. After reviewing the pathologic reports of these patients, we included 52 patients with peripheral chondrosarcomas of the pelvis who had an osteochondroma-like lesion at the base of the tumor and a cartilage cap with malignant cells in resected specimens. To be eligible for this study, a patient had to have a minimum of 1 year of follow-up. Two patients were excluded because they had less than 1 year of follow-up, leaving 50 patients for inclusion in this study. The median follow-up duration was 7.0 years (interquartile range 2.1-10 years). The median age was 37 years (IQR 29-54 years). The ilium was the most frequently affected bone (in 36 of 50 patients; 72%). The histologic status of the surgical margin was defined as microscopically positive (0 mm), negative < 1 mm, or negative ≥ 1 mm. Thirteen of the 50 patients (26%) had local recurrence. Seven of 34 patients had Grade I tumors, five of 13 had Grade II tumors, and one of three had a Grade III tumor. Nine of 16 patients had multiple local recurrences. Two patients with Grade I tumors and two with Grade II tumors died because of pressure effects caused by local recurrence.Results: The 10-year disease-specific and local recurrence-free survival rates were 90% (95% confidence interval, 70-97) and 69% (95% CI, 52-81), respectively. A surgical margin ≥ 1 mm (n = 16) was associated with a better local recurrence-free survival rate than a surgical margin < 1 mm (n = 17) or 0 mm (n = 11) (10-year local recurrence-free survival: resection margin ≥ 1 mm = 100% versus < 1 mm = 52% [95% CI, 31 to 70]; p = 0.008). No patients with a surgical margin ≥ 1 mm had local recurrence, metastasis, or disease-related death, irrespective of tumor grade. Patients with local recurrence (n = 13) showed worse disease-specific survival than those without local recurrence (n = 37) (10-year disease-specific survival: local recurrence [+] = 59% [95% CI, 16 to 86] versus local recurrence [-] = 100%; p=0.001]). The preoperative biopsy results correctly determined the tumor grade in 15 of 41 patients (37%). The most frequent complication after surgery was local recurrence (13 of 50 patients, 26%). Deep infection was the most frequent nononcologic complication (four patients).Conclusions: We found a high local recurrence rate after surgical treatment of a peripheral pelvic chondrosarcoma, which was related to the width of the surgical margin. These local recurrences led to inoperable recurrent tumors and death. The tumor grade as determined by preoperative biopsy was inaccurate in 2/3 of patients compared with the final histologic assessment. Therefore, we believe every attempt should be made to achieve a negative margin during the initial resection to lessen the likelihood of local recurrence of peripheral chondrosarcoma of the pelvis of all grades. A margin of 1 mm or more appeared to be sufficient in these patients.Level Of Evidence: Level III, therapeutic study. [ABSTRACT FROM AUTHOR]

Dickinsonia is one of the oldest macroscopic metazoans in the fossil record. Determining the biological characters of this extinct taxon is critical to our understanding of the early evolution of life. Preservation of abundant specimens from the Ediacara Member (Rawnsley Quartzite), South Australia, in a variety of taphonomic states allows the unparalleled opportunity to compare the biomechanical responses of Dickinsonia tissue to various forces with those typical of modern organisms. Dickinsonia are found as lifted, transported, folded, rolled, ripped, and expanded or contracted individuals, while maintaining diagnostic morphology. This suite of characters indicates that Dickinsonia was composed of material that was flexible, difficult to rip, and capable of elastic and plastic deformation. While none of these traits are diagnostic of a single biomaterial component, we find many similarities with modern biopolymers, particularly collagen, keratin, and elastin. Maintenance of significant relief following complete tearing suggests that Dickinsonia was composed of relatively thick tissues, signifying higher oxygen requirements than previously hypothesized. The ability to be transported and still be preserved as recognizable fossils is unique amongst the Ediacara Biota and demonstrates that Dickinsonia was a taphonomic elite. Combined with discovery in multiple environmental settings, this indicates that the absence of Dickinsonia represents the likely extinction of this organism prior to the Nama assemblage, possibly due to a decrease in the global availability of oxygen in the latest Ediacaran. [ABSTRACT FROM AUTHOR]

Mobility represents a key innovation in the evolution of complex animal life. The ability to move allows for the exploration of new food sources, escapes from unfavorable environmental conditions, enhanced ability to exchange genetic material, and is one of the major reasons for the diversity and success of animal life today. The oldest widely accepted trace fossils of animal mobility are found in Ediacaran‐aged rocks (635–539 Ma). The earliest definitive evidence for movement associated with exploitation of resources for feeding occurs in the White Sea assemblage of the Ediacara Biota—macroscopic, soft‐bodied fossils of Ediacaran age. Here, we evaluate potential support for mobility in dickinsoniomorphs, presenting new data regarding abundant Dickinsonia and associated trace fossils from the Ediacara Member, South Australia. Results quantitatively demonstrate that Dickinsonia was capable of mobility on relatively short, ecological timescales. This organism was bilaterally symmetrical, likely moved via muscular peristalsis, and left trace fossils due to active removal of the organic mat related to feeding. Analogous structures associated with Yorgia indicate that it was also mobile and fed in a similar manner. Morphological evidence suggests that two other modular taxa, Andiva and Spriggina, were able to move but did not feed in a manner that impacted the organic mat. Together, these data suggest that mobility was present in multiple disparate bilaterally symmetrical Ediacaran taxa. [ABSTRACT FROM AUTHOR]