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Ribosome structure and activity are challenged at high temperatures, often demanding modifications to ribosomal RNAs (rRNAs) to retain translation fidelity. LC-MS/MS, bisulfite-sequencing, and high-resolution cryo-EM structures of the archaeal ribosome identified an RNA modification, N4,N4-dimethylcytidine (m42C), at the universally conserved C918 in the 16S rRNA helix 31 loop. Here, we characterize and structurally resolve a class of RNA methyltransferase that generates m4 2C whose function is critical for hyperthermophilic growth. m42C is synthesized by the activity of a unique family of RNA methyltransferase containing a Rossman-fold that targets only intact ribosomes. The phylogenetic distribution of the newly identified m42C synthase family implies that m42C is biologically relevant in each domain. Resistance of m42C to bisulfite-driven deamination suggests that efforts to capture m5C profiles via bisulfite sequencing are also capturing m42C. [ABSTRACT FROM AUTHOR]

PCAB (prednisone, cyclophosphamide, doxorubicin, carmustine) is a single‐day regimen previously used for induction and now in relapsed/refractory multiple myeloma (RRMM). We retrospectively analysed the outcomes of 85 patients from five Australian centres. These included 30 patients (35.3%) who received PCAB with one additional agent (bortezomib most frequently). Median age of the patients was 65 years (37–80), with a median of four (1–8) prior lines of therapy. ORR was 37% (CR 4.9%). Median progression free survival and overall survival were 4.4 months (95% CI 3.5–6.7) and 7.4 months (95% CI 6.4–10.2), respectively. Extramedullary disease (EMD) was associated with shorter survival. Grade 3 or 4 cytopenia and febrile neutropenia occurred in 76.2% and 39.1%, respectively, with six (7.1%) treatment‐related mortalities. Median inpatient stay was 3.3 days/28‐day cycle (IQR 0.6–13), and for patients who died, a median of 20.2% of days alive were spent inpatient (IQR 6.4–39.1%). Three patients were successfully bridged to CAR T‐cell therapy using PCAB, despite being penta‐exposed and having EMD. PCAB may be considered as a useful salvage therapy amongst other polychemotherapy regimens in late relapse. Further studies is warranted to investigate and define its role as a bridging therapy to novel therapeutics. [ABSTRACT FROM AUTHOR]

Summary: A decade after International Myeloma Working Group (IMWG) biomarkers (SLiM criteria) were introduced, this real‐world study examined their impact on diagnosis, therapy and outcomes in myeloma. Using the ANZ MRDR, 3489 newly diagnosed patients from 2013 to 2023, comprising 3232 diagnosed by CRAB ('CRAB patients', including 1758 who also satisfied ≥1 SLiM criteria) and 257 by SLiM ('SLiM patients') criteria were analysed. CRAB patients had higher R‐ISS and lower performance status, with no difference in cytogenetic risk. SLiM patients had improved progression‐free survival (PFS, 37.5 vs. 32.2 months, hazard ratio [HR] 1.31 [1.08–1.59], p = 0.003), overall survival (80.9 vs. 73.2 months, HR 1.64 [1.26–2.13], p < 0.001) and PFS2 (54.6 vs. 40.3 months, HR 1.51 [1.22–1.86], p < 0.001) compared with CRAB patients, partially explained by earlier diagnosis, with no differential impact between the plasma cell and light‐chain criteria on PFS. However, 34% of CRAB patients did not manifest SLiM characteristics, raising the possibility that SLiM features are associated with different biological behaviours contributing to a better prognosis, for example, improved PFS2 in SLiM patients suggested less disease resistance at first relapse. These data support earlier initiation of therapy by SLiM. The superior survival outcomes of SLiM versus CRAB patients highlight the importance of defining these subgroups when interpreting therapeutic outcomes at induction and first relapse. [ABSTRACT FROM AUTHOR]

Context. Investigating the flow of material along filamentary structures towards the central core can help provide insights into high-mass star formation and evolution. Aims. Our main motivation is to answer the question of what the properties of accretion flows are in star-forming clusters. We used data from the ALMA Evolutionary Study of High Mass Protocluster Formation in the Galaxy (ALMAGAL) survey to study 100 ALMAGAL regions at a ∼1″ resolution, located between ∼2 and 6 kpc. Methods. Making use of the ALMAGAL ∼1.3 mm line and continuum data, we estimated flow rates onto individual cores. We focus specifically on flow rates along filamentary structures associated with these cores. Our primary analysis is centered around position velocity cuts in H2CO (30, 3–20, 2), which allow us to measure the velocity fields surrounding these cores. Combining this work with column density estimates, we were able to derive the flow rates along the extended filamentary structures associated with cores in these regions. Results. We selected a sample of 100 ALMAGAL regions, covering four evolutionary stages from quiescent to protostellar, young stellar objects (YSOs), and HII regions (25 each). Using a dendrogram and line analysis, we identify a final sample of 182 cores in 87 regions. In this paper, we present 728 flow rates for our sample (4 per core), analysed in the context of evolutionary stage, distance from the core, and core mass. On average, for the whole sample, we derived flow rates on the order of ∼10−4 M⊙ yr−1 with estimated uncertainties of ±50%. We see increasing differences in the values among evolutionary stages, most notably between the less evolved (quiescent and protostellar) and more evolved (YSO and HII region) sources and we also see an increasing trend as we move further away from the centre of these cores. We also find a clear relationship between the calculated flow rates and core masses ∼M2/3, which is in line with the result expected from the tidal-lobe accretion mechanism. The significance of these relationships is tested with Kolmogorov–Smirnov and Mann-Whitney U tests. Conclusions. Overall, we see an increasing trend in the relationships between the flow rate and the three investigated parameters, namely: evolutionary stage, distance from the core, and core mass. [ABSTRACT FROM AUTHOR]

Background: Sickle cell disease (SCD) is the most common monogenic disorder worldwide. In deoxygenated conditions, the altered beta chain (haemoglobin S [HbS]) polymerises and distorts the erythrocyte, resulting in pain crises, vasculopathy and end‐organ damage. Clinical complications of SCD cause substantial morbidity, and therapy demands expertise and resources. Optimising care for patients and planning resource allocation for the future requires an understanding of the disease in the Australian population. The Australian Haemoglobinopathy Registry (HbR) is a collaborative initiative of specialist centres collating and analysing data on patients with haemoglobin disorders. Aims: To provide a snapshot of SCD in Australia over a 12‐month period based on data from the HbR. Methods: Patients with a clinically significant sickling disorder across 12 clinical sites were included for analysis. Data include demographic and diagnostic details, as well as details of the clinical management of the condition over a 12‐month period. Results: Data on 359 SCD patients demonstrate a shift in the demographic of patients in Australia, with a growing proportion of sub‐Saharan African ethnicities associated with the HbSS genotype. Acute and chronic complications are common, and patients require significant outpatient and inpatient support. Prevalence of disease complications and therapeutic trends are in keeping with other high‐income countries. Conclusions: This study provides the first national picture of SCD in Australia, describing the characteristics and needs of SCD patients, elucidating demand for current and novel therapy and facilitating the planning of services for this vulnerable population. [ABSTRACT FROM AUTHOR]

Background: In the last few decades, the life expectancy of patients with transfusion‐dependent thalassaemia (TDT) and sickle cell disease (SCD) has improved significantly, in part because of improved iron chelation. Fertility challenges and pregnancy complications have historically limited reproductive options in this group; however, improved multi‐disciplinary care has made infertility a chronic disease complication requiring attention. Despite this, there are very few reports and no Australian data describing fertility and pregnancy outcomes in this population. Aims: To identify the rate of assisted reproductive technologies (ART) utilisation in our female transfusion‐dependent haemoglobinopathy patients and to establish the nature of maternal and neonatal complications in this cohort. Methods: A 20‐year retrospective analysis (1997–2017) at an Australian centre captured data on conception rates, use of assisted reproductive techniques (ART), and pregnancy and neonatal outcomes in female transfusion‐dependent haemoglobinopathy patients. Results: Conception was attempted in 14 women (11 TDT and three SCD) during the study period. A total of 28 pregnancies resulting in 25 live births were recorded. ART supported 13 conceptions. A positive association was not identified between elevated mean serum ferritin and ART use; however, all patients with an established diagnosis of hypogonadotropic hypogonadism (HH) required ART. Maternal complications included gestational diabetes mellitus and post‐partum haemorrhage. There were no cardiac complications. Two‐thirds of women underwent lower segment caesarean section, with prematurity complicating 20% of births. There were no neonatal or maternal deaths. Conclusion: Pregnancy is an achievable goal for women with transfusion‐dependent haemoglobinopathies, although the support of ART may be required in a subset of patients. [ABSTRACT FROM AUTHOR]

Background: Information and communication technologies (ICTs) improve quality and efficiency of healthcare, but effective practices for implementing new ICTs are unknown. From 2019 to 2021, the Veterans Health Administration (VHA) implemented FLOW3, an ICT that facilitates prosthetic limb care. The goal of this study was to compare the impact of two facilitation strategies on FLOW3 adoption, implementation, and sustainment. Methods: FLOW3 is a computerized workflow management system comprised of three applications that facilitate the three steps for prosthesis authorization. During VHA's implementation of FLOW3, we randomized 60 VHA sites to basic or enhanced facilitation groups. Basic facilitation included a manualized training toolkit and office hours. Enhanced facilitation included basic facilitation plus monthly learning collaboratives and site-specific performance reports. Outcomes included time to adoption of FLOW3 and complete FLOW3 utilization rates during implementation and sustainment periods. We compared outcomes between sites assigned to basic versus enhanced facilitation groups. Results were calculated using both intent-to-treat (ITT) and dose–response analyses. The dose–response analysis used a per-protocol approach and required sites in the enhanced facilitation group to join two of six learning collaboratives; sites that attended fewer were reassigned to the basic group. Results: Randomization assigned 30 sites to enhanced facilitation and 30 to basic. Eighteen of 30 randomized sites were included in the enhanced facilitation group for dose–response analysis. During the implementation period, enhanced facilitation sites were significantly more likely to completely utilize FLOW3 than basic facilitation sites (HR: 0.17; 95% CI: 1.18, 4.53, p = 0.02) based on ITT analysis. In the dose–response analysis, the enhanced group was 2.32 (95% CI: 1.18, 4.53) times more likely to adopt FLOW3 than basic group (p = 0.014). Conclusions: Enhanced facilitation including a learning collaborative and customized feedback demonstrated greater likelihood for sites to complete a prosthetics consult using FLOW3 throughout our study. We identified statistically significant differences in likelihood of adoption using the dose–response analysis and complete utilization rate using ITT analysis during the implementation period. All sites that implemented FLOW3 demonstrated improvement in completion rate during the sustainment period, but the difference between facilitation groups was not statistically significant. Further study to understand sustainability is warranted. [ABSTRACT FROM AUTHOR]

Adherence to anti-platelet medications is critical following coronary stenting, but prior studies indicate that clinician assessment and patient self-assessment of adherence are poorly correlated with future medication-taking behavior. We therefore sought to determine if integrated pharmacy data can be used to identify patients at high risk of non-adherence after percutaneous coronary interventions (PCI).Methods: Using Veteran Affairs (VA) Clinical Assessment, Reporting, and Tracking (CART) data linked with pharmacy records, we assessed adherence to cardiovascular medications from 2012 to 2018. Adherence was defined as the proportion of days covered (PDC) ≥ 0.80. We assessed the association of pre-PCI adherence with post-PCI adherence to P2Y12 inhibitors and clinical outcomes using logistic regression and Cox proportional hazard models, respectively.Results: Among 56,357 patients, 66.0% filled at least 1 cardiovascular medication within VA for the year prior to PCI and were evaluable for adherence. Pre-PCI non-adherence was 20.7%, and non-adherent patients were more likely to be younger and present non-electively. Non-adherent patients were less likely to adhere to P2Y12 inhibitor therapy after PCI (Adjusted OR 0.45 C.I. 0.41– 0.46), compared with adherent patients, and had a higher adjusted risk of mortality (HR 1.17 C.I. 1.03– 1.33).Conclusion: Adherence to cardiovascular medications prior to PCI can be assessed for most patients using pharmacy data, and past adherence is associated with future adherence and mortality after PCI. Use of integrated pharmacy data to identify high-risk patients could improve outcomes and cost-effectiveness of adherence interventions.Plain Language Summary: Why was the study done?: Non-adherence to anti-platelet medications is common following coronary stenting procedures and is associated with worse outcomes, but predicting non-adherence is challenging.What did the researchers do and find?: The researchers examined pharmacy fill-based adherence assessments before and after stenting procedures. Pharmacy data can provide adherence estimates for most patients receiving percutaneous coronary intervention, and these estimates are associated with downstream medication-taking behavior and clinical outcomes.What do the results mean?: Health systems should seek to integrate pharmacy-based adherence estimates into routine care for patients with cardiovascular disease. Identification and targeting of patients at high-risk for non-adherence may improve the impact and cost-effectiveness of future research and health policy interventions aimed at improving adherence. [ABSTRACT FROM AUTHOR]

Embedded pragmatic clinical trials (ePCTs) play a vital role in addressing current population health problems, and their use of electronic health record (EHR) systems promises efficiencies that will increase the speed and volume of relevant and generalizable research. However, as the number of ePCTs using EHR-derived data grows, so does the risk that research will become more vulnerable to biases due to differences in data capture and access to care for different subsets of the population, thereby propagating inequities in health and the healthcare system. We identify 3 challenges—incomplete and variable capture of data on social determinants of health, lack of representation of vulnerable populations that do not access or receive treatment, and data loss due to variable use of technology—that exacerbate bias when working with EHR data and offer recommendations and examples of ways to actively mitigate bias. [ABSTRACT FROM AUTHOR]

Using observations with e-MERLIN and the Karl G. Jansky Very Large Array (VLA), together with archival data from the Atacama Large Millimeter/submillimeter Array (ALMA), we obtain high-resolution radio images of two binary YSOs: L1551 IRS 5 and L1551 NE, covering a wide range of frequencies from 5 to 336 GHz, and resolving emission from the radio jet on scales of only ∼15 au. By comparing these observations to those from a previous epoch, it is shown that there is a high degree of variability in the free-free emission from the jets of these sources. In particular, the northern component of L1551 IRS 5 shows a remarkable decline in flux density of a factor of ∼5, suggesting that the free-free emission of this source has almost disappeared. By fitting the spectra of the sources, the ionised mass-loss rates of the jets were derived and it was shown that there is significant variability of up to a factor of ∼6 on timescales of ∼20 years. Using radiative transfer modelling, we also obtained a model image for the jet of the southern component of L1551 IRS 5 to help study the inner region of the ionised high-density jet. The findings favour the X-wind model launched from a very small innermost region. [ABSTRACT FROM AUTHOR]

Background/Objective: The Veterans Health Administration (VHA) has prioritized timely access to care and has invested substantially in research aimed at optimizing veteran access. However, implementing research into practice remains challenging. Here, we assessed the implementation status of recent VHA access-related research projects and explored factors associated with successful implementation. Design: We conducted a portfolio review of recent VHA-funded or supported projects (1/2015–7/2020) focused on healthcare access ("Access Portfolio"). We then identified projects with implementable research deliverables by excluding those that (1) were non-research/operational projects; (2) were only recently completed (i.e., completed on or after 1/1/2020, meaning that they were unlikely to have had time to be implemented); and (3) did not propose an implementable deliverable. An electronic survey assessed each project's implementation status and elicited barriers/facilitators to implementing deliverables. Results were analyzed using novel Coincidence Analysis (CNA) methods. Participants/Key Results: Among 286 Access Portfolio projects, 36 projects led by 32 investigators across 20 VHA facilities were included. Twenty-nine respondents completed the survey for 32 projects (response rate = 88.9%). Twenty-eight percent of projects reported fully implementing project deliverables, 34% reported partially implementing deliverables, and 37% reported not implementing any deliverables (i.e., resulting tool/intervention not implemented into practice). Of 14 possible barriers/facilitators assessed in the survey, two were identified through CNA as "difference-makers" to partial or full implementation of project deliverables: (1) engagement with national VHA operational leadership; (2) support and commitment from local site operational leadership. Conclusions: These findings empirically highlight the importance of operational leadership engagement for successful implementation of research deliverables. Efforts to strengthen communication and engagement between the research community and VHA local/national operational leaders should be expanded to ensure VHA's investment in research leads to meaningful improvements in veterans' care. Lay Summary: The Veterans Health Administration (VHA) has prioritized timely access to care and has invested substantially in research aimed at optimizing veteran access. However, implementing research findings into clinical practice remains challenging, both within and outside VHA. Here, we assessed the implementation status of recent VHA access-related research projects and explored factors associated with successful implementation. Only two factors were identified as "difference-makers" to adoption of project findings into practice: (1) engagement with national VHA leadership or (2) support and commitment from local site leadership. These findings highlight the importance of leadership engagement for successful implementation of research findings. Efforts to strengthen communication and engagement between the research community and VHA local/national leaders should be expanded to ensure VHA's investment in research leads to meaningful improvements in veterans' care. [ABSTRACT FROM AUTHOR]

Keywords: bioinformatics; hemoglobinopathy; inherited anaemia; molecular genetics; next-generation sequencing; whole exome sequencing EN bioinformatics hemoglobinopathy inherited anaemia molecular genetics next-generation sequencing whole exome sequencing 161 164 4 06/09/23 20230701 NES 230701 Novelty statements What is new aspect of your work? This is the first reported case describing the clinical and laboratory features of a patient with co-inherited heterozygous haemoglobin Lepore and a congenital dyserythropoietic anaemia. Alkaline and acid haemoglobin electrophoresis revealed abnormal bands consistent with haemoglobin Lepore. [Extracted from the article]

Background: Blood transfusions can serve as a life-saving treatment, but inappropriate blood product transfusions can result in patient harm and excess costs for health systems. Despite published evidence supporting restricted packed red blood cell (pRBC) usage, many providers transfuse outside of guidelines. Here, we report a novel prospective, randomized control trial to increase guideline-concordant pRBC transfusions comparing three variations of clinical decision support (CDS) in the electronic health record (EHR). Methods: All inpatient providers at University of Colorado Hospital (UCH) who order blood transfusions were randomized in a 1:1:1 fashion to the three arms of the study: (1) general order set improvements, (2) general order set improvements plus non-interruptive in-line help text alert, and (3) general order set improvements plus interruptive alert. Transfusing providers received the same randomized order set changes for 18 months. The primary outcome of this study is the guideline-concordant rate of pRBC transfusions. The primary objective of this study is to compare the group using the new interface (arm 1) versus the two groups using the new interface with interruptive or non-interruptive alerts (arms 2 and 3, combined). The secondary objectives compare guideline-concordant transfusion rates between arm 2 and arm 3 as well as comparing all of arms of the study in aggregate to historical controls. This trial concluded after 12 months on April 5, 2022. Discussion: CDS tools can increase guideline-concordant behavior. This trial will examine three different CDS tools to determine which type is most effective at increasing guideline-concordant blood transfusions. Trial registration: Registered on ClinicalTrials.gov 3/20/21, NCT04823273. Approved by University of Colorado Institutional Review Board (19–0918), protocol version 1 4/19/2019, approved 4/30/2019. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a disease of older people, yet factors relating to comorbidity and frailty may threaten treatment tolerability for many of this heterogenous group. There has been increasing interest in defining specific and clinically relevant frailty assessment tools within the MM population, with the goal of using these frailty scores, not just as a prognostic instrument, but also as a predictive tool to allow for a frailty‐adapted treatment approach. This paper reviews the various frailty assessment frameworks used in the evaluation of patients with MM, including the International Myeloma Working Group Frailty Index (IMWG‐FI), the Mayo Frailty Index and the simplified frailty scale. While the IMWG‐FI remains the most widely accepted tool, the simplified frailty scale is the most user‐friendly in busy day‐to‐day clinics based on its ease of use. This paper summarises the recommendations from the Myeloma Scientific Advisory Group (MSAG) of Myeloma Australia, on the use of frailty assessment tools in clinical practice and proposes a frailty‐stratified treatment algorithm to aid clinicians in tailoring therapy for this highly heterogeneous patient population. [ABSTRACT FROM AUTHOR]

The structures and associated functions of biological molecules are driven by noncovalent interactions, which have classically been dominated by the hydrogen bond (H‐bond). Introduction of the σ‐hole concept to describe the anisotropic distribution of electrostatic potential of covalently bonded elements from across the periodic table has opened a broad range of nonclassical noncovalent (ncNC) interactions for applications in chemistry and biochemistry. Here, we review how halogen bonds, chalcogen bonds and tetrel bonds, as they are found naturally or introduced synthetically, affect the structures, assemblies, and potential functions of peptides and proteins. This review intentionally focuses on examples that introduce or support principles of stability, assembly and catalysis that can potentially guide the design of new functional proteins. These three types of ncNC interactions have energies that are comparable to the H‐bond and, therefore, are now significant concepts in molecular recognition and design. However, the recently described H‐bond enhanced X‐bond shows how synergism among ncNC interactions can be exploited as potential means to broaden the range of their applications to affect protein structures and functions. [ABSTRACT FROM AUTHOR]

The article discusses the integration of physical therapy (PT) into emergency departments (ED) to benefit patients' health. Topics include use of PT in the ED has been established has been adopted in the U.S.; and the efficacy of ED-based PT intervention, especially for older adults with musculoskeletal injuries, pain management, functional deficits, gait disturbances, and vestibular management.

Rationale: In patients with pneumonia requiring intensive care unit (ICU) admission, alcohol misuse is associated with increased mortality, but the relationship between other commonly misused substances and mortality is unknown. Objectives: We sought to establish whether alcohol misuse, cannabis misuse, opioid misuse, stimulant misuse, or misuse of more than one of these substances was associated with differences in mortality among ICU patients with pneumonia. Methods: This was a retrospective cohort study of hospitals participating in the Premier Healthcare Database between 2010 and 2017. Patients were included if they had a primary or secondary diagnosis of pneumonia and received antibiotics or antivirals within 1 day of admission. Substance misuse related to alcohol, cannabis, stimulants, and opioids, or more than one substance, were identified from the International Classification of Diseases (Ninth and Tenth Editions). The associations between substance misuse and in-hospital mortality were the primary outcomes of interest. Secondary outcomes included the measured associations between substance misuse disorders and mechanical ventilation, as well as vasopressor and continuous paralytic administration. Analyses were conducted with multivariable mixed-effects logistic regression modeling adjusting for age, comorbidities, and hospital characteristics. Results: A total of 167,095 ICU patients met inclusion criteria for pneumonia. Misuse of alcohol was present in 5.0%, cannabis misuse in 0.6%, opioid misuse in 1.5%, stimulant misuse in 0.6%, and misuse of more than one substance in 1.2%. No evidence of substance misuse was found in 91.1% of patients. In unadjusted analyses, alcohol misuse was associated with increased in-hospital mortality (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.06–1.19), whereas opioid misuse was associated with decreased in-hospital mortality (OR, 0.46; 95% CI, 0.39–0.53) compared with no substance misuse. These findings persisted in adjusted analyses. Although cannabis, stimulant, and more than one substance misuse (a majority of which were alcohol in combination with another substance) were associated with lower odds for in-hospital mortality in unadjusted analyses, these relationships were not consistently present after adjustment. Conclusions: In this study of ICU patients hospitalized with severe pneumonia, substance misuse subtypes were associated with different effects on mortality. Although administrative data can provide epidemiologic insight regarding substance misuse and pneumonia outcomes, biases inherent to these data should be considered when interpreting results. [ABSTRACT FROM AUTHOR]

(C, D) Patient OS and PFS according to the R2ISS scoring in the R-ISS II cohort only. Keywords: cancer cytogenetics; myeloma; prognostic factors EN cancer cytogenetics myeloma prognostic factors e17 e21 5 01/16/23 20230115 NES 230115 To evaluate the performance of the second revision of the International Staging System 2 (R2ISS)[1] in a real-world cohort, we applied the scoring system to patients with newly-diagnosed multiple myeloma (NDMM) in the Myeloma and Related Diseases Registry (MRDR). The second revision of the International Staging System (R2-ISS) stratifies progression-free and overall survival in multiple myeloma: Real world data results in an Australian and New Zealand Population. [Extracted from the article]

Objectives: While chest radiograph (CXR) is the first-line imaging investigation in patients with respiratory symptoms, differentiating COVID-19 from other respiratory infections on CXR remains challenging. We developed and validated an AI system for COVID-19 detection on presenting CXR. Methods: A deep learning model (RadGenX), trained on 168,850 CXRs, was validated on a large international test set of presenting CXRs of symptomatic patients from 9 study sites (US, Italy, and Hong Kong SAR) and 2 public datasets from the US and Europe. Performance was measured by area under the receiver operator characteristic curve (AUC). Bootstrapped simulations were performed to assess performance across a range of potential COVID-19 disease prevalence values (3.33 to 33.3%). Comparison against international radiologists was performed on an independent test set of 852 cases. Results: RadGenX achieved an AUC of 0.89 on 4-fold cross-validation and an AUC of 0.79 (95%CI 0.78–0.80) on an independent test cohort of 5,894 patients. Delong's test showed statistical differences in model performance across patients from different regions (p < 0.01), disease severity (p < 0.001), gender (p < 0.001), and age (p = 0.03). Prevalence simulations showed the negative predictive value increases from 86.1% at 33.3% prevalence, to greater than 98.5% at any prevalence below 4.5%. Compared with radiologists, McNemar's test showed the model has higher sensitivity (p < 0.001) but lower specificity (p < 0.001). Conclusion: An AI model that predicts COVID-19 infection on CXR in symptomatic patients was validated on a large international cohort providing valuable context on testing and performance expectations for AI systems that perform COVID-19 prediction on CXR. Key Points: • An AI model developed using CXRs to detect COVID-19 was validated in a large multi-center cohort of 5,894 patients from 9 prospectively recruited sites and 2 public datasets. • Differences in AI model performance were seen across region, disease severity, gender, and age. • Prevalence simulations on the international test set demonstrate the model's NPV is greater than 98.5% at any prevalence below 4.5%. [ABSTRACT FROM AUTHOR]

Background: Asthma exacerbations with respiratory failure (AERF) are associated with hospital mortality of 7% to 15%. Extracorporeal membrane oxygenation (ECMO) has been used as salvage therapy for refractory AERF, but controlled studies showing its association with mortality have not been performed.Research Question: Is treatment with ECMO associated with lower mortality in refractory AERF compared with standard care?Study Design and Methods: This is a retrospective, epidemiologic, observational cohort study using a national, administrative data set from 2010 to 2020 that includes 25% of US hospitalizations. People were included if they were admitted to an ECMO-capable hospital with an asthma exacerbation, and were treated with short-acting bronchodilators, systemic corticosteroids, and invasive ventilation. People were excluded for age < 18 years, no ICU stay, nonasthma chronic lung disease, COVID-19, or multiple admissions. The main exposure was ECMO vs No ECMO. The primary outcome was hospital mortality. Key secondary outcomes were ICU length of stay (LOS), hospital LOS, time receiving invasive ventilation, and total hospital costs.Results: The study analyzed 13,714 patients with AERF, including 127 with ECMO and 13,587 with No ECMO. ECMO was associated with reduced mortality in the covariate-adjusted (OR, 0.33; 95% CI, 0.17-0.64; P = .001), propensity score-adjusted (OR, 0.36; 95% CI, 0.16-0.81; P = .01), and propensity score-matched models (OR, 0.48; 95% CI, 0.24-0.98; P = .04) vs No ECMO. Sensitivity analyses showed that mortality reduction related to ECMO ranged from OR 0.34 to 0.61. ECMO was also associated with increased hospital costs in all three models (P < .0001 for all) vs No ECMO, but not with decreased ICU LOS, hospital LOS, or time receiving invasive ventilation.Interpretation: ECMO was associated with lower mortality and higher hospital costs, suggesting that it may be an important salvage therapy for refractory AERF following confirmatory clinical trials. [ABSTRACT FROM AUTHOR]

Summary: The frequency and causes of early mortality in patients with newly diagnosed multiple myeloma (NDMM) have not been well described in the era of novel agents. We investigated early mortality in a prospective cohort study of all patients with NDMM registered on the Australian and New Zealand Myeloma and Related Diseases Registry (MRDR) at 36 institutions between July 2011 and March 2020. Early mortality was defined as death from any cause within the first 12 months after diagnosis. A total of 2377 patients with NDMM were included in the analysis, with a median (interquartile range) age of 67.4 (58.9–74.60 years, and 60% were male. Overall, 216 (9.1%) patients died within 12 months, with 119 (4.5%) having died within 6 months. Variables that were independent predictors of early mortality after adjustment in multivariable regression included age (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.05–1.08; p < 0.001), Eastern Cooperative Oncology Group performance status (OR 1.50, 95% CI 1.26–1.79; p < 0.001), serum albumin (OR 0.95, 95% CI 0.93–0.98; p < 0.001), cardiac disease (OR 1.96, 95% CI 1.35–2.86; p < 0.001) and International Staging System (OR 1.40, 95% CI 1.07–1.82; p = 0.01). For those with a primary cause of death available, it was reported as disease‐related in 151 (78%), infection 13 (7%), other 29 (15%). Infection was listed as a contributing factor for death in 38% of patients. [ABSTRACT FROM AUTHOR]

Background: The Veterans Access Research Consortium (VARC), a Department of Veterans Affairs (VA) Consortium of Research focused on access to healthcare, has been funded by VA's Health Services Research and Development Service (HSR&D) to develop a research roadmap for healthcare access. The goal of the roadmap is to identify operationally aligned research questions that are most likely to lead to meaningful improvements in Veterans' healthcare access. Objectives: To describe the process of soliciting diverse stakeholder perspectives about key priorities on which VA's HSR&D access agenda should focus and identify the results of that process. Methods: We used a modified Delphi approach to engage researchers and VA operational partners in a process to develop recommendations regarding the access-related research questions VA should prioritize. We then collaborated with three Veteran Engagement Groups (VEGs) across the country to solicit Veterans' reactions to the Delphi results and their perspectives about access-related issues affecting access to VA health care. Results: The Delphi panel consisted of 22 research and operational experts, both internal and external to VA. The Delphi process resulted in five research questions identified by the panelists as highest priority for VA to pursue, each representing one of the following domains: (1) measurement of access, (2) barriers to access, (3) equity and subpopulations, (4) effective interventions to improve access, and (5) consequences of poor/better access. Veterans' perspectives focused primarily on the barriers to access domain. Veterans indicated several barriers that might be addressed through research or operational initiatives, including poor communication about services, weak connections to and partnerships with local community care facilities, and poor provision of telehealth resources and education. Conclusions: Engaging multiple methods to solicit stakeholder perspectives enables more nuanced understanding of access-related priorities for VA. Future research should consider utilizing such an approach to identify additional research and/or operational priorities. [ABSTRACT FROM AUTHOR]

Insights into the mechanisms of protein homeostasis and proteasomal degradation have led to new strategies of redirecting the ubiquitin–proteasome system (UPS) to reduce or eliminate proteins or survival factors key to malignant pathobiology, multiple myeloma (MM) in particular. These strategies have enabled researchers to target proteins that were previously considered difficult to modulate by pharmacological means. This review provides a brief overview of UPS biology, particularly the role of the CRL4CRBN E3 ubiquitin ligase complex, and summarizes current strategies for co-opting the UPS, including CELMoD compounds, SNIPERs, PROTACs, and degronimids. A detailed discussion is provided on lead CELMoD compounds iberdomide and mezigdomide, which are currently being evaluated in clinical trials in patients with MM. Since a high proportion of patients develop drug resistance, it is vital to have novel therapeutic agents for treating relapsed patients with MM more effectively. It is encouraging that the expanding pathophysiological insight into cellular signaling pathways in MM increasingly translates into the development of novel therapeutic agents such as targeted protein degraders. This holds promise for improving outcomes in MM and beyond. [ABSTRACT FROM AUTHOR]

The preparation of thin ferromagnetic films with thermally stable properties in the high frequency gigahertz range is crucial for applications in different advanced devices. However, it is a challenge to attain such films as the mechanism and correlation between the crystallographic structure and dynamic magnetic properties remain unclear. Herein, through an appropriate annealing process involving a temperature of 510-580K and an applied strong magnetic field of 10 kOe along the easy-axis of electrodeposited FeCo films, magnetic properties of the films (300-450 nm) in the gigahertz range are significantly improved. Typically, the magnetic soft nanofilms display highly stable dynamic microwave properties from room temperature to 420 K, even in the presence of a high frequency of ∼1.5 GHz and a large magnetic permeability of ∼460 (the maximum value in real part). The origin of the high thermal stability is attributed to the recrystallized uniformity in crystalline orientations and larger particle sizes after the annealing, which leads to slightly increased anisotropy, stress, Curie temperature, and difference in the magnetic coercivity between the easy and hard axes for the crystalline films, thus giving rise to the steady static magnetic properties (e.g., magnetic moment of 2.02-2.05 T) against environmental temperature fluctuation. This is in contrast to conventional as-prepared thin films without annealing or annealed in a transverse applied field. This method can be applied to other ferromagnetic films to improve their thermal stability for the utilization in various high frequency devices. [ABSTRACT FROM AUTHOR]

Objective: We identified challenges and solutions to using electronic health record (EHR) systems for the design and conduct of pragmatic research.Materials and Methods: Since 2012, the Health Care Systems Research Collaboratory has served as the resource coordinating center for 21 pragmatic clinical trial demonstration projects. The EHR Core working group invited these demonstration projects to complete a written semistructured survey and used an inductive approach to review responses and identify EHR-related challenges and suggested EHR enhancements.Results: We received survey responses from 20 projects and identified 21 challenges that fell into 6 broad themes: (1) inadequate collection of patient-reported outcome data, (2) lack of structured data collection, (3) data standardization, (4) resources to support customization of EHRs, (5) difficulties aggregating data across sites, and (6) accessing EHR data.Discussion: Based on these findings, we formulated 6 prerequisites for PCTs that would enable the conduct of pragmatic research: (1) integrate the collection of patient-centered data into EHR systems, (2) facilitate structured research data collection by leveraging standard EHR functions, usable interfaces, and standard workflows, (3) support the creation of high-quality research data by using standards, (4) ensure adequate IT staff to support embedded research, (5) create aggregate, multidata type resources for multisite trials, and (6) create re-usable and automated queries.Conclusion: We are hopeful our collection of specific EHR challenges and research needs will drive health system leaders, policymakers, and EHR designers to support these suggestions to improve our national capacity for generating real-world evidence. [ABSTRACT FROM AUTHOR]

Almost 50% of patients with cardiovascular diseases face challenges in taking medications and increased morbidity and mortality. Text messaging may impact medication refill behavior and can be delivered at scale to patients by texting mobile phones. To obtain feedback from persons with chronic conditions on the design of interactive text messages and determine language of message for making messages that can motivate patients to refill medications on time. We purposively sampled 35 English and Spanish speaking patients with at least one chronic condition from three large healthcare delivery systems to participate in N-of-1 video-based synchronous interviews. Research assistants shared ideas for theory-informed text messages with content intended to persuade patients to refill their medication. We transcribed recorded interviews and conducted a content analysis to identify strategies to employ generating a dynamic interactive text message library intended to increase medication refill. Those interviewed were of diverse age and race/ethnicity and typical of persons with multiple chronic conditions. Several participants emphasized that personally tailored and positively framed messages would be more persuasive than generic and/or negative messages. Some patients appreciated humor and messages that could evoke a sense of social support from their providers and rejected the use of emojis. Messages to remind patients to refill medications may facilitate improvements in adherence, which in turn can improve chronic care. Designing messages that are persuasive and can prompt action is feasible and should be considered given the ease with which such messages can be delivered automatically at scale. [ABSTRACT FROM AUTHOR]

Vaccinations and anti-vaccination attitudes have reclaimed the spotlight as a crucial health behavior because of the recent surge in outbreaks of preventable diseases. One factor that may be contributing to this trend is the outspoken role that anti-vaccination celebrities play. The main purpose of the present study was to determine whether anti-vaccination attitudes are related to celebrity admiration. We hypothesized a positive correlation between anti-vaccination attitudes and celebrity interest and admiration. We also hypothesized that persons who are very concerned about the commercial profiteering of vaccinations will also tend to believe in conspiracies. Participants (N = 320, 40% female, mean age = 36.28, SD = 11.32) completed the Celebrity Attitude Scale (CAS) and the Vaccination Attitudes Examination Scale (VAX) through an online survey management system. We found significant positive associations between anti-vaccination attitudes and celebrity admiration and interest. However, celebrity admiration and interest did not correlate with mistrust of vaccine benefits, as measured by a subdomain of the VAX. Additionally, we found that concerns about commercial profiteering from vaccines correlated with beliefs in conspiracy theories. Our study suggests a new way of approaching people's anti-vaccination attitudes that may be used to effectively educate the public about the importance of vaccinations. [ABSTRACT FROM AUTHOR]