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Abstract Current therapies for high-grade TP53-mutated myeloid neoplasms (≥10% blasts) do not offer a meaningful survival benefit except allogeneic stem cell transplantation in the minority who achieve a complete response to first line therapy (CR1). To identify reliable pre-therapy predictors of complete response to first-line therapy (CR1) and outcomes, we assembled a cohort of 242 individuals with TP53-mutated myeloid neoplasms and ≥10% blasts with well-annotated clinical, molecular and pathology data. Key outcomes examined were CR1 & 24-month survival (OS24). In this elderly cohort (median age 68.2 years) with 74.0% receiving frontline non-intensive regimens (hypomethylating agents +/- venetoclax), the overall cohort CR1 rate was 25.6% (50/195). We additionally identified several pre-therapy factors predictive of inferior CR1 including male gender (P = 0.026), ≥2 autosomal monosomies (P 25% (P = 0.002), TP53 splice junction mutations (P = 0.007) and antecedent treated myeloid neoplasm (P = 0.001). In addition, mutations/deletions in CUX1, U2AF1, EZH2, TET2, CBL, or KRAS (‘EPI6’ signature) predicted inferior OS24 (HR = 2.0 [1.5–2.8]; P

Abstract This study compared cardiovascular and metabolic responses during concentric and eccentric stepping. Eight participants (5 m, 3f; 22 ± 2 years) performed maximal concentric and eccentric ramp incremental tests on a modified stepping ergometer. Subsequently, three randomized 15‐min constant‐power tests were performed (1) concentric stepping at 90% of the concentric lactate threshold (LT), (2) eccentric stepping at the same power, and (3) eccentric stepping at the same oxygen uptake (V̇O2). At equivalent power (36 ± 6 W, p = 0.62), eccentric stepping resulted in 46 ± 8% lower V̇O2, 16 ± 6% lower heart rate (HR), and 11 ± 5% lower mean arterial blood pressure compared to concentric (p

AbstractExertional dyspnea, a key complaint of patients with chronic obstructive pulmonary disease (COPD), ultimately reflects an increased inspiratory neural drive to breathe. In non-hypoxemic patients with largely preserved lung mechanics – as those in the initial stages of the disease – the heightened inspiratory neural drive is strongly associated with an exaggerated ventilatory response to metabolic demand. Several lines of evidence indicate that the so-called excess ventilation (high ventilation-CO2 output relationship) primarily reflects poor gas exchange efficiency, namely increased physiological dead space. Pulmonary function tests estimating the extension of the wasted ventilation and selected cardiopulmonary exercise testing variables can, therefore, shed unique light on the genesis of patients’ out-of-proportion dyspnea. After a succinct overview of the basis of gas exchange efficiency in health and inefficiency in COPD, we discuss how wasted ventilation translates into exertional dyspnea in individual patients. We then outline what is currently known about the structural basis of wasted ventilation in “minor/trivial” COPD vis-à-vis the contribution of emphysema versus a potential impairment in lung perfusion across non-emphysematous lung. After summarizing some unanswered questions on the field, we propose that functional imaging be amalgamated with pulmonary function tests beyond spirometry to improve our understanding of this deeply neglected cause of exertional dyspnea. Advances in the field will depend on our ability to develop robust platforms for deeply phenotyping (structurally and functionally), the dyspneic patients showing unordinary high wasted ventilation despite relatively preserved FEV1.

Introduction: Early lung cancer detection programs improve surgical resection rates and survival but may skew toward more indolent cancers. Methods: Hypothesizing that differences in stage-stratified survival indicate differences in biological aggressiveness and possible length-time and overdiagnosis bias, we assessed a cohort who had curative-intent resection, categorized by diagnostic pathways: screening, incidental pulmonary nodule program, and non–program based. Survival was analyzed using Kaplan-Meier plots, log-rank tests, and Cox regression, comparing aggregate and stage-stratified survival across cohorts with Tukey’s method for multiple testing. Results: Of 1588 patients, 111 patients (7%), 357 patients (22.5%), and 1120 patients (70.5%) were diagnosed through screening, pulmonary nodule, and non–program-based pathways; 0% versus 9% versus 6% were older than 80 years (p = 0.0048); 17%, 23%, and 24% had a Charlson Comorbidity score greater than or equal to 2 (p = 0.0143); 7%, 6%, and 9% had lepidic adenocarcinoma; 26%, 31%, and 34% had poorly or undifferentiated tumors (p = 0.1544); and 93%, 87%, and 77% had clinical stage I (p < 0.0001).Aggregate 5-year survival was 87%, 72%, and 65% (p = 0.0009), including 95%, 74%, and 74% for pathologic stage I. Adjusted pairwise comparisons showed similar survival in screening and nodule program cohorts (p = 0.9905). Nevertheless, differences were significant between screening and non–program-based cohorts (p = 0.0007, adjusted hazard ratio 0.33 [95% confidence interval: 0.18–0.6]) and between nodule and nonprogram cohorts (adjusted hazard ratio 0.77 [95% confidence interval: 0.61–0.99]). Stage I comparisons yielded p = 0.2256, 0.1131, and 0.911. In respective pathways, 0%, 2%, and 2% of patients with stage I disease who were older than 80 years had a Charlson score greater than or equal to 2 (p = 0.3849). Conclusions: Neither length-time nor overdiagnosis bias was evident in NSCLC diagnosed through screening or incidental pulmonary nodule programs.

Background Although electronic consults (e-consults) are utilized in healthcare systems by medical professionals, use of e-consults by pharmacy remains novel outside of niche disease states. Additional research is required to fill literature gaps to assist in optimizing the pharmacist’s role in e-consult programs. Objective This study aimed to assess the impact of pharmacist expertise on e-consult outcomes. Methods This study was a retrospective review of all pharmacy e-consults completed by pharmacists at a large academic health system between March 1st, 2020, and August 31st, 2022. This was deemed quality improvement and did not require Institutional Review Board approval. E-consults were identified using a report. Key data collection points included e-consult disease state, ordering provider, pharmacists' specialty, and recommendation result. The primary outcome was the difference in acceptance rates of expert versus non-expert pharmacist recommendations. Secondary outcomes included the overall implementation rate, implementation rate over time, acceptance rate between provider types, time to implementation, and pharmacist response time. Acceptance rates were compared between expert/non-expert dichotomy via Pearson chi-square test. Results A total of 375 e-consults met inclusion criteria and spanned 19 unique disease states. The three most common included diabetes mellitus (27.0%), pain management (13.1%), and mental health (11.0%). Nearly 60% of e-consults were in a disease with an expert. The provider acceptance rate was higher when e-consults were completed by an expert versus non-expert (62.6% versus 39.6% respectively, p = 0.002). The overall implementation rate was 51.8%. Physicians (MD/DOs) accepted the pharmacist’s recommendations 55.6% of the time, advanced practice registered nurses (APRNs) 64.7%, physician assistants (PAs) 100.0%, and other professionals 25.0% (p = 0.033). Mean time to recommendation implementation was 16.5 days (SD = 29.4 days). Mean time to pharmacist response was 1.1 days (SD = 1.4 days). Conclusions Comprehensive e-consult programs are more successful when integrating expert pharmacists.

Abstract. Introduction:. Psychological, social, and lifestyle factors contribute to the knee osteoarthritis (OA) pain experience. These factors could be measured more accurately using smartphone ecological momentary assessment (EMA). Objectives:. The objective of this study was to characterise the pain experiences of those with knee OA by a smartphone EMA survey and explain how momentary psychological and social states influence knee OA pain experiences. Methods:. A smartphone EMA survey was designed and piloted. Eligible participants completed smartphone EMA assessing the knee OA pain experience 3 times daily for 2 weeks. Descriptive statistics were used to characterise factors involved in knee OA pain followed by the development of mixed-effects location scale models to explore heterogeneity and relationships between symptoms involved in the knee OA pain experience. Results:. Eighty-six community-dwelling volunteers with knee OA were recruited. Pain, psychosocial, and lifestyle factors involved in knee OA pain experience were heterogeneous and variable. Those with greater variability in pain, fatigue, negative affect, and stress had worse levels of these symptoms overall. In addition, fatigue, negative affect, stress, anxiety, loneliness, and joint stiffness demonstrated within-person relationships with knee OA pain outcomes. Conclusions:. Knee OA pain is a heterogeneous biopsychosocial condition. Momentary experiences of psychological, social, fatigue, and joint stiffness explain individual and between-individual differences in momentary knee OA pain experiences. Addressing these momentary factors could improve pain and functional outcomes in those with knee OA. Validation studies, including individuals with more severe knee OA presentations, are required to support findings and guide clinical interventions to improve outcomes for those with knee OA.

Background and objectives: Knee Osteoarthritis (OA) is a prevalent musculoskeletal condition that often results in pain and disability. Determining factors predicting variability in pain experience is critical to improving clinical outcomes. Underlying pain sensitization and its clinical manifestations, such as activity-related pain, may better predict the knee OA pain experience. This study aimed to determine whether Quantitative Sensory Testing (QST) derived sensitization measures and activity-related pain predict knee OA pain experiences collected via smartphone ecological momentary assessment (EMA). Design: Individuals with knee OA were recruited from an urban community in New Zealand. Those eligible to participate underwent baseline QST with clinical measures of activity-related pain also being collected. The knee OA pain experience was collected via smartphone EMA three times daily for two weeks. Mixed effects location scale models were developed using a multilevel modelling approach. Results: Eighty-six participants with knee OA participated in the study. Mean age was 67.3 years, with most of the participants being female (64%) and New Zealand European (90.6%). Activity-related pain predicted worse and more variable pain intensity, pain interference, and bothersomeness outcomes within and between individuals with knee OA. Widespread cold hyperalgesia and local mechanical hyperalgesia were shown to predict higher within-person variability in pain intensity and pain interference respectively, while mechanical temporal summation predicted less within-person variability in pain intensity and interference. Discussion: Those demonstrating activity-related pain and sensitization could be at risk of experiencing worse and more variable knee OA pain in the subsequent weeks. Testing for sensitization in clinical practice could therefore identify those at greatest risk of higher and more variable knee OA pain experiences and in greatest need of treatment. Larger validation studies are required, which include individuals with more severe knee OA.

Introduction: Low-dose computed tomography screening (LDCT) and lung nodule programs (LNP) promote early lung cancer detection, improve survival; Multidisciplinary Care Programs (MDC) promote guideline-concordant care. The impact of such program-based care on “real-world” lung cancer survival is unquantified. We evaluated outcomes of lung cancer care delivered through structured programs in a community health care system. Methods: We conducted a cohort study linking institutional prospective observational LDCT, LNP and MDC databases with Tumor Registry of Baptist Cancer Center facilities. We categorized all patients diagnosed with lung cancer between 2011 and 2021 into program-based care versus non-program-based care cohorts. We compared patient characteristics, stage distribution, treatment modalities, survival and mortality in each pathway of care. Results: Of 12,148 patients, 237, 1,165, 1,140 and 9,606 were diagnosed through the LDCT, LNP, MDC or no program, respectively; non-program-based care sequentially diminished from 96.3% to 66.5%, diagnosis through LDCT increased from 0.5% to 7.1%, LNP from 3.5% to 20.8%; and MDC alone decreased from a high of 12.8% in 2014 to 5.6% in 2021. Program-based care was associated with earlier stage (p < 0.001), higher surgical resection rates (p < 0.001), greater use of adjuvant therapy (p < 0.001), better aggregate and stage-stratified survival (p < 0.001), and lower all-cause and lung cancer-specific mortality (p < 0.001). Recipients of non-program-based care were considerably less likely to receive lung cancer treatment; results remained consistent when patients receiving no treatment were excluded. Conclusions: Program-based care was associated with substantially better survival. Increasing access to program-based care should be explored as a matter of urgent public policy.

Background: The burden of cardiovascular disease (CVD) is particularly high in several US states, which include the state of Michigan. Hypertension and smoking are two major risk factors for mortality due to CVD. Rural Michigan is disproportionally affected by CVD and by primary care shortages. The Healthy Hearts for Michigan (HH4M) study aims to promote hypertension management and smoking cessation through practice facilitation and quality improvement efforts and is part of the multi-state EvidenceNOW: Building State Capacity initiative to provide external support to primary care practices to improve care delivery. Methods: Primary care practices in rural and underserved areas of Michigan were recruited to join HH4M, a pragmatic, single-arm hybrid Type 2 effectiveness-implementation study during which practice facilitation was delivered at the practice level for 12 months, followed by a 3-month maintenance period. Results: Fifty-four practices were enrolled over a 12-month recruitment period. At baseline, the mean proportion (standard deviation) of patients at the practice level meeting the clinical quality measures were: blood pressure, 0.72 (0.12); tobacco screening, 0.80 (0.30); tobacco cessation intervention, 0.57 (0.28); tobacco screening and cessation intervention: 0.78 (0.26). Conclusion: This three-year research program will evaluate the ability of rural and medically underserved primary care practices to implement the quality improvement model by identifying drivers of and barriers to sustainable implementation, and test whether the model improves (a) blood pressure control and (b) tobacco use screening and cessation.

We analyze the outer regions of M33, beyond 15 kpc in projected distance from its center, using Subaru/Hyper Suprime-Cam multicolor imaging. We identify red giant branch (RGB) stars and red clump (RC) stars using the surface-gravity-sensitive NB515 filter for the RGB sample and a multicolor selection for both samples. We construct the radial surface density profiles of these RGB and RC stars and find that M33 has an extended stellar population with a shallow power-law index of α > −3, depending on the intensity of the contamination. This result represents a flatter profile than the stellar halo that was detected by the previous study focusing on the central region, suggesting that M33 may have a double-structured halo component, i.e., inner/outer halos or a very extended disk. Also, the slope of this extended component is shallower than those typically found for halos in large galaxies, implying intermediate-mass galaxies may have different formation mechanisms (e.g., tidal interaction) from large spirals. We also analyze the radial color profiles of RC/RGB stars and detect a radial gradient, consistent with the presence of an old and/or metal-poor population in the outer region of M33, thereby supporting our proposal that the stellar halo extends beyond 15 kpc. Finally, we estimate that the surface brightness of this extended component is μ _V = 35.72 ± 0.08 mag arcsec ^−2 . If our detected component is the stellar halo, this estimated value is consistent with the detection limit of previous observations.

The stellar initial mass function (IMF) describes the distribution of stellar masses that form in a given star formation event. The long main-sequence lifetimes of low-mass stars mean that the IMF in this regime (below ∼ 1 M _⊙ ) can be investigated through star counts. Ultrafaint dwarf galaxies are low-luminosity systems with ancient, metal-poor stellar populations. We investigate the low-mass IMF in four such systems (Reticulum II, Ursa Major II, Triangulum II, and Segue 1), using Hubble Space Telescope imaging data that reaches to ≲ 0.2 M _⊙ in each galaxy. The analysis techniques that we adopt depend on the number of low-mass stars in each sample. We use Kolmogorov–Smirnov tests for all four galaxies to determine whether their observed apparent magnitude distributions can reject a given combination of IMF parameters and binary fraction for the underlying population. We forward model 1000 synthetic populations for each combination of parameters, and reject those parameters only if each of the 1000 realizations reject the null hypothesis. We find that all four galaxies reject a variety of IMFs, and the IMFs that they cannot reject include those that are identical, or similar, to that of the stellar populations of the Milky Way. We determine the best-fit parameter values for the IMF in Reticulum II and Ursa Major II and find that the IMF in Reticulum II is generally consistent with that of the Milky Way, while the IMF in Ursa Major II is more bottom heavy. The interpretation of the results for Ursa Major II is complicated by possible contamination from two known background galaxy clusters.

Abstract Background The IO Score is a 27-gene immuno-oncology (IO) classifier that has previously predicted benefit to immune checkpoint inhibitor (ICI) therapy in triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC). It generates both a continuous score and a binary result using a defined threshold that is conserved between breast and lung. Herein, we aimed to evaluate the IO Score’s binary threshold in ICI-naïve TCGA bladder cancer patients (TCGA-BLCA) and assess its clinical utility in metastatic urothelial cancer (mUC) using the IMvigor210 clinical trial treated with the ICI, atezolizumab. Methods We identified a list of tumor immune microenvironment (TIME) related genes expressed across the TCGA breast, lung squamous and lung adenocarcinoma cohorts (TCGA-BRCA, TCGA-LUSQ, and TCGA-LUAD, 939 genes total) and then examined the expression of these 939 genes in TCGA-BLCA, to identify patients as having high inflammatory gene expression. Using this as a test of classification, we assessed the previously established threshold of IO Score. We then evaluated the IO Score with this threshold in the IMvigor210 cohort for its association with overall survival (OS). Results In TCGA-BLCA, IO Score positive patients had a strong concordance with high inflammatory gene expression (p

In this paper, I reflect upon the methodological implications of digitization and digital methods for situational analysis. I carefully read Noortje MARRES's argument for and development of what she called situational analytics. I ask how her proposal would be incorporated within a situational analysis project of digitization and funerals. I develop a provisional research design, as a kind of thought experiment, weaving my reflections on situational analysis and digital methods through an autoethnographic account of mourning in the enforced digital of the COVID-19 pandemic. I conclude with the argument that such digital methods are necessary for situational analysis to reckon with, and yet also pose a risk of erasing the embodied and affective elements of a situation. I contend that the poiesis of ethnographic research—where mediated and embodied interactions qua situations are experienced and written into language, and writing forms a necessary but always also impossible task—remains rooted in bodies and affects that are always also elements in situational analysis. We cannot lose track of those elements that also defy the digitized elements of any given situation.

Knee Osteoarthritis (OA) is a prevalent musculoskeletal condition, commonly resulting in pain and disability. However, pain and disability in this population are poorly related with the degree of structural joint damage. Underlying pain mechanisms, including activity-related pain and sensitization assessed via Quantitative Sensory Testing (QST), may better predict pain and functional outcomes of those with knee OA. Therefore, the aim of this study was to explore whether activity-related pain and sensitization assessed via QST predict future pain, function, fatigue, physical performance and quality of life outcomes in those living in the community with knee OA. Eighty-six participants with knee OA were recruited in Dunedin, New Zealand. Those eligible to participate underwent baseline testing including QST as well as measures of activity-related pain including Movement-evoked Pain (MEP) and Sensitivity to Physical Activity (SPA). Outcome measures exploring pain, function, fatigue and quality of life outcomes were collected at baseline, and two follow-up periods (two and nine weeks). Univariable linear regression models were developed followed by multivariable linear regression models for each prognostic marker adjusting for age, gender, BMI, OA duration, baseline pain intensity and socioeconomic status. Activity-related measures of pain, including MEP and SPA, demonstrated predictive associations with pain and functional outcomes prospectively in those with knee OA. Therefore, those demonstrating activity-related pain are at future risk of greater pain, disability and reduced quality of life. Larger, externally validated longitudinal studies are required which include individuals with more severe knee OA.