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Background: Multiple factors, such as less complex U.S. adult pneumococcal recommendations that could increase vaccination rates, childhood pneumococcal vaccination indirect effects that decrease adult vaccination impact, and increased vaccine hesitancy (particularly in underserved minorities), could diminish the cost‐effectiveness of programs to increase pneumococcal vaccination in older adults. Prior analyses supported the economic favorability of these programs. Methods: A Markov model compared no vaccination and current recommendations (either 20‐valent pneumococcal conjugate vaccine [PCV20] alone or 15‐valent pneumococcal conjugate vaccine plus the 23‐valent pneumococcal polysaccharide vaccine [PCV15/PPSV23]) without or with programs to increase vaccine uptake in Black and non‐Black 65‐year‐old cohorts. Pre‐pandemic population‐ and serotype‐specific pneumococcal disease risk and illness/vaccine costs came from U.S. databases. Program costs were $2.19 per vaccine‐eligible person and increased absolute vaccination likelihood by 7.5%. Delphi panel estimates and trial data informed vaccine effectiveness values. Analyses took a healthcare perspective, discounting at 3%/year over a lifetime time horizon. Results: Uptake programs decreased pneumococcal disease overall. In Black cohorts, PCV20 without program cost $216,805 per quality‐adjusted life year (QALY) gained compared with no vaccination; incremental cost‐effectiveness was $245,546/QALY for PCV20 with program and $425,264/QALY for PCV15/PPSV23 with program. In non‐Black cohorts, all strategies cost >$200,000/QALY gained. When considering the potential indirect effects from childhood vaccination, all strategies became less economically attractive. Increased vaccination with less complex strategies had negligible effects. In probabilistic sensitivity analyses, current recommendations with or without programs were unlikely to be favored at thresholds <$200,000/QALY gained. Conclusion: Current U.S. pneumococcal vaccination recommendations for older adults were unlikely to be economically reasonable with or without programs to increase vaccine uptake. Alternatives to current pneumococcal vaccines that include pneumococcal serotypes associated with adult disease should be considered. See related Editorial by Melissa K. Andrew in this issue. [ABSTRACT FROM AUTHOR]

The article titled "More on Measuring Project Performance" by Dr. Kenneth Smith discusses the topic of measuring project performance. The author mentions their previous letter on measuring work performance with unweighted milestones and goes on to discuss the concept of Earned Value analysis, which involves assessing integrated work, schedule, and cost performance. The author introduces their integrated 13-point Project Performance scale called IPPSTAT, which incorporates traditional SPI and CPI indicators. They acknowledge that their approach may not be adopted by the US Government but suggest that other organizations may find it useful. [Extracted from the article]

Objective: To compare the cost-effectiveness of serial non-echo planar diffusion weighted MRI (non-EP DW MRI) versus planned second look surgery following initial canal wall up tympanomastoidectomy for the treatment of cholesteatoma. Methods: A decision-analytic model was developed. Model inputs including residual cholesteatoma rates, rates of non-EP DW MRI positivity after surgery, and health utility scores were abstracted from published literature. Cost data were derived from the 2022 Centers for Medicare and Medicaid Services fee rates. Efficacy was defined as increase in quality-adjusted life year (QALY). One- and 2-way sensitivity analyses were performed on variables of interest to probe the model. Total time horizon was 50 years with a willingness to pay (WTP) threshold set at $50 000/QALY. Results: Base case analysis revealed that planned second-look surgery ($11 537, 17.30 QALY) and imaging surveillance with non-EP DWMRI ($10 439, 17.26 QALY) were both cost effective options. Incremental cost effectiveness ratio was $27 298/QALY, which is below the WTP threhshold. One-way sensitivity analyses showed that non-EP DW MRI was more cost effective than planned second-look surgery if the rate of residual disease after surgery increased to 48.3% or if the rate of positive MRI was below 45.9%. A probabilistic sensitivity analysis at WTP of $50 000/QALY found that second-look surgery was more cost-effective in 56.7% of iterations. Conclusion: Non-EP DW MRI surveillance is a cost-effect alternative to planned second-look surgery following primary canal wall up tympanomastoidectomy for cholesteatoma. Cholesteatoma surveillance decisions after initial canal wall up tympanomastoidectomy should be individualized. Level of Evidence: V. [ABSTRACT FROM AUTHOR]

Background. The Mobility and Vitality Lifestyle Program (MOVE UP) is a behavioral weight-management intervention for improving mobility among community-dwelling older adults. We examined program factors that affect implementation outcomes and participant-level health outcomes. Methods. The MOVE UP program was implemented in the greater Pittsburgh area from January 2015 to June 2019 to improve lower extremity performance in community-dwelling older adults who were overweight or obese. Thirty-two sessions were delivered over 13 months. All sessions were designed to be 1-hour in length, on-site, group-based, and led by trained and supported community health workers (CHWs). Participants completed weekly Lifestyle Logs for self-monitoring of body weight, diet, and physical activity. We evaluated the MOVE UP program using the RE-AIM framework, and collected quantitative data at baseline, 5-, 9-, and 13-months. Multilevel linear regression models assessed the impacts of program factors (site, CHW, and participant characteristics) on implementation outcomes and participant-level health outcomes. Results. Twenty-two CHWs delivered MOVE UP program to 303 participants in 26 cohorts. Participants were similar to the target source population in weight but differed in some demographic characteristics. The program was effective for weight loss and lower extremity function in both intervention and maintenance periods (p s <.01), with an independent effect for Lifestyle Logs submission but not session attendance. Discussion. CHWs were able to deliver a multi-component weight loss intervention effectively in community settings. CHW and site characteristics had independent impacts on participants' adherence. Lifestyle Log submission may be a more potent measure of adherence in weight loss interventions than attendance. [ABSTRACT FROM AUTHOR]

We examined the seasonality of photosynthesis in 46 evergreen needleleaf (evergreen needleleaf forests (ENF)) and deciduous broadleaf (deciduous broadleaf forests (DBF)) forests across North America and Eurasia. We quantified the onset and end (StartGPP and EndGPP) of photosynthesis in spring and autumn based on the response of net ecosystem exchange of CO2 to sunlight. To test the hypothesis that snowmelt is required for photosynthesis to begin, these were compared with end of snowmelt derived from soil temperature. ENF forests achieved 10% of summer photosynthetic capacity ∼3 weeks before end of snowmelt, while DBF forests achieved that capacity ∼4 weeks afterward. DBF forests increased photosynthetic capacity in spring faster (1.95% d−1) than ENF (1.10% d−1), and their active season length (EndGPP–StartGPP) was ∼50 days shorter. We hypothesized that warming has influenced timing of the photosynthesis season. We found minimal evidence for long‐term change in StartGPP, EndGPP, or air temperature, but their interannual anomalies were significantly correlated. Warmer weather was associated with earlier StartGPP (1.3–2.5 days °C−1) or later EndGPP (1.5–1.8 days °C−1, depending on forest type and month). Finally, we tested whether existing phenological models could predict StartGPP and EndGPP. For ENF forests, air temperature‐ and daylength‐based models provided best predictions for StartGPP, while a chilling‐degree‐day model was best for EndGPP. The root mean square errors (RMSE) between predicted and observed StartGPP and EndGPP were 11.7 and 11.3 days, respectively. For DBF forests, temperature‐ and daylength‐based models yielded the best results (RMSE 6.3 and 10.5 days). Plain Language Summary: We used records of forest‐atmosphere carbon dioxide exchange and weather to determine when photosynthesis begins and ends each year in 46 northern hemisphere forests. We used observations of soil temperature to determine the timing of the end of the snowmelt period. We found that evergreen needleleaf forests began photosynthesis ∼3 weeks before snowmelt ended, while deciduous broadleaf forests (DBF) waited until ∼4 weeks after snowmelt ended. The DBF type ramped up photosynthesis in spring, and ramped down in autumn, faster than the ENF, and the length of the photosynthesis (or "growing") season was ∼50 days shorter for DBF forests. Abundant evidence suggests that spring is occurring earlier in recent decades. We checked whether these forests are starting photosynthesis earlier by looking at forests with long‐term records. We found minimal support for changes in photosynthetic phenology over time, but very strong connections between temperature and the timing of spring and autumn transitions. We tested 19 models that use weather data to predict plant phenological events. We used gridded weather data to drive the models, and the best models were able to predict the spring and autumn photosynthetic transitions to within ∼10 days. Key Points: Evergreen forests began photosynthesis in spring ∼3 weeks before end of snowmelt, deciduous forests ∼4 weeks after end of snowmeltThere is little evidence for lengthening of the photosynthetic season in the northern hemisphere forest flux tower recordInterannual variation in onset and end of photosynthesis was related to air temperature [ABSTRACT FROM AUTHOR]

Introduction: Therapeutic alliance (TA), or the extent to which patients feel a sense of caring and trust with their physician, may have an impact on health care utilization. We sought to determine if TA is associated with: (1) emergency department (ED) visits within 30 days of death and (2) hospice enrollment. Methods and Materials: This is a secondary analysis of data from a randomized clinical trial. We used restricted cubic splines to assess the relationship between TA scores and health care utilization. Results: Six hundred seventy-two patients were enrolled in the study, with 331 (49.3%) dying within 12 months. Patients with higher TA were less likely to have an ED visit in the last 30 days of life, but there was no evidence of a relationship between TA and enrollment in hospice. Conclusions: Higher TA was associated with decreased ED visits within 30 days of death. There was no association between TA and rates of hospice enrollment. Clinical Registration Number: NCT02712229. [ABSTRACT FROM AUTHOR]

Evergreen needleleaf forests (ENFs) play a sizable role in the global carbon cycle, but the biological and physical controls on ENF carbon cycle feedback loops are poorly understood and difficult to measure. To address this challenge, a growing appreciation for the stress physiology of photosynthesis has inspired emerging techniques designed to detect ENF photosynthetic activity with optical signals. This Overview summarizes how fundamental plant biological and biophysical processes control the fate of photons from leaf to globe, ultimately enabling remote estimates of ENF photosynthesis. We demonstrate this using data across four ENF sites spanning a broad range of environmental conditions and link leaf- and stand-scale observations of photosynthesis (i.e. needle biochemistry and flux towers) with tower- and satellite-based remote sensing. The multidisciplinary nature of this work can serve as a model for the coordination and integration of observations made at multiple scales. [ABSTRACT FROM AUTHOR]

Visual loss in acute optic neuritis is typically attributed to axonal conduction block due to inflammatory demyelination, but the mechanisms remain unclear. Recent research has highlighted tissue hypoxia as an important cause of neurological deficits and tissue damage in both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) and, here, we examine whether the optic nerves are hypoxic in experimental optic neuritis induced in Dark Agouti rats. At both the first and second peaks of disease expression, inflamed optic nerves labelled significantly for tissue hypoxia (namely, positive for hypoxia inducible factor-1α (HIF1α) and intravenously administered pimonidazole). Acutely inflamed nerves were also labelled significantly for innate markers of oxidative and nitrative stress and damage, including superoxide, nitric oxide and 3-nitrotyrosine. The density and diameter of capillaries were also increased. We conclude that in acute optic neuritis, the optic nerves are hypoxic and come under oxidative and nitrative stress and damage. Tissue hypoxia can cause mitochondrial failure and thus explains visual loss due to axonal conduction block. Tissue hypoxia can also induce a damaging oxidative and nitrative environment. The findings indicate that treatment to prevent tissue hypoxia in acute optic neuritis may help to restore vision and protect from damaging reactive oxygen and nitrogen species. [ABSTRACT FROM AUTHOR]

Aims Cardiac involvement is common in patients hospitalized with COVID-19 and correlates with an adverse disease trajectory. While cardiac injury has been attributed to direct viral cytotoxicity, serum-induced cardiotoxicity secondary to serological hyperinflammation constitutes a potentially amenable mechanism that remains largely unexplored. Methods and results To investigate serological drivers of cardiotoxicity in COVID-19 we have established a robust bioassay that assessed the effects of serum from COVID-19 confirmed patients on human embryonic stem cell (hESC)-derived cardiomyocytes. We demonstrate that serum from COVID-19 positive patients significantly reduced cardiomyocyte viability independent of viral transduction, an effect that was also seen in non-COVID-19 acute respiratory distress syndrome (ARDS). Serum from patients with greater disease severity led to worse cardiomyocyte viability and this significantly correlated with levels of key inflammatory cytokines, including IL-6, TNF-α, IL1-β, IL-10, CRP, and neutrophil to lymphocyte ratio with a specific reduction of CD4+ and CD8+ cells. Combinatorial blockade of IL-6 and TNF-α partly rescued the phenotype and preserved cardiomyocyte viability and function. Bulk RNA sequencing of serum-treated cardiomyocytes elucidated specific pathways involved in the COVID-19 response impacting cardiomyocyte viability, structure, and function. The observed effects of serum-induced cytotoxicity were cell-type selective as serum exposure did not adversely affect microvascular endothelial cell viability but resulted in endothelial activation and a procoagulant state. Conclusion These results provide direct evidence that inflammatory cytokines are at least in part responsible for the cardiovascular damage seen in COVID-19 and characterise the downstream activated pathways in human cardiomyocytes. The serum signature of patients with severe disease indicates possible targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Background: The fear of taking away hope hinders clinicians' willingness to share serious news with patients with advanced disease. Unrealistic illness expectations, on the other hand, can complicate decision making and end-of-life care outcomes. Exploration of the association between hope and illness expectations can support clinicians in better communication with their patients. Aim: The aim of this study was to explore whether realistic illness expectations are associated with reduced hope in people with advanced cancer. Design: This is a cross-sectional secondary analysis of baseline data from a primary palliative care cluster-randomized trial CONNECT (data collected from July 2016 to October 2020). Hope was measured by Herth Hope Index. Illness expectations were measured by assessing patients' understanding of their treatment goals, life expectancy, and terminal illness acknowledgement. Multivariable regression was performed, adjusting for demographical and clinical confounders. Setting/participants: Adult patients with advanced solid cancers recruited across 17 oncology clinics. Results: Data from 672 patients were included in the study, with mean age of 69.3 years (±10.2), 53.6% were female. Proportion of patients indicating realistic expectations varied based on which question was asked from 10% to 46%. Median level of hope was 39 (IQR = 36–43). Multivariate non-inferiority regression did not find any significant differences in hope between patients with more and less realistic illness expectations. Conclusions: Our results suggest that hope can be sustained while holding both realistic and unrealistic illness expectations. Communication about serious news should focus on clarifying the expectations as well as supporting people's hopes. [ABSTRACT FROM AUTHOR]

One goal of the Social Work Grand Challenge is to positively influence the applications of technology. Nowhere is the challenge of integrating innovative technology more apparent than in field education settings. However, current technology trends, challenges, as well as interns' use of technology, which is often used in field education settings, particularly after the major shift to virtual platforms due to the COVID-19 Global Pandemic, are not well documented. During Fall 2021, the authors sought to evaluate field educators' (1) current use of technology in social service agencies, (2) perceptions and concerns about technology, and (3) plans for training and engaging student interns with technology. Semi-structured interviews were conducted with fifteen field educators recruited from one social work program. A rigorous thematic analysis approach then was used among six coders to report thematic findings. In this study, we report (1) benefits and limitations of using technology, (2) informal and formal technology training offered to student interns in social service agencies, and (3) recommendations for engaging and training students with technology. Two emerging themes were consistent: (1) generational differences related to technology perspectives of student interns and clients and (2) that the benefits and limitations of technology often are mixed. [ABSTRACT FROM AUTHOR]

David Temperley's book, "The Musical Language of Rock," explores the conventions and language of rock music. Temperley argues that experienced rock listeners unconsciously understand these conventions and can detect deviations from them. The book combines theory and analysis, using musical examples to develop theoretical models. Temperley examines various aspects of rock music, including harmony, emotion, complexity, melody, rhythm, and form. He also considers the historical development of rock and its formal functions. The book offers new insights and perspectives on the musical language of rock. [Extracted from the article]

Business students have long been noted for their differential proclivity to engage in academic misconduct. Unfortunately, the potential for misconduct has been exacerbated in recent years by rapid advances in technology, easy access to information, competitive pressures, and the proliferation of websites that provide students access to information that allows them to directly circumvent the learning process. Using a convenience sample of 631 students matriculating in various business majors at four U.S. universities and structural equations modeling procedures, this study assesses the effects of psychological factors on business students' propensities to utilize the services of homework assistance websites. Specifically, we examine how "Dark Triad" personality traits (i.e., narcissism, Machiavellianism, and psychopathy) interact with Fraud Diamond elements to influence student decisions to engage the services of these websites. We find that each Dark Triad trait exerts a significant influence on at least one of the Fraud Diamond elements, which in turn have a significant direct or indirect positive association with students' reported intentions to utilize, and reported utilization of, these websites. [ABSTRACT FROM AUTHOR]

Trees continuously regulate leaf physiology to acquire CO2 while simultaneously avoiding excessive water loss. The balance between these two processes, or water use efficiency (WUE), is fundamentally important to understanding changes in carbon uptake and transpiration from the leaf to the globe under environmental change. While increasing atmospheric CO2 (iCO2) is known to increase tree intrinsic water use efficiency (iWUE), less clear are the additional impacts of climate and acidic air pollution and how they vary by tree species. Here, we couple annually resolved long‐term records of tree‐ring carbon isotope signatures with leaf physiological measurements of Quercus rubra (Quru) and Liriodendron tulipifera (Litu) at four study locations spanning nearly 100 km in the eastern United States to reconstruct historical iWUE, net photosynthesis (Anet), and stomatal conductance to water (gs) since 1940. We first show 16%–25% increases in tree iWUE since the mid‐20th century, primarily driven by iCO2, but also document the individual and interactive effects of nitrogen (NOx) and sulfur (SO2) air pollution overwhelming climate. We find evidence for Quru leaf gas exchange being less tightly regulated than Litu through an analysis of isotope‐derived leaf internal CO2 (Ci), particularly in wetter, recent years. Modeled estimates of seasonally integrated Anet and gs revealed a 43%–50% stimulation of Anet was responsible for increasing iWUE in both tree species throughout 79%–86% of the chronologies with reductions in gs attributable to the remaining 14%–21%, building upon a growing body of literature documenting stimulated Anet overwhelming reductions in gs as a primary mechanism of increasing iWUE of trees. Finally, our results underscore the importance of considering air pollution, which remains a major environmental issue in many areas of the world, alongside climate in the interpretation of leaf physiology derived from tree rings. [ABSTRACT FROM AUTHOR]

Background: The decline in skeletal muscle mass experienced following a short-term period (days to weeks) of muscle disuse is mediated by impaired rates of muscle protein synthesis (MPS). Previous RCTs of exercise or nutrition prehabilitation interventions designed to mitigate disuse-induced muscle atrophy have reported limited efficacy. Hence, the aim of this study is to investigate the impact of a complex prehabilitation intervention that combines β-lactoglobulin (a novel milk protein with a high leucine content) supplementation with resistance exercise training on disuse-induced changes in free-living integrated rates of MPS in healthy, young adults. Methods/design: To address this aim, we will recruit 24 healthy young (18–45 years) males and females to conduct a parallel, double-blind, 2-arm, randomised placebo-controlled trial. The intervention group will combine a 7-day structured resistance exercise training programme with thrice daily dietary supplementation with 23 g of β-lactoglobulin. The placebo group will combine the same training programme with an energy-matched carbohydrate (dextrose) control. The study protocol will last 16 days for each participant. Day 1 will be a familiarisation session and days 2–4 will be the baseline period. Days 5–11 represent the ‘prehabilitation period’ whereby participants will combine resistance training with their assigned dietary supplementation regimen. Days 12–16 represent the muscle disuse-induced ‘immobilisation period’ whereby participants will have a single leg immobilised in a brace and continue their assigned dietary supplementation regimen only (i.e. no resistance training). The primary endpoint of this study is the measurement of free-living integrated rates of MPS using deuterium oxide tracer methodology. Measurements of MPS will be calculated at baseline, over the 7-day prehabilitation period and over the 5-day immobilisation period separately. Secondary endpoints include measurements of muscle mass and strength that will be collected on days 4 (baseline), 11 (end of prehabilitation) and 16 (end of immobilisation). Discussion: This novel study will establish the impact of a bimodal prehabilitation strategy that combines ß-lactoglobulin supplementation and resistance exercise training in modulating MPS following a short-term period of muscle disuse. If successful, this complex intervention may be translated to clinical practice with application to patients scheduled to undergo, for example, hip or knee replacement surgery. Trial registration: NCT05496452. Registered on August 10, 2022. Protocol version: 16-12-2022/1 [ABSTRACT FROM AUTHOR]

The streptothricin natural product mixture (also known as nourseothricin) was discovered in the early 1940s, generating intense initial interest because of excellent gram-negative activity. Here, we establish the activity spectrum of nourseothricin and its main components, streptothricin F (S-F, 1 lysine) and streptothricin D (S-D, 3 lysines), purified to homogeneity, against highly drug-resistant, carbapenem-resistant Enterobacterales (CRE) and Acinetobacter baumannii. For CRE, the MIC50 and MIC90 for S-F and S-D were 2 and 4 μM, and 0.25 and 0.5 μM, respectively. S-F and nourseothricin showed rapid, bactericidal activity. S-F and S-D both showed approximately 40-fold greater selectivity for prokaryotic than eukaryotic ribosomes in in vitro translation assays. In vivo, delayed renal toxicity occurred at >10-fold higher doses of S-F compared with S-D. Substantial treatment effect of S-F in the murine thigh model was observed against the otherwise pandrug-resistant, NDM-1-expressing Klebsiella pneumoniae Nevada strain with minimal or no toxicity. Cryo-EM characterization of S-F bound to the A. baumannii 70S ribosome defines extensive hydrogen bonding of the S-F steptolidine moiety, as a guanine mimetic, to the 16S rRNA C1054 nucleobase (Escherichia coli numbering) in helix 34, and the carbamoylated gulosamine moiety of S-F with A1196, explaining the high-level resistance conferred by corresponding mutations at the residues identified in single rrn operon E. coli. Structural analysis suggests that S-F probes the A-decoding site, which potentially may account for its miscoding activity. Based on unique and promising activity, we suggest that the streptothricin scaffold deserves further preclinical exploration as a potential therapeutic for drug-resistant, gram-negative pathogens. Streptothricins were discovered in the early 1940's to have excellent gram-negative antibiotic activity, but how do they work? A combination of microbiological and structural biology studies reveals their mechanism of action, highlighting unique interactions with the 30S ribosomal subunit. [ABSTRACT FROM AUTHOR]

Background: We aimed to evaluate costs from transplant to discharge in children who had undergone intestine transplant. Methods: We performed a cross‐sectional observational study of pediatric intestine transplant recipients from 2004 through 2020, utilizing the Pediatric Health Information System database. Standardized costs were applied to all charges and converted to 2021 US dollars. We analyzed the association of cost from transplant to discharge with age, sex, race and ethnicity, length of stay, insurance type, transplant year, short bowel syndrome diagnosis, liver‐containing graft, hospitalization status, and immunosuppressive regimen. Predictors with a P value <0.20 in univariable analysis were included in a multivariable model, which was reduced using backwards selection with a P value of 0.05. Results: We identified 376 intestinal transplant recipients across nine centers (median age, 2 years; 44% female). Most patients had short bowel syndrome (294; 78%). The liver was included in 218 transplants (58%). Median posttransplant cost was $263,724 (interquartile range [IQR], $179,564–$384,147), and length of stay was 51.5 days (IQR, 34–77). In the final model, increased cost from transplant to hospital discharge was associated with liver‐containing graft (+$31,805; P = 0.028), T‐cell–depleting antibody use (+$77,004; P < 0.001), and mycophenolate mofetil use (+$50,514; P = 0.012) while controlling for insurance type and length of stay. A 60‐day posttransplant hospital stay would cost an estimated $272,533. Conclusions: Intestine transplant has high immediate cost and long length of stay that varies by center, graft type, and immunosuppression regimen. Future work will examine the cost‐effectiveness of various management strategies before and after transplant. [ABSTRACT FROM AUTHOR]

Purpose: Primary palliative care (PPC) interventions are needed to address unmet symptom needs within standard oncology care. We designed an oncology nurse-led PPC intervention using shared care planning to facilitate patient engagement. This analysis examines the prevalence and severity of symptoms reported by patients and how symptoms were addressed on shared care plans (SCPs). Methods: Secondary analysis of a cluster randomized PPC intervention trial. Adult patients with metastatic solid tumors whose oncologist "would not be surprised if the patient died within a year" were included. Twenty-three oncology nurses received PPC training and conducted up to three monthly visits with patients. Symptom prevalence and severity were assessed before each visit using the Edmonton Symptom Assessment Scale (ESAS). Nurses collaboratively developed treatment strategies with patients, targeting the most bothersome symptoms for improvement. Results: Among 571 nurse-led PPC visits with 235 patients, the most prevalent and severe symptoms were tiredness (reported at 86% of visits; ESAS ≥4 in 55% of visits), low sense of wellbeing (78%; ESAS ≥4 in 38%), and poor appetite (69%; ESAS ≥4 in 42%). Moderately severe symptoms were addressed on SCPs ranging from 4% (drowsiness) to 35% (tiredness) of the time. Symptom management plans developed by PPC-trained oncology nurses primarily focused on nonpharmaceutical interventions (70%) compared with pharmaceutical interventions (30%). Conclusion: The symptoms that patients report most frequently and as most severe on SCPs were addressed less frequently than expected. Further research is needed to understand how PPC interventions can be designed to more effectively target and improve bothersome symptoms for patients with advanced cancer. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT02712229 [ABSTRACT FROM AUTHOR]

Introduction: Ageing skeletal muscles become both insulin resistant and atrophic. The hormone glucagon-like peptide 1 (GLP-1) facilitates postprandial glucose uptake as well as augmenting muscle perfusion, independent of insulin action. We thus hypothesized exogenous GLP-1 infusions would enhance muscle perfusion and positively affect glucose metabolism during fed-state clamps in older people. Methods: Eight men (71±1 years) were studied in a randomized crossover trial. Basal blood samples were taken before postprandial (fed-state) insulin and glucose clamps, accompanied by amino acid infusions, for 3 hours. Reflecting this, following insertions of peripheral and femoral vessels cannulae and baseline measurements, peripheral IV infusions of octreotide, insulin (Actrapid), 20% glucose, and mixed amino acids; Vamin 14-EF with or without a femoral arterial GLP-1 infusion were started. GLP-1, insulin, and C-peptide were measured by ELISA. Muscle microvascular blood flow was assessed via contrast enhanced ultrasound. Whole-body glucose handling was assayed by assessing glucose infusion rate parameters. Results: Skeletal muscle microvascular blood flow significantly increased in response to GLP-1 vs feeding alone (5.0±2.1 vs 1.9±0.7 foldchange from basal, respectively; P=0.008), while also increasing whole-body glucose uptake (area under the curve 16.9 ±1.7 vs 11.4 ± 1.8 mg/kg-1/180 minutes-1, P=0.02±GLP, respectively). Conclusions: The beneficial effects of GLP-1 on whole-body glycemic control are evident with insulin clamped at fed-state levels. GLP-1 further enhances the effects of insulin on whole-body glucose uptake in older men, underlining its role as a therapeutic target. The effects of GLP-1 in enhancing microvascular flow likely also affects other glucose-regulatory organs, reflected by greater whole-body glucose uptake. [ABSTRACT FROM AUTHOR]

The >5,000‐year radiocarbon age (14C‐age) of much of the 630 ± 30 Pg C oceanic dissolved organic carbon (DOC) reservoir remains an enigma in the marine carbon cycle. The fact that DOC is significantly older than dissolved inorganic carbon at every depth in the ocean forms the basis of our current framing of the marine DOC cycle, where some component persists over multiple cycles of ocean mixing. As a result, 14C‐depleted, aged DOC is hypothesized to be present as a uniform reservoir with a constant 14C signature and concentration throughout the water column. However, key requirements of this model, including direct observations of DOC with similar 14C signatures in the surface and deep ocean, have never been met. Despite decades of research, the distribution of Δ14C values in marine DOC remains a mystery. Here, we applied a thermal fractionation method to compare operationally defined refractory DOC (RDOC) from different depths in the North Pacific Ocean. We found that RDOC shares chemical characteristics (as recorded by OC bond strength) throughout the water column but does not share the same 14C signature. Our results support one part of the current paradigm—that RDOC is comprised of structurally related components throughout the ocean that form a "background" reservoir. However, in contrast to the current paradigm, our results are consistent with a vertical concentration gradient and a vertical and inter‐ocean Δ14C gradient for RDOC. The observed Δ14C gradient is compatible with the potential addition of pre‐aged DOC to the upper ocean. Plain Language Summary: Ocean water contains a large reservoir of carbon that is stored as dissolved organic carbon (DOC). It is currently unknown how or on what timescales this reservoir interacts with the global carbon cycle. As such, the sensitivity of this reservoir to perturbations in the climate system remains unconstrained. The average radiocarbon age of this reservoir suggests that some components are unreactive (refractory) and spend an average time of >5,000 years in the ocean. In this study, we find that refractory DOC as isolated by our analytical approach shares chemical characteristics in the surface and deep ocean—a finding that is demonstrated with confidence for the first time. However, while this refractory DOC is depleted in radiocarbon, its old "age" is not the same throughout the water column and may be changing with time. Furthermore, these results suggest that the refractory DOC reservoir in the surface ocean is larger than previously assumed. The gradient we observe in radiocarbon age allows for alternative pathways by which refractory DOC may be introduced into the upper ocean, such as from continental margin sediments, with important consequences for the rate of carbon exchange between reservoirs of the active global carbon cycle. Key Points: Thermal oxidation reveals broad compositional similarity in the refractory dissolved organic carbon (DOC) reservoir with depthRefractory DOC does not have a constant radiocarbon signature with depth but instead exhibits a vertical gradientRamped oxidation fails to separate unique radiocarbon populations from throughout the marine water column [ABSTRACT FROM AUTHOR]

This study's purpose is to examine whether resilience, conceptualized by Connor and Davidson (2003) as one's capacity to persevere and rebound under adversity, was a potential mitigating and/or moderating factor in the dynamic between both psychological distress and academic burnout, and student attrition. We concurrently distributed a survey containing a series of psychometric instruments to a convenience sample of 1,119 students pursuing various business majors at four geographically diverse U.S. universities. Via structural equations modeling analysis, we measured the associations between psychological distress, academic burnout, and departure intentions, and investigated whether student resilience levels are associated with lower distress, burnout, and departure intentions levels. The results indicated significant positive associations between psychological distress and each of the elements of academic burnout, and significant positive associations between the academic burnout elements and departure intentions. However, while resilience did not moderate those associations, it did attenuate them through its direct negative associations with both psychological distress and the cynicism and academic inefficacy elements of academic burnout. Based on these findings, we discuss implications for business educators seeking to enhance individual resilience levels as a coping strategy to combat voluntary student turnover, and better prepare students for the demands of the workplace. [ABSTRACT FROM AUTHOR]

This chapter combines quantitative studies of the connections between stressors and performance in accounting settings and identifies the mediators and moderators of stressors–performance relationships. Using meta-analyses and path analyses, this research compiles 72 studies to investigate the relationships of stressors with accountant and auditor performance. As hypothesized, bivariate meta-analyses results indicate that work-related stressors negatively affect performance, and burnout and stress are negatively related to performance, whereas motivation is positively related to performance. Moreover, a meta-analytical structural equation modeling indicates that role stressors have significant direct and indirect effects (through burnout and stress) on job performance. Accumulation of multiple samples through meta-analysis bolsters statistical power compared to single-sample studies and thus reveals the sign of residual direct effects of role stressors on job performance in accounting settings. [ABSTRACT FROM AUTHOR]

Rationale: Obesity affects 40% of US adults, is associated with a pro-inflammatory state, and presents a significant risk factor for the development of severe COVID-19. To date, there is limited information on how obesity might affect immune cell responses in SARS-CoV-2 infection.Objectives: To determine the impact of obesity on respiratory tract immunity in COVID-19 across human lifespan.Methods: We analysed single cell transcriptomes from bronchiolar lavage in three ventilated adult cohorts with (n=24) or without COVID-19 (n=9), from nasal immune cells in children with (n=14) or without COVID-19 (n=19), and from peripheral blood mononuclear cells in an independent adult COVID-19 cohort (n=42), comparing obese (Ob) and non-obese subjects (N-Ob).Measurements and Main Results: Surprisingly, we found that adult Ob subjects had attenuated lung immune/inflammatory responses in SARS-CoV-2 infection, with decreased expression of interferon (IFN)α, IFNγ and tumour necrosis factor (TNF) alpha response gene signatures in almost all lung epithelial and immune cell subsets, and lower expression of IFNG and TNF in specific lung immune cells. Peripheral blood immune cells in an independent adult cohort showed a similar, but less marked, reduction in type I IFN and IFNγ response genes, as well as decreased serum IFNα in Ob patients with SARS-CoV-2. Nasal immune cells from Ob children with COVID-19 also showed reduced enrichment of IFNα and IFNγ response genes.Conclusions: These findings show blunted tissue immune responses in Ob COVID-19 patients, with implications for treatment stratification, supporting the specific application of inhaled recombinant type I IFNs in this vulnerable subset. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/). [ABSTRACT FROM AUTHOR]

Exercise training can induce adaptive changes to tendon tissue both structurally and mechanically; however, the underlying compositional changes that contribute to these alterations remain uncertain in humans, particularly in the context of the ageing tendon. The aims of the present study were to determine the molecular changes with ageing in patellar tendons in humans, as well as the responses to exercise and exercise type (eccentric (ECC) and concentric (CON)) in young and old patellar tendon. Healthy younger males (age 23.5 ± 6.1 years; n = 27) and older males (age 68.5 ± 1.9 years; n = 27) undertook 8 weeks of CON or ECC training (3 times per week; at 60% of 1 repetition maximum (1RM)) or no training. Subjects consumed D2O throughout the protocol and tendon biopsies were collected after 4 and 8 weeks for measurement of fractional synthetic rates (FSR) of tendon protein synthesis and gene expression. There were increases in tendon protein synthesis following 4 weeks of CON and ECC training (P < 0.01; main effect by ANOVA), with no differences observed between young and old males, or training type. At the transcriptional level however, ECC in young adults generally induced greater responses of collagen and extracellular matrix-related genes than CON, while older individuals had reduced gene expression responses to training. Different training types did not appear to induce differential tendon responses in terms of protein synthesis, and while tendons from older adults exhibited different transcriptional responses to younger individuals, protein turnover changes with training were similar for both age groups. [ABSTRACT FROM AUTHOR]

Aims: Axonal injury in multiple sclerosis (MS) and experimental models is most frequently detected in acutely demyelinating lesions. We recently reported a compensatory neuronal response, where mitochondria move to the acutely demyelinated axon and increase the mitochondrial content following lysolecithin-induced demyelination. We termed this homeostatic phenomenon, which is also evident in MS, the axonal response of mitochondria to demyelination (ARMD). The aim of this study is to determine whether ARMD is consistently evident in experimental demyelination and how its perturbation relates to axonal injury. Methods: In the present study, we assessed axonal mitochondrial content as well as axonal mitochondrial respiratory chain complex IV activity (cytochrome c oxidase or COX) of axons and related these to axonal injury in nine different experimental disease models. We used immunofluorescent histochemistry as well as sequential COX histochemistry followed by immunofluorescent labelling of mitochondria and axons. Results: We found ARMD a consistent and robust phenomenon in all experimental disease models. The increase in mitochondrial content within demyelinated axons, however, was not always accompanied by a proportionate increase in complex IV activity, particularly in highly inflammatory models such as experimental autoimmune encephalomyelitis (EAE). Axonal complex IV activity inversely correlated with the extent of axonal injury in experimental disease models. Conclusions: Our findings indicate that ARMD is a consistent and prominent feature and emphasise the importance of complex IV activity in the context of ARMD, especially in autoimmune inflammatory demyelination, paving the way for the development of novel neuroprotective therapies. [ABSTRACT FROM AUTHOR]