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Introduction: In this study we aimed to investigate the effects of incorporating Swedish-style fika (coffee) breaks into the didactic schedule of emergency medicine residents on their sleepiness levels during didactic sessions. Fika is a Swedish tradition that involves a deliberate decision to take a break during the workday and usually involves pastries and coffee. We used the Karolinska Sleepiness Scale to assess changes in sleepiness levels before and after the implementation of fika breaks. Methods: The study design involved a randomized crossover trial approach, with data collected from emergency medicine residents over a specific period. This approach was done to minimize confounding and to be statistically efficient. Results: Results revealed the average sleepiness scale was 4.6 and 5.5 on fika and control days, respectively (P = 0.004). Conclusion: Integration of fika breaks positively influenced sleepiness levels, thus potentially enhancing the educational experience during residency didactics.

In order to explore the potential of biochar produced from poultry manure for sustainable waste utilization, carbon sequestration, and agricultural development, this study examines the impact of biochar on the growth of the halophyte plant Salicornia herbacea L., or glasswort. Because of their properties of morphological and chemical properties, biochar has been gaining interest as a potential solution to addressing both the concerns of climate change and unsustainable agriculture. In this study, the characteristics of biochar were analyzed and its impact on plant growth by stem length was measured over 15 weeks. Poultry-based biochar was created through pyrolysis at the temperatures of 400, 500, and 700 °C. Various amounts of biochar produced from pyrolysis at 500 °C were put to soil. However, the average surface area and average pore size values of poultry manure biochar produced from temperatures 400, 500, and 700 °C were similar enough to be negligible. The biochar sample produced from the pyrolysis temperature of 500 °C had an average pore size of 17.18 nm and a surface area of 18.06 m2/g. From weeks 4 to 15, all groups exhibited increased stem length, with the most significant differences observed between the biochar 0% (control) and biochar 10% groups, with biochar 0% and biochar 10% denoting 0% and 10% weight concentrations of biochar, respectively. While biochar 5% and biochar 7% groups showed minimal differences in stem length, biochar 10% demonstrated a significant increase, suggesting an optimal biochar percentage for enhancing plant growth. Carbon credit estimations have suggested that 1 ton of poultry manure biochar produced from pyrolysis at 500 C° equates to an estimate of 0.5248 ± 0.0580 carbon credits, the highest of all three biochar samples. All three samples (biochar produced from 400, 500, and 700 °C pyrolysis temperatures) had increased heavy metal contents and a wider range of functional groups. The findings indicate that biochar can effectively improve soil health and plant performance overall, with biochar 10% showing the most significant impact on Salicornia growth.

Abstract Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values

Abstract Background Data on the clinical value of second opinions in oncology are limited. We examined diagnostic and treatment changes resulting from second opinions and the expected impact on morbidity and prognosis. Methods This retrospective cohort study included patients presenting in 2018 to a high‐volume cancer center for second opinions about newly diagnosed colorectal, head and neck, lung, and myeloma cancers or abnormal results. Two sub‐specialty physicians from each cancer type reviewed 30 medical records (120 total) using a process and detailed data collection guide meant to mitigate institutional bias. The primary outcome measure was the rate of treatment changes that were “clinically meaningful”, i.e., expected to impact morbidity and/or prognosis. Among those with treatment changes, another outcome measure was the rate of clinically meaningful diagnostic changes that led to treatment change. Results Of 120 cases, forty‐two had clinically meaningful changes in treatment with positive expected outcomes (7 colorectal, 17 head and neck, 11 lung, 7 myeloma; 23–57%). Two patients had negative expected outcomes from having sought a second opinion, with worse short‐term morbidity and unchanged long‐term morbidity and prognosis. All those with positive expected outcomes had improved expected morbidity (short‐ and/or long‐term); 11 (0–23%) also had improved expected prognosis. Nine involved a shift from treatment to observation; 21 involved eliminating or reducing the extent of surgery, compared to 6 adding surgery or increasing its extent. Of the 42 with treatment changes, 13 were due to clinically meaningful diagnostic changes (1 colorectal, 5 head and neck, 3 lung, 4 myeloma; 3%–17%) . Conclusions Second‐opinion consultations sometimes add clinical value by improving expected prognoses; more often, they offer treatment de‐escalations, with corresponding reductions in expected short‐ and/or long‐term morbidity. Future research could identify subgroups of patients most likely to benefit from second opinions.

Abstract Hypothalamic oxytocin (OXT) and arginine-vasopressin (AVP) neurons have been at the center of several physiological and behavioral studies. Advances in viral vector biology and the development of transgenic rodent models have allowed for targeted gene expression to study the functions of specific cell populations and brain circuits. In this study, we compared the efficiency of various adeno-associated viral vectors in these cell populations and demonstrated that none of the widely used promoters were, on their own, effective at driving expression of a down-stream fluorescent protein in OXT or AVP neurons. As anticipated, the OXT promoter could efficiently drive gene expression in OXT neurons and this efficiency is solely attributed to the promoter and not the viral serotype. We also report that a dual virus approach using an OXT promoter driven Cre recombinase significantly improved the efficiency of viral transduction in OXT neurons. Finally, we demonstrate the utility of the OXT promoter for conducting functional studies on OXT neurons by using an OXT specific viral system to record neural activity of OXT neurons in lactating female rats across time. We conclude that extreme caution is needed when employing non-neuron-specific viral approaches/promoters to study neural populations within the paraventricular nucleus of the hypothalamus.

Accomplishing a communication task in the real world requires the ability not only to do the task per se but also to manage aspects of the context in which it occurs. For this reason, simulations of target language use contexts have been incorporated into the design of communicative language tests as a way of enhancing the authenticity of assessment task performance. Although some contextual factors may increase extraneous cognitive load and distract learners from focusing on the task at hand (Sweller, 1994), they represent important design considerations in task-based language assessment (TBLA), where the purpose of assessment is to determine what second language (L2) learners can do with the target language in the real world. In that sense, the extraneous cognitive load might well be part of the construct we are interested in assessing. Accordingly, the current study simulated aspects of a real-world task performance context as part of an email writing task assessment. Simulated context was operationalized as (a) additional information about the task scenario, (b) a visual image to simulate the physical context, and (c) an audio to replicate the real-world experience. A total of 276 L2 English learners performed the email task, half with simulated context and the other half without it. Findings revealed that, when presented with simulated context, the tasks were perceived by participants to have induced more time pressure and to be more interesting. In terms of performance effects, the provision of simulated context negatively affected the syntactic complexity of participants' writing but positively affected their syntactic fluency. It also led to greater discrimination among learners at different proficiency levels on various measures of language performance. The paper concludes by highlighting implications for task design and validity evaluation, especially in TBLA.

Abstract Background For communities of people living with hemophilia and other genetic conditions, gene therapy could represent a paradigm shift in treatment strategies. As investigational therapeutic modalities such as gene therapy become more widely used and discussed, there is a critical need for all stakeholders to communicate using a lexicon that is intelligible, accurate, consistent, and representative of novel treatments. In doing so, expectations can be more carefully managed and potential risks, benefits, and limitations better understood. In recognition of this need, a first-ever study of gene therapy lexicon was conducted using established methods of market research and linguistic analysis. Methods Ninety-four participants representing hematologists, nurses, caregivers, and people with hemophilia A, in six countries (US, UK, Spain, Germany, France, Italy) took part in a series of in-depth interviews, face-to-face focus groups, an advisory board meeting, and online group interviews to develop, refine, and test verbal, written, and pictorial language concepts through a three-phase iterative process. Sessions were conducted in local languages using detailed discussion guides. Feedback from participants was captured using real-time instant-response dial testing to measure moment-by-moment emotional responses to language stimuli. Semiquantitative analysis of the responses informed selection of preferred language concepts for final testing, and qualitative discussion explored preference rationale. Participants also completed polling and forced rank and choice written exercises. Results Study feedback showed that the hemophilia community has preferences around consistent lexicon to describe hemophilia and its management. Expert linguistic analysis of feedback from the three phases enabled agreement of a consensus lexicon of vocabulary and an optimized summary narrative for talking about gene therapy amongst people affected by hemophilia A. Preferences were largely consistent across audiences and countries, although some country-specific recommendations were made. A representative summary phrase was agreed: “Gene therapy is being studied in clinical trials with the aim to allow the body to produce factor VIII protein on its own”. Conclusions The use of preferred language across different stakeholders increases understanding and comfort during discussions of novel and complex therapeutic modalities such as gene therapy. Consistent use of community-informed lexicon minimizes miscommunication and facilitates informed decision-making regarding potential future treatment opportunities.

Abstract Differentiating pseudoprogression from true tumor progression has become a significant challenge in follow-up of diffuse infiltrating gliomas, particularly high grade, which leads to a potential treatment delay for patients with early glioma recurrence. In this study, we proposed to use a multiparametric MRI data as a sequence input for the convolutional neural network with the recurrent neural network based deep learning structure to discriminate between pseudoprogression and true tumor progression. In this study, 43 biopsy-proven patient data identified as diffuse infiltrating glioma patients whose disease progressed/recurred were used. The dataset consists of five original MRI sequences; pre-contrast T1-weighted, post-contrast T1-weighted, T2-weighted, FLAIR, and ADC images as well as two engineered sequences; T1post–T1pre and T2–FLAIR. Next, we used three CNN-LSTM models with a different set of sequences as input sequences to pass through CNN-LSTM layers. We performed threefold cross-validation in the training dataset and generated the boxplot, accuracy, and ROC curve, AUC from each trained model with the test dataset to evaluate models. The mean accuracy for VGG16 models ranged from 0.44 to 0.60 and the mean AUC ranged from 0.47 to 0.59. For CNN-LSTM model, the mean accuracy ranged from 0.62 to 0.75 and the mean AUC ranged from 0.64 to 0.81. The performance of the proposed CNN-LSTM with multiparametric sequence data was found to outperform the popular convolutional CNN with a single MRI sequence. In conclusion, incorporating all available MRI sequences into a sequence input for a CNN-LSTM model improved diagnostic performance for discriminating between pseudoprogression and true tumor progression.

Expansion of an initial population of T cells is essential for cellular immunotherapy. In Chronic Lymphocytic Leukemia (CLL), expansion is often complicated by lack of T cell proliferation, as these cells frequently show signs of exhaustion. This report seeks to identify specific biomarkers or measures of cell function that capture the proliferative potential of a starting population of cells. Mixed CD4+/CD8+ T cells from healthy donors and individuals previously treated for CLL were characterized on the basis of proliferative potential and in vitro cellular functions. Single-factor analysis found little correlation between the number of populations doublings reached during expansion and either Rai stage (a clinical measure of CLL spread) or PD-1 expression. However, inclusion of in vitro IL-2 secretion and the propensity of cells to align onto micropatterned features of activating proteins as factors identified three distinct groups of donors. Notably, these group assignments provided an elegant separation of donors with regards to proliferative potential. Furthermore, these groups exhibited different motility characteristics, suggesting a mechanism that underlies changes in proliferative potential. This study describes a new set of functional readouts that augment surface marker panels to better predict expansion outcomes and clinical prognosis.

Background Although the Society for Immunotherapy of Cancer (SITC) Immunotherapy Resistance Taskforce recently defined primary and secondary resistance to anti-programmed cell death protein 1 (anti-PD-1) therapy, there is lack of real-world data regarding differences in these resistance subtypes with respect to radiological dynamics and clinical manifestations.Methods We performed single-blind re-evaluations of radiological images by independent radiologists on a retrospectively assembled cohort of patients with advanced melanoma (n=254, median follow-up 31 months) receiving anti-PD-1 monotherapy at Massachusetts General Hospital and Peking University Cancer Hospital. Radiological characteristics and timing at multiple crucial time points were analyzed and correlated with each other and with survival. Primary and secondary resistance was defined as per the SITC Immunotherapy Resistance Taskforce definitions.Results The most significant target lesion measurement change took place within the first 3 months after anti-PD-1 initiation. Patients with stable disease with versus without tumor shrinkage at the initial evaluation exhibited distinct disease trajectory, as the rate of further upgrade to a partial or complete remission (CR/PR) was 44% and 0%, respectively. Eleven per cent of PR patients ultimately achieved a CR. In multivariate analyses, deeper response depth was independently associated with a more limited progression pattern, fewer involved organs, lower tumor burden, slower growth rate at disease progression (PD) (all p≤0.001), and longer post-progression survival (PPS) (bivariate analysis, p=0.005). Compared with primary resistance, secondary resistance was associated with less widespread PD pattern, lower tumor burden and slower tumor growth (all p≤0.001). Patients with secondary resistance were less likely to receive further systemic therapy (28% vs 57%, p

Metastatic melanoma is one of the most immunogenic malignancies due to its high rate of mutations and neoantigen formation. Response to BRAF inhibitors (BRAFi) may be determined by intratumoral immune activation within melanoma metastases. To evaluate whether CD8+ T cell infiltration and distribution within melanoma metastases can predict clinical response to BRAFi, we developed a methodology to integrate immunohistochemistry with automated image analysis of CD8+ T cell position. CD8+ distribution patterns were correlated with gene expression data to identify and quantify “hot” areas within a tumor. Furthermore, the relative activation of CD8+cells, based on transcriptomic analysis, and their relationship to other CD8+ T cells and non-CD8+ cells within the tumor suggested a less crowded distribution of cells around activated CD8+ T cells. Furthermore, the relative activation of these CD8+ T cells was associated with improved clinical outcomes and decreased tumor cell proliferation. This study demonstrates the potential of digital pathomics to incorporate immune cell spatial distribution within metastases and RNAseq analysis to predict clinical response to BRAF inhibition in metastatic melanoma.

The Seoul Metropolitan Area (SMA) has a population of 24 million and frequently experiences unhealthy levels of ozone (O3). In this work, measurements taken during the Korea-United States Air Quality Study (KORUS-AQ, 2016) are used to explore regional gradients in O3 and its chemical precursors, and an observationally-constrained 0-D photochemical box model is used to quantify key aspects of O3 production including its sensitivity to precursor gases. Box model performance was evaluated by comparing modeled concentrations of select secondary species to airborne measurements. These comparisons indicate that the steady state assumption used in 0-D box models cannot describe select intermediate species, highlighting the importance of having a broad suite of trace gases as model constraints. When fully constrained, aggregated statistics of modeled O production rates agreed with observed changes in O3, indicating that the box model was able to represent the majority of O3 chemistry. Comparison of airborne observations between urban Seoul and a downwind receptor site reveal a positive gradient in O3 coinciding with a negative gradient in NOx, no gradient in CH2O, and a slight positive gradient in modeled rates of O3 production. Together, these observations indicate a radical-limited (VOC-limited) O3 production environment in the SMA. Zero-out simulations identified C7+ aromatics as the dominant VOC contributors to O3 production, with isoprene and anthropogenic alkenes making smaller but appreciable contributions. Simulations of model sensitivity to decreases in NOx produced results that were not spatially uniform, with large increases in O3 production predicted for urban Seoul and decreases in O3 production predicted for far-outlying areas. The policy implications of this work are clear: Effective O3 mitigation strategies in the SMA must focus on reducing local emissions of C7+ aromatics, while reductions in NOx emissions may increase O3 in some areas but generally decrease the regional extent of O3 exposure.

Abstract Mutant Cu/Zn superoxide dismutase (SOD1) causes mitochondrial alterations that contribute to motor neuron demise in amyotrophic lateral sclerosis (ALS). When mitochondria are damaged, cells activate mitochondria quality control (MQC) mechanisms leading to mitophagy. Here, we show that in the spinal cord of G93A mutant SOD1 transgenic mice (SOD1‐G93A mice), the autophagy receptor p62 is recruited to mitochondria and mitophagy is activated. Furthermore, the mitochondrial ubiquitin ligase Parkin and mitochondrial dynamics proteins, such as Miro1, and Mfn2, which are ubiquitinated by Parkin, and the mitochondrial biogenesis regulator PGC1α are depleted. Unexpectedly, Parkin genetic ablation delays disease progression and prolongs survival in SOD1‐G93A mice, as it slows down motor neuron loss and muscle denervation and attenuates the depletion of mitochondrial dynamics proteins and PGC1α. Our results indicate that Parkin is a disease modifier in ALS, because chronic Parkin‐mediated MQC activation depletes mitochondrial dynamics‐related proteins, inhibits mitochondrial biogenesis, and worsens mitochondrial dysfunction.

Prescription renewal requests were reviewed by student pharmacists on advanced pharmacy practice experiences (APPE) at a primary care and family medicine clinic. Student pharmacists reviewed requests and triaged them to the respective primary care provider (PCP), along with any recommendations to optimize the medication regimen. This study aims to assess the acceptance of these recommendations as well as the student’s perception of this activity as a learning tool. A total of 35 4th-year pharmacy students participated in this activity during APPE rotations from May 2019 to March 2021. A total of 184 recommendations were made, with 128 (70%) being accepted by PCPs. Based on a post-rotation anonymous survey, students reported high levels of agreeance that this activity had a positive impact on their education in a variety of ways. This prescription renewal request review process has been shown to have a positive impact on patient care and clinic workflow while also providing pharmacy students with a helpful educational activity.

A novel deep learning architecture was explored to create synthetic CT (MRCT) images that preserve soft tissue contrast necessary for support of patient positioning in Radiation therapy. A U-Net architecture was applied to learn the correspondence between input T1-weighted MRI and spatially aligned corresponding CT images. The network was trained on sagittal images, taking advantage of the left-right symmetry of the brain to increase the amount of training data for similar anatomic positions. The output CT images were divided into three channels, representing Hounsfield Unit (HU) ranges of voxels containing air, soft tissue, and bone, respectively, and simultaneously trained using a combined Mean Absolute Error (MAE) and Mean Squared Error (MSE) loss function equally weighted for each channel. Training on 9192 image pairs yielded resulting synthetic CT images on 13 test patients with MAE of 17.6+/−3.4 HU (range 14–26.5 HU) in soft tissue. Varying the amount of training data demonstrated a general decrease in MAE values with more data, with the lack of a plateau indicating that additional training data could further improve correspondence between MRCT and CT tissue intensities. Treatment plans optimized on MRCT-derived density grids using this network for 7 radiosurgical targets had doses recalculated using the corresponding CT-derived density grids, yielding a systematic mean target dose difference of 2.3% due to the lack of the immobilization mask on the MRCT images, and a standard deviation of 0.1%, indicating the consistency of this correctable difference. Alignment of MRCT and cone beam CT (CBCT) images used for patient positioning demonstrated excellent preservation of dominant soft tissue features, and alignment comparisons of treatment planning CT scans to CBCT images vs. MRCT to CBCT alignment demonstrated differences of −0.1 (σ 0.2) mm, −0.1 (σ 0.3) mm, and −0.2 (σ 0.3) mm about the left-right, anterior-posterior and cranial-caudal axes, respectively.

Two clinical pharmacy faculty members from a college of pharmacy provide comprehensive medication management in a rural family medicine clinic. The data was assessed for patients with diabetes managed by the pharmacists from 1 January 2017 through to 31 December 2019 to determine the service’s impact on patient outcomes. The primary outcome of this study is the change in the goal attainment rates of the three clinical goals of hemoglobin A1c, blood pressure, and appropriate statin therapy after pharmacist intervention. A total of 207 patients were included. At baseline, the patients had an average of 1.13 of the three goals met, improving to an average of 2.02 goals met after pharmacist intervention (p < 0.001). At baseline, 4.8% of the patients had met all three clinical goals, improving to 30.9% after pharmacist intervention (p < 0.001). There were significant improvements for the individual goal attainment rates of hemoglobin A1c (24.15% vs. 51.21%, p < 0.001), blood pressure (42.51% vs. 85.51%, p < 0.001), and appropriate statin therapy (45.89% vs. 65.70%, p < 0.001). This data adds to the evidence supporting the integration of clinical pharmacists into primary care clinics to improve patient outcomes related to diabetes.

The Elicited Imitation Task (EIT) is a popular technique for efficiently measuring global proficiency in multiple languages, and accumulated evidence indicates high reliability and strong relationships with other proficiency measures. Nevertheless, several dimensions of EIT design remain open to investigation, including the assumption that a pause is required in between the aural stimulus and oral response, to ensure processing of the input and prevent so-called parroting. This study investigated the relationship between three poststimulus pause conditions, learners' proficiency and working memory, and their EIT scores as well as their perceptions of task difficulty, mental effort, focus, and interest. Findings indicated no differences in performances or perceptions between the 0-second pause, 2-second pause, and 5-second pause conditions, and a weak relationship between EIT performance and working memory. Across all conditions, the EIT distinguished consistently among proficiency levels, correlated strongly with a criterion proficiency measure, and produced remarkably reliable scores.

BACKGROUND: As a result of rising levels of drug resistance to conventional monotherapy, the World Health Organization (WHO) and other international organisations have recommended that malaria endemic countries move to combination therapy, ideally with artemisinin-based combinations (ACTs). Cost is a major barrier to deployment. There is little evidence from field trials on the cost-effectiveness of these new combinations. METHODS AND FINDINGS: An economic evaluation of drug combinations was designed around a randomised effectiveness trial of combinations recommended by the WHO, used to treat Tanzanian children with non-severe slide-proven malaria. Drug combinations were: amodiaquine (AQ), AQ with sulfadoxine-pyrimethamine (AQ+SP), AQ with artesunate (AQ+AS), and artemether-lumefantrine (AL) in a six-dose regimen. Effectiveness was measured in terms of resource savings and cases of malaria averted (based on parasitological failure rates at days 14 and 28). All costs to providers and to patients and their families were estimated and uncertain variables were subjected to univariate sensitivity analysis. Incremental analysis comparing each combination to monotherapy (AQ) revealed that from a societal perspective AL was most cost-effective at day 14. At day 28 the difference between AL and AQ+AS was negligible; both resulted in a gross savings of approximately US1.70 dollars or a net saving of US22.40 dollars per case averted. Varying the accuracy of diagnosis and the subsistence wage rate used to value unpaid work had a significant effect on the number of cases averted and on programme costs, respectively, but this did not change the finding that AL and AQ+AS dominate monotherapy. CONCLUSIONS: In an area of high drug resistance, there is evidence that AL and AQ+AS are the most cost-effective drugs despite being the most expensive, because they are significantly more effective than other options and therefore reduce the need for further treatment. This is not necessarily the case in parts of Africa where recrudescence following SP and AQ treatment (and their combination) is lower so that the relative advantage of ACTs is smaller, or where diagnostic services are not accurate and as a result much of the drug goes to those who do not have malaria.

Tissue regeneration entails replenishing of damaged cells, appropriate cell differentiation and inclusion of regenerated cells into functioning tissues. In adult humans, the capacity of the injured spinal cord and muscle to self-repair is limited. In contrast, the amphibian larva can regenerate its tail after amputation with complete recovery of muscle, notochord and spinal cord. The cellular and molecular mechanisms underlying this phenomenon are still unclear. Here we show that upon injury muscle cell precursors exhibit Ca(2+) transients that depend on Ca(2+) release from ryanodine receptor-operated stores. Blockade of these transients impairs muscle regeneration. Furthermore, inhibiting Ca(2+) transients in the regenerating tail prevents the activation and proliferation of muscle satellite cells, which results in deficient muscle replenishment. These findings suggest that Ca(2+)-mediated activity is critical for the early stages of muscle regeneration, which may lead to developing effective therapies for tissue repair.