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The bromodomain and extra terminal (BET) family of proteins are an integral part of human epigenome regulation, the dysregulation of which is implicated in multiple oncology and inflammatory diseases. Disrupting the BET family bromodomain acetyl-lysine (KAc) histone protein-protein interaction with small-molecule KAc mimetics has proven to be a disease-relevant mechanism of action, and multiple molecules are currently undergoing oncology clinical trials. This work describes an efficiency analysis of published GSK pan-BET bromodomain inhibitors, which drove a strategic choice to focus on the identification of a ligand-efficient KAc mimetic with the hypothesis that lipophilic efficiency could be drastically improved during optimization. This focus drove the discovery of the highly ligand-efficient and structurally distinct benzoazepinone KAc mimetic. Following crystallography to identify suitable growth vectors, the benzoazepinone core was optimized through an explore-exploit structure-activity relationship (SAR) approach while carefully monitoring lipophilic efficiency to deliver I-BET432 (

Opioid prescribing for postoperative pain management is challenging because of inter-patient variability in opioid response and concern about opioid addiction. Tramadol, hydrocodone, and codeine depend on the cytochrome P450 2D6 (CYP2D6) enzyme for formation of highly potent metabolites. Individuals with reduced or absent CYP2D6 activity (i.e., intermediate metabolizers [IMs] or poor metabolizers [PMs], respectively) have lower concentrations of potent opioid metabolites and potentially inadequate pain control. The primary objective of this prospective, multicenter, randomized pragmatic trial is to determine the effect of postoperative CYP2D6-guided opioid prescribing on pain control and opioid usage. Up to 2020 participants, age ≥8 years, scheduled to undergo a surgical procedure will be enrolled and randomized to immediate pharmacogenetic testing with clinical decision support (CDS) for CYP2D6 phenotype-guided postoperative pain management (intervention arm) or delayed testing without CDS (control arm). CDS is provided through medical record alerts and/or a pharmacist consult note. For IMs and PM in the intervention arm, CDS includes recommendations to avoid hydrocodone, tramadol, and codeine. Patient-reported pain-related outcomes are collected 10 days and 1, 3, and 6 months after surgery. The primary outcome, a composite of pain intensity and opioid usage at 10 days postsurgery, will be compared in the subgroup of IMs and PMs in the intervention (n = 152) versus the control (n = 152) arm. Secondary end points include prescription pain medication misuse scores and opioid persistence at 6 months. This trial will provide data on the clinical utility of CYP2D6 phenotype-guided opioid selection for improving postoperative pain control and reducing opioid-related risks.

This paper presents the findings from a detailed study investigating UK undergraduate students’ experience of practical science in their post-16 studies during the COVID-19 pandemic. It also examines the perceived confidence and preparedness of the students in relation to areas of practical science skills at the start of their degree courses. The study employed an exploratory sequential mixed methods design, with the findings from focus groups with students at the end of their post-16 studies used to support the development of a comprehensive quantitative survey for incoming undergraduate students. Survey data were collected in September and October 2021 from 275 students commencing Biological Science/Life Science, Chemistry, Physics and Natural Science degrees at two universities in England.The research is significant for its finding that although almost all students had the opportunity to undertake practical work as part of their post-16 studies during the COVID-19 pandemic, there was significant variation in students’ experiences. The data indicate that students’ self-efficacy in relation to practical science was impacted by the closures of post-16 education establishments, ongoing social distancing and the removal of the assessment criteria for students to have ‘routinely and consistently’ undertaken each of the practical assessment requirements. The research presents important considerations which are relevant for educators supporting students’ transition from post-16 to Higher Education.

Systemic or structural racism describes an embedded pattern of explicit and implicit racial biases that, through policy and action, systematically confer advantage to white people and disadvantage Black, indigenous, and other people of color. Hospice and palliative care journals participate in this broader system of racial discrimination. Building on palliative care's explicit focus on patients' goals and values, which may in and of itself comprise a form of social justice in healthcare, palliative care journals and their publishers have an opportunity to lead others in cultivating anti-racist practices and explicitly promoting equity. The publication life cycle of submission and solicitation, manuscript peer-review, and publication provide a framework for examining the structures, processes, and outcomes by which palliative care and other journals might address systemic racism. We describe the current academic publishing landscape, which diminishes the voices and experiences of racial and ethnic minority patients and undermines the careers of under-represented scholars. We then propose reforms that we believe will improve publication equity and quality as well as healthcare outcomes. These include an Equity in Publication checklist, solicitation of manuscripts on equity-relevant topics, promotion of scholars through editorial structures and peer review processes, and a standard Equity Rating for publications. Greater efforts to include non-dominant voices in every aspect of publication, through appropriate recognition of their scholarship and remuneration for their efforts, will drive equity in health outcomes. By pursuing an anti-racist and equity-focused publishing agenda, hospice and palliative medicine journals and their publishers have an opportunity to transform healthcare.

Background: Experts consider goal-concordant care an important healthcare outcome for individuals with serious illness. Despite their relationship to the patient and knowledge about the patient’s wishes and values, little is known about bereaved family caregivers’ perceptions of how end-of-life care aligns with patient goals and preferences. Aim: To understand caregivers’ perceptions about patients’ care experiences, the extent to which care was perceived as goal-concordant, and the factors that contextualized the end-of-life care experience. Design: Qualitative interview study employing a semi-structured interview guide based on the National Health and Aging Trends Survey end-of-life planning module. Template analysis was used to identify themes. Setting/participants: Nineteen recently bereaved family caregivers of people with serious illness in two academic medical centers in the Northeastern United States. Results: Most caregivers reported goal-concordant care, though many also recalled experiences of goal discordance. Three themes characterized care perceptions and related to perceived quality: communication, relationships and humanistic care, and care transitions. Within communication, caregivers described the importance of clear communication, inadequate prognostic communication, and information gaps that undermined caregiver confidence in decision making. Patient-clinician relationships enriched care and were considered higher-quality when felt to be humanistic. Finally, care transitions impacted goal discordance when marked by logistical barriers, a need to establish relationships with new providers, inadequate information transfer, and poor care coordination. Conclusions: Bereaved caregivers commonly rated care as goal-concordant while also identifying areas of disappointing and low-quality care. Communication, relationships and humanistic care, and care transitions are modifiable quality improvement targets for patients with advanced cancer.

Made available in DSpace on 2022-04-29T08:31:13Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-11-01 Savanna tree communities occurring in confluence zones with other biomes likely experience different environmental pressures, resulting in shifts in the selection of individual traits, the combinations of such traits, and species composition. In seasonally dry fire-prone environments, plant survival is presumably associated with adaptive changes in bark properties related to fire protection and water storage. Here, we integrated the multiple functions of the bark to investigate whether different selective pressures could influence patterns of variation in bark structure and allocation across species in a broad geographical range. We measured thickness, density, and water content of the inner and outer bark in branches and the main stem of the 51 most abundant species in three savanna communities differing in climatic aridity, one located at the core region of Cerrado in Central Brazil and the other two at its periphery, in the transition zones with Amazonia and Atlantic forest biomes. We found no difference in outer bark thickness but markedly difference in inner bark thickness between the three plant communities. In the central region, where dry season is long and fire is frequent, branches and main stem showed thicker inner bark. Contrastingly, in the south periphery region, where dry season is short, species showed thinner inner bark in both branches and main stem. Species from the north periphery region, where mean annual precipitation is higher, but fire is frequent and the dry season is also long, showed similar main stem inner bark thickness, but thinner branch inner bark compared to core region species. Our findings support the idea that investing in inner bark thickness and bark moisture may be the most advantageous strategy in plant communities that suffer from high evaporative demand during a long period and are at a high risk of fire. Programa de Pós-Graduação em Ecologia e Conservação Universidade Federal do Paraná Departamento de Biologia Faculdade de Ciências Agrárias e Veterinárias Universidade Estadual Paulista Environmental Change Institute School of Geography and the Environment University of Oxford Departamento de Botânica Universidade Federal de São Carlos Department of Biological Sciences Macquarie University Departamento de Zoologia Universidade Federal do Paraná Laboratório de Ecologia Funcional de Comunidades (LABEF) Departamento de Botânica Universidade Federal do Paraná Department of Plant & Microbial Biology North Carolina State University Programa de Pós-graduação em Ecologia e Conservação Universidade do Estado de Mato Grosso – UNEMAT Laboratório de Ecofisiologia Vegetal Departamento de Botânica Instituto de Ciências Biológicas Universidade de Brasília Select Carbon Pty Ltd Departamento de Biologia Faculdade de Ciências Agrárias e Veterinárias Universidade Estadual Paulista

In the past decade, the demand for home-based care has been amplified by the COVID-19 pandemic. Home-based care has significant benefits for patients, their families, and healthcare systems, but relies on the often invisible workforce of family and friend caregivers who shoulder essential health care responsibilities often with inadequate training and support. Hematopoietic cell transplantation (HCT), a potentially curative but intensive treatment for many patients with blood disorders, is increasingly offered in home-based care settings and necessitates the involvement of family caregivers for significant patient care responsibilities. However, guidelines for supporting and preparing HCT caregivers to effectively care for their loved ones at home have not yet been established. Informed by extant literature and our collective experiences as clinicians and researchers who care for diverse patients with hematologic malignancies undergoing HCT, we provide considerations and recommendations to better support and prepare family caregivers in home-based HCT and, by extension, family caregivers supporting patients with other serious illnesses at home. We suggest tangible ways to screen family caregivers for distress and care delivery challenges, educate and train them to prepare for their caregiving role, and create an infrastructure of support for family caregivers within this emerging care delivery model.

We simulate two sets of dissolution experiments in which CO2-saturated solutions are injected into calcite formations. We explore the impact of non-linear reaction kinetics and charge-coupled ion transport in systems representing different levels of flow and mineralogical complexity. First, we flow CO2-saturated water and brine through cylindrical channels drilled through solid calcite cores and compare directly with experimental dissolution rates. We find that simulations using a linear saturation model match experimental results much better than the batch-reactor-derived non-linear saturation model. The use of a coupled diffusion model causes only a very small increase in the overall dissolution rate compared to a single diffusion coefficient, due to the increase in transport rates of reaction products, particularly the highly charged Ca2+ ion. We also determine the relative importance of the two calcite dissolution pathways, with H+ and H2CO3, and conclude that the H2CO3 – calcite reaction is by far the more dominant, in contrast with common assumptions in the literature. Then, we compare to the experiments of Menke et al. (2015) in which CO2-saturated brine was injected into a microporous Ketton carbonate, and compare dissolution rates over time. We find that including non-linear saturation behaviour markedly changes the simulated dissolution rate, by up to a factor of 0.7 in the case of the experimentally derived saturation model of Anabaraonye (2017), however neither case matches the experimental result which is several times slower than the simulation. Including the effects of coupled ion transport lead to virtually no change in overall dissolution rate due to the convection dominated behaviour. The model also shows differences in the trend of the dissolution rate over time observed in Menke et al, with an approximately linear relationship with time compared to the experimental square-root dependence on time. We conclude that the geochemical model may need to include other effects such as dissolution inside microporous regions.

The proper balance of synthesis, folding, modification, and degradation of proteins, also known as protein homeostasis, is vital to cellular health and function. The unfolded protein response (UPR) is activated when the mechanisms maintaining protein homeostasis in the endoplasmic reticulum become overwhelmed. However, prolonged or strong UPR responses can result in elevated inflammation and cellular damage. Previously, we discovered that the enzyme filamentation induced by cyclic-AMP (Fic) can modulate the UPR response via posttranslational modification of binding immunoglobulin protein (BiP) by AMPylation during homeostasis and deAMPylation during stress. Loss of fic in Drosophila leads to vision defects and altered UPR activation in the fly eye. To investigate the importance of Fic-mediated AMPylation in a mammalian system, we generated a conditional null allele of Fic in mice and characterized the effect of Fic loss on the exocrine pancreas. Compared to controls, Fic −/− mice exhibit elevated serum markers for pancreatic dysfunction and display enhanced UPR signaling in the exocrine pancreas in response to physiological and pharmacological stress. In addition, both fic −/− flies and Fic −/− mice show reduced capacity to recover from damage by stress that triggers the UPR. These findings show that Fic-mediated AMPylation acts as a molecular rheostat that is required to temper the UPR response in the mammalian pancreas during physiological stress. Based on these findings, we propose that repeated physiological stress in differentiated tissues requires this rheostat for tissue resilience and continued function over the lifetime of an animal.

BACKGROUND: The use of metaphyseal cones and sleeves has improved the ability to manage tibial bone loss in revision total knee arthroplasty (TKA). The purpose of this study was to compare the outcomes of three systems used for tibial metaphyseal reconstruction in revision TKA. METHODS: We performed a retrospective review of a consecutive series of 723 revision TKAs, including 145 (20%) knee revisions using tibial cones or sleeves. We compared porous tantalum (TM) cones, titanium (Ti) cones and titanium sleeves. The mean follow-up was 2.5 years. RESULTS: The rate of revision for any reason was similar among all groups. Revision-free survival rates were similar among all systems studied at a mean follow-up of 2.5 years (TM cones 93%, Ti cones 94%, titanium sleeves 89%). Ti cones had a lower complication rate (6%) compared to TM cones (24%) and sleeves (29%). TM cones (15%) and titanium sleeves (13%) had higher reoperation rates (for any cause) than Ti cones (2%). Radiographic loosening was higher for sleeves (11%) than TM and Ti cones (2%). CONCLUSION: Metaphyseal reconstruction for tibial bone loss in revision TKA using tantalum cones, titanium cones and titanium sleeves showed successful and comparable early clinical outcomes at a mean follow-up of 2.5 years with higher rates of radiographic loosening for titanium sleeves. Level of Evidence: III

Objectives: This study aimed to understand the experiences of youth who had been prescribed antipsychotics but did not have psychosis, mania, autism spectrum disorder, or developmental disability. Methods: Twenty-three qualitative telephone interviews were conducted with youth aged 11–18 who had been prescribed an antipsychotic medication but did not have a diagnosis of psychotic disorder, bipolar disorder, autism spectrum disorder, or developmental disability. Participants were recruited from four U.S. healthcare systems participating in the pragmatic trial Safer Use of Antipsychotics in Youth (SUAY). Interviews were recorded, transcribed and analyzed using template analysis techniques. Results: Prior to initiating an antipsychotic medication, most participants experienced behavioral health crises; many felt that they had no options other than to start the medication. Other core themes included: (1) antipsychotics had both positive psychosocial outcomes, such as improvement of family life, and adverse effects, such as drowsiness or weight gain, (2) antipsychotics were only one part of a broader treatment plan, (3) efforts were made to maximize benefits and minimize side effects through careful titration, (4) feedback from friends and family was important in the decision to continue. Conclusions: The findings provide valuable insights into how to engage youth in conversations around the use of antipsychotics.

Objective Electronic health record documentation by intensive care unit (ICU) clinicians may predict patient outcomes. However, it is unclear whether physician and nursing notes differ in their ability to predict short-term ICU prognosis. We aimed to investigate and compare the ability of physician and nursing notes, written in the first 48 hours of admission, to predict ICU length of stay and mortality using 3 analytical methods. Materials and Methods This was a retrospective cohort study with split sampling for model training and testing. We included patients ≥18 years of age admitted to the ICU at Beth Israel Deaconess Medical Center in Boston, Massachusetts, from 2008 to 2012. Physician or nursing notes generated within the first 48 hours of admission were used with standard machine learning methods to predict outcomes. Results For the primary outcome of composite score of ICU length of stay ≥7 days or in-hospital mortality, the gradient boosting model had better performance than the logistic regression and random forest models. Nursing and physician notes achieved area under the curves (AUCs) of 0.826 and 0.796, respectively, with even better predictive power when combined (AUC, 0.839). Discussion Models using only nursing notes more accurately predicted short-term prognosis than did models using only physician notes, but in combination, the models achieved the greatest accuracy in prediction. Conclusions Our findings demonstrate that statistical models derived from text analysis in the first 48 hours of ICU admission can predict patient outcomes. Physicians’ and nurses’ notes are both uniquely important in mortality prediction and combining these notes can produce a better predictive model.

Background: Nurses are well positioned to initiate advance care planning (ACP) conversations because of their unique strength in communication and central patient-facing role in the interdisciplinary team. Nurse-led ACP conversations have demonstrated promising results in settings outside of the emergency department (ED). Understanding ED nurses' perspectives regarding ACP conversations is needed before implementing similar practices in the ED. Objective: To explore ED nurses' perception of facilitating ACP conversations. Design: We conducted a cross-sectional survey to assess ED nurses' perceptions of facilitating ACP conversations in the ED. Setting: ED nurses at one academic hospital and one community hospital located within the northeastern region of the United States. Results: Seventy-seven (53.1%) out of 145 eligible ED nurses completed the survey. All participants perceived ACP conversations in the ED as at least somewhat important. Forty (51.9%) felt somewhat comfortable in facilitating these conversations. The majority of participants (77.9%) agreed that a specially trained nurse consultation model might be helpful in the ED. We found a correlation between total clinical experience and interest in facilitating ACP conversations in the ED (p = 0.045). Conclusion: ED nurses are well positioned to help patients clarify their goals-of-care and end-of-life care preferences. They perceived ACP conversations to be important and felt comfortable to facilitate them in the ED. Additional studies are needed to empirically test its implementation.

Total Joint Replacement (TJR) surgeries are one of the most prevalent operations that are undergone by the elderly population. With the world population aging, the number of surgeries will continue to increase. A small portion of these surgeries result in complications that require readmissions. These readmissions amount to a significant financial and time burden for both the patients and the hospitals. In the past decade machine learning and wearable sensors have both been used extensively in the healthcare domain but the contribution to the prediction/evaluation and management of TJR is limited. What’s more, to our best knowledge there has been no effort in summarizing the findings from these studies. Therefore, this study highlights what has been achieved by using machine learning and wearable sensors in the TJR context and point out possible research avenues.

Orthopaedic surgeons account for the largest proportion of opioid prescriptions in the United States among surgical specialties. In total joint arthroplasty, increased opioid use has been associated with poorer clinical and functional outcomes. Despite an abundance of literature on opioid mitigation strategies, most fail to provide personalized prescriptions. Typically, most protocols prescribe the same opioid regimen regardless of patient factors or the extent of the planned procedure. We present a simple opioid stratification pathway that can be used by physicians and office staff as they prepare patients for arthroplasty. We have found this to be easy to implement, effective, and sustainable at a tertiary academic institution and allows for iterative improvements over time.

Palliative care (PC) subspecialists and clinical ethics consultants often engage in parallel work, as both function primarily as interprofessional consultancy services called upon in complex clinical scenarios and challenging circumstances. Both practices utilize active listening, goals-based communication, conflict mediation or mitigation, and values explorations as care modalities. In this set of tips created by an interprofessional team of ethicists, intensivists, a surgeon, an attorney, and pediatric and adult PC nurses and physicians, we aim to describe some paradigmatic clinical challenges for which partnership may improve collaborative, comprehensive care.

While the supporting role of families and friends has been widely recognized in cancer care, little data exist on how they influence patients’ decisions regarding clinical trial participation, accounting for patients’ decisional preferences. The goal of our study was to examine the process of clinical trial decision-making from the perspective of adults with cancer and their decision partners. Semi-structured interviews were conducted with 12 patients and 12 decision partners—family and friends engaged in the medical decision-making. Themes included: (1) having the ability and confidence to make decisions; (2) gaining insight about clinical trials; (3) trusting someone in the process; and (4) realizing readiness and context. Our findings will enhance understanding of how patients make clinical trial decisions based on decisional preferences from the perspectives of patients and decision partners. The findings may also help to increase clinician awareness and inclusion of decision partners in conversations regarding clinical trials.

Senescent cells (SnCs) contribute to normal tissue development and repair but accumulate with aging where they are implicated in a number of pathologies and diseases. Despite their pathological role and therapeutic interest, SnC phenotype and function in vivo remains unclear due to the challenges in identifying and isolating these rare cells. Here, we developed an in vivo-derived senescence gene expression signature using a model of the foreign body response (FBR) fibrosis in a p16Ink4a-reporter mouse, a cell cycle inhibitor commonly used to identify SnCs. We identified stromal cells (CD45-CD31- CD29+) as the primary p16Ink4a expressing cell type in the FBR and collected the cells to produce a SnC transcriptomic signature with bulk RNA sequencing. To computationally identify SnCs in bulk and single-cell data sets across species and tissues, we used this signature with transfer learning to generate a SnC signature score (SenSig). We found senescent pericyte and cartilage-like fibroblasts in newly collected single cell RNAseq (scRNASeq) data sets of murine and human FBR suggesting populations associated with angiogenesis and secretion of fibrotic extracellular matrix, respectively. Application of the senescence signature to human scRNAseq data sets from idiopathic pulmonary fibrosis (IPF) and the basal cell carcinoma microenvironment identified both conserved and tissue-specific SnC phenotypes, including epithelial-derived basaloid and endothelial cells. In a wound healing model, ligand-receptor signaling prediction identified putative interactions between SnC SASP and myeloid cells that were validated by immunofluorescent staining and in vitro coculture of SnCs and macrophages. Collectively, we have found that our SenSig transfer learning strategy from an in vivo signature outperforms in vitro-derived signatures and identifies conserved and tissue-specific SnCs and their SASP, independent of p16Ink4a expression, and may be broadly applied to elucidate SnC identity and function in vivo.

Background The Risk Assessment and Prediction Tool (RAPT) was developed and validated to predict discharge disposition after primary total hip and knee arthroplasty (THA/TKA). To date, there are no studies evaluating the applicability and accuracy of RAPT for revision THA/TKA. This study aims to determine the predictive accuracy of the RAPT for revision THA/TKA. Methods Prospectively collected data from a single tertiary academic medical center were retrospectively analyzed for patients undergoing revision THA/TKA between January 2016 and July 2019. RAPT score was used to predict their postoperative discharge destination and its predictive accuracy was calculated. Patient risk (low, intermediate, and high) for postoperative inpatient rehabilitation facilities or skilled nursing facilities were determined based on the predictive accuracy of each RAPT score. Other factors evaluated included patient-reported discharge expectation, body mass index, and American Society of Anesthesiologists scores. Results A total of 716 consecutive revision THA/TKA episodes were analyzed. Overall, predictive accuracy of RAPT for discharge disposition was 83%. RAPT scores 8 were deemed high and low risk of discharge to a post–acute care facility, respectively. RAPT scores of 4 to 7 were still accurate 65%-71% of the time and were deemed to be intermediate-risk. RAPT score and patient-reported discharge expectation had the strongest correlation with actual discharge disposition. Conclusion The RAPT has high predictive accuracy for discharge planning in revision THA/TKA patients. Patient-expected discharge destination is a powerful modulator of the RAPT score and we suggest that it be taken into consideration for preoperative discharge planning.

Root-released carboxylates enhance the availability of manganese (Mn), which enters roots through transporters with low substrate specificity. Leaf Mn concentration ([Mn]) has been proposed as a signature for phosphorus (P)-mobilising carboxylates in the rhizosphere. Here we test whether leaf [Mn] provides a signature for root functional types related to P acquisition. Across 727 species at 66 sites in Australia and New Zealand, we measured leaf [Mn] as related to root functional type, while also considering soil and climate variables. To further assess the specific situations under which leaf [Mn] is a suitable proxy for rhizosphere carboxylate concentration, we studied leaf [Mn] along a strong gradient in water availability on one representative site. In addition, we focused on two systems where a species produced unexpected results. Controlling for background site-specific variation in leaf [Mn] with soil pH and mean annual precipitation, we established that mycorrhizal species have significantly lower leaf [Mn] than non-mycorrhizal species with carboxylate-releasing root structures, e.g., cluster roots. In exception to the general tendency, leaf [Mn] did not provide information about root functional types under seasonally waterlogged conditions, which increase iron availability and thereby interfere with Mn-uptake capacity. Two further exceptions were scrutinised, leading to the conclusion that they were ‘anomalous’ in not functioning like typical species in their families, as expected according to the literature. Leaf [Mn] variation provides considerable insights on differences in belowground functioning among co-occurring species. Using this approach, we concluded that, within typical mycorrhizal families, some species actually depend on a carboxylate-releasing P-mobilising strategy. Likewise, within families that are known to produce carboxylate-releasing cluster roots, some do not produce functional cluster roots when mature. An analysis of leaf [Mn] can alert us to such ‘anomalous’ species.