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Background Inappropriate diagnosis of infections results in antibiotic overuse and may delay diagnosis of underlying conditions. Here we describe the development and characteristics of 2 safety measures of inappropriate diagnosis of urinary tract infection (UTI) and community-acquired pneumonia (CAP), the most common inpatient infections on general medicine services. Methods Measures were developed from guidelines and literature and adapted based on data from patients hospitalized with UTI and CAP in 49 Michigan hospitals and feedback from end-users, a technical expert panel (TEP), and a patient focus group. Each measure was assessed for reliability, validity, feasibility, and usability. Results Two measures, now endorsed by the National Quality Forum (NQF), were developed. Measure reliability (derived from 24 483 patients) was excellent (0.90 for UTI; 0.91 for CAP). Both measures had strong validity demonstrated through (a) face validity by hospital users, the TEPs, and patient focus group, (b) implicit case review (ĸ 0.72 for UTI; ĸ 0.72 for CAP), and (c) rare case misclassification (4% for UTI; 0% for CAP) due to data errors (<2% for UTI; 6.3% for CAP). Measure implementation through hospital peer comparison in Michigan hospitals (2017 to 2020) demonstrated significant decreases in inappropriate diagnosis of UTI and CAP (37% and 32%, respectively, P <.001), supporting usability. Conclusions We developed highly reliable, valid, and usable measures of inappropriate diagnosis of UTI and CAP for hospitalized patients. Hospitals seeking to improve diagnostic safety, antibiotic use, and patient care should consider using these measures to reduce inappropriate diagnosis of CAP and UTI. [ABSTRACT FROM AUTHOR]

Background Despite antibiotic stewardship programs existing in most acute care hospitals, there continues to be variation in appropriate antibiotic use. While existing research examines individual prescriber behavior, contextual reasons for variation are poorly understood. Methods We conducted an explanatory, sequential mixed-methods study of a purposeful sample of 7 hospitals with varying discharge antibiotic overuse. For each hospital, we conducted surveys, document analysis, and semi-structured interviews with antibiotic stewardship and clinical stakeholders. Data were analyzed separately and mixed during the interpretation phase, where each hospital was examined as a case, with findings organized across cases using a strengths, weaknesses, opportunities, and threats framework to identify factors accounting for differences in antibiotic overuse across hospitals. Results Surveys included 85 respondents. Interviews included 90 respondents (31 hospitalists, 33 clinical pharmacists, 14 stewardship leaders, 12 hospital leaders). On surveys, clinical pharmacists at hospitals with lower antibiotic overuse were more likely to report feeling: respected by hospitalist colleagues (P =.001), considered valuable team members (P =.001), and comfortable recommending antibiotic changes (P =.02). Based on mixed-methods analysis, hospitals with low antibiotic overuse had 4 distinguishing characteristics: (1) robust knowledge of and access to antibiotic stewardship guidance; (2) high-quality clinical pharmacist–physician relationships; (3) tools and infrastructure to support stewardship; and (4) highly engaged infectious diseases physicians who advocated stewardship principles. Conclusions This mixed-methods study demonstrates the importance of organizational context for high performance in stewardship and suggests that improving antimicrobial stewardship requires attention to knowledge, interactions, and relationships between clinical teams and infrastructure that supports stewardship and team interactions. [ABSTRACT FROM AUTHOR]

Simple Summary: This study focuses on the spontaneous lesions observed in a captive colony of geriatric Julia Creek dunnarts, an endangered carnivorous marsupial. Despite their conservation status, no prior research has focused on the conditions affecting captive individuals attaining senescence. We examined one wild and thirty-five captive-born, mostly elderly dunnarts that failed to reproduce over several breeding periods. From these, ten dunnarts had normal findings. Among females, the most common issue was cystic glandular hyperplasia (eight cases); cutaneous lesions were infrequent (two cases). Males showed testicular degeneration, aspermatogenesis, or atrophy (three cases). Cutaneous lesions compatible with epitheliotropic T cell lymphomas were observed in both sexes (five cases) and thus, an underlying oncogenic viral etiology is suspected. This is the first study that documents spontaneous diseases in aging Julia Creek dunnarts, shedding light on geriatric conditions within a conservation context. Julia Creek dunnarts are an endangered species of carnivorous marsupials and the focus of multiple conservation strategies involving significant resources such as captive breeding programs. Despite the relevance for conservation, no study to date has focused on evaluating geriatric diseases in dunnarts. This study describes the pathology findings in a group of one wild and thirty-five captive-born, mostly geriatric Julia Creek dunnarts that failed to produce offspring over multiple breeding periods. A total of 20 females and 16 males were submitted for a postmortem examination, with ages ranging from 9 to 42 and 12 to 42 months for females and males, respectively. Of these, 10 had unremarkable findings. The most common condition in females was cystic glandular hyperplasia (n = 8), typical of hormonal dysregulation profiles in senescence, particularly hyperestrogenism. Rarely, cutaneous disease represented by unidentified dermal round cell infiltrates was observed in females (n = 2). Primary reproductive hormonal dysregulation was also suspected in males diagnosed with testicular degeneration, aspermatogenesis and/or atrophy (n = 3). Cutaneous round cell infiltrates, possibly compatible with epitheliotropic lymphomas, were seen in males (n = 3), and 2/3 affected males also had concurrent testicular degeneration or atrophy, indicating male sex could be a predictor for lymphoid neoplasia in aged dunnarts, especially in individuals with concurrent testosterone-luteinizing hormone dysregulation as it occurs in gonadectomized animals. The role of an underlying viral etiology is also explored. This study is the first to describe major spontaneous diseases in endangered aged Julia Creek dunnarts, providing an important understanding of senescence and geriatric diseases within a conservation context. [ABSTRACT FROM AUTHOR]

Background: Antibiotic overuse at hospital discharge is common, costly, and harmful. While discharge-specific antibiotic stewardship interventions are effective, they are resource-intensive and often infeasible for hospitals with resource constraints. This weakness impacts generalizability of stewardship interventions and has health equity implications as not all patients have access to the benefits of stewardship based on where they receive care. There may be different pathways to improve discharge antibiotic prescribing that vary widely in feasibility. Supporting hospitals in selecting interventions tailored to their context may be an effective approach to feasibly reduce antibiotic overuse at discharge across diverse hospitals. The objective of this study is to evaluate the effectiveness of the Reducing Overuse of Antibiotics at Discharge Home multicomponent implementation strategy ("ROAD Home") on antibiotic overuse at discharge for community-acquired pneumonia and urinary tract infection. Methods: This 4-year two-arm parallel cluster-randomized trial will include three phases: baseline (23 months), intervention (12 months), and postintervention (12 months). Forty hospitals recruited from the Michigan Hospital Medicine Safety Consortium will undergo covariate-constrained randomization with half randomized to the ROAD Home implementation strategy and half to a "stewardship as usual" control. ROAD Home is informed by the integrated-Promoting Action on Research Implementation in Health Services Framework and includes (1) a baseline needs assessment to create a tailored suite of potential stewardship interventions, (2) supported decision-making in selecting interventions to implement, and (3) external facilitation following an implementation blueprint. The primary outcome is baseline-adjusted days of antibiotic overuse at discharge. Secondary outcomes include 30-day patient outcomes and antibiotic-associated adverse events. A mixed-methods concurrent process evaluation will identify contextual factors influencing the implementation of tailored interventions, and assess implementation outcomes including acceptability, feasibility, fidelity, and sustainment. Discussion: Reducing antibiotic overuse at discharge across hospitals with varied resources requires tailoring of interventions. This trial will assess whether a multicomponent implementation strategy that supports hospitals in selecting evidence-based stewardship interventions tailored to local context leads to reduced overuse of antibiotics at discharge. Knowledge gained during this study could inform future efforts to implement stewardship in diverse hospitals and promote equity in access to the benefits of quality improvement initiatives. Trial registration: Clinicaltrials.gov NCT06106204 on 10/30/23 [ABSTRACT FROM AUTHOR]

The thymus is a unique primary lymphoid organ that supports the production of self‐tolerant T‐cells essential for adaptive immunity. Intrathymic microenvironments are microanatomically compartmentalised, forming defined cortical, and medullary regions each differentially supporting critical aspects of thymus‐dependent T‐cell maturation. Importantly, the specific functional properties of thymic cortical and medullary compartments are defined by highly specialised thymic epithelial cells (TEC). For example, in the medulla heterogenous medullary TEC (mTEC) contribute to the enforcement of central tolerance by supporting deletion of autoreactive T‐cell clones, thereby counterbalancing the potential for random T‐cell receptor generation to contribute to autoimmune disease. Recent advances have further shed light on the pathways and mechanisms that control heterogeneous mTEC development and how differential mTEC functionality contributes to control self‐tolerant T‐cell development. Here we discuss recent findings in relation to mTEC development and highlight examples of how mTEC diversity contribute to thymus medulla function. [ABSTRACT FROM AUTHOR]

As the primary site of T-cell development, the thymus dictates immune competency of the host. The rates of thymus function are not constant, and thymus regeneration is essential to restore new T-cell production following tissue damage from environmental factors and therapeutic interventions. Here, we show the alarmin interleukin (IL) 33 is a product of Sca1+ thymic mesenchyme both necessary and sufficient for thymus regeneration via a type 2 innate immune network. IL33 stimulates expansion of IL5-producing type 2 innate lymphoid cells (ILC2), which triggers a cellular switch in the intrathymic availability of IL4. This enables eosinophil production of IL4 to re-establish thymic mesenchyme prior to recovery of thymopoiesis-inducing epithelial compartments. Collectively, we identify a positive feedback mechanism of type 2 innate immunity that regulates the recovery of thymus function following tissue injury. Although thymic function declines with age, the thymus also has the ability to regenerate following injury. Here, the authors demonstrate that IL-33 and type-2 innate lymphoid cells trigger the expansion of eosinophils following radiation injury, which in turn produce IL-4 to stimulate the recovery of the thymus mesenchyme during thymus regeneration. [ABSTRACT FROM AUTHOR]

Exploratory analysis to conceptualize and evaluate the potential cost-effectiveness and economic drivers of using a novel tissue valve compared with mechanical heart valves for surgical aortic valve replacement (SAVR) in people aged 55–64 and 65+ with aortic stenosis (AS) from a National Health Service (NHS) UK perspective. A decision-analytic model was developed using a partitioned survival model. Parameter inputs were obtained from published literature. Deterministic and probabilistic sensitivity analyses (DSA and PSA) were conducted to explore the uncertainty around the parameters. The novel tissue valve was potentially associated with higher quality-adjusted life years (QALYs) of 0.01 per person. Potential cost savings were greatest for those aged 55–64 (£408) versus those aged 65+(£53). DSA indicated the results to be most dependent on relative differences in general mortality, procedure costs, and reoperation rates. PSA estimated around 75% of the iterations to be cost-effective at £20,000 per QALY for those aged 55–64, and 57% for those aged 65+. The exploratory analysis suggests that the novel tissue valve could be a cost-effective intervention for people over the age of 55 with AS who are suitable for SAVR in the UK. [ABSTRACT FROM AUTHOR]

The network of thymic stromal cells provides essential niches with unique molecular cues controlling T cell development and selection. Recent single-cell RNA sequencing studies have uncovered previously unappreciated transcriptional heterogeneity among thymic epithelial cells (TEC). However, there are only very few cell markers that allow a comparable phenotypic identification of TEC. Here, using massively parallel flow cytometry and machine learning, we deconvoluted known TEC phenotypes into novel subpopulations. Using CITEseq, these phenotypes were related to corresponding TEC subtypes defined by the cells' RNA profiles. This approach allowed the phenotypic identification of perinatal cTEC and their physical localisation within the cortical stromal scaffold. In addition, we demonstrate the dynamic change in the frequency of perinatal cTEC in response to developing thymocytes and reveal their exceptional efficiency in positive selection. Collectively, our study identifies markers that allow for an unprecedented dissection of the thymus stromal complexity, as well as physical isolation of TEC populations and assignment of specific functions to individual TEC subtypes. T cell development requires functionally diverse thymic epithelial cell (TEC) populations performing specific functions. Here, using massively parallel flow cytometry and machine learning, the authors examine in mice the TEC compartment from the perinatal period to adulthood, identify novel phenotypic markers and characterize the function of perinatal cortical TEC. [ABSTRACT FROM AUTHOR]

γδT cells are produced in the thymus throughout life and provide immunity at epithelial‐rich sites. Unlike conventional αβT cells, γδT‐cell development involves intrathymic acquisition of effector function, with priming for either IL17 or IFN‐γ production occurring during embryonic or adult life, respectively. How the thymus controls effector‐primed γδT‐cell generation in adulthood is poorly understood. Here, we distinguished de novo γδT cells from those undergoing thymus recirculation and/or retention using Rag2GFP mice alongside markers of maturation/effector priming including CD24, CD25, CD73, and IFN‐γ, the latter by crossing with IFN‐γYFP GREAT mice. We categorize newly developing γδT‐cells into an ordered sequence where CD25+CD73−IFN‐γYFP− precursors are followed sequentially by CD25−CD73+IFN‐γYFP− intermediates and CD25−CD73+IFN‐γYFP+ effectors. To determine intrathymic requirements controlling this sequence, we examined γδT‐cell development in Relb−/− thymus grafts that lack medullary microenvironments. Interestingly, medulla deficiency did not alter CD25+ γδT‐cell precursor generation, but significantly impaired development of effector primed stages. This impact on γδT‐cell priming was mirrored in plt/plt mice lacking the medullary chemoattractants CCL19 and CCL21, and also Ccl21a−/− but not Ccl19−/− mice. Collectively, we identify the medulla as an important site for effector priming during adult γδT‐cell development and demonstrate a specific role for the medullary epithelial product CCL21 in this process. [ABSTRACT FROM AUTHOR]

This paper presents an innovative and fully automatic solution of generating as-built computer-aided design (CAD) drawings for landscape architecture (LA) with three dimensional (3D) reality data scanned via drone, camera, and LiDAR. To start with the full pipeline, 2D feature images of ortho-image and elevation-map are converted from the reality data. A deep learning-based light convolutional encoder–decoder was developed, and compared with U-Net (a binary segmentation model), for image pixelwise segmentation to realize automatic site surface classification, object detection, and ground control point identification. Then, the proposed elevation clustering and segmentation algorithms can automatically extract contours for each instance from each surface or object category. Experimental results showed that the developed light model achieved comparable results with U-Net in landing pad segmentation with average intersection over union (IoU) of 0.900 versus 0.969. With the proposed data augmentation strategy, the light model had a testing pixel accuracy of 0.9764 and mean IoU of 0.8922 in the six-class segmentation testing task. Additionally, for surfaces with continuous elevation changes (i.e., ground), the developed algorithm created contours only have an average elevation difference of 1.68 cm compared to dense point clouds using drones and image-based reality data. For objects with discrete elevation changes (i.e., stair treads), the generated contours accurately represent objects' elevations with zero difference using light detection and ranging (LiDAR) data. The contribution of this research is to develop algorithms that automatically transfer the scanned LA scenes to contours with real-world coordinates to create as-built computer-aided design (CAD) drawings, which can further assist building information modeling (BIM) model creation and inspect the scanned LA scenes with augmented reality. The optimized parameters for the developed algorithms are analyzed and recommended for future applications. [ABSTRACT FROM AUTHOR]

An analysis of the budget impact of using a bovine pericardial aortic bioprosthesis (BPAB) or a mechanical valve (MV) in aortic stenosis (AS) patients in Romania. A decision-tree with a partitioned survival model was used to predict the financial outcomes of using either a BPAB (the Carpentier-Edwards Perimount Magna Ease Valve) or MV in aortic valve replacement (AVR) procedure over a 5-year period. The budget impact of various resource consumption including disabling strokes, reoperations, minor thromboembolic events, major bleeding, endocarditis, anticoagulation treatment and monitoring, and echocardiogram assessments were compared for both types of valves. One-way sensitivity analyses (OWSA) were conducted on the input costs and probabilities. The use of BPAB compared to MV approaches budget neutrality due to incremental savings year-on-year. The initial surgical procedure and reoperation costs for BPAB are offset by savings in acenocoumarol use, disabling strokes, major bleeding, minor thromboembolic events, and anticoagulation complications. The cost of the initial procedure per patient is 460 euros higher for a BPAB due to the higher valve acquisition cost, although this is partially offset by a shorter hospital stay. The OWSA shows that the total procedure costs, including the hospital stay, are the primary cost drivers in the model. Results are limited by cost data aggregation in the DRG system, exclusion of costs for consumables and capital equipment use, possible underestimation of outpatient complication costs, age-related variations of event rates, and valve durability. Adopting BPAB as a treatment option for AS patients in Romania can lead to cost savings and long-term economic benefits. By mitigating procedure costs and increasing anticoagulation treatment costs, BPAB offers a budget-neutral option that can help healthcare providers, policymakers, and patients alike manage the growing burden of AS in Romania. [ABSTRACT FROM AUTHOR]

Background Strategies to optimize antibiotic prescribing at discharge are not well understood. Methods In fall 2019, we surveyed 39 Michigan hospitals on their antibiotic stewardship strategies. The association of reported strategies with discharge antibiotic overuse (unnecessary, excess, suboptimal fluoroquinolones) for community-acquired pneumonia (CAP) and urinary tract infection (UTI) was evaluated in 2 ways: (1) all strategies assumed equal weight and (2) strategies were weighted based on the ROAD (Reducing Overuse of Antibiotics at Discharge) Home Framework (ie, Tier 1—Critical infrastructure, Tier 2—Broad inpatient interventions, Tier 3—Discharge-specific strategies) with Tier 3 strategies receiving the highest weight. Results Between 1 July 2017 and 30 July 2019, 39 hospitals with 20 444 patients (56.5% CAP; 43.5% UTI) were included. Survey response was 100%. Hospitals reported a median (interquartile range [IQR]) 12 (9–14) of 34 possible stewardship strategies. On analyses of individual stewardship strategies, the Tier 3 intervention, review of antibiotics prior to discharge, was the only strategy consistently associated with lower antibiotic overuse at discharge (adjusted incident rate ratio [aIRR] 0.543, 95% confidence interval [CI]:.335–.878). On multivariable analysis, weighting by ROAD Home tier predicted antibiotic overuse at discharge for both CAP and UTI. For diseases combined, having more weighted strategies was associated with lower antibiotic overuse at discharge (aIRR 0.957, 95% CI:.927–.987, per weighted intervention); discharge-specific stewardship strategies were associated with a 12.4% relative decrease in antibiotic overuse days at discharge. Conclusions The more stewardship strategies a hospital reported, the lower its antibiotic overuse at discharge. However, Tier 3, or discharge-specific strategies, appeared to have the largest effect on antibiotic prescribing at discharge. [ABSTRACT FROM AUTHOR]

Protecting future generations from the effects of climate change is an important issue, especially considering how much the United States has struggled to implement climate policy. Two recent European judicial decisions, Notre Affaire à Tous v. France and Neubauer v. Germany, may provide helpful guidance to the United States because they demonstrate a commitment to protecting future generations from climate change and reducing greenhouse gas emissions. In these decisions, both courts relied on their respective civil codes and constitutions to determine that their countries had either exceeded their carbon emissions reduction goals, as was the case in Notre Affaire à Tous, or that their commitments were not aggressive enough, as in Neubauer.1 However, these cases will likely prove difficult for the United States to emulate because it is not a civil law country, does not rely on international environmental agreements, and contains no federal constitutional environmental provisions. Therefore, the United States may have to rely on other methods of protecting future generations. First, this Note will explain these judicial decisions, including background on the French and German civil legal systems. Then, it will explore the various ways that the United States can similarly protect future generations from emissions, including through federal constitutional amendments, due process arguments, state constitutional provisions and amendments, and executive orders. Ultimately, this Note concludes that, besides a federal amendment to the Constitution, each of these can ensure the United States addresses the climate crisis to protect future generations. [ABSTRACT FROM AUTHOR]

Therapeutic interventions used for cancer treatment provoke thymus damage and limit the recovery of protective immunity. Here, we show that eosinophils are an essential part of an intrathymic type 2 immune network that enables thymus recovery after ablative therapy. Within hours of damage, the thymus undergoes CCR3-dependent colonization by peripheral eosinophils, which reestablishes the epithelial microenvironments that control thymopoiesis. Eosinophil regulation of thymus regeneration occurs via the concerted action of NKT cells that trigger CCL11 production via IL4 receptor signaling in thymic stroma, and ILC2 that represent an intrathymic source of IL5, a cytokine that therapeutically boosts thymus regeneration after damage. Collectively, our findings identify an intrathymic network composed of multiple innate immune cells that restores thymus function during reestablishment of the adaptive immune system. [ABSTRACT FROM AUTHOR]

Deficits in sequence-specific learning (SSL) may be a product of Parkinson's disease (PD) but this deficit could also be related to dopamine replacement. The purpose of this study was to determine whether dopamine replacement affected acquisition and retention of a standing Continuous Tracking Task in individuals with PD. SSL (difference between random/repeated Root Mean Square Error across trials) was calculated over 2 days of practice and 1 day of retention for 4 groups; 10 healthy young (HY), 10 healthy elders, 10 individuals with PD on, 9 individuals with PD off their usual dosage of dopamine replacement. Improvements in acquisition were observed for all groups; however, only the HY demonstrated retention. Therefore, age appeared to have the largest effect on SSL with no significant effect of medication. Additional research is needed to understand the influence of factors such as practice amount, task difficulty, and dopamine replacement status on SSL deficits during postural tasks. [ABSTRACT FROM AUTHOR]

The role of calcium in blood pressure has been widely studied among hypertensive patients; however, no study has explored the role of calcium in hypertensive crises. The primary objective of this study is to evaluate the differences in serum calcium levels between hypertensive crises patients and a 1:1 random matched controls (age‐, sex‐, race‐, diabetes, and body mass index matched). This study is a single‐center, retrospective, chart review, case‐control study of patients with hypertensive crises (case group) and patients without hypertensive crises (control group). Patients were included in the case group if they were 18 years of age or older with hypertensive crises and have a documented calcium level. The control group patients were required to be 18 years of age or older, have a documented calcium level, and have no diagnosis of hypertensive crises. The primary outcome of the study was to compare the mean serum calcium in patients with hypertensive crises vs patients without hypertensive crises. Five hundred and sixty‐six patients were included in the study: 283 patients in both the case group and control group. The primary outcome results showed that serum calcium concentration was not significantly different between the case group (8.99 ± 0.78 mg/dL) and control group (8.96 ± 0.75 mg/dL) (P =.606). This study found no significant difference in serum calcium levels in patients with hypertensive crises compared to a random matched control group. Larger observational or experimental studies may be useful to evaluate the effect of calcium on blood pressure in hypertensive crises. [ABSTRACT FROM AUTHOR]

The impact of planned parental follow-up on compliance with opioids disposal following pediatric surgery A research associate called willing participants 4 weeks following surgery assessing opioid usage, storage, and disposal. Prescribed opioids can unfortunately increase the risk of future substance abuse disorders and drug misuse.1 Previous studies have identified significant overprescribing following pediatric surgery, and these unused opioids are a source for opioid overdose in children and adolescents.2 Consequently, educational interventions on opioid stewardship including disposal of unused medication may reduce access to opioids in children and adolescents.3 Studies using commercially available disposal bags have found varying rates of return.3,4 The aim of this study was to determine whether a planned telephone follow-up to a parent/caregiver would increase the rate of disposal of unused opioids following pediatric surgery. [Extracted from the article]

The article explores the decline in the population of wild horses in the U.S., which highlights the need for an amendment of the Wild Free-Roaming Horses and Burros Act (WHBA). Topics discussed include the lawsuit filed by the American Wild Horse Campaign against the U.S. Bureau of Land Management for violating the WHBA, the ways in which BLM manages wild horse populations, and a history of the WHBA.

αβT cells are an essential component of effective immune responses. The heterogeneity that lies within them includes subsets that express diverse self-MHC-restricted αβT cell receptors, which can be further subdivided into CD4+ helper, CD8+ cytotoxic, and Foxp3+ regulatory T cells. In addition, αβT cells also include invariant natural killer T cells that are very limited in αβT cell receptor repertoire diversity and recognise non-polymorphic CD1d molecules that present lipid antigens. Importantly, all αβT cell sublineages are dependent upon the thymus as a shared site of their development. Ongoing research has examined how the thymus balances the intrathymic production of multiple αβT cell subsets to ensure correct formation and functioning of the peripheral immune system. Experiments in both wild-type and genetically modified mice have been essential in revealing complex cellular and molecular mechanisms that regulate thymus function. In particular, studies have demonstrated the diverse and critical role that the thymus medulla plays in shaping the peripheral T cell pool. In this review, we summarise current knowledge on functional properties of the thymus medulla that enable the thymus to support the production of diverse αβT cell types. [ABSTRACT FROM AUTHOR]

Autoimmune regulator+ (Aire) medullary thymic epithelial cells (mTECs) play a critical role in tolerance induction. Several studies demonstrated that Aire+mTECs differentiate further into Post‐Aire cells. Yet, the identification of terminal stages of mTEC maturation depends on unique fate‐mapping mouse models. Herein, we resolve this limitation by segmenting the mTEChi(MHCIIhiCD80hi) compartment into mTECA/hi (CD24−Sca1−), mTECB/hi (CD24+Sca1−), and mTECC/hi (CD24+Sca1+). While mTECA/hi included mostly Aire‐expressing cells, mTECB/hi contained Aire+ and Aire− cells and mTECC/hi were mainly composed of cells lacking Aire. The differential expression pattern of Aire led us to investigate the precursor‐product relationship between these subsets. Strikingly, transcriptomic analysis of mTECA/hi, mTECB/hi, and mTECC/hi sequentially mirrored the specific genetic program of Early‐, Late‐ and Post‐Aire mTECs. Corroborating their Post‐Aire nature, mTECC/hi downregulated the expression of tissue‐restricted antigens, acquired traits of differentiated keratinocytes, and were absent in Aire‐deficient mice. Collectively, our findings reveal a new and simple blueprint to survey late stages of mTEC differentiation. [ABSTRACT FROM AUTHOR]

Successful pregnancies rely on adaptations within the mother1, including marked changes within the immune system2. It has long been known that the thymus, the central lymphoid organ, changes markedly during pregnancy3. However, the molecular basis and importance of this process remain largely obscure. Here we show that the osteoclast differentiation receptor RANK4,5 couples female sex hormones to the rewiring of the thymus during pregnancy. Genetic deletion of Rank (also known as Tnfrsf11a) in thymic epithelial cells results in impaired thymic involution and blunted expansion of natural regulatory T (Treg) cells in pregnant female mice. Sex hormones, in particular progesterone, drive the development of thymic Treg cells through RANK in a manner that depends on AIRE+ medullary thymic epithelial cells. The depletion of Rank in the mouse thymic epithelium results in reduced accumulation of natural Treg cells in the placenta, and an increase in the number of miscarriages. Thymic deletion of Rank also results in impaired accumulation of Treg cells in visceral adipose tissue, and is associated with enlarged adipocyte size, tissue inflammation, enhanced maternal glucose intolerance, fetal macrosomia, and a long-lasting transgenerational alteration in glucose homeostasis, which are all key hallmarks of gestational diabetes. Transplantation of Treg cells rescued fetal loss, maternal glucose intolerance and fetal macrosomia. In human pregnancies, we found that gestational diabetes also correlates with a reduced number of Treg cells in the placenta. Our findings show that RANK promotes the hormone-mediated development of thymic Treg cells during pregnancy, and expand the functional role of maternal Treg cells to the development of gestational diabetes and the transgenerational metabolic rewiring of glucose homeostasis. RANK promotes the hormone-mediated development of thymic regulatory T cells during pregnancy; loss of RANK is associated with impaired maturation of maternal regulatory T cells, leading to fetal loss and the development of gestational diabetes. [ABSTRACT FROM AUTHOR]

While the concept event has been an important tool in our thinking about causation and action, the concept process has not been appealed to so readily. However, recently, several philosophers have argued that the distinction between events and processes is of much greater metaphysical significance than previously thought. Many of these philosophers have suggested that recognising process as a distinctive ontological category is important for understanding action and agency. One theory of processes which has become popular is a theory I call the "temporal stuff view" of processes. According to the temporal stuff view, processes are the "temporal stuffs" from which events are composed. I propose an alternative to the temporal stuff view. On my theory, processes are a special kind of universal. I suggest that engaging in a process is analogous to instantiating a property, and that events are instances of processes. On this proposal, a substance's engagement in a process is a special sort of state of affairs (a dynamic state of affairs). I argue that this alternative theory of processes does better than the temporal stuff view when it comes to helping us understand action and agency. [ABSTRACT FROM AUTHOR]

The thymus supports multiple αβ T cell lineages that are functionally distinct, but mechanisms that control this multifaceted development are poorly understood. Here we examine medullary thymic epithelial cell (mTEC) heterogeneity and its influence on CD1d-restricted iNKT cells. We find three distinct mTEClow subsets distinguished by surface, intracellular and secreted molecules, and identify LTβR as a cell-autonomous controller of their development. Importantly, this mTEC heterogeneity enables the thymus to differentially control iNKT sublineages possessing distinct effector properties. mTEC expression of LTβR is essential for the development thymic tuft cells which regulate NKT2 via IL-25, while LTβR controls CD104+CCL21+ mTEClow that are capable of IL-15-transpresentation for regulating NKT1 and NKT17. Finally, mTECs regulate both iNKT-mediated activation of thymic dendritic cells, and iNKT availability in extrathymic sites. In conclusion, mTEC specialization controls intrathymic iNKT cell development and function, and determines iNKT pool size in peripheral tissues. Thymus is a unique environment hosting the development of many T cell subsets with distinct functions. Here the authors show that medullary thymic epithelial cells (mTEC) are functionally diverse, with LTβR signaling serving differential regulation of mTEC for specific control of multiple lineages of invariant natural killer T cells. [ABSTRACT FROM AUTHOR]

Correlates the symptoms of exercise intolerance at high work rates with aging. Risks of maximal exercise in older adults; Increase in the number of health difficulties; Use of maximal oxygen consumption to measure the integrated response of the cardiovascular system.

Purpose: We examined the effect of race-effort cycling exercise with and without heat stress on post-exercise perceptions of fatigue and pain, as well as mRNA expression in genes related to exercise responses.Methods: Trained cyclists (n = 20) completed 40 km time trials during temperate (TC, 21 °C) and hot (HC, 35 °C) conditions. Blood lactates were measured 1 and 5 min post-exercise. Venous blood samples and ratings of fatigue and pain perceptions were obtained at baseline and at 0.5, 8, 24, and 48 h post-exercise. Leukocyte mRNA expression was performed for metabolite detecting, adrenergic, monoamine, and immune receptors using qPCR.Results: Significantly lower mean power (157 ± 32.3 vs 187 ± 40 W) and lactates (6.4 ± 1.7 vs 8.8 ± 3.2 and 4.2 ± 1.5 vs 6.6 ± 2.7 mmol L(-1) at 1- and 5-min post-exercise) were observed for HC versus TC, respectively (p < 0.05). Increases (p < 0.05) in physical fatigue and pain perception during TTs did not differ between TC and HC (p > 0.30). Both trials resulted in significant post-exercise decreases in metabolite detecting receptors ASIC3, P2X4, TRPV1, and TRPV4; increases in adrenergic receptors α2a, α2c, and β1; decreases in adrenergic β2, the immune receptor TLR4, and dopamine (DRD4); and increases in serotonin (HTR1D) and IL-10 (p < 0.05). Post-exercise IL-6 differed between TC and HC, with significantly greater increases observed following HC (p < 0.05).Conclusions: Both TT performances appeared to be regulated around a specific sensory perception of fatigue and pain. Heat stress may have compensated for lower lactate during HC, thereby matching changes in metabolite detecting and other mRNAs across conditions. [ABSTRACT FROM AUTHOR]

Respiratory therapy is a profession with the depth and breadth required to care for clients by "evaluating, treating, and maintaining cardiopulmonary (heart and lung) function" [1]. Registered Respiratory Therapists (RRTs) work in a variety of settings from critical and acute care to primary and home care. After a brief overview of the models and competencies that underpin the work of the Calgary COPD & Asthma Program, the article provides a description of the program and discuss how RRT Certified Respiratory Educators provide services within the program. These services include health promotion through self-management education rooted in the Chronic Care Model [2] and supported by the National Alliance of Respiratory Therapy Regulatory Bodies' National Competency Framework for the Profession of Respiratory Therapy [3]. The authors hope the success of this program will encourage others to embrace the role of the RRT in a primary health care setting [ABSTRACT FROM AUTHOR]

Background We hypothesized that propofol, a unique general anesthetic that engages N-methyl-D-aspartate and gamma-aminobutyric acid receptors, has antidepressant properties. This open-label trial was designed to collect preliminary data regarding the feasibility, tolerability, and efficacy of deep propofol anesthesia for treatment-resistant depression. Methods Ten participants with moderate-to-severe medication-resistant depression (age 18–45 years and otherwise healthy) each received a series of 10 propofol infusions. Propofol was dosed to strongly suppress electroencephalographic activity for 15 minutes. The primary depression outcome was the 24-item Hamilton Depression Rating Scale. Self-rated depression scores were compared with a group of 20 patients who received electroconvulsive therapy. Results Propofol treatments were well tolerated by all subjects. No serious adverse events occurred. Montreal Cognitive Assessment scores remained stable. Hamilton scores decreased by a mean of 20 points (range 0–45 points), corresponding to a mean 58% improvement from baseline (range 0–100%). Six of the 10 subjects met the criteria for response (>50% improvement). Self-rated depression improved similarly in the propofol group and electroconvulsive therapy group. Five of the 6 propofol responders remained well for at least 3 months. In posthoc analyses, electroencephalographic measures predicted clinical response to propofol. Conclusions These findings demonstrate that high-dose propofol treatment is feasible and well tolerated by individuals with treatment-resistant depression who are otherwise healthy. Propofol may trigger rapid, durable antidepressant effects similar to electroconvulsive therapy but with fewer side effects. Controlled studies are warranted to further evaluate propofol's antidepressant efficacy and mechanisms of action. ClinicalTrials.gov: NCT02935647. [ABSTRACT FROM AUTHOR]

Abstract: Members of the innate lymphoid cell (ILC) family have been implicated in the development of thymic microenvironments and the recovery of this architecture after damage. However, a detailed characterization of this family in the thymus is lacking. To better understand the thymic ILC compartment, we have utilized multiple in vivo models including the fate mapping of inhibitor of DNA binding‐2 (Id2) expression and the use of Id2 reporter mice. Our data demonstrate that ILCs are more prominent immediately after birth, but were rapidly diluted as the T‐cell development program increased. As observed in the embryonic thymus, CCR6+NKp46− lymphoid tissue inducer (LTi) cells were the main ILC3 population present, but numbers of these cells swiftly declined in the neonate and ILC3 were barely detectable in adult thymus. This loss of ILC3 means ILC2 are the dominant ILC population in the thymus. Thymic ILC2 were able to produce IL‐5 and IL‐13, were located within the medulla, and did not result from ILC3 plasticity. Furthermore, in WT mice, thymic ILC2 express little RANKL (receptor activator of nuclear factor kappa‐B ligand) arguing that functionally, these cells provide different signals to LTi cells in the thymus. Collectively, these data reveal a dynamic switch in the ILC populations of the thymus during neonatal development. [ABSTRACT FROM AUTHOR]

Mutations in the filaggrin gene (Flg) are associated with increased systemic levels of Th17 cells and increased IL-17A production following antigen exposure in both humans and mice. In addition to Th17 cells, γδ T cells can produce IL-17A. The differentiation of γδ T cells to either IFNγ or IL-17A-producing (γδT17) cells is mainly determined in the thymus. Interestingly, it has been reported that filaggrin is expressed in the Hassall bodies in the human thymic medulla. However, whether filaggrin affects γδ T cell development is not known. Here, we show that filaggrin-deficient flaky tail (ft/ft) mice have an increased number of γδT17 cells in the spleen, epidermis, and thymus compared to wild-type (WT) mice. We demonstrate that filaggrin is expressed in the mouse thymic medulla and that blocking the egress of cells from the thymus results in accumulation of Vγ2+ γδT17 cells in the thymus of adult ft/ft mice. Finally, we find increased T cell receptor expression levels on γδ T cells and increased levels of IL-6 and IL-23 in the thymus of ft/ft mice. These findings demonstrate that filaggrin is expressed in the mouse thymic medulla and that production of Vγ2+ γδT17 cells is dysregulated in filaggrin-deficient ft/ft mice. [ABSTRACT FROM AUTHOR]

Abstract: In the thymus, medullary thymic epithelial cells (mTEC) determine the fate of newly selected CD4+ and CD8+ single positive (SP) thymocytes. For example, mTEC expression of Aire controls intrathymic self‐antigen availability for negative selection. Interestingly, alterations in both Foxp3+ Regulatory T‐cells (T‐Reg) and conventional SP thymocytes in Aire−/− mice suggest additional, yet poorly understood, roles for Aire during intrathymic T‐cell development. To examine this, we analysed thymocytes from Aire−/− mice using Rag2GFP and Foxp3 expression, and a recently described CD69/MHCI subset definition of post‐selection CD4+ conventional thymocytes. We show that while Aire is dispensable for de novo generation of conventional αβT‐cells, it plays a key role in controlling the intrathymic T‐Reg pool. Surprisingly, a decline in intrathymic T‐Reg in Aire−/− mice maps to a reduction in mature recirculating Rag2GFP− T‐Reg that express CCR6 and re‐enter the thymus from the periphery. Furthermore, we show mTEC expression of the CCR6 ligand CCL20 is reduced in Aire−/− mice, and that CCR6 is required for T‐Reg recirculation back to the thymus. Collectively, our study re‐defines requirements for late stage intrathymic αβT‐cell development, and demonstrates that Aire controls a CCR6‐CCL20 axis that determines the developmental makeup of the intrathymic T‐Reg pool. [ABSTRACT FROM AUTHOR]

BDSM relationships have only recently become widely known in American culture despite their clear existence throughout history. The film and novel series Fifty Shades of Grey has further introduced BDSM contracts, which are used in many BDSM relationships. BDSM contracts should be declared as improperly formed and unenforceable. The tenets of contract law formation suggest that these contracts may not be properly formed based on the intent not to be bound or a lack of consideration in the context of meretricious relationships. Even if BDSM contracts are properly formed, they should be unenforceable based on relatable public policy matters such as pornography and other obscene materials, human trafficking, forced labor, sexual assault, the sale of human organs, consent to bodily injury, and the intentional, reckless, or negligent commission of a tort because these matters are highly regulated or prohibited altogether. Specific performance should not be a remedy to BDSM contracts in order to protect the existence of consent. [ABSTRACT FROM AUTHOR]

The thymus is a primary lymphoid tissue that supports the generation of αβT cells. In this review, we describe the processes that give rise to the thymus medulla, a site that nurtures self-tolerant T-cell generation following positive selection events that take place in the cortex. To summarize the developmental pathways that generate medullary thymic epithelial cells ( mTEC) from their immature progenitors, we describe work on both the initial emergence of the medulla during embryogenesis, and the maintenance of the medulla during postnatal stages. We also investigate the varying roles that receptors belonging to the tumor necrosis factor receptor superfamily have on thymus medulla development and formation, and highlight the impact that T-cell development has on thymus medulla formation. Finally, we examine the evidence that the thymic medulla plays an important role during the intrathymic generation of distinct αβT-cell subtypes. Collectively, these studies provide new insight into the development and functional importance of medullary microenvironments during self-tolerant T-cell production in the thymus. [ABSTRACT FROM AUTHOR]

Summary Despite the key role of primary and secondary lymphoid organ stroma in immunity, our understanding of the heterogeneity and ontogeny of these cells remains limited. Here, we identify a functionally distinct subset of BP3 − PDPN + PDGFRβ + /α + CD34 + stromal adventitial cells in both lymph nodes (LNs) and thymus that is located within the vascular niche surrounding PDPN − PDGFRβ + /α − Esam-1 + ITGA7 + pericytes. CD34 + adventitial cells developed in late embryonic thymus and in postnatal LNs and in the thymus originated, along with pericytes, from a common anlage-seeding progenitor population. Using lymphoid organ re-aggregate grafts, we demonstrate that adult CD34 + adventitial cells are capable of differentiating into multiple lymphoid stroma-like subsets including pericyte-, FRC-, MRC-, and FDC-like cells, the development of which was lymphoid environment-dependent. These findings extend the current understanding of lymphoid mesenchymal cell heterogeneity and highlight a role of the CD34 + adventitia as a potential ubiquitous source of lymphoid stromal precursors in postnatal tissues. [ABSTRACT FROM AUTHOR]

Objective: To determine if independent candidate genes can be grouped into meaningful biologic factors, and whether these factors are associated with the diagnosis of chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FMS), while controlling for comorbid depression, sex, and age.Methods: We included leukocyte messenger RNA gene expression from a total of 261 individuals, including healthy controls (n = 61), patients with FMS only (n = 15), with CFS only (n = 33), with comorbid CFS and FMS (n = 79), and with medication-resistant (n = 42) or medication-responsive (n = 31) depression. We used exploratory factor analysis (EFA) on 34 candidate genes to determine factor scores and regression analysis to examine whether these factors were associated with specific diagnoses.Results: EFA resulted in 4 independent factors with minimal overlap of genes between factors, explaining 51% of the variance. We labeled these factors by function as 1) purinergic and cellular modulators, 2) neuronal growth and immune function, 3) nociception and stress mediators, and 4) energy and mitochondrial function. Regression analysis predicting these biologic factors using FMS, CFS, depression severity, age, and sex revealed that greater expression in factors 1 and 3 was positively associated with CFS and negatively associated with depression severity (Quick Inventory for Depression Symptomatology score), but not associated with FMS.Conclusion: Expression of candidate genes can be grouped into meaningful clusters, and CFS and depression are associated with the same 2 clusters, but in opposite directions, when controlling for comorbid FMS. Given high comorbid disease and interrelationships between biomarkers, EFA may help determine patient subgroups in this population based on gene expression. [ABSTRACT FROM AUTHOR]

Pregabalin, an approved treatment for fibromyalgia (FM), has been shown to decrease sympathetic nervous system (SNS) activity and inhibit sympathetically maintained pain, but its effects on exercise responses have not been reported. Methods. Using a randomized double-blind crossover design, we assessed the effect of 5 weeks of pregabalin (versus placebo) on acute cardiovascular and subjective responses to moderate exercise in 19 FM patients. Blood pressure (BP), heart rate (HR), and ratings of perceived exertion (RPE) during exercise and ratings of pain, physical fatigue, and mental fatigue before, during, and for 48 hours after exercise were compared in patients on pregabalin versus placebo and also versus 18 healthy controls. Results. On placebo, exercise RPE and BP were significantly higher in FM patients than controls (p<0.04). Pregabalin responders (n=12, defined by patient satisfaction and symptom changes) had significantly lower exercise BP, HR, and RPE on pregabalin versus placebo (p<0.03) and no longer differed from controls (p>0.26). Cardiovascular responses of nonresponders (n=7) were not altered by pregabalin. In responders, pregabalin improved ratings of fatigue and pain (p<0.04), but negative effects on pain and fatigue were seen in nonresponders. Conclusions. These preliminary findings suggest that pregabalin may normalize cardiovascular and subjective responses to exercise in many FM patients. [ABSTRACT FROM AUTHOR]

Introduction: Preliminary evidence in adults with spinal muscular atrophy (SMA) and in SMA animal models suggests exercise has potential benefits in improving or stabilizing muscle strength and motor function.Methods: We evaluated feasibility, safety, and effects on strength and motor function of a home-based, supervised progressive resistance strength training exercise program in children with SMA types II and III. Up to 14 bilateral proximal muscles were exercised 3 times weekly for 12 weeks.Results: Nine children with SMA, aged 10.4 ± 3.8 years, completed the resistance training exercise program. Ninety percent of visits occurred per protocol. Training sessions were pain-free (99.8%), and no study-related adverse events occurred. Trends in improved strength and motor function were observed.Conclusions: A 12-week supervised, home-based, 3-day/week progressive resistance training exercise program is feasible, safe, and well tolerated in children with SMA. These findings can inform future studies of exercise in SMA. [ABSTRACT FROM AUTHOR]