Cell surface IL-1α trafficking is specifically inhibited by interferon-γ, and associates with the membrane via IL-1R2 and GPI anchors

IL-1 is a powerful cytokine that drives inflammation and modulates adaptive immunity. Both IL-1α and IL-1β are translated as proforms that require cleavage for full cytokine activity and release, while IL-1α is reported to occur as an alternative plasma membrane-associated form on many cell types. However, the existence of cell surface IL-1α (csIL-1α) is contested, how IL-1α tethers to the membrane is unknown, and signaling pathways controlling trafficking are not specified. Using a robust and fully validated system, we show that macrophages present bona fide csIL-1α after ligation of TLRs. Pro-IL-1α tethers to the plasma membrane in part through IL-1R2 or via association with a glycosylphosphatidylinositol-anchored protein, and can be cleaved, activated, and released by proteases. csIL-1α requires de novo protein synthesis and its trafficking to the plasma membrane is exquisitely sensitive to inhibition by IFN-γ, independent of expression level. We also reveal how prior csIL-1α detection could occur through inadvertent cell permeabilisation, and that senescent cells do not drive the senescent-associated secretory phenotype via csIL-1α, but rather via soluble IL-1α. We believe these data are important for determining the local or systemic context in which IL-1α can contribute to disease and/or physiological processes.     

Comparison of Sealer Penetration Using the EndoVac Irrigation System and Conventional Needle Root Canal Irrigation

Introduction

The aim of this study was to compare the effect of the EndoVac irrigation system (SybronEndo, Orange, CA) and conventional endodontic needle irrigation on sealer penetration into dentinal tubules.

Methods

Forty single-rooted, recently extracted human maxillary central incisors were randomly divided into 2 groups according to the irrigation technique used: conventional endodontic needle irrigation and EndoVac irrigation. All teeth were instrumented using the ProFile rotary system (Dentsply Maillefer, Ballaigues, Switzerland) and obturated with gutta-percha and AH Plus sealer (Dentsply DeTrey, Konstanz, Germany) labeled with fluorescent dye. Transverse sections at 1, 3, and 5 mm from the root apex were examined using confocal laser scanning microscopy. The total percentage and maximum depth of sealer penetration were then measured.

Results

Mann-Whitney test results showed that EndoVac irrigation resulted in a significantly higher percentage of sealer penetration than conventional irrigation at both the 1- and 3-mm levels (P < .05). However, no difference was found at the 5-mm level. The 5-mm sections in each group showed a significantly higher percentage and maximum depth of sealer penetration than did the 1- and 3-mm sections (P < .05).

Conclusions

The EndoVac irrigation system significantly improved the sealer penetration at the 1- to 3-mm level over that of conventional endodontic needle irrigation.     

Comparison of tissue disruption caused by excimer and midinfrared lasers in clinical simulation

Laser coronary angioplasty is a useful therapy for selected complex coronary lesions. Laser-induced acoustic trauma is postulated to be a cause of dissection and acute vessel occlusion. Controversy exists regarding the relative degree of photoacoustic effects of midinfrared and excimer lasers in clinical practice. To date, these systems have not been compared at clinical energy doses and with clinical pulsing strategies. Therefore, we studied the photoacoustic effects of both midinfrared and excimer lasing at clinically accepted doses. Human atherosclerotic iliofemoral artery segments were obtained at autopsy (n = 36) and placed lumen side up in a saline bath. Clinical laser catheters were advanced over an 0.018′ guide wire, perpendicular to the tissue. A 10-g down force was applied to the catheter for full-thickness lasing. Pulsing strategies were, for midinfrared laser: 5 pulses, 1-sec pause, 5 pulses, 1-sec pause, 5 pulses, withdraw; for excimer: 5 sec of pulses, wait 10 sec, 5 sec of pulses. Several clinically acceptable energy levels were used; for excimer: 25 mJ/mm², 40 mJ/mm², 60 mJ/mm²; for midinfrared: 3 W (400 mJ/mm²), 3.5 W (467 mJ/mm²). Photoacoustic effect was assessed histologically by determining the number of lateral cleavage planes (dissections) arising from the lased crater border and extending into the surrounding tissue. In normal tissue, midinfrared lasing produced less acoustic damage than excimer lasing (2.79 ± 0.78 vs. 5.27 ± 0.75 cleavage planes, mean ± SD, P < 0.05, data for lowest energy for each system). The same was true in noncalcified atheroma (2.48 ± 0.71 vs. 6.43 ± 1.09, P < 0.05) and calcified atheroma (2.47 ± 1.21 vs. 6.27 ± 1.13, P < 0.05). This effect was similar at all energy levels, with a trend for more damage at higher energies in both systems. This study demonstrates that midinfrared lasing causes less acoustic damage than excimer lasing when using clinical catheters, energy levels, and pulsing strategies. This effect is independent of tissue-type but tends to be dose-related. These findings may explain, in part, the differences in dissection rates seen clinically. © 1996 Wiley-Liss, Inc.     

Factor V Q 506 mutation in children with thrombosis

The factor V Leiden mutation in 12 children with thrombosis and in 20 controls was investigated. Five heterozygous individuals and 1 homozygous individual among the cases with thrombosis and 1 heterozygous individual among controls were found. Central nervous system thromboses were increased in children with the factor V mutation, associated with protein S deficiency. © 1996 Wiley-Liss, Inc.     

What Is the Risk of Reactivation in Patients with Resolved and Past HBV Infection During Immunosuppressive Therapy If HBV-DNA Negative before Treatment?

BackgroundReactivation of Hepatitis B (HBVr) related to immunosuppressive drug therapy (ISDT) in patients with resolved and past infection is a challenging entity. The number of prospective long-term studies is limited.MethodsTwo groups of patients with resolved and past HBV infection were analyzed prospectively. The patients were further categorized as 266 patients receiving ISDT (group 1) and 246 patients receiving antineoplastic therapy (group 2).ResultsWe did not detect any cases of HBVr among 108 patients receiving rituximab (71 of which were anti-HBc positive only), 111 patients receiving tumor necrosis factor inhibitors (66 of which were anti-HBc positive only), and 42 patients receiving high-dose glucocorticoids for more than 4 weeks (24 of which were anti-HBc positive only) during a mean follow-up time of more than 24 months. Subgroup analysis of the anti-HBs (+) patients showed that in group A (anti-HBs >1000 mIU/mL) the antibody levels did not change; in group B (anti-HBs between 100 and 1000 mIU/mL) the antibody levels changed non-significantly (P = .25), and in Group C (anti-HBs between 0 and 100 mIU/mL) the antibody levels declined significantly (P = .002). Furthermore, 16 patients in Group C had an anti-HBs loss during follow-up, but no HBVr was detected.ConclusionThe risk of HBVr by immunosuppressive therapy in this group may be lower than that suspected in the literature and anti-HBs levels may not seem to correlate with the risk of reactivation.     

Victimization,Poverty, and Resilience Resources: Stress Process Considerations for Adolescent Mental Health

School Mental Health - Growing evidence suggests that exposure to early-life adversity poses risk to youth development, with impaired mental health a central concern. This population-representative...     

Imaging of vitreous cortex hyalocyte dynamics using non-confocal quadrant-detection adaptive optics scanning light ophthalmoscopy in human subjects

Vitreous cortex hyalocytes are resident macrophage cells that help maintain the transparency of the media, provide immunosurveillance, and respond to tissue injury and inflammation. In this study, we demonstrate the use of non-confocal quadrant-detection adaptive optics scanning light ophthalmoscopy (AOSLO) to non-invasively visualize the movement and morphological changes of the hyalocyte cell bodies and processes over 1-2 hour periods in the living human eye. The average velocity of the cells 0.52 ± 0.76 µm/min when sampled every 5 minutes and 0.23 ± 0.29 µm/min when sampled every 30 minutes, suggesting that the hyalocytes move in quick bursts. Understanding the behavior of these cells under normal physiological conditions may lead to their use as biomarkers or suitable targets for therapy in eye diseases such as diabetic retinopathy, preretinal fibrosis and glaucoma.     

Closer to or Farther away from an Ideal Model of Care? Lessons Learned from Geographic Cohorting

Geographic “cohorting,” “co-location,” “regionalization,” or “localization” refers to the assignation of a hospitalist team to a specific inpatient unit. Its benefits may be related to the formation of a team and the additional interventions like interdisciplinary rounding that the enhanced proximity facilitates. However, cohorting is often adopted in isolation of the bundled approach within which it has proven beneficial. Cohorting may also be associated with unintended consequences such as increased interruptions and increased indirect care time. Institutions may increase patient loads in anticipation of the efficiency gained by cohorting—leading to further increases in interruptions and time away from the bedside. Fragmented attention and increases in indirect care may lead to a perception of increased workload, errors, and burnout. As hospital medicine evolves, there are lessons to be learned by studying cohorting. Institutions and inpatient units should work in synergy to shape the day-to-day work which directly affects patient and clinician outcomes—and ultimately culminates in the success or failure of the parent organization. Such synergy can manifest in workflow design and metric selection. Attention to workloads and adopting the principles of continuous quality improvement are also crucial to developing models of care that deliver excellent care.

Geographic “cohorting,” “co-location,” “regionalization,” or “localization” refers to the practice of assigning a hospitalist team to a specific inpatient unit with the expectation that the majority of the team’s patients will be on their assigned unit. The benefits are thought to be rooted in the enhanced physical proximity between clinicians, bedside nurses, patients, and the interprofessional team—with gains expected in efficiency, communication, collaboration, and patient centeredness.^1,2 Pre-pandemic, cohorting was adopted by nearly a third of the non-teaching services of US hospital medicine groups surveyed.³ Cohorting is complex and like therapeutic decisions is associated with benefits, risks, and unintended consequences. Examining this complexity provides insights that may allow us to design better models of care.Each inpatient unit can be viewed as a clinical microsystem—the functional unit of the entire organization—the place where the work happens and where the outcomes that coalesce into the success or failure of the organization originate.⁴ Models of care utilizing bundled unit-based interventions to improve the care of hospitalized patients have demonstrated improvements in lengths of stay, costs of care, and mortality.^5,6 In these models, cohorting was deployed alongside other mutually reinforcing interventions such as interdisciplinary rounding and leadership dyads, which become practical only when the proximity facilitated by cohorting and the creation of a team is assured. Yet, the adoption of unit-based interventions to improve care appears to be piece-meal across institutions with few deploying a bundled approach and many instituting cohorting alone.³A survey of hospitalists in the USA revealed that the strong positive perceptions of cohorting cluster around the benefits of collaboration with bedside nursing colleagues, improved nursing satisfaction, increased patient centeredness, and improved efficiency and team building. Strong negative perceptions were reported around increases in interruptions, erosion of group camaraderie, discontinuity in patient care, and issues related to implementation. Academic practices and longer durations of cohorting were associated with positive perceptions while higher patient loads were associated with negative perceptions.² Studies investigating the impact of cohorting as a stand-alone intervention have shown some results supporting and others refuting these perceptions.The proportion of bedside nursing colleagues agreeing with the statement “I experience good collaboration with house staff” increased from 10 to 40% following the implementation of cohorting.⁷ More patients perceived that their physicians spent more than four minutes with them and discussed their anxiety and emotions following cohorting.⁷ Cohorting has also been associated with increases in the likelihood of repeated visits to a patient in a day and increased time spent on the unit.⁸Cohorting, however, is not a panacea—with the gains accompanied by downsides. Despite intending to foster patient-centered care, cohorting has not been associated with improvements in Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) scores and in some settings may be associated with increases in length of stay. ^9–11 In a single-center time-motion study, cohorted hospitalists were interrupted as often as once every eight minutes—rates similar to those seen in Emergency Department settings—and were also noted to spend more time in computer interactions than their non-cohorted counterparts.⁸ These findings are consequential—interruptions erode attention, increase perceived workload, increase the risk of errors, and increase the time it takes to complete tasks.¹² Tasks that detract from direct patient care contribute to burnout—rates of which have increased among hospitalists since the onset of the pandemic. ¹³ Fragmented attention can lead to bias and failure to recognize the declining trajectory of a patient.¹⁴ Interruptions, inattention, and their consequences are difficult to measure—with few studies in hospital medicine quantifying their burden and impact. With careful attention to design and implementation, cohorting may be successful in improving communication without increasing unnecessary interruptions—but such refinement requires close monitoring and continuous improvement which are often lacking in strained hospital medicine environments.Workload, communication, and outcomes are inexorably linked in hospital medicine. While cohorting may be associated with modest increases in the duration of each patient care encounter, these gains are fragile—and may be easily lost or reversed by increases in patient loads.⁸ The evidence also suggests that while cohorting increases shallow availability or “reachability” and the quantity of communication, it may not alone ensure deeper interpersonal communication or improve the quality of communication.^14,15 Perversely, this increased reachability and decreased travel time may be used to rationalize increases in daily patient loads for cohorted teams. A focus on increasing productivity in turn may further increase interruptions, decreasing attention and impacting downstream outcomes that are not routinely monitored—such as the quality of communication, cognitive load, cognitive bias, diagnostic errors, and satisfaction with a job well done.“Every system is perfectly designed to get the results it gets”—and it is time to scrutinize the systems in which hospitalists work every day. The complexities of geographic cohorting we have examined provide insights that may allow us to design better models of care. We propose attention to the following principles (Fig. ​(Fig.11):

1. Strengthening synergies between the clinical microsystem and the institution

Open in a separate windowFig. 1The connectedness between the inpatient unit, institution, patient, and outcomes.In many instances, the COVID-19 pandemic clearly demonstrated what effective synergies can achieve. Driven by the crisis of the pandemic and potential personal protective equipment shortages, many institutions successfully and rapidly deployed hospitalist cohorting, a feat many previously struggled to achieve. However, in many cases, cohorting was quickly dismantled—highlighting the barriers that institutions and hospitalists face to prioritize and sustain geography—and which neither can overcome alone.¹⁶ While each inpatient unit represents a microcosm of the parent organization and drives its outcomes, it in turn relies on its parent organization—and the links between the work done within the clinical microsystem every day with that of the organization need to be strengthened. Workspace design, staffing targets, electronic medical record performance, and non-clinical administrative tasks all impact cognitive load and outcomes but are beyond the control of individuals. These complex issues require monitoring, feedback between the frontline and administrators, and a commitment to drive change at every level of the institution.

• 2.Defining and standardizing measures of success to reflect shared priorities

Effective collaboration between the clinical microsystem and the institution is also crucially conveyed by what is measured and organizations signal their priorities by the metrics audited. To date, hospitalist literature has focused heavily on length of stay, and cohorting has been associated with increases, decreases, or no changes in length of stay. Such findings raise the question of whether the intervention was well-designed to impact the outcome measured and/or whether different metrics would better reflect the benefits of the intervention. Selected metrics should represent the shared mission of the frontline clinicians and the organization. Hospital medicine groups should carefully evaluate how they (or others) measure their quality and value, and what the measures drive. There are pitfalls in metric selection that may frustrate hospitalists, and metrics should reflect what is valued, impactful, within the locus of control of hospitalists and not based on what is expedient to measure.¹⁷ As hospitalists evolve into problem solvers, communicators, educators, researchers, advocates, and boundary spanners, our metrics should mature in tandem to prevent stagnation and drive progress. This evolution will require a thoughtful investment in the infrastructure of each hospital medicine group.

• 3.Re-imagine and re-define optimal workload

Few studies have evaluated optimal daily patient loads for hospitalists—with fifteen patients per day often cited as the threshold past which outcomes suffer.¹⁸ However, the landscape in hospital medicine has changed seismically—nursing shortages and turnover impede team building and team communication, acuity of illness continues to increase, text-based messaging may have further increased the quantity of communication, and the COVID-19 pandemic has amplified the focus on length of stay and hospital capacity while eroding the optimism and resilience of the workforce. These factors necessitate an urgent reevaluation of optimum hospitalist workloads. In trying to maximize short-term productivity measured by the numbers of patients seen and relative value units generated, we may jeopardize the very gains we are trying to achieve. For example, increasing patient loads are associated with negative hospitalist perceptions about cohorting’s impact on patient safety, collaboration with nursing colleagues, and hospitalist satisfaction² whereas reducing patient loads for hospitalists may actually yield cost savings for institutions.¹⁹ Initiatives to increase productivity must be accompanied by an assessment of the impact on the hospitalist, and on patient and institutional outcomes. As we reimagine workloads, we must account for the cognitive intensity of the hospitalist workday. In addition to patient volume, the cognitive burden is also influenced by patient acuity, hospitalist experience, the work environment and processes, interruptions, tasks, and the performance of the electronic medical record—factors that on some days may outstrip the impact of patient numbers alone.

• 4.Adopting a continuous quality improvement approach to drive improvements

Certain other principles emerge as we create frameworks for the way forward. Before deploying practice models, the purpose should be clearly defined—is it a way to improve patient experience? to improve the quality of communication? Studies on cohorting have measured and reported outcomes as diverse as the number of steps walked in a day, the number of pages received, agreement on the plan of care between physicians and nursing colleagues, and length of stay. Each institution may have its own unique priorities that need to be addressed, and the problem that is being solved for should be explicitly identified and the solution optimized specifically to address the issue. Without such forethought, plans may be subverted by the expectation of creating a “silver bullet” intervention—a solution viewed as the answer to multiple problems—and thus fall short by the resulting dilution of the original intent by the tacking on of adjacent issues. Interventions need to be specific not only to the issues, but to each setting. The environment of each hospital and each hospital unit is unique, and interventions should be tailored accordingly. For example, when nursing or physician turnover is high, how do you form relationships and foster psychological safety within the team? Cohorting alone may not overcome the barriers to team building in such a setting. Continuous improvement also requires attention to the current and emerging data around models of care. Adopting cohorting alone, without the associated interventions that have been linked with improved outcomes, may invoke all the downsides without achieving potential gains. Different combinations of elements of care, some of which may not include cohorting at all, could influence specific outcomes more than others.²⁰ When interpreting literature, we should be mindful that many investigations report favorable short-term pre-post outcomes but do not reflect the downstream emergence of unintended consequences. An infrastructure that supports the continuous monitoring of outcomes, surveillance for unintended consequences, and agile course correction when needed should be developed and deployed alongside models of care.Lessons learned from examining the strengths and weaknesses of cohorting provide a roadmap for building better systems. The stressors that undermine the gains from unit-based interventions may be beyond the locus of control of any inpatient unit and require synergy between the unit and the organization. This synergy is reflected in patient loads, workspaces, and metric selections that impact the models we deploy at the level of the unit. What we do every single day—and how we do it—has implications for our patients, our communities, our wellbeing, and the future of hospital medicine.