Modeling of relationships between pharmacokinetics and blockade of agonist-induced elevation of intraurethral pressure and mean arterial pressure in conscious dogs treated with alpha(1)-adrenoceptor antagonists.

Fiduxosin is a new alpha(1)-adrenoceptor antagonist targeted for the treatment of symptomatic benign prostatic hyperplasia. The purpose of this study was to determine and compare the potencies of the alpha(1)-adrenoceptor antagonists terazosin, doxazosin, tamsulosin, and fiduxosin, based on relationships between plasma drug concentrations and blockade of phenylephrine (PE)-induced intraurethral (IUP) and mean arterial pressure (MAP) responses after single oral dosing in conscious male beagle dogs. Magnitude of blockade and plasma concentrations were evaluated at selected time points over 24 h. All drugs produced dose-dependent antagonism of PE-induced IUP and MAP responses. When IUP and MAP blockade effects were plotted against drug plasma concentrations, direct relationships were observed that were well described by the sigmoidal maximal effect model. IUP IC(50) values for terazosin, doxazosin, tamsulosin, and fiduxosin were 48.6, 48.7, 0.42, and 261 ng/ml, respectively. MAP IC(50) values were 12.2, 13.8, 1.07, and 1904 ng/ml, respectively. Uroselectivity index values, defined as MAP IC(50)/IUP IC(50), were 0.25, 0.28, 2.6, and 7.3, respectively. These results extend previous observations with terazosin in this model, showing that doxazosin exhibits a uroselectivity index comparable to terazosin, consistent with the lack of alpha(1)-adrenoceptor subtype selectivity or uroselectivity of these drugs. Tamsulosin, an alpha(1a)-/alpha(1d)-subtype selective agent, had an index value approximately 10-fold greater than the nonselective drugs. Based on its pharmacokinetic profile and a relative uroselectivity 29-fold greater than the nonselective drugs, fiduxosin is expected to exhibit greater selectivity for urethral compared with vascular alpha(1)-adrenoceptors in human and should be a novel, long-acting, uroselective alpha(1)-adrenoceptor antagonist.     

MMPI‐2 assessed post‐traumatic stress disorder related to job stress,coping, and personality in police agencies

The PK and PS scales of the MMPI‐2 were developed to index the degree of post‐traumatic stress disorder (PTSD). These scales were applied to a sample of 254 mostly male sworn and civilian law enforcement employees from four police agencies. Participants also completed surveys measuring their perceived levels of job stress, their use of a set of coping strategies, and their performance on measures of five global personality domains. The two PTSD scales appeared to have good internal structures and relatively high reliabilities. Employees at greater risk for PTSD reported higher levels of work‐related stress, seemed to use more maladaptive coping strategies, were more neurotic, and tended to be less extraverted, agreeable, and conscientious. Copyright © 2004 John Wiley & Sons, Ltd.     

Asymmetric and Axisymmetric Constant Curvature Liquid-Gas Interfaces in Pulmonary Airways

Airway closure and gas trapping can occur during lung deflation and inflation when fluid menisci form across the lumina of respiratory passageways. Previous analyses of the behavior of liquid in airways have assumed that the airway is completely wetted or that the contact angle of the liquid-gas interface with the airway wall is 0, and thus that the airway fluid forms an axisymmetric surface. However, some investigators have suggested that liquid in the airways is discontinuous and that contact angles can be as high as 67. In this study we consider the characteristics of constant curvature surfaces that could form a stable liquid-gas interface in a cylindrical airway. Our analysis suggests that, for small liquid volumes, asymmetric droplets are more likely to form than axisymmetric toroids. In addition, if the fluid contact angle is greater than 13, asymmetric droplets can sustain larger liquid volumes than axisymmetric toroids before collapsing to form menisci. These results suggest that (1) fluid formations other than axisymmetric toroids could occur in the airways; and (2) the analysis of the behavior of fluids and the development of liquid menisci within the lungs should include the potential role of asymmetric droplets.     

Splice variants of the relaxin and INSL3 receptors reveal unanticipated molecular complexity

LGR7 and LGR8 are G protein-coupled receptors that belong to the leucine-rich repeat-containing G-protein coupled receptor (LGR) family, including the thyroid-stimulating hormone (TSH), LH and FSH receptors. LGR7 and LGR8 stimulate cAMP production upon binding of the cognate ligands, relaxin and insulin-like peptide 3 (INSL3), respectively. We cloned several novel splice variants of both LGR7 and LGR8 and analysed the function of four variants. LGR7.1 is a truncated receptor, including only the N-terminal region of the receptor and two leucine rich repeats. In contrast, LGR7.2, LGR7.10 and LGR 8.1 all contain an intact seven transmembrane domain and most of the extracellular region, lacking only one or two exons in the ectodomain. Our analysis demonstrates that although LGR7.10 and LGR8.1 are expressed at the cell surface, LGR7.2 is predominantly retained within cells and LGR7.1 is partially secreted. mRNA expression analysis revealed that several variants are co-expressed in various tissues. None of these variants were able to stimulate cAMP production following relaxin or INSL3 treatment. Unexpectedly, we did not detect any direct specific relaxin or INSL3 binding on any of the splice variants. The large number of receptor splice variants identified suggests an unforeseen complexity in the physiology of this novel hormone-receptor system.     

Correction to: Paramagnetic Fluorinated Nanoemulsions for In Vivo F-19 MRI

Molecular Imaging and Biology -     

Autocrine motility-stimulatory pathways of oral premalignant lesion cells

Patients with premalignant oral lesions have varying levels of risk of developing oral squamous cell carcinoma (OSCC), whose aggressiveness requires increased motility. Not known is if and how premalignant oral lesion cells acquire the increased motility characteristic of OSCC. This was addressed by immunohistochemical analysis of banked premalignant lesion tissues and by functional analyses using cultures established from premalignant oral lesions and OSCC. These studies showed premalignant oral lesion cells and OSCC to be more motile than normal keratinocytes. Concomitantly, levels of ceramide were reduced. The activity of the protein phosphatase PP-2A, which restricts motility and which can be activated by ceramide, was also diminished. This was due to IL-10 released from premalignant lesion cells. Treatment with a membrane-permeable ceramide restored PP-2A activity and blocked migration. These studies show an autocrine motility-stimulatory pathway that is mediated in premalignant lesion cells by IL-10 through its reduction of ceramide levels and inhibition of PP-2A activity.     

Bioenergetics of photobiomodulated osteoblast mitochondrial cells derived from human pulp stem cells: systematic review

Lasers in Medical Science - Dental pulp cells are a source of multipotent mesenchymal stem cells with a high proliferation rate and multilineage differentiation potential. This study investigated...     

Working memory training and brain structure and function in extremely preterm or extremely low birth weight children

This study in children born extremely preterm (EP; <28 weeks’ gestational age) or extremely low birth weight (ELBW; <1,000 g) investigated whether adaptive working memory training using Cogmed® is associated with structural and/or functional brain changes compared with a placebo program. Ninety‐one EP/ELBW children were recruited at a mean (standard deviation) age of 7.8 (0.4) years. Children were randomly allocated to Cogmed or placebo (45‐min sessions, 5 days a week over 5–7 weeks). A subset had usable magnetic resonance imaging (MRI) data pretraining and 2 weeks posttraining (structural, n = 48; diffusion, n = 43; task‐based functional, n = 18). Statistical analyses examined whether cortical morphometry, white matter microstructure and blood oxygenation level‐dependent (BOLD) signal during an n‐back working memory task changed from pretraining to posttraining in the Cogmed and placebo groups separately. Interaction analyses between time point and group were then performed. There was a significant increase in neurite density in several white matter regions from pretraining to posttraining in both the Cogmed and placebo groups. BOLD signal in the posterior cingulate and precuneus cortices during the n‐back task increased from pretraining to posttraining in the Cogmed but not placebo group. Evidence for group‐by‐time interactions for the MRI measures was weak, suggesting that brain changes generally did not differ between Cogmed and placebo groups. Overall, while some structural and functional MRI changes between the pretraining and posttraining period in EP/ELBW children were observed, there was little evidence of training‐induced neuroplasticity, with changes generally identified in both groups. Trial registration Australian New Zealand Clinical Trials Registry, anzctr.org.au ; ACTRN12612000124831.     

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.