An Observational Study of Physicians' Workflow Interruptions in Outpatient Departments in China.

Background: Workflow interruptions are frequent in hospital outpatient clinics. Eventually, not only reducing the work efficiency and quality, but also further threatening patient safety. Over the last 10-15 years, research on workflow interruptions in inpatient care has increased, but there is a lack of research on the interruptions in outpatient clinics. The present study aimed to study the differences in physicians' workflow interruptions among outpatient departments in the tertiary hospital in China. Methods: In a tertiary hospital, a standardized observational study of 32 doctors' workflow in outpatient department of four typical clinical specialties was conducted. The record of workflow interruptions was based on a self-made observation instrument after verifying its reliability and validity. Linear regression methods were used to assess outpatient characteristics as predictors of the number of interruptions. The Kruskal-Wallis test was used to analyze the difference about the duration of interruptions among specialties, and the Chi-Square Test was used to examine the sources of interruptions among different specialties, to determine whether interruption source is associated with specialty. Results: The number of patients was the significant independent predictor of the number of interruptions (p < 0.001). In terms of work tasks being interrupted, the highest interruption rate occurred when physicians were asking health history: 19.95 interruptions per hour. The distribution of interruption sources among the four clinical specialties were statistically different (X2 = 16.988, p = 0.049). Conclusion: The findings indicate that physicians' workflow interruptions are connected with many contents in the work system. Further emphasis should be placed on the effective application of hospital management measures in an interrupted environment to promote a safe and efficiency outpatient care.

Identifying the Subtypes and Characteristics of Mental Workload Among Chinese Physicians in Outpatient Practice: A Latent Profile Analysis.

Objective: The purpose of this study is to investigate the mental workload level of physicians in outpatient practice since the normalization of prevention and control of the COVID-19 pandemic in China and explore the subtypes of physicians regarding their mental workload. Methods: A cross-sectional survey of 1,934 physicians primarily in 24 hospitals in 6 provinces in Eastern, Central, and Western China was conducted from November 2020 to February 2021. A latent profile analysis was performed to identify clusters based on the six subscales of the Chinese version of physician mental workload scale developed by our research team. Chi-square tests were performed to explore the differences in demographic characteristics of the subtypes among the subgroups, and multinomial logistic regression analysis was further conducted to identify the determinants of the subtypes of physicians. Results: Overall, the participating physicians reported high levels of task load but with high self-assessed performance (68.01 ± 14.25) while performing communication work tasks characterized by direct patient interaction in outpatient clinics. About 33.8% of the participating physicians were identified as "high workload and high self-assessment" subtype, compared to 49.7% "medium workload and medium self-assessment" subtype and 16.4% "low workload and low self-assessment" subtype. Physicians in "high workload and high self-assessment" subtype had the highest mean mental workload score. Physicians who were female, younger, married, worse health status, those who had lower educational level and an average monthly income of 5,001-10,000 RMB, those who worked in tertiary A hospitals, more hours per week and more than 40 h per week in outpatient clinics, and those who saw more outpatients per day, and spent more time per patient but with higher outpatient satisfaction were more likely to belong to "high workload and high self-assessment" subtype. Conclusion: Our findings can help provide a solid foundation for developing targeted interventions for individual differences across physicians regarding their mental workload. We suggest the hospital managers should pay more attention to those physicians with characteristics of the "high workload and high self-assessment" subtype and strengthen the management of the workload of this subtype of physicians to reduce the risks of their mental health, and to maintain their high work performance in outpatient clinics.

A Scale to Measure the Joy in Work of Doctors: Development, Validity, and Reliability.

Background: The aim of this study is to develop a scale and evaluate its' validity and reliability to measure the joy in work of doctors. Methods: Based on literature review and panel discussion, the scale framework and item pool were determined. Next, the items were modified by two rounds of expert consultation. Then the pre-investigation was applied and the formal version of scale was formed. Last, the reliability and validity of the scale were tested with 426 physicians. Results: The scale was composed of four dimensions: work autonomy needs, competency identification needs, competency perception needs and work relationship needs. Each dimension had 7 items, and both reliability and validity were acceptable. The Cronbach α coefficient and half-reliability coefficient of the whole scale were 0.954 (>0.9) and 0.974 (>0.9). The Spearman correlations of item-total score ranged from 0.556 to 0.749, indicating a good-item total score correlation. The χ 2/ df, RMSEA, RMR, GFI, CFI, and TLI, CFA of the maximum likelihood method supported a good fit with the model. Conclusions: Based on the self-determination theory, this study develops a scale to measure the joy in work of doctors. It has good validation and reliability, which is useful for doctors and medical institutions to take steps to improve happiness.

Determinants of Patients' Intention to Use the Online Inquiry Services Provided by Internet Hospitals: Empirical Evidence From China.

BACKGROUND: Internet hospitals show great potential for adequately fulfilling people's demands for high-quality outpatient services, and with the normalization of the epidemic prevention and control of COVID-19, internet hospitals play an increasingly important role in delivering health services to the public. However, the factors that influence patients' intention to use the online inquiry services provided by internet hospitals remain unclear. Understanding the patients' behavioral intention is necessary to support the development of internet hospitals in China and promote patients' intention to use online inquiry services provided by internet hospitals during the prevention and control of the COVID-19 epidemic. OBJECTIVE: The purpose of this study is to identify the determinants of patients' intention to use the online inquiry services provided by internet hospitals based on the theory of planned behavior (TPB). METHODS: The hypotheses of our research model were developed based on the TPB. A questionnaire was developed through patient interviews, verified using a presurvey, and used for data collection for this study. The cluster sampling technique was used to include respondents with chronic diseases. Structural equation modeling was used to test the research hypotheses. RESULTS: A total of 638 valid responses were received from patients with chronic diseases. The goodness-of-fit indexes corroborated that the research model was a good fit for the collected data. The model explained 45.9% of the variance in attitude toward the behavior and 60.5% of the variance in behavioral intention. Perceived behavioral control and perceived severity of disease had the strongest total effects on behavioral intention (ß=.624, P=.004 and ß=.544, P=.003, respectively). Moreover, perceived convenience, perceived information risk, emotional preference, and health consciousness had indirect effects on behavioral intention, and these effects were mediated by attitude toward the behavior. Among the four constructs, perceived convenience had the highest indirect effect on behavioral intention (ß=.207; P=.001). CONCLUSIONS: Perceived behavioral control and perceived severity of disease are the most important determinants of patients' intention to use the online inquiry services provided by internet hospitals. Therefore, internet hospitals should further optimize the design of online service delivery and ensure a reasonable assembly of high-quality experts, which will benefit the promotion of patients' adoption intention toward online inquiry services for health purposes. Perceived convenience, emotional preference, and perceived risks also have effects on behavioral intention. Therefore, the relevant quality control standards and regulations for internet hospitals should be further developed and improved, and the measures to protect personal information should be strengthened to ensure the patient safety. Our study supports the use of the TPB in explaining patients' intention to use online inquiry services provided by internet hospitals.

Curcumin synergizes with 5-fluorouracil by impairing AMPK/ULK1-dependent autophagy, AKT activity and enhancing apoptosis in colon cancer cells with tumor growth inhibition in xenograft mice.

BACKGROUND: Chemoresistance is a major obstacle that limits the benefits of 5-Fluorouracil (5-Fu)-based chemotherapy for colon cancer patients. Autophagy is an important cellular mechanism underlying chemoresistance. Recent research advances have given new insights into the use of natural bioactive compounds to overcome chemoresistance in colon cancer chemotherapy. As one of the multitargeted and safer phytomedicines, curcumin has been reported to work as cancer-specific chemosensitizer, presumably via induction of autophagic signaling pathways. The precise therapeutic effect of curcumin on autophagy in determining tumorous cells' fate, however, remains unclear. This study was conducted to investigate the differential modulations of the treatments either with 5-Fu alone or 5-Fu combined with curcumin on cellular autophagic responses and viabilities in the human colon cancer cells HCT116 and HT29, and explore molecular signaling transductions underlying the curcumin-mediated autophagic changes and potentiation of 5-Fu's cytotoxicity in vitro and in vivo. METHODS: Cell proliferation assay and morphology observation were used to identify the cytotoxicity of different combinations of curcumin and 5-Fu in HCT116 and HT29 cells. Cell immunofluorescence assay, Flow cytometry and Western blot were employed to detect changes of autophagy and the autophagy-related signaling pathways in the colon cancer cells and/or xenograft mice. RESULTS: Curcumin could significantly augment the cytotoxicity of 5-Fu to the tumorous cells, and the pre-treatment with curcumin followed by 5-Fu (pre-Cur) proved to be the most effective one compared to other two combinations. The chemosensitizing role of curcumin might attribute to the autophagy turnover from being activated in 5-Fu mono-treatment to being inhibited in the pre-Cur treatment as indicated by the changes in expression of beclin-1, p62 and LC3II/LC3I and the intensity of Cyto-ID Green staining. The autophagic alterations appeared to be contributed by down-regulation of not only the phospho-Akt and phospho-mTOR expressions but the phospho-AMPK and phospho-ULK1 levels as well. The cellular activation of AMPK by addition of A-769662 to the pre-Cur combination resulted in reversed changes in expressions of the autophagy protein markers and apoptotic status compared to those of the pre-Cur combination treatment. The findings were validated in the xenograft mice, in which the tumor growth was significantly suppressed in the mice with 25-day combination treatment, and meanwhile expressions of the autophagy markers, P-AMPK and P-ULK1 were all reversely altered in line with those observed in HCT116 cells. CONCLUSION: Pre-treatment with curcumin followed by 5-Fu may mediate autophagy turnover both in vitro and in vivo via AMPK/ULK1-dependent autophagy inhibition and AKT modulation, which may account for the increased susceptibility of the colon cancer cells/xenograft to the cytotoxicity of 5-Fu.

ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery.

Angiogenic response is essential for ischemic brain repair. The von Willebrand factor (VWF)-cleaving protease disintegrin and metalloprotease with thrombospondin type I motif, member 13 (ADAMTS13) is required for endothelial tube formation in vitro, but there is currently no in vivo evidence supporting a function of ADAMTS13 in angiogenesis. Here we show that mice deficient in ADAMTS13 exhibited reduced neovascularization, brain capillary perfusion, pericyte and smooth muscle cell coverage on microvessels, expression of the tight junction and basement membrane proteins, and accelerated blood-brain barrier (BBB) breakdown and extravascular deposits of serum proteins in the peri-infarct cortex at 14 days after stroke. Deficiency of VWF or anti-VWF antibody treatment significantly increased microvessels, perfused capillary length, and reversed pericyte loss and BBB changes in Adamts13-/- mice. Furthermore, we observed that ADAMTS13 deficiency decreased angiopoietin-2 and galectin-3 levels in the isolated brain microvessels, whereas VWF deficiency had the opposite effect. Correlating with this, overexpression of angiopoietin-2 by adenoviruses treatment or administration of recombinant galectin-3 normalized microvascular reductions, pericyte loss, and BBB breakdown in Adamts13-/- mice. The vascular changes induced by angiopoietin-2 overexpression and recombinant galectin-3 treatment in Adamts13-/- mice were abolished by the vascular endothelial growth factor receptor-2 antagonist SU1498. Importantly, treating wild-type mice with recombinant ADAMTS13 at 7 days after stroke markedly increased neovascularization and vascular repair and improved functional recovery at 14 days. Our results suggest that ADAMTS13 controls key steps of ischemic vascular remodeling and that recombinant ADAMTS13 is a putative therapeutic avenue for promoting stroke recovery.

von Willebrand factor contributes to poor outcome in a mouse model of intracerebral haemorrhage.

Spontaneous intracerebral haemorrhage (ICH) is the most devastating stroke subtype and has no proven treatment. von Willebrand factor (VWF) has recently been demonstrated to promote inflammation processes. The present study investigated the pathophysiological role of VWF after experimental ICH. Functional outcomes, brain edema, blood-brain barrier (BBB) permeability, cerebral inflammation and levels of intercellular adhesion molecule-1 (ICAM-1) and matrix metalloproteinase-9 (MMP-9) were measured in a mouse model of ICH induced by autologous blood injection. We show that VWF were increased in the plasma and was accumulated in the perihematomal regions of mice subjected to ICH. Injection of VWF resulted in incerased expression of proinflammatory mediators and activation of ICAM-1 and MMP-9, associated with elevated myeloperoxidase, recruitment of neutrophils and microglia. Moreover, mice treated with VWF showed dramatically decreased pericyte coverage, more severe BBB damage and edema formation, and neuronal injury was increased compared with controls. In contrast, blocking antibodies against VWF reduced BBB damage and edema formation and improved neurological function. Together, these data identify a critical role for VWF in cerebral inflammation and BBB damage after ICH. The therapeutic interventions targeting VWF may be a novel strategy to reduce ICH-related injury.

Tissue Plasminogen Activator Neurotoxicity is Neutralized by Recombinant ADAMTS 13.

Tissue plasminogen activator (tPA) is an effective treatment for ischemic stroke, but its neurotoxicity is a significant problem. Here we tested the hypothesis that recombinant ADAMTS 13 (rADAMTS 13) would reduce tPA neurotoxicity in a mouse model of stroke. We show that treatment with rADAMTS 13 in combination with tPA significantly reduced infarct volume compared with mice treated with tPA alone 48 hours after stroke. The combination treatment significantly improved neurological deficits compared with mice treated with tPA or vehicle alone. These neuroprotective effects were associated with significant reductions in fibrin deposits in ischemic vessels and less severe cell death in ischemic brain. The effect of rADAMTS13 on tPA neurotoxicity was mimicked by the N-methyl-D-aspartate (NMDA) receptor antagonist M-801, and was abolished by injection of NMDA. Moreover, rADAMTS 13 prevents the neurotoxicity effect of tPA, by blocking its interaction with the NMDA receptor NR2B and the attendant phosphorylation of NR2B and activation of ERK1/2. Finally, the NR2B-specific NMDA receptor antagonist ifenprodil abolished tPA neurotoxicity and rADAMTS 13 treatment had no further beneficial effect. Our data suggest that the combination of rADAMTS 13 and tPA may provide a novel treatment of ischemic stroke by diminishing the neurotoxic effects of exogenous tPA.

Extremely low-frequency electromagnetic fields enhance the proliferation and differentiation of neural progenitor cells cultured from ischemic brains.

In the mammalian brain, neurogenesis persists throughout the embryonic period and adulthood in the subventricular zone of the lateral ventricle and the granular zone (dentate gyrus) of the hippocampus. Newborn neural progenitor cells (NPCs) in the two regions play a critical role in structural and functional plasticity and neural regeneration after brain injury. Previous studies have reported that extremely low-frequency electromagnetic fields (ELF-EMF) could promote osteogenesis, angiogenesis, and cardiac stem cells' differentiation, which indicates that ELF-EMF might be an effective tool for regenerative therapy. The present studies were carried out to examine the effects of ELF-EMF on hippocampal NPCs cultured from embryonic and adult ischemic brains. We found that exposure to ELF-EMF (50 Hz, 0.4 mT) significantly enhanced the proliferation capability both in embryonic NPCs and in ischemic NPCs. Neuronal differentiation was also enhanced after 7 days of cumulative ELF-EMF exposure, whereas glial differentiation was not influenced markedly. The expression of phosphorylated Akt increased during the proliferation process when ischemic NPCs were exposed to ELF-EMF. However, blockage of the Akt pathway abolished the ELF-EMF-induced proliferation of ischemic NPCs. These data show that ELF-EMF promotes neurogenesis of ischemic NPCs and suggest that this effect may occur through the Akt pathway.Video abstract, Supplemental Digital Content 1, http://links.lww.com/WNR/A347.

Recombinant ADAMTS 13 Attenuates Brain Injury After Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Inflammatory responses and blood-brain barrier (BBB) dysfunction play important roles in brain injury after intracerebral hemorrhage (ICH). The metalloprotease ADAMTS 13 (a disintegrin and metalloprotease with thrombospondin type I motif, member 13) was shown to limit inflammatory responses through its proteolytic effects on von Willebrand factor. In the present study, we addressed the role of ADAMTS 13 after experimental ICH. METHODS: ICH was induced in mice by intracerebral infusion of autologous blood. The peri-hematomal inflammatory responses, levels of matrix metalloproteinase-9 and intercellular adhesion molecule-1, pericyte coverage on brain capillaries, and BBB permeability were quantified at 24 hours. Functional outcomes, cerebral edema, and hemorrhagic lesion volume were quantified at day 3. RESULTS: Treatment with recombinant ADAMTS 13 (rADAMTS 13) reduced the levels of chemokines and cytokines, myeloperoxidase activity, and microglia activation and neutrophil recruitment after ICH. rADAMTS 13 also decreased interleukin-6 expression in brain endothelial cells stimulated by lipopolysaccharide, whereas recombinant von Willebrand factor reversed this effect. The anti-inflammatory effect of rADAMTS 13 was accompanied by reduced expression of intercellular adhesion molecule-1 and less activation of matrix metalloproteinase, enhanced pericyte coverage of brain microvessels, and attenuated BBB disruption. Furthermore, neutrophil depletion protected against BBB damage, and rADAMTS 13 treatment had no further beneficial effect. Finally, treatment of mice with rADAMTS 13 reduced cerebral edema and hemorrhagic lesion volume and improved neurological functions. CONCLUSIONS: Our findings reveal the importance of rADAMTS 13 in regulating pathological inflammation and BBB function and suggest that rADAMTS 13 may provide a new therapeutic strategy for ICH.

Caspase-3 modulates regenerative response after stroke.

Stroke is a leading cause of long-lasting disability in humans. However, currently there are still no effective therapies available for promoting stroke recovery. Recent studies have shown that the adult brain has the capacity to regenerate neurons after stroke. Although this neurogenic response may be functionally important for brain repair after injury, the mechanisms underlying stroke-induced neurogenesis are not known. Caspase-3 is a major executioner and has been identified as a key mediator of neuronal death in the acute stage of stroke. Recently, however, accumulating data indicate that caspase-3 also participates in various biological processes that do not cause cell death. Here, we show that cleaved caspase-3 was increased in newborn neuronal precursor cells (NPCs) in the subventricular zone (SVZ) and the dentate gyrus during the period of stroke recovery, with no evidence of apoptosis. We observed that cleaved caspase-3 was expressed by NPCs and limited its self-renewal without triggering apoptosis in cultured NPCs from the SVZ of ischemic mice. Moreover, we revealed that caspase-3 negatively regulated the proliferation of NPCs through reducing the phosphorylation of Akt. Importantly, we demonstrated that peptide inhibition of caspase-3 activity significantly promoted the proliferation and migration of SVZ NPCs and resulted in a significant increase in subsequent neuronal regeneration and functional recovery after stroke. Together, our data identify a previously unknown caspase-3-dependent mechanism that constrains stroke-induced endogenous neurogenesis and should revitalize interest in targeting caspase-3 for treatment of stroke.

Recombinant ADAMTS13 reduces tissue plasminogen activator-induced hemorrhage after stroke in mice.

OBJECTIVE: Tissue plasminogen activator (tPA) is approved for treatment of acute ischemic stroke, but it increases the risk of cerebral hemorrhage. Accumulating evidence suggests that von Willebrand factor (VWF) plays a pivotal role in thrombus formation and microcirculatory disturbances after ischemic stroke. By cleaving VWF, ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) protects mice from stroke. Therefore, we hypothesized that recombinant ADAMTS13 (rADAMTS13) could increase the safety of tPA thrombolysis in stroke. METHODS: We examined blood-brain barrier (BBB) permeability after intraventricular injection of tPA, VWF, and rADAMTS13 in nonischemic mice. We investigated the role of rADAMTS13 on reducing tPA-induced BBB dysfunction and cerebral hemorrhage in a mouse stroke model. RESULTS: Intraventricular injection of tPA or VWF under nonischemic conditions resulted in a significant increase in BBB permeability. In contrast, rADAMTS13 blocked both tPA- and VWF-induced BBB opening. BBB disruption following stroke was exacerbated by intravenous administration of tPA, but this was attenuated by injection of rADAMTS13. Correspondingly, tPA-associated hemorrhage after stroke was significantly reduced by rADAMTS13. The antihemorrhagic effect of rADAMTS13 was reversed by injection of recombinant VWF. We also showed that rADAMTS13 inhibited tPA-mediated upregulation of vascular endothelial growth factor (VEGF) in vascular endothelium after stroke. The upregulation of VEGF was suppressed by either an Akt inhibitor wortmannin or a Rho kinase inhibitor fasudil. Furthermore, rADAMTS13 downregulated tPA-induced phosphorylation of Akt and activation of RhoA. INTERPRETATION: These findings demonstrate that the VWF-cleaving protease rADAMTS13 reduced tPA-induced hemorrhage by regulating BBB integrity, and suggest that this effect may occur through the Akt/RhoA-mediated VEGF pathways.

Gaining weights... and feeling good about it!

Two problems that dog current microarrays analyses are (i) the relatively arbitrary nature of data preprocessing and (ii) the inability to incorporate spot quality information in inference except by all-or-nothing spot filtering. In this chapter we propose an approach based on using weights to overcome these two problems. The first approach uses weighted p-values to make inference robust to normalization and the second approach uses weighted spot intensity values to improve inference without any filtering.