Digital Twin technology is an emerging concept that has become the centre of attention for industry and, in more recent years, academia. The advancements in industry 4.0 concepts have facilitated its ...growth, particularly in the manufacturing industry. The Digital Twin is defined extensively but is best described as the effortless integration of data between a physical and virtual machine in either direction. The challenges, applications, and enabling technologies for Artificial Intelligence, Internet of Things (IoT) and Digital Twins are presented. A review of publications relating to Digital Twins is performed, producing a categorical review of recent papers. The review has categorised them by research areas: manufacturing, healthcare and smart cities, discussing a range of papers that reflect these areas and the current state of research. The paper provides an assessment of the enabling technologies, challenges and open research for Digital Twins.
Quantitative measurements of diffusion can provide important information about how proteins and lipids interact with their environment within the cell and the effective size of the diffusing species. ...Confocal fluorescence recovery after photobleaching (FRAP) is one of the most widely accessible approaches to measure protein and lipid diffusion in living cells. However, straightforward approaches to quantify confocal FRAP measurements in terms of absolute diffusion coefficients are currently lacking. Here, we report a simplified equation that can be used to extract diffusion coefficients from confocal FRAP data using the half time of recovery and effective bleach radius for a circular bleach region, and validate this equation for a series of fluorescently labeled soluble and membrane‐bound proteins and lipids. We show that using this approach, diffusion coefficients ranging over three orders of magnitude can be obtained from confocal FRAP measurements performed under standard imaging conditions, highlighting its broad applicability.
Multivalent glycolipid binding toxins such as cholera toxin have the capacity to cluster glycolipids, a process thought to be important for their functional uptake into cells. In contrast to the ...highly dynamic properties of lipid probes and many lipid-anchored proteins, the B-subunit of cholera toxin (CTxB) diffuses extremely slowly when bound to its glycolipid receptor GM(1) in the plasma membrane of living cells. In the current study, we used confocal FRAP to examine the origins of this slow diffusion of the CTxB/GM(1) complex at the cell surface, relative to the behavior of a representative GPI-anchored protein, transmembrane protein, and fluorescent lipid analog. We show that the diffusion of CTxB is impeded by actin- and ATP-dependent processes, but is unaffected by caveolae. At physiological temperature, the diffusion of several cell surface markers is unchanged in the presence of CTxB, suggesting that binding of CTxB to membranes does not alter the organization of the plasma membrane in a way that influences the diffusion of other molecules. Furthermore, diffusion of the B-subunit of another glycolipid-binding toxin, Shiga toxin, is significantly faster than that of CTxB, indicating that the confined diffusion of CTxB is not a simple function of its ability to cluster glycolipids. By identifying underlying mechanisms that control CTxB dynamics at the cell surface, these findings help to delineate the fundamental properties of toxin-receptor complexes in intact cell membranes.
There are numerous reasons for the increased use of telemedicine in orthopaedic surgery, one of which is the perception that virtual visits are more cost-effective than in-person visits. However, to ...our knowledge, no studies have compared the cost and time investment of virtual versus in-person visits using the time-driven activity-based costing (TDABC) method. Unlike methods that estimate cost based on charges for services rendered, TDABC provides a more precise measurement of costs, which is essential for assessing cost-effective innovations and moving to value-based healthcare.
(1) Are virtual visits less costly than analogous in-person visits, as measured by TDABC? (2) Does TDABC yield cost estimates that are lower or higher than the ratio of costs to charges (RCC), which is a simple, frequently used costing method? (3) Do the total time commitments of healthcare personnel, and that of the surgeon specifically, vary between the virtual and in-person settings?
Patients for this prospective, observational study were recruited from the practices of the highest-volume virtual-visit surgeons of three subspecialties (joints, hand, and sports) in a multihospital, tertiary-care academic institution in a metropolitan area in the Midwestern United States. Each surgeon had at least 10 years of clinical practice. Between June 2021 and September 2021, we analyzed both in-person and virtual return visits with patients who had an established relationship with the surgeon, because this represented the most frequent type of virtual visits and enabled a direct comparison between the two settings. New patients were not included in the study because of the limited availability of new-patient virtual visits; such patients often benefit from in-person physical examinations and on-site imaging. Additionally, patients seen for routine postoperative care were excluded because they were primarily seen in person by a physician assistant. Data were acquired during this period until 90 in-person and 90 virtual visits were collected according to selection criteria; no patients were lost to follow-up. Distinct process maps, which represent the steps involved in a clinic visit used to measure healthcare personnel time invested, were constructed for in-person and virtual clinic visits and used to compare total personnel and surgeon time spent. To calculate TDABC-derived costs, time allocated by personnel to complete each step was measured and used to calculate cost based on each personnel member's yearly salary. From the accounting department of our hospital, we acquired RCC cost data according to the level of service for a return visit.
The total median cost, as measured by TDABC, was USD 127 (IQR USD 111 to 163) for an in-person visit and USD 140 (IQR USD 113 to 205) for a virtual visit (median difference USD 13; p = 0.16). RCC overestimated TDABC-calculated direct variable cost in five of six service levels (in-person levels 3, 4, and 5 and virtual levels 3 and 5) by a range of USD 25 to 88. Additionally, we found that virtual visits consumed 4 minutes less of total personnel time (in-person: 17 minutes IQR 13.5 to 23.5 minutes, virtual: 13 minutes IQR 11 to 19 minutes; p < 0.001); however, this difference in personnel time did not equate to cost savings because surgeons spent 2 minutes longer on virtual visit activities than they did on in-person activities (in-person: 6 minutes IQR 4.5 to 9.5 minutes, virtual: 8 minutes IQR 5.5 to 13 minutes; p = 0.003).
Orthopaedic virtual visits did not deliver cost savings compared with in-person visits because surgeons spent more time on virtual visits and participated in virtual visits at the clinical site. Additionally, as anticipated, RCC overestimated costs as calculated by TDABC. These findings suggest that cost is not a primary advantage of transitioning to virtual visits, and that factors such as patient preference and satisfaction should be considered instead.
Level II, economic and decision analysis.
The COVID-19 pandemic and the mandated cessation of surgical procedures for a substantial portion of the 2020 year placed tremendous strain, both clinically and financially, on the health-care system ...in the United States. As a surgical specialty that accounts for nearly a quarter of all hospital net income, the revenue recovery of orthopaedic service lines (OSLs) is of particular importance to the financial recovery of their broader health-care institutions. In this American Orthopaedic Association (AOA) symposium report, the OSL leaders from 4 major academic medical institutions explain and reflect on their approaches to address their revenue deficits. Cost-reduction strategies, such as tightening budgets, adopting remote-work models, and limiting costs of human capital, were vital to stabilizing departmental finances at the onset of the pandemic, while strategies that focused on expanding surgical volume, such as those that improve efficiency in clinical and surgical settings, were important in growing revenue once elective procedures resumed. Institutional policy, payer administrative procedures, and the overall context of an ongoing public health crisis all placed limitations on recovery efforts, but engaging relevant stakeholders and working with available resources helped OSLs overcome these limitations. Due to clear strategic actions that were taken to address their deficits, each OSL represented in this AOA symposium saw substantial improvement in its year-end financial performance compared with its financial status at the end of the period of mandatory cessation of elective surgical cases.
The plasma membrane of mammalian cells is involved in a wide variety of cellular processes, including, but not limited to, endocytosis and exocytosis, adhesion and migration, and signaling. The ...regulation of these processes requires the plasma membrane to be highly organized and dynamic. Much of the plasma membrane organization exists at temporal and spatial scales that cannot be directly observed with fluorescence microscopy. Therefore, approaches that report on the membrane's physical parameters must often be utilized to infer membrane organization. As discussed here, diffusion measurements are one such approach that has allowed researchers to understand the subresolution organization of the plasma membrane. Fluorescence recovery after photobleaching (or FRAP) is the most widely accessible method for measuring diffusion in a living cell and has proven to be a powerful tool in cell biology research. Here, we discuss the theoretical underpinnings that allow diffusion measurements to be used in elucidating the organization of the plasma membrane. We also discuss the basic FRAP methodology and the mathematical approaches for deriving quantitative measurements from FRAP recovery curves. FRAP is one of many methods used to measure diffusion in live cell membranes; thus, we compare FRAP with two other popular methods: fluorescence correlation microscopy and single-particle tracking. Lastly, we discuss various plasma membrane organization models developed and tested using diffusion measurements.
Maloriented chromosomes can evade the spindle assembly checkpoint and generate aneuploidy, a common feature of tumorigenesis. But chromosome missegregation in non-transformed cells triggers a ...p53-dependent fail-safe mechanism that blocks proliferation of normal cells that inadvertently become aneuploid. How this fail-safe is triggered is not known. Here we identify a conserved feedback mechanism that monitors missegregating chromosomes during anaphase through the differential phosphorylation of histone H3.3 at Ser31. We do this by inducing transient chromosome missegregation in diploid cells. During anaphase, H3.3 Ser31 is phosphorylated along the arms of lagging or misaligned chromosomes. Within minutes, Ser31 phosphorylation (Ser31P) spreads to all of the chromatids of both daughter cells, which persists into G1. Masking H3.3 Ser31P by antibody microinjection prevents nuclear p53 accumulation in the aneuploid daughters. Previous work demonstrated that prolonged prometaphase and DNA damage during abnormal mitosis can activate p53. We show that p53 activation in response to chromosome missegregation can occur without prolonged mitosis or DNA damage. Our study provides insight into how aneuploidy caused by chromosome missegregation is normally monitored and suppressed.
Despite the heavy demand for and knowledge of the benefits of diversity, there is a persistent lack of racial, ethnic, and gender diversity in orthopaedic surgery. Since the implementation of ...diversity initiatives, data have shown that general surgery has been one of the top competitive surgical fields and has demonstrated growth in racial, ethnic, and gender diversity, making general surgery a good point of reference and comparison when analyzing racial and ethnic growth in orthopaedic surgery.
(1) What were the growth rates for Black and Hispanic orthopaedic residency applicants and residents between 2015 and 2022? (2) How did the growth rates of Black and Hispanic individuals in orthopaedic surgery compare with those of general surgery? (3) How did applicant recruitment and resident acceptance differ between Black and Hispanic people in orthopaedic surgery?
Applicant data were obtained from historical specialty-specific data from the Association of American Medical Colleges Electronic Residency Application Service Statistics database between 2018 and 2022, and resident data were obtained from the Accreditation Council of Graduate Medical Education Data Resource Book between 2015 and 2021. Between 2018 and 2022, the number of residency applicants totaled 216,677, with 17,912 Black residency applicants and 20,413 Hispanic residency applicants. Between 2015 and 2021, the number of active residents totaled 977,877, with 48,600 Black residents and 62,605 Hispanic residents. Because the applicant and resident data do not overlap throughout all years of observation, a sensitivity analysis of overlapping years (between 2018 and 2021) was conducted to ensure observed trends were consistent and valid throughout the study. All datasets obtained were used to establish the different racial and ethnic proportions of Black and Hispanic residency applicants and residents in four nonsurgical primary care specialties and four surgical subspecialties. A reference slope was created using data from the Association of American Medical Colleges and Accreditation Council of Graduate Medical Education to represent the growth rate for total residency applicants and residents, independently, across all residency specialties reported in each database. This slope was used for comparison among the resident and applicant growth rates for all eight selected specialties. Datapoints were placed into a scatterplot with regression lines, using slope equations to depict rate of growth and R2 values to depict linear fit. Applicant growth corresponded to applicant recruitment and resident growth corresponded to resident acceptance. Chi-square tests were used to compare residents and residency applicants for the Black and Hispanic populations, separately. Two-way analysis of variance with a time-by-specialty interaction term (F-test) was conducted to determine differences between growth slopes.
There was no difference in the growth rate of Black orthopaedic surgery applicants between 2018 and 2022, and there was no difference in the growth rate of Hispanic orthopaedic surgery applicants (R2 = 0.43; p = 0.23 and R2 = 0.63; p = 0.11, respectively). However, there was a very slight increase in the growth rate of Black orthopaedic surgery residents between 2015 and 2021, and a very slight increase in the growth rate of Hispanic orthopaedic surgery residents (R2 = 0.73; p = 0.02 and R2 = 0.79; p = 0.01, respectively). There were no differences in orthopaedic and general surgery rates of growth for Black applicants between 2018 and 2022 (0.004 applicants/year versus -0.001 applicants/year; p = 0.22), and no differences were found in orthopaedic and general surgery rates of growth for Black residents between 2015 and 2021 (0.003 residents/year versus 0.002 residents/year; p = 0.59). Likewise, Hispanic orthopaedic applicant growth rates did not differ between 2018 and 2022 from the rates of general surgery (0.004 applicants/year versus 0.005 applicants/year; p = 0.68), and there were no differences in orthopaedic and general surgery rates of growth for Hispanic residents (0.007 residents/year versus 0.01 residents/year; p = 0.35). Furthermore, growth rate comparisons between Black orthopaedic applicants and residents between 2018 and 2021 showed applicant growth was larger than resident growth, illustrating that the recruitment of Black applicants increased slightly more rapidly than resident acceptance. Growth rate comparisons between Hispanic applicants and residents showed a larger rate of resident growth, illustrating Hispanic resident acceptance increased slightly faster than applicant recruitment during that time.
We found low acceptance of Black residents compared with the higher recruitment of Black applicants, as well as overall low proportions of Black and Hispanic applicants and residents. Future studies might explore the factors contributing to the higher acceptances of Hispanic orthopaedic residents than Black orthopaedic residents.
We recommend that more emphasis should be placed on increasing Black and Hispanic representation at the department level to ensure cultural considerations remain at the forefront of applicant recruitment. Internal or external reviews of residency selection processes should be considered, and more immersive, longitudinal orthopaedic surgery clerkships and research mentorship experiences should be targeted toward Black and Hispanic students. Holistic reviews of applications and selection processes should be implemented to produce an increased racially and ethnically diverse applicant pool and a diverse residency work force, and implicit bias training should be implemented to address potential biases and diversity barriers that are present in residency programs and leadership.
Histone post-translational modifications modulate gene expression through epigenetic gene regulation. The core histone H3 family members, H3.1, H3.2, and H3.3, play a central role in epigenetics. H3 ...histones can acquire many post-translational modifications, including the trimethylation of H3K27 (H3K27me3), which represses transcription. Triple methylation of H3K27 is performed by the histone methyltransferase Enhancer of Zeste Homologue 2 (EZH2), a component of the Polycomb Repressive Complex 2. Both global increases and decreases in H3K27me3 have been implicated in a wide range of cancer types. Here, we explore how opposing changes in H3K27me3 contribute to cancer by highlighting its role in two vastly different cancer types; (1) a form of glioma known as diffuse midline glioma H3K27-altered and (2) epithelial ovarian cancer. These two cancers vary widely in the age of onset, sex, associated mutations, and cell and organ type. However, both diffuse midline glioma and ovarian cancer have dysregulation of H3K27 methylation, triggering changes to the cancer cell transcriptome. In diffuse midline glioma, the loss of H3K27 methylation is a primary driving factor in tumorigenesis that promotes glial cell stemness and silences tumor suppressor genes. Conversely, hypermethylation of H3K27 occurs in late-stage epithelial ovarian cancer, which promotes tumor vascularization and tumor cell migration. By using each cancer type as a case study, this review emphasizes the importance of H3K27me3 in cancer while demonstrating that the mechanisms of histone H3 modification and subsequent gene expression changes are not a one-size-fits-all across cancer types.
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