Regular Time Research Articles

팬데믹과 뉴노멀 시대에 있어서 4차산업혁명과 법치주의의 과제

The post-COVID era is clearly a time requiring the convergence of law and science, navigating through both pandemic and endemic situations. The era has witnessed the implementation of stringent social measures, such as social distancing, movement and location tracking, restrictions on gatherings and protests, mandatory vaccinations, vaccine passports, business operation limits, school attendance timing restrictions, mask mandates, utilization of non-contact transactions, enforced quarantine, and lockdowns. These measures have necessitated a confluence of law and science. While South Korea has rapidly addressed this convergence from a rule-of-law perspective, there remain shortcomings in this approach. Particularly, the introduction of Fourth Industrial Revolution technologies like artificial intelligence, big data, and the Internet of Things in the post-COVID era presents new challenges to legal principles, necessitating legitimate and constitutional justifications.
 Despite the fact that various disease control measures utilizing Fourth Industrial Revolution technologies would not have been easily accepted under normal circumstances, they have been widely adopted and utilized under the public interest pretext of combating the pandemic during emergency legislative and administrative measures. While specific and concrete rules are most commonly employed in regular times, the pandemic has led to an increase in general disposals, extensive use of regulatory orders beyond legal mandates, and the deployment of administrative rules and guidelines without sufficient authorization considerations. These legislative and administrative measures, as tools in the fight against COVID-19, often failed to adequately reflect the demands of rule-of-law. Particularly, the pandemic has paved the way for the unprecedented use of Fourth Industrial Revolution technologies in this new normal era, necessitating continuous consideration of rule-of-law principles.
 From a legal theory perspective, a balanced approach is required in weighing safety and freedom, safety and discrimination, and permissible risks, harmonizing these within a risk society where science and technology challenge existing norms. Although the use of Fourth Industrial Revolution technologies and enhanced vaccination efforts have enabled us to emerge from the dire pandemic, continuous legislative and administrative efforts are needed to address the deepening digital divide.
 From a policy perspective, a critical view has been developed regarding specific measures, discussing improvements and alternatives. Topics include fine-tuning rule-of-law in response to disease control measures, adjusting to the dominance of algorithms, restoring normalcy and fundamental rights, the resilient recovery of markets, overcoming the limits of traditional regulations, utilizing self-regulation and regulated self-regulation, addressing new challenges related to various epidemic measures, data privacy, and Big Brother concerns.
 As we move from pandemic to endemic, the tasks of rule-of-law in this era are evolving. Emergency legal and administrative measures need to be re-evaluated under normal rule-of-law standards. This paper has analyzed various measures in response to the pandemic and endemic situations from legal theory and policy perspectives, arguing the need for ongoing contemplation and policy efforts towards new challenges of rule-of-law.

Pediatric Nutritional Assessment

Background: Pediatric nutrition plays a vital role in the growth and development of children. It not only meets the daily nutritional needs of healthy children but also supports their normal growth. In contrast, for unhealthy children, it aims to prevent growth delays and developmental issues, especially in cognitive functions. The situation in Indonesia presents a unique challenge with the coexistence of undernutrition and overnutrition, both having significant short-term and long-term health impacts. Discussion: In the realm of pediatric nutrition, malnutrition manifests in various forms. Nutritional deficiencies such as wasting, stunting, and being underweight arise from inadequate dietary intake. Additionally, there are concerns about micronutrient malnutrition, which includes both deficiencies and excesses of vital nutrients. Overnutrition, leading to obesity and associated chronic diseases, is also a significant problem. The approach to pediatric nutritional care is multi-faceted, involving the assessment of nutritional status, determination of individual caloric needs, and selecting the appropriate method for nutrition delivery, whether it be oral, enteral, or parenteral. Monitoring and evaluating the effectiveness of these interventions is a critical ongoing process. An important aspect of preventive care includes educating parents about proper feeding techniques, such as establishing regular meal times and understanding the child's hunger and satiety signals, to avoid feeding difficulties. For cases like Failure to Thrive (FTT), where children do not meet standard growth metrics, careful management is necessary to ensure adequate nutrition and to prevent complications like refeeding syndrome. Conclusion: Effective pediatric nutrition requires a holistic and personalized approach. It is crucial in addressing the dual burden of undernutrition and overnutrition in Indonesia. By implementing proper nutritional care and structured feeding practices, children's health outcomes can be significantly improved, supporting their growth and developmental processes.

ILUVIEN® in diabetic macular edema that persists or recurs despite treatment: Results from the Retina.pt® RIVER audit.

Persistent diabetic macular edema (DME) remains a problem in clinical practice, with many patients having a suboptimal response to the standard of care (SOC). Evidence supports the long-term efficacy of intravitreal fluocinolone acetonide (FAc) implant (ILUVIEN®) in patients that have responded sub-optimally, although there is still scarce data from real-world Portuguese practices. We aimed to monitor the current SOC in selected Portuguese practices prior to FAc implantation and then assess the long-term effectiveness and safety of the FAc implant. The study included patient data from five Portuguese public hospitals. This was a non-interventional, multicenter audit of data collected from Retina.pt registry from patients with persistent or recurrent DME despite treatment. Outcome measures included changes in best-corrected visual acuity (BCVA), central macular thickness (CMT), and intraocular pressure (IOP). Results were compared at regular times over 36 months. This study included 222 eyes from 152 patients. A significant decrease in BCVA (P < 0.001) and a significant increase in CMT (P = 0.013) were observed prior to FAc. A significant increase in BCVA was registered at 6 months after FAc implant administration (P < 0.001), which was maintained during follow-up. No relevant changes in IOP were observed. Treatment burden was reduced as a result of treatment with FAc (P < 0.001 for anti-VEGF, corticosteroids, or both treatments) in the full population. In Portuguese practice, data showed that pre-FAc implantation, some patients did not respond to SOC treatment and/or they were undertreated. Following FAc implant administration, there were rapid, sustained, long-term visual and anatomical improvements, and a marked reduction in treatment burden.

Automated filtering of façade defect images using a similarity method for enhanced inspection documentation

ABSTRACT Unmanned Aerial Vehicles (UAVs) are routinely utilized to capture images of building façades for structural health inspections. These images are often taken at regular time intervals, capturing overlapping views to ensure complete coverage of the façade. However, this practice generates numerous highly similar images, leading to inefficiencies in documentation and potentially biased analysis due to redundant data. Hence, this study proposes an automated image data filtering method based on defect similarity. Given façade images where defects are detected, this method applies key point detection and descriptor matching to measure image similarity concerning defect presence. Subsequently, a selection strategy is proposed to produce a minimal set of representative images covering all defects. This method was validated using a dataset of UAV-captured façade images across three façades, successfully deriving the set to six representative images. Overall, the proposed method offers a practical solution to reduce the quantity of images required for documentation, thereby enhancing the efficiency of UAV deployments for façade inspection.

Embryonic exposure to decitabine induces multiple neural tube defects in developing zebrafish.

Neural tube defects are severe congenital disorders of the central nervous system that originate during embryonic development when the neural tube fails to close completely. It affects one to two infants per 1000 births. The aetiology is multifactorial with contributions from both genetic and environmental factors. Dysregulated epigenetic mechanisms, in particular the abnormal genome-wide methylation during embryogenesis, have been linked to developmental abnormalities including neural tube defects. The current study investigated the influence of decitabine (DCT), a DNA methylation inhibitor, on embryonic development in zebrafish, with a focus on neural tube formation. The developing zebrafish embryos were exposed to graded concentrations of decitabine (from 13.69 μM to 1 mM) before the onset of neurulation. The developmental process was monitored at regular time intervals post fertilization. At 120 h post fertilization, the developing embryos were inspected individually to determine the incidence and severity of neural tube defects. Using alizarin red staining, the cranial and caudal neural tube morphology was examined in formaldehyde fixed larvae. Anomalies in neural tube and somite development, as well as a delay in hatching, were discovered at an early stage of development. As development continued, neural tube defects became increasingly evident, and there was a concentration-dependent rise in the prevalence and severity of various neural tube defects. 90% of growing embryos in the group exposed to decitabine 1 mM had multiple neural tube malformations, and 10% had isolated neural tube defects. With several abnormalities, the caudal region of the neural tube was seriously compromised. The histopathological studies supported the malformations in neural tube. Our study revealed the harmful impact of decitabine on the development of the neural tube in growing zebrafish. Moreover, these findings support the hypothesis that the hypomethylation during embryonic development causes neural tube defects.

Deep Learning‐Based Bluetooth Low‐Energy 5.1 Multianchor Indoor Positioning with Attentional Data Filtering

Indoor positioning system (IPS) technologies have widespread applications in logistics, intelligent manufacturing, healthcare monitoring, etc. The recently released Bluetooth low‐energy (BLE) 5.1 specification enables in‐phase and quadrature‐phase (I/Q) data measurements. It allows angle of arrival estimation and becomes a natural choice for IPS implementation. Conventional BLE 5.1 IPSs use multiple anchors to provide massive redundancy to improve system robustness. It however demands effective approaches to leverage redundancy. Besides, interference due to various environmental factors can introduce severe errors to I/Q data and affect positioning accuracy. Facing these challenges, herein, a novel deep learning‐based multianchor BLE 5.1 IPS is proposed. The system aggregates measurements from multiple anchors and makes them available at regular time steps. Then, a novel attentional filtering network tailored to infer high‐quality I/Q sample data is developed and a spatial regularization loss incorporating spatial location relationships to strengthen the feature embedding discrimination is proposed. Two multianchor BLE 5.1 I/Q sample datasets are developed and released for public download. Numerical experiments are carried out to compare the proposed method with previous BLE 5.1 IPS methods and methods utilizing other radio frequency data. Results indicate that the proposed method consistently achieves submeter accuracy and significantly outperforms the state‐of‐the‐art approaches.

Twelve tips for medical educators to optimize their curricula vitae

A good curriculum vitae (CV) highlights medical educators’ academic achievements and supports their professional goals. Many faculty struggle with timely updates and strategic formatting. These twelve tips will help medical educators optimize their CV to best showcase their strengths and accomplishments. The first three tips outline a process: identify a system to collect potential entries and schedule regular time for updates. Tips four and five detail how to tailor traditional CV formatting to best describe the work of medical educators. The next few tips offer concrete strategies and examples of CV entries to consider for inclusion. The remaining tips remind faculty to ask for help from colleagues, who can share a sample CV and identify overlooked activities. Our intention is to transform a task that can be burdensome into a process that seamlessly captures the breadth of our work as medical educators and allows for introspection and growth.

Time flies, but you’re in control: the mediating effect of self-control between time attitude and academic procrastination

BackgroundAcademic procrastination has become an increasing concern in the educational sector. Prior studies identified various correlations among academic procrastination, time attitude and self-control. Nevertheless, few studies have examined the past time attitude and the mechanism underlying those relationships, and the existing studies have been implemented during regular school time. To fill those gaps, the present study includes all three dimensions of time attitude (past-oriented, present-oriented and future-oriented in both positive and negative perspectives), and proposes self-control as a mediator between academic procrastination and time attitude. The study was carried out during an extraordinary winter holiday in China, with final exams waiting at the end of the holiday.MethodsA total of 323 middle school students in China (178 girls and 145 boys, 12–19 years old) completed an online survey with questions on their academic procrastination, time attitude and self-control. The collected data were analyzed using IBM SPSS Statistics 25 and Hayes SPSS macro PROCESS (Model 4).ResultsThe results showed that academic procrastination was negatively associated with all three positive time attitudes and positively correlated with the present negative time attitude. Moreover, self-control significantly mediates the relationship between academic procrastination and all three positive time attitudes.ConclusionBased on these findings, self-control could be the underlying mechanism in the relationship between academic procrastination and time attitude. This study broadens the scope of relevant empirical research to the past time attitude, and determines the mechanism that underlies the association between academic procrastination and time attitude under a novel context. Further implications for teaching regulation and intervention are discussed.

Fast relocking and afterslip-seismicity evolution following the 2015 Mw 8.3 Illapel earthquake in Chile

Large subduction earthquakes induce complex postseismic deformation, primarily driven by afterslip and viscoelastic relaxation, in addition to interplate relocking processes. However, these signals are intricately intertwined, posing challenges in determining the timing and nature of relocking. Here, we use six years of continuous GNSS measurements (2015–2021) to study the spatiotemporal evolution of afterslip, seismicity and locking after the 2015 Illapel earthquake (M_w 8.3). Afterslip is inverted from postseismic displacements corrected for nonlinear viscoelastic relaxation modeled using a power-law rheology, and the distribution of locking is obtained from the linear trend of GNSS stations. Our results show that afterslip is mainly concentrated in two zones surrounding the region of largest coseismic slip. The accumulated afterslip (corresponding to M_w 7.8) exceeds 1.5 m, with aftershocks mainly occurring at the boundaries of the afterslip patches. Our results reveal that the region experiencing the largest coseismic slip undergoes rapid relocking, exhibiting the behavior of a persistent velocity weakening asperity, with no observed aftershocks or afterslip within this region during the observed period. The rapid relocking of this asperity may explain the almost regular recurrence time of earthquakes in this region, as similar events occurred in 1880 and 1943.

A pathwise regularization by noise phenomenon for the evolutionary p-Laplace equation

We study an evolutionary p-Laplace problem whose potential is subject to a translation in time. Provided the trajectory along which the potential is translated admits a sufficiently regular local time, we establish existence of solutions to the problem for singular potentials for which a priori bounds in classical approaches break down, thereby establishing a pathwise regularization by noise phenomena for this nonlinear problem.

Predicting aortic stenosis progression using a video-based deep learning model of aortic stenosis built for single-view two-dimensional echocardiography

Abstract Background We have recently described a deep learning (DL) model that relies on 2-dimensional parasternal long axis (PLAX) videos from transthoracic echocardiography (TTE) without Doppler imaging to identify severe aortic stenosis (AS) at the point-of-care. However, the timely diagnosis of AS has traditionally required skilled examination with Doppler imaging at regular time intervals. Purpose To explore the role of a DL model previously trained to detect severe AS based on 2D-PLAX videos in predicting the rate of AS progression among patients with no, mild, or moderate AS. Methods In this retrospective cohort study, a random sample of 2354 individuals undergoing serial monitoring with at least two separate TTEs and available Doppler parameters of AS severity (peak aortic valve velocity, AV Vmax) between 2016 and 2021 in the Yale-New Haven Health system were included. Eligible participants had a left ventricular ejection fraction (LVEF) &amp;gt;=50% and no evidence of severe AS at baseline. After automated selection of PLAX videos using an automated view classifier, the baseline deep learning-based AS probability index (DL-ASi) was calculated for each patient. The absolute change in the AV Vmax was divided by the time difference between each pair of consecutive TTE studies, and then averaged to derive the mean rate of AS progression. The association between the baseline DL-ASi and the mean rate of AS progression was assessed using ordinary least squares regression with adjustment for the patient’s sex, age, and baseline LVEF and AV Vmax. To visualize the interaction between the baseline DL-ASi and AV Vmax in predicting the rate of AS progression, an interaction term was included and a contour plot was plotted for both men and women. Results We included 8473 TTE studies from 2354 unique individuals (mean age 70±14 years, n=1138 [48.3%] women) performed over a median 2.5 (IQR 1.4-3.7) years (A). Higher DL-ASi at baseline was independently associated with a more rapid rate of AS progression (βadj 0.27 [95% CI 0.20-0.33, P&amp;lt;0.001]). The rates of AV Vmax progression ranged from 0.06±0.01 m/sec/year in the &amp;lt;0.2 DL-ASi group, to 0.29±0.04 m/sec/year in the ≥0.8 DL-ASi group (B). Contour plots illustrate how, for a given AV Vmax value, DL-ASi stratified the risk of AS progression in women and men (C). Conclusion In individuals with mild to moderate AS or no AS, a DL model trained to detect features of severe AS identifies individuals with a higher rate of AS severity progression, as assessed by the mean rate of AV Vmax change. This represents a promising approach for the longitudinal, point-of-care monitoring of patients with non-severe AS outside specialized centers.

Beyond working hours: the association between long working hours, the use of work-related communication devices outside regular working hours, and anxiety symptoms.

The present study aimed to identify and compare the associations between long working hours and use of work-related communication devices outside regular working hours and anxiety symptoms, thereby providing insight into redefining working hours. Based on the cross-sectional data from the sixth Korean Working Conditions Survey (KWCS), specifically the responses from 46 055 workers, the use of work-related communication devices outside of regular working hours, long working hours, and anxiety symptoms were assessed. To investigate the associations between using work-related communication devices outside regular working hours or long working hours with anxiety symptoms, odds ratios (ORs) and 95% CIs were calculated using multiple logistic regression models. Among 46 055 participants, 25 659 (55.7%) used work-related communication devices outside working hours, 8145 (17.7%) worked long hours, and 2664 (5.8%) experienced anxiety symptoms. Compared with the reference group, those who used work-related communication devices outside regular working hours without working long hours, had higher OR of anxiety symptoms (OR: 2.18; 95% CI, 1.97-2.41) than those who worked long hours without using work-related communication devices during off-hours (OR: 1.32; 95% CI, 1.09-1.59). Furthermore, the group that both worked long hours and used work-related communication devices outside working hours exhibited the highest OR of anxiety symptoms (OR: 2.57; 95% CI, 2.24-2.97). Using work-related communication devices outside regular working hours is associated with a higher risk of anxiety symptoms compared with long working hours. This result suggests that using work-related devices outside regular working hours, in addition to regular work time, should be considered when redefining working hours.

Safety Evaluation of an Intranasally Applied Cocktail of Lactococcus lactis Strains in Pigs.

Three Lactococcus lactis strains from the nasal microbiota of healthy pigs were identified as candidates for reducing MRSA in pigs. The safety of nasal administration of a cocktail of these strains was examined in new-born piglets. Six days pre-farrowing, twelve sows were assigned to the placebo or cocktail group (n = 6/group). After farrowing, piglets were administered with either 0.5 mL of the placebo or the cocktail to each nostril. Health status and body weight were monitored at regular time points. Two piglets from three sows/treatment group were euthanised at 24 h, 96 h and 14 d after birth, and conchae, lung and tonsil samples were collected for histopathological and gene expression analysis. Health scores were improved in the cocktail group between d1-5. Body weight and daily gains did not differ between groups. Both groups displayed histological indications of euthanasia and inflammation in the lungs, signifying the findings were not treatment related. The expression of pBD2, TLR9 and IL-1β in the nasal conchae differed between groups, indicating the cocktail has the potential to modulate immune responses. In summary, the L. lactis cocktail was well tolerated by piglets and there was no negative impact on health scores, growth or lung histopathology indicating that it is safe for administration to new-born piglets.

Extracorporeal shockwave therapy of the perineum for male patients with chronic pelvic pain syndrome: a pilot study

BackgroundChronic pelvic pain syndrome (CPPS) is a complex condition that is often difficult to treat and may sometimes require a multidisciplinary team. Among the wide array of treatment options is extracorporeal shockwave therapy (ESWT). However, its role in CPPS remains controversial. The purpose of our study is to assess the efficacy and safety of ESWT of the perineum in male patients with CPPS. MethodsFourteen patients aged between 21 and 85 years were recruited in this single-center, single-arm prospective trial from October 2018 to October 2020. ESWT was delivered to the perineum weekly for up to 8 weeks. Assessment was done via International Index for Erectile Function, International Prostate Symptom Score, King's Health Questionnaire, National Institutes of Health – Chronic Prostatitis Symptom Index, Visual Analogue Scale, Analgesic Questionnaire, and UPOINT (urinary symptoms [U], psychosocial dysfunction [P], organ-specific symptoms [O], infection-related symptoms [I], neurological/systemic conditions [N], tenderness of skeletal muscles [T]) phenotype system. The parameters are assessed before the start and end of treatment as well as at regular time points on follow-up appointments up to 20 weeks. ResultsThirteen patients completed the study. There was improvement in the Visual Analogue Scale pain score, Tenderness domain on UPOINT, King's Health Questionnaire, and National Institutes of Health – Chronic Prostatitis Symptom Index scores. In terms of erectile function, improvement in the erectile function domain of International Index for Erectile Function was observed. There was also significant improvement in lower urinary tract symptoms assessed on International Prostate Symptom Score. There were no adverse events reported post treatment and during the follow-up period. ConclusionsESWT improved pain and quality of life of male patients with CPPS. It can be a safe and effective treatment modality in the armamentarium of CPPS.

Visible and near infrared spectroscopy for predicting soil nitrogen mineralization rate: Effect of incubation period and ancillary soil properties

Soil nitrogen mineralization rate (SNMR) influences crop N uptake and nitrate leaching leading to environmental pollution. This study aims at (i) examining whether visible and near-infrared reflectance spectroscopy (vis-NIRS) can predict SNMR and (ii) investigating if incubation periods and ancillary soil attributes can improve the prediction accuracy. Total 133 soil samples collected from seven fields were incubated under aerobic conditions for 60 days with seven batches of sub-samples. Mineral N was measured at regular time intervals and soil samples were scanned using a vis-NIRS sensor (Tec5 Technology, Germany) parallelly. SNMR was determined by fitting a zero-order kinetic to the net mineralized N as a function of the incubation time. Soil total nitrogen (TN), total carbon (TC) and electrical conductivity (EC) were determined once. Partial least squares regression (PLSR) models were calibrated individually for each field both for vis-NIR spectra and its combinations with TN, TC and EC. Six out of seven batches of sub-samples were used for calibrating PLSR when remaining one batch was used for model validation, and it rotated across all seven batches. Vis-NIRS alone predicted SNMR with moderate accuracy in five of seven fields (coefficient of determination, 0.53 ≤ R2 ≥ 0.66, ratio of prediction to deviation, 1.51 ≤ RPD ≥ 1.76), while models were poor in two fields (R2 = 0.23–0.26, RPD = 1.18 – 1.20). Inclusion of soil TC, TN and/or EC was expected to improve accuracy, but improvements varied across fields (R2 = 0.23–0.79, RPD = 1.18 – 2.26). Similarly, the incubation period increased vis-NIRS prediction accuracy, but frequently occurred among 2nd to 6th batches (R2 = 0.35–0.82, RPD = 1.28 – 2.44). Even incorporating secondary properties and increasing incubation duration hardly improved predictions, improvement can be compromised since it is not significant mostly and often underperformed or remained unchanged. Considering the time and effort required to incubate and analyze soil properties, this study suggests using a vis-NIRS sensor to estimate SNMR in fresh soil conditions i.e., without incubation and incorporation of secondary properties.

SARS-CoV-2 specific immune responses in overweight and obese COVID-19 patients.

Obesity is a known risk factor for severe respiratory tract infections. In this prospective study, we assessed the impact of being obese or overweight on longitudinal SARS-CoV-2 humoral and cellular responses up to 18 months after infection. 274 patients provided blood samples at regular time intervals up to 18 months including obese (BMI ≥30, n=32), overweight (BMI 25-29.9, n=103) and normal body weight (BMI 18.5-24.9, n=134) SARS-CoV-2 patients. We determined SARS-CoV-2 spike-specific IgG, IgA, IgM levels by ELISA and neutralising antibody titres by neutralisation assay. RBD- and spike-specific memory B cells were investigated by ELISpot, spike- and non-spike-specific IFN-γ, IL-2 and IFN-γ/IL-2 secreting T cells by FluoroSpot and T cell receptor (TCR) sequencing was performed. Higher BMI correlated with increased COVID-19 severity. Humoral and cellular responses were stronger in overweight and obese patients than normal weight patients and associated with higher spike-specific IgG binding titres relative to neutralising antibody titres. Linear regression models demonstrated that BMI, age and COVID-19 severity correlated independently with higher SARS-CoV-2 immune responses. We found an increased proportion of unique SARS-CoV-2 specific T cell clonotypes after infection in overweight and obese patients. COVID-19 vaccination boosted humoral and cellular responses irrespective of BMI, although stronger immune boosting was observed in normal weight patients. Overall, our results highlight more severe disease and an over-reactivity of the immune system in overweight and obese patients after SARS-CoV-2 infection, underscoring the importance of recognizing overweight/obese individuals as a risk group for prioritisation for COVID-19 vaccination.

One Tube 23 Color Full Spectral Flow Cytometry Panel in Detecting Minimal Residual Disease in Pediatric B-Cell Acute Lymphoblastic Leukemia

Introduction Minimal residual disease (MRD) is a normalized tool for risk stratification in the treatment of pediatric acute lymphoblastic leukemia (ALL) and has been introduced into many standardized chemotherapy regimens. Flow cytometry (FC) plays an important role in the monitoring of MRD. However, FC-MRD can't reliably detect residual leukemic cells below level of 0.01% in real clinical scenarios and some patients with negative MRD relapsed, suggesting the current used set of markers are not sensitive enough or specific enough. Published studies has shown that more markers with more reliable combination of antibodies may help improve the sensitivity and specificity of FC-MRD. Spectral multicolor flow cytometry (SMFC) has shown an advantage over traditional FC that more fluorescent markers could be applied simultaneously and more complex marker combinations could be exploited to distinguish leukemic blasts from normal B cell precursors with high specificity. Here we designed a SMFC-based panel of 26 markers with 23 fluorescent colors in one tube to monitor B-ALL MRD. Method The one-tube 23-color panels was designed according to previously published studies and our clinical experience based on standardized EuroFlow 8-color MRD panel. All the leukemia-associated immunophenotypes (LAIPs) were defined based on its deviation from hematogones. For CD10, CD19, CD22, CD34, CD58, CD73, CD86, CD123, CD200and CD304, the overexpression was considered as LAIP, while the under-expression was considered as LAIP for CD24, CD38, CD45 and CD81. Asynchronous co-expression of CD34 and CD20, CD34 and CD21 were also included. The aberrant cross-lineage expression was taken as LAIP for CD2, CD56, CD65, CD15, CD13, CD33, CD66c, NG2 and CD133. For CD44, under-expression or overexpression can both be considered as LAIP. To verify the effectiveness of the panel, 317 bone marrow samples from 317 patients with B-ALL diagnosed between 2009 to 2014 at the Shanghai Children's Medical Center (SCMC) were included. These samples were collected at day 19 to 283 (median: day 35), with 213 (67.19%) collected at around day 35, which was a regular time point to monitor MRD and to readjust the risk stratification. The results were compared with those of conventional 8-color FC-MRD. Results The limit of blank (LOB), limit of detection (LOD), and lower limit of quantitation (LLOQ) were firstly determined, the results showed reproducible sensitivity up to 0.001% (1-in-10 5) after acquisition of 4.8 million cells for 23-color panel. The 8-color and 23-color MRD panels showed high correlation of the quantitation of MRD (r 2=0.80, p&amp;lt;0.0001). Among cases of discordant between 8-color MRD negative (with cutoff &amp;lt;0.01%) and 23-color MRD negative (with cutoff &amp;lt;0.001%), relapse only occurred in patients with 23-color MRD positive and 8-color MRD negative, rather than patients with 23-color MRD negative and 8-color MRD positive, suggesting a higher sensitivity and specificity for 23-color MRD assay (See Figure). Patients with detectable MRD by either 8-color or 23-color had a significantly higher incidence of relapse (CIR, p&amp;lt;0.05) and shorter event free survival (EFS, p&amp;lt;0.05). Positive 23-color MRD seemed to be an even stronger factor impacting CIR and EFS. Compared to patients with 8-color MRD negative and 23-color MRD positive, patients with 8-color MRD positive and 23-color MRD negative had a significantly lower CIR (p&amp;lt;0.05) and a better EFS (p=0.068). Patients with positive 23-color MRD lower than 0.01% showed a trend towards poorer EFS and OS (p=0.083% and p=0.061%, respectively) compared to patients with 23-color MRD negative. Conclusion Based on these evidences, SMFC-based one-tube 23-color MRD panel for B-ALL was convenient and maneuverable with higher sensitivity and specificity compared to conventional 8-color FC-MRD panel. It would be a promising method to improve the risk stratification.

Impact of Sarcopenia and Subsequent Muscle Loss on Post-CAR T-Cell Outcomes in Relapsed/Refractory Large B-Cell Lymphoma

Background: Sarcopenia is a hallmark of cachexia commonly found in cancer patients that is caused by immune and metabolic mediators of catabolism. Chimeric antigen receptor (CAR) T-cell therapy is used to treat cancer and is characterized by the release of inflammatory cytokines and other potentially catabolic mediators. Previously, we showed that baseline sarcopenia and other immuno-nutritional scores were associated with poor outcomes after CD19-directed CAR T-cell therapies in patients with R/R LBCL (Rejeski et al. Cancer Immunol. Res. 2023). Here we examined the relationship between body composition and serum metabolite levels over time after CAR T-cell infusion. Methods: This is a single-center retrospective study of N=83 patients with R/R LBCL who received CAR T-cell therapy. The median clinical follow-up was 18.4 months. Muscle and adipose tissue distribution were calculated from clinical pre-lymphodepletion, day (d) 30, and day (d) 90 CT imaging using Slice-O-Matic software (v5.0, Tomovision). Baseline sarcopenia status was determined using established criteria (SMI 52.4 cm2/m2 for Males and 38.5 cm2/m2 for Females) . Immuno-nutritional scores included: GPS Score: CRP ≤ 10 mg/L = 0; CRP &amp;gt; 10 mg/L and albumin &amp;gt; 3.5 g/dL = 1; CRP &amp;gt; 10 mg/L and albumin &amp;lt; 3.5 g/dL = 2. PNI Score: Albumin (g/L) + 5 × total lymphocyte count (10^9/L). Muscle loss at d30 or d90 after CAR T-cell therapy was defined by a decrease of &amp;gt; 10% in their skeletal muscle index (SMI) from baseline. Patients who had relapsed, died or had missing scans were censored during the analysis. Univariate and multivariable Cox regression models using LASSO regularization assessed the association between various factors and survival outcomes. Serum metabolites were profiled at baseline and at regular time points up to 4 weeks after CAR T cell therapy (n=55) as previously described (Fahrmann et al. Cell Rep. Medicine 2022). Results: Patients with baseline sarcopenia (n=44) had worse progression-free (PFS) and overall survival (OS) after CD19 CAR T cell therapy for R/R LBCL compared to non-sarcopenic patients (n=39) (OS: HR=2.5, 95% CI: 1.3-4.9, P=0.008; PFS: HR=1.8, 95% CI: 1.0-3.2, P=0.037). In multivariable Cox fits (MVA) for OS, male gender (HR=3.3, 95% CI: 1.3-8.8, P=0.014), and GPS score of 2 (HR=3.8, 95% CI: 1.4-10.6, P=0.011) were associated with worse OS. On MVA for PFS, a lower PNI score was mildly associated with worse outcomes (HR=0.9, 95% CI: 0.8-1.0, P=0.039). Muscle loss occurred between baseline and d30 and d90 after CAR T-cell therapy in 34% and 32% of patients, respectively. Muscle loss correlated with concurrent adipose tissue loss and overall weight loss. Patients who had baseline sarcopenia had more pronounced muscle loss at d30 and d90 compared to patients who were non-sarcopenic at baseline. Associations with d30 muscle loss included ICANS grade 2 or higher (P=0.046) and baseline LDH (P=0.033). Further, patients with ICANS grade 2 or higher had a significantly higher d30 median muscle loss compared to patients with grade 0-1 ICANS (9.1% versus 6.4%; p=0.049). However, whether landmarked at d30 or d90, muscle loss after CAR T-cell therapy did not significantly associate with the risk of subsequent progression or death. Individual serum metabolites that significantly decreased between pre-infusion and after CAR T-cell infusion included those potentially associated with gut microbiome alterations (indole-3-acetate and xanthosine). Pathway analysis revealed changes in purine and pyrimidine metabolism over time after CAR T-cell therapy. Subgroup analyses comparing metabolites over time in sarcopenia versus non-sarcopenia, as well as based on muscle loss are in progress. Conclusions: Sarcopenia is highly prevalent (53%) in R/R DLBCL patients presenting for CAR-T and approximately 1/3 of patients lose muscle mass during the course of therapy, with the greatest risk noted in those with baseline sarcopenia. High immuno-nutritional scores are associated with inferior outcomes. Muscle loss was associated with a higher disease burden and higher-grade toxicities. Further study is needed to understand the association between antibiotics use and clinical factors for microbiome-related metabolites that change over time after CAR T-cell infusion. Interventional approaches to improve functional and nutritional reserve to optimize outcomes are warranted.

Business resilience and growth strategy transformation post crisis

AbstractThe recent crisis world experienced (Covid-19) undoubtedly changed many aspects of business, such as operations, growth, sales, etc. A business needs capability and strategy to survive, and this paper considers resilience and growth suitable for encountering a crisis. Following that, this paper argues that resilience not only results from a crisis, as mentioned in previous studies but is a process. We also argue that growth strategy and its stages differ between regular times and times of crisis. This paper aims to elaborate on changes in business resilience and growth strategies as a reaction to a crisis by building line-by-line coding, patterns, and themes. This study develops a conceptual model for forming business sustainability after a crisis with resilience and growth as pillars. This qualitative study used snowball sampling with 13 case studies and conducted semi-structured interviews, Focus Group Discussion (FGD), and observation with dependability, credibility, confirmability, and transferability as the triangulation processes. This inductive study demonstrates resilience and growth steps that can assist entrepreneurs in avoiding misleading strategies. The findings also indicated that digital imperatives could hasten both processes to attain sustainability. This paper draws on organizational resilience theory to discuss the theoretical implications of this research. This study discovers three main stages in the resilience process: resilience awareness, adaptation, and action, and growth stages in crisis time, namely no growth, growth support, growth force, and sustainable growth. On a practical level, the proposed model can also assist entrepreneurs in dealing with a crisis regarding what to do and understanding their conditions. This study contributes to the ongoing debate on how to respond to crisis and provides complete stages in resilience response and growth strategies for a business. For future research, this paper recommends a longitudinal study to understand and analyse the implementation and effectiveness of the models.

This Dead or That Dead: Framing Effects in the Evaluation of Health States

ObjectivesCurrent approaches to health state valuation rely on credible classification of states as either “better than dead” or “worse than dead” (WTD). We investigate how such evaluations of health states are affected by the framing in pairwise comparison tasks. MethodsWe conducted an online survey with 361 participants to compare the propensity to evaluate a state as WTD under 6 frames: (A) using a regular time trade-off (TTO) choice task, (B) using a lead-time TTO choice task, (C) excluding the immediacy of death, (D) avoiding reference to the process of dying, (E) focusing on longevity, and (F) focusing on improvements in quality of life. Each participant evaluated 9 EQ-5D-5L health states using 3 frames. The frames were compared using several statistical approaches to confirm robustness to indirect comparisons or respondent heterogeneity and inattentiveness. ResultsThe odds of a state being evaluated as WTD, compared with frame A, increase 2.7-fold and 1.5-fold in frame B and E, respectively, and decrease >5-fold in frame F. Frames C and D do not differ significantly from frame A. ConclusionsDifferent framings for questions about whether a state is WTD or better than dead, even if theoretically equivalent, yield substantially different results. Notably, whether a state is evaluated as WTD differs greatly between the regular TTO and lead-time TTO choice tasks and when either final outcomes or improvements over time are considered.