Hospitalizations among people living with HIV (PLWH) are frequent and costly. This study examined the association between psychiatric, HIV-related, and demographic factors and hospitalization rates among PLWH using data from the Einstein–Rockefeller-City University of New York Center for AIDS Research Clinical Cohort Database. Of the 10,215 PLWH included in the sample, 45% had at least one non-psychiatric hospitalization between 2009 and 2018, with significant risk factors including prior psychiatric outpatient visits, depression, or alcohol-related disorder diagnoses, female sex, older age, CD4 count < 500 cells/uL, and detectable viral load. Additionally, 14% had an HIV-related hospitalization, with significant risk factors including prior psychiatric outpatient visits, alcohol- and substance-related disorder diagnoses, female sex, older age, CD4 count < 500 cells/uL, and detectable viral load. The study emphasizes the need for tailored interventions, including integrated treatment and comprehensive case management, for PLWH with comorbid psychiatric disorders, women, and older adults.The online version contains supplementary material available at 10.1007/s10461-023-04064-6. Hospitalizations among people living with HIV (PLWH) are frequent, avoidable and costly, yet also present a critical opportunity for medical and behavioral health intervention –3. AnnuaIn this study, we aimed to identify psychiatric risk factors for hospitalization, including number of outpatient psychiatric visits prior to hospitalization, and types of psychiatric diagnoses in a patient’s chart prior to hospitalization. Little is known about psychiatric predictors of hospitalization, particularly for non-psychiatric hospitalization among PLWH. Medical drivers are well-documented , with thThere also may be disparities in terms of associations between psychiatric health and hospitalizations, and intersecting demographic factors, among diverse cohorts of PLWH . PsychiaTo this end, we measured associations of psychiatric, demographic, and HIV-related factors with any non-psychiatric or HIV-related hospitalization. Data are from the Einstein-Rockefeller-City University of New York Center for AIDS Research (ERC-CUNY) Clinical Cohort Database, a clinical database described below. We tested three hypotheses: Hypothesis 1: Patients with more past visits to treat a psychiatric disorder will have a higher hazard for any non-psychiatric hospitalization, and HIV-related hospitalization in particular. Hypothesis 2: Patients with depression, anxiety, drug-related diagnoses and alcohol-related diagnoses will have a higher hazard for hospitalization than those without these diagnoses. Hypothesis 3: Patients with more significant HIV-related factors  and certain demographic factors  will have a higher hazard of hospitalization.In doing so, we aimed to identify particular risk factors for hospitalization, in order to prevent inpatient stays earlier in patients’ care continua, and/or make better use of hospitalizations as an opportunity for secondary prevention , 3. ResuWe conducted a retrospective cohort study of all patients with a laboratory-confirmed diagnosis of HIV and > 1 visit at Montefiore Health System (Montefiore), an integrated health care delivery system with 4 hospitals and > 50 ambulatory care sites and one of the oldest wraparound HIV centers in the United States . MontefiData for this paper come from the ERC-CFAR Clinical Cohort Database, which contains clinical data on patients living with HIV and receiving care within Montefiore , 22. ThiThe outcomes of interest were time to the first one of two types of hospitalization: any non-psychiatric  hospitalization; and HIV-related hospitalization in particular. Hospitalizations were classified based on diagnosis codes, operationalized as International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, through 2015 or International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes, 2015 and later, assigned at discharge. Non-psychiatric hospitalizations and HIV-related hospitalizations were not mutually exclusive. HIV-related hospitalizations were coded as a particular subset of non-psychiatric hospitalization and analyzed in a separate model. Both outcomes were analyzed as time-to-event outcomes from a patient’s index visit, their first visit in the database , or January 1, 2009 if they received care prior to the study period.The primary exposure of interest was psychiatric comorbidity. Specifically, we identified two psychiatric factors as exposures: the number of outpatient psychiatric visits prior to hospitalization; and the type of psychiatric diagnoses in patients’ charts. For the first factor, we counted the number of outpatient psychiatric visits prior to incident hospitalization, to capture potential associations between outpatient psychiatric services utilization and time to incident inpatient visit. Outpatient visits were classified as psychiatric based on the assignment of an ICD-9-CM code (ranging from 290 to 319) or ICD-10-CM code (ranging from F01-F99) for treatment of a mental, behavioral, or neurodevelopmental disorder.For the second factor, we classified patients as having a particular type of psychiatric diagnosis if they had at least one visit prior to incident hospitalization assigned an ICD-9-CM or ICD-10-CM code indicating treatment of: alcohol related disorder, substance related disorder, anxiety, and/or depression. These were not mutually exclusive, and patients were often classified as having multiple types of psychiatric diagnoses. See Table S1 in supplement for the coding scheme.We extracted additional patient-level characteristics to account for potential confounding by demographic or HIV-related factors. Demographic factors included patient age (in years), sex assigned at birth , and race/ethnicity . HIV-related factors included CD4 T-cell count , and viral load . Viral load was classified as undetectable based on the assay used. Most commonly, a threshold of < 40 copies/mL was used in this analysis.First, we calculated descriptive statistics  to describe the characteristics of the sample. Second, we examined differences in non-psychiatric and HIV-related hospitalizations by psychiatric, demographic, and HIV-related factors, using a cause-specific calendar-time stratified Cox proportional-hazards regression model with a counting process approach . In doinp-values ≤ 0.05 were considered statistically significant. All analyses were completed using SAS version 9.4 .Each outcome was examined separately. For both outcomes, we examined each variable first as a singular predictor in the model using unadjusted analyses. All models were then adjusted for all other variables, as well as stratified by calendar period , to allow for differences in the baseline hazard of hospitalization . Because multiple exposures and confounders were time-varying , we defined each as the most recent value prior to or at the start of the risk interval. This allowed us to update the value of these predictors when new visits occurred, or new laboratory results were available. Hazard ratios, 95% confidence intervals and corresponding p-values for the model coefficient were generated. Trend tests were computed via statistical contrasts using a Cox proportional-hazards regression model, assuming a linear relationship between an ordinal predictor and hospitalization risk. The consistency of the observed effects within each calendar period was examined through the addition of interaction terms in the model and calendar period-specific analyses. Two-sided n = 1091) and viral load (n = 1060) within 90 days of their index visit, we imputed missing HIV-related data in two ways . There was no indication that the observed effects due to the number or type of mental health diagnoses changed meaningfully across calendar period. Patients with a history of alcohol-related disorder  and/or a depression disorder  had higher risk than those without. In terms of demographic characteristics, patients had higher adjusted hazard if they were female compared to male  or older , though lower if their race/ethnicity was Other/Unknown compared to White Non-Hispanic . In terms of HIV-related factors, hazard was higher for patients with CD4 counts < 500 cells/uL had higher hazard , as compared to those with CD4 count > 500 cells/uL . Adjusted hazard was significantly higher for those with detectable viral load . Sensitivity analyses did not meaningfully change results. Specifically, after imputing missing HIV-related data using two separate methods, associations of psychiatric, HIV-related, and demographic factors with any non-psychiatric hospitalization remained stable.Table In adjusted analyses, the hazard of HIV-related hospitalization again was again significantly higher with the any number of previous outpatient psychiatric visits > 0 . Particular psychiatric diagnoses significantly associated with hazard for HIV-related hospitalizations included alcohol-related disorder  and/or substance-related disorder . Demographic and clinical factors mirrored those associated with any psychiatric hospitalization. Specifically, female sex  and older age  were associated with higher hazard, as were CD4 count < 500 cells/uL  and detectable viral load .Again, sensitivity analyses did not meaningfully change results and there was no indication that the observed effects varied across calendar period. Associations of psychiatric, demographic, and HIV-related factors with HIV-related hospitalizations were consistent after imputing missing CD4/viral load data.Results of the current study show that a considerable proportion of PLWH in our study were hospitalized for non-psychiatric concerns, with a median time to incident hospitalization of 30.8 months. Similarly, a substantial proportion were hospitalized for HIV-related concerns, with a median time to incident HIV-related hospitalization of 54.5 months. Consistent with hypotheses 1–2, results suggest that a history of a higher number of prior outpatient psychiatric visits and a history of depression were associated with increased hazard for any non-psychiatric hospitalization. Consistent with hypothesis 3, demographic characteristics such as being female or older, and HIV-related characteristics such as having a CD4 count < 500 cells/uL were also associated with increased risk for any non-psychiatric hospitalization. Having an undetectable viral load was associated with lower risk.In terms of HIV-related hospitalization, consistent with hypotheses, results suggest a higher number of previous outpatient psychiatric visits, a past diagnosis of alcohol- or substance-related disorders, and CD4 count < 500 cells/uL or a detectable viral load were associated with increased risk. Female sex and age were associated with increased risk, while race/ethnicity was not. These results suggest that more severe and complex psychiatric disorders, which may require more frequent psychiatric visits, are associated with higher hazard of hospitalization. Patients with increased service utilization may have had greater medical needs due to higher (or more chronic) psychiatric concerns, and/or may have been screened more often and referred to inpatient care.Patients with depression, substance-related, and alcohol-related disorders seem to be at the most elevated risk. This was particularly evident when comparing unadjusted versus adjusted analyses. In unadjusted analyses, any type of psychiatric diagnostic history  was significantly associated with both outcomes. Depression, the most common psychiatric comorbidity for PLWH with prevalence ranging from 20 to 40% across studies , remaineResults suggest that sex  and age (older) are associated with higher risk for hospitalization. Indeed, older women living with HIV are disparately affected by depression, due largely to social stigma and discrimination, inequities in access to healthcare and HIV-related support services, and an unequal burden of physiological effects of aging with the virus  , 28. ThuIn terms of HIV-related hospitalizations, the only types of psychiatric diagnoses that remained significantly associated in adjusted models were alcohol- and substance-related disorders. Similar to depression, alcohol- and substance-related disorders impact medication adherence, accelerate disease progression, and result in spikes in viral load and treatment avoidance/dropout [15]. Indeed, PLWH with comorbid alcohol- and substance-related diagnoses are more likely to utilize emergency services (rather than outpatient preventative medicine) and thus may be more likely to be referred to an inpatient stay , 8. ThesThe study’s findings must be considered in the context of its limitations, particularly the biases inherent in EHR-based secondary data analysis, including that the data were collected retrospectively. Our reliance on billing codes as a proxy for psychiatric and HIV-related health was inherently limited, due to the possibility of provider/human error. Our reliance on hospital billing codes as the sole indicator of patient psychiatric health also threatens internal validity. Billing codes are not always a reliable indicator of psychiatric health or diagnosis, as admitting providers may provide a diagnosis in the absence of a thorough assessment due staffing and time limitations, or to facilitate insurance coverage for patients who do not meet diagnostic criteria. Future retrospective electronic medical record review studies might consider validating diagnoses in a subset using more detailed chart review.Similarly, the cohort for the current study is limited to patients engaged in care at Montefiore, and thus we cannot report services utilized beyond this healthcare system. It is thus possible that patients in the sample had additional inpatient visits and/or psychiatric diagnoses and treatment not captured within this healthcare system’s EHR. All participants in this study were confirmed to have HIV and thus were receiving care for HIV, biasing the sample to treatment-engaged individuals. Thus, our study’s conclusions may not generalize to a broader population of PLWH who also include those who are not in active care for HIV. Understanding the links between psychiatric diagnosis and risk for hospitalization must therefore be investigated in non-care-seeking PLWH. Our analyses did not control for variations in healthcare system-level differences, as we did not measure visit location, provider, or setting. This may be an important inquiry for future studies to determine which locations, providers, and/or settings patients visit may be associated with increased or decreased likelihood for hospitalization. For a full understanding of service utilization beyond one healthcare system, future studies may integrate EHR data across multiple systems or utilize insurance claims data.Further, there are inherent limitations of grouping demographic characteristics in EHR data, particularly in categorizing patient sex as binary and categorizing race and ethnicity in fixed, monoracial groups, effectively erasing transgender, nonbinary and multiracial identities. Future studies that integrate patient and provider self-report data  with routinely collected health record data may tell a more comprehensive story about which intervention targets and opportunities would benefit patients the most.Despite limitations, results echo calls for a comprehensive, integrated response to support mental health and HIV-related health among diverse patient populations. Suggestions for healthcare system interventions include: integrated care, whereby HIV and mental health services are integrated to ensure interdisciplinary providers collaborate to address comorbid symptomatology , 29; andResults provide further support for studies and interventions that target behavioral and socio-cultural mechanisms accelerating links between mental health and hospitalization. These may include targeting the roles of stigma, sexism, and ageism in the lives of PLWH, especially women and older adults . Further work is needed to identify specific pathways by which behavioral and psychological factors  may lead to increased rates of hospitalization in order to bolster material, psychological, and behavioral support for people PLWH.These findings provide a fruitful avenue for future clinical inquiry, highlighting questions about how and why different diagnoses confer differential risk for non-psychiatric hospitalizations. Future research is needed to clarify individual-level mechanisms which are driven by social determinants of health. Last, we hope these findings echo the need to develop community-grounded, wraparound interventions to promote positive conditions of living to improve health outcomes for PLWH.Supplementary file1 (DOCX 16 KB)Below is the link to the electronic supplementary material.


Surface electromyography (sEMG) is a standard method for psycho-physiological research to evaluate emotional expressions or in a clinical setting to analyze facial muscle function. High-resolution sEMG shows the best results to discriminate between different facial expressions. Nevertheless, the test-retest reliability of high-resolution facial sEMG is not analyzed in detail yet, as good reliability is a necessary prerequisite for its repeated clinical application.Thirty-six healthy adult participants  were included. Electromyograms were recorded from both sides of the face using an arrangement of electrodes oriented by the underlying topography of the facial muscles (Fridlund scheme) and simultaneously by a geometric and symmetrical arrangement on the face (Kuramoto scheme). In one session, participants performed three trials of a standard set of different facial expression tasks. On one day, two sessions were performed. The two sessions were repeated two weeks later. Intraclass correlation coefficient (ICC) and coefficient of variation statistics were used to analyze the intra-session, intra-day, and between-day reliability.Fridlund scheme, mean ICCs per electrode position: Intra-session: excellent (0.935–0.994), intra-day: moderate to good (0.674–0.881), between-day: poor to moderate (0.095–0.730). Mean ICC’s per facial expression: Intra-session: excellent (0.933–0.991), intra-day: good to moderate (0.674–0.903), between-day: poor to moderate (0.385–0.679). Kuramoto scheme, mean ICC’s per electrode position: Intra-session: excellent (0.957–0.970), intra-day: good (0.751–0.908), between-day: moderate (0.643–0.742). Mean ICC’s per facial expression: Intra-session: excellent (0.927–0.991), intra-day: good to excellent (0.762–0.973), between-day: poor to good (0.235–0.868). The intra-session reliability of both schemes were equal. Compared to the Fridlund scheme, the ICCs for intra-day and between-day reliability were always better for the Kuramoto scheme.For repeated facial sEMG measurements of facial expressions, we recommend the Kuramoto scheme. Facial electromyography (EMG) is a standard tool in clinical studies and psychological experiments to assess facial muscles during specific facial expressions and to analyze the association to specific emotions . The recIn a typical psychological or clinical experiment, participants or patients are examined several times, for instance by varying the stimuli or at different days before and after an intervention. Hence, it has to be guaranteed that the respective sEMG scheme can be applied in a reliable manner to exclude a variability of the EMG recording related to variability of the electrode application. Any fixed sEMG scheme is influenced by the inter-electrode distances, crosstalk, and the influence of both on the sEMG recordings. Surprisingly, although very important, the test-retest reliability of facial high-resolution sEMG has not been analyzed in detail yet . If onlyTherefore, we wanted to study the test-retest reliability of both the sEMG electrode schemes of Fridlund and Cacioppo and of The study included the same 36 healthy adult volunteers as published recently . NineteeThe participants were instructed about the sequence of the examination. The instructions for the facial expressions presented by a video were explained. Details of the video tutorial are presented elsewhere . BrieflyThe sEMG protocol was published recently . BrieflyTo ensure the use of identical electrode positions at t1 and t2, rigid laminated foils were used at both time points . PunchedAll statistical analyses were performed using IBM SPSS Statistics 25 . Intraclass correlation coefficient (ICC) statistics expressed with lower and upper borders  were used to analyze the retest reliability of the normalized EMG amplitudes between (a) the three trials in each session (intra-session reliability), (b) between the two sessions at one day (intra-day reliability), and (c) between the two days of measurement (between-day reliability). The higher the ICC value, the more precise is the estimate. ICC values less than 0.5 are indicative of poor reliability, values between 0.5 and 0.75 indicate moderate reliability, values between 0.75 and 0.9 indicate good reliability, and values greater than 0.90 indicate excellent reliability . To alloIn all tables minimum ICC values, the mean ICCs , and the maximal ICC values are shown, respectively.The intra-session reliability of both schemes were equal. Compared to the Fridlund scheme, the mean ICCs and especially the lower border ICCs for the intra-day and between-day reliability were larger for the Kuramoto scheme.Again, the intra-session reliability of both schemes were equal. Compared to the Fridlund scheme, the mean ICCs and especially the lower border ICCs for the intra-day and between-day reliability were always better for the Kuramoto scheme when focusing on the facial expressions.The CVs are presented as means and standard deviation of the study group. The results are summarized in the Regarding the recordings from different facial muscles, the CVs were good for the intra-session reliability for both schemes, but better for the Kuramoto scheme  than for the Fridlund scheme (3.32–14.09). The intra-day reliability was mainly moderate for the Fridlund scheme (13.99–36.18), whereas the Kuramoto scheme (7.28–20.21) showed sometimes good estimates. The between-day reliability was moderate or below moderate for the Fridlund scheme (19.08–36.34), and moderate for the Kuramoto scheme (15.96–23.46). The central electrodes showed worse results for the intra-session reliability than the other electrodes .Regarding the EMG recordings during the different facial movement tasks, the CV values were overall worse than for the recordings from different facial muscles. The CVs were good to moderate for the intra-session reliability for both schemes . The intra-day reliability was moderate to good for both schemes, but better for the Kuramoto scheme (16.83–16.97) than for the Fridlund scheme (24.65–20.75). The between-day reliability was moderate or below moderate, or even worse for the Fridlund scheme (24.65–74.33), and moderate for the Kuramoto scheme (16.83–24.64). The central electrodes showed good to moderate results for all three interval settings (5.21–23.74).Overall, the Kuramoto scheme produces better CV estimates than the Fridlund scheme.Facial sEMG is an important and standard instrument for the evaluation of emotional expressions or as a diagnostic tool to analyze facial muscle function. Typically, participants or patients are examined several times, for instance by varying the stimuli, or at different days before and after an intervention . To deteTraditionally, the placement of the sEMG electrodes on the facial skin is oriented to topography of the subdermal topographical position of the facial muscles and the direction of the muscle fibers. The electrode scheme of In general, it is surprising that test-retest reliability data for any sEMG scheme that is following the muscle topography (as the most frequent approach) are sparse. A critical factor during different sessions is the reproducible positioning of the electrodes when using the classical Fridlund scheme. Any repeated electrode application has also influences on inter-electrode distances and therefore electrode crosstalk variability. The EMG signal is highly sensitive to changes of the electrode positions with respect to the facial muscles . TherefoThe present study has limitations. Using the video self-tutorial to demonstrate the facial movement tasks seems to us as the most reliable instruction technique . NeverthHigh-resolution sEMG recordings of healthy probands showed an excellent intra-session test-retest reliability in regard of the Fridlund and the Kuramoto scheme, both in regard of the electrode positions and for the different facial expressions. The test-retest intra-day reliability and the between-day reliability was consistently better for the Kuramoto scheme. When using the Kuramoto scheme, a good to excellent mean intra-day and between-day reliability seems to be achievable.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of the Jena University Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.OG-L, GFV, and CA: conceptualization and supervision. OG-L and CA: first draft preparation. VT, NM, A-MK, and MH: data acquisition. VT, NM, and CA: data analysis. All authors contributed to the article and approved the final version.


The increase in orthopedic injuries after earthquakes imposes a significant burden on the health system. However, the impact of earthquakes on outpatient admissions remains unclear. This study compared patient admissions to the orthopedics and traumatology outpatient clinics before and after earthquakes.The study was conducted at a tertiary university hospital near the earthquake zone. In total, 8549 outpatient admissions were retrospectively analyzed. The study population was divided into pre-earthquake (pre-EQ) and post-earthquake (post-EQ) groups. Factors such as gender, age, city of origin, and diagnosis were compared between the groups. In addition, unnecessary outpatient utilization (UOU) was defined and analyzed.p < 0.001). UOU was the most common reason for admission in both groups. The distribution of diagnoses differed significantly between the pre-EQ and post-EQ groups, with an increase in the number of trauma-related diagnoses  and a decrease in UOU  after the earthquake.The pre-EQ and post-EQ groups included 4318 and 4231 patients, respectively. The two groups had no significant differences in age and sex distribution. However, the proportion of non-local patients increased after the earthquake (9.6% vs. 24.4%, Patient admission patterns at orthopedics and traumatology outpatient clinics changed significantly after the earthquake. The number of non-local patients and trauma-related diagnoses increased, whereas the number of unnecessary outpatients decreased.Level of evidence Observational study. Earthquakes are the most destructive form of natural disaster, with nearly 720,000 people worldwide losing their lives between 2000 and 2018 . On 6 FeEarthquakes have a significant impact on healthcare systems . AlthougThe province of Mersin, located roughly 300 km away from the earthquake epicenter, remained undamaged, making it a new destination for the internal migration of earthquake victims. This migration has caused significant changes in the number of admissions to medical departments, particularly in orthopedics and traumatology, which are predominantly focused on treating earthquake-related injuries.The impact of earthquakes on health care outcomes, such as outpatient admissions, has received limited attention in previous studies , 7. UndeThis study compared changes outpatient admissions to the orthopedics and traumatology department between pre-earthquake (pre-EQ) and post-earthquake (post-EQ) groups.The Institutional Clinical Research Review Board of Mersin University approved the study protocol (2023/239). The study was conducted at a tertiary university hospital located near the earthquake zone; admissions to the orthopedics and traumatology outpatient clinics were retrospectively analyzed. Data were extracted from our hospital digital archive system. Diagnoses were recorded based on the International Classification of Diseases, 10th revision (ICD-10). The study included patients who visited the orthopedics and traumatology outpatient clinic and had their diagnostic codes entered into the digital archive system. Only the first admission was considered in the analysis of patients with multiple admissions at different times. The period 6–16 February 2023 was excluded, as no routine outpatient service was provided during this time. Two authors (ZMA and EG) recorded and classified the diagnosis.This study compared patient admissions between the pre-EQ (6 December 2022–6 February 2023) and post-EQ (16 February 2023–16 April 2023) groups. The parameters analyzed included gender, age, city of origin, and diagnosis. Patients were categorized as local  or non-local (coming from other cities); cities of origin of non-local patients were analyzed. Diagnoses were classified into nine categories based on orthopedics and traumatology subspecialties . Furthermore, the archived information of patients with nonspecific diagnosis codes, such as M79  and M25.5 (pain in the joint), was evaluated. Patients who sought outpatient care for their needs, which could have been solved in another medical setting, such as primary care or preventive care, were classified as “unnecessary outpatient utilization (UOU)”. The patients classified as UOU did not have any specific orthopedic diagnosis.p-value < 0.05 was considered statistically significant.Descriptive data are presented as percentages, frequencies, means, and standard deviations. Categorical variables were compared using cross-tables and chi-square tests. The t-test was used to compare independent groups. A In total, 8549 patients, including 4252 females and 4297 males, were included in the study. Of these, 4318  and 4231  patients were in the pre- and post-EQ groups, respectively. The mean age of the patients in the pre- and post-EQ groups was 38.3 and 40.4 years, respectively .  and Hatay (60%) experienced the largest population declines, leading to a significant increase in population in provinces less affected by the earthquake . Our stu). Table . Hatay pOur orthopedic department is a leading referral center in the eastern Mediterranean region of Turkey, where four separate outpatient clinics receive approximately 200 patients daily. However, many of these admissions do not require primary care from an orthopedic specialist. Although not the primary objective of this study, we also investigated admissions not primarily related to orthopedics, referred to as “unnecessary outpatient utilization.” Our findings revealed a UOU rate of 36.7% Table , which iThe distribution of diagnoses among patients attending orthopedic outpatient clinics can vary. For instance, a pediatric orthopedics center would see admissions related to that field. In one of the largest trauma centers in India, Banerjee et al.  reportedVon Schreeb et al.  demonstrOur study had some limitations. The most significant limitation was the use of ICD-10 codes for diagnosing patients, which may be inadequate in some cases. We conducted detailed analyses in cases where the diagnosis code was ambiguous, and some diagnoses were classified as “other.” This approach maintained the integrity of the sample and reflected reality. Another limitation is that the study compared different periods within the same year because of missing information in our outpatient diagnostic records over the past few years. A more accurate comparison could have been made using the same period of different years. In addition, no studies in the literature have examined the functioning of orthopedic and traumatology outpatient clinics during an earthquake, making our study unique.In conclusion, the total number of orthopedic outpatient admissions did not change during the post-earthquake period. However, the rate of non-local patients increased, and the rate of local patients decreased. In the diagnosis-based analysis, the rate of trauma-related diagnoses increased the most. The rate of unnecessary admissions decreased during the post-earthquake period. We recommend that health systems near earthquake zones prepare accordingly for significant changes in patient populations after the earthquake.


We further consider the role that these COVID-19 vaccine development programs have played in prophylaxis at the global scale. Well-established vaccine technologies have proved especially important to making vaccines accessible in low- and middle-income countries. Vaccine development programs that use established platforms have been undertaken in a much wider range of countries than those using nucleic acid-based technologies, which have been led by wealthy Western countries. Therefore, these vaccine platforms, though less novel from a biotechnological standpoint, have proven to be extremely important to the management of SARS-CoV-2.Over the past 150 years, vaccines have revolutionized the relationship between people and disease. During the COVID-19 pandemic, technologies such as mRNA vaccines have received attention due to their novelty and successes. However, more traditional vaccine development platforms have also yielded important tools in the worldwide fight against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A variety of approaches have been used to develop COVID-19 vaccines that are now authorized for use in countries around the world. In this review, we highlight strategies that focus on the viral capsid and outwards, rather than on the nucleic acids inside. These approaches fall into two broad categories: whole-virus vaccines and subunit vaccines. Whole-virus vaccines use the virus itself, in either an inactivated or an attenuated state. Subunit vaccines contain instead an isolated, immunogenic component of the virus. Here, we highlight vaccine candidates that apply these approaches against SARS-CoV-2 in different ways. In a companion article (H. M. Rando, R. Lordan, L. Kolla, E. Sell, et al., mSystems 8:e00928-22, 2023, IMPORTANCE The development, production, and distribution of vaccines is imperative to saving lives, preventing illness, and reducing the economic and social burdens caused by the COVID-19 pandemic. Vaccines that use cutting-edge biotechnology have played an important role in mitigating the effects of SARS-CoV-2. However, more traditional methods of vaccine development that were refined throughout the 20th century have been especially critical to increasing vaccine access worldwide. Effective deployment is necessary to reducing the susceptibility of the world’s population, which is especially important in light of emerging variants. In this review, we discuss the safety, immunogenicity, and distribution of vaccines developed using established technologies. In a separate review, we describe the vaccines developed using nucleic acid-based vaccine platforms. From the current literature, it is clear that the well-established vaccine technologies are also highly effective against SARS-CoV-2 and are being used to address the challenges of COVID-19 globally, including in low- and middle-income countries. This worldwide approach is critical for reducing the devastating impact of SARS-CoV-2. One way in which the COVID-19 pandemic differs from prior global health crises is that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome was sequenced, assembled, and released very early in the course of the pandemic (January 2020). This genomic information has informed the biomedical response to this novel pathogen across several dimensions Understanding vaccine development programs that are using well-established technologies is important for a global perspective on COVID-19. As of 2 December 2022, 50 SARS-CoV-2 vaccines have been approved for use in at least one country . A resouAnother difference between prior global health crises and the COVID-19 pandemic is the way that vaccines are evaluated. A vaccine’s success is often discussed in terms of vaccine efficacy (VE), which describes the protection conferred during clinical trials . The durHowever, efficacy is not a static value, and both trial efficacy and real-world effectiveness can vary across location and over time. Shifts in effectiveness in particular have been an especially heightened topic of concern since late 2021 given the potential for variants of SARS-CoV-2 to influence VE. Due to viral evolution, vaccine developers are in an arms race with a pathogen that benefits from mutations that reduce its susceptibility to adaptive immunity. The evolution of several variants of concern (VOC) presents significant challenges for vaccines developed based on the index strain identified in Wuhan, China, in late 2019. We discuss these variants in depth elsewhere . To dateBeyond the variability introduced by time and geography, efficacy within a trial and effectiveness in the real-world setting can also differ due to cohort differences. Patients participating in a clinical trial are likely to receive more medical oversight, resulting in better follow-up, adherence, and patient engagement . AdditioWhile the relationship between a vaccine and a pathogen is not static, the data clearly demonstrate that a variety of efficacious vaccines have been developed against SARS-CoV-2. Here, we discuss a selection of programs that use well-established vaccine biotechnologies. These programs have been undertaken worldwide, in complement to the more cutting-edge approaches developed and distributed in the United States, the European Union, the United Kingdom, and Russia . In thisWhole-virus vaccines have the longest history among vaccine development approaches. Variolation, which is widely considered the first vaccination strategy in human history, is one example , 15. Fam14–Live attenuated virus vaccines (LAVs), also known as replication-competent vaccines, use a weakened, living version of a disease-causing virus or a version of a virus that is modified to induce an immune response . Whetherin vitro  or the culturing of a virus in vitro , 16. Todin vitro , or forein vitro . LAVs tein vitro , and somin vitro .Today, LAVs are used globally to prevent diseases caused by viruses such as poliovirus and measles, mumps, rubella, influenza, varicella-zoster, and yellow fever viruses . There wTo date, LAVs have not been widely deployed against SARS-CoV-2 and COVID-19. All the same, there are several COVID-19 LAV candidates in the early  stages of investigation. These candidates utilize different approaches. Interestingly, several candidates  are administered intranasally, potentially improving accessibility by eliminating the need for sterile needles and reducing manufacturing costs, targeting conferring mucosal immunity, and reducing some issues related to vaccine hesitancy , 28. Add(i) YF-S0. One candidate in the preclinical stage is YF-S0, a single-dose LAV developed at Belgium’s Katholieke Universiteit Leuven that uses live attenuated yellow fever virus 17D (YF17D) as a vector for a noncleavable prefusion conformation of the spike (S) antigen of SARS-CoV-2  COVI-VAC. Other programs are developing codon-deoptimized LAV candidates  Meissa Vaccines’ MV-014-212. Another company, Meissa Vaccines in Kansas (USA), which also develops vaccines for respiratory syncytial virus (RSV), has developed an intranasal live attenuated chimeric vaccine, MV-014-212  Bacillus Calmette-Guerin vaccines. Finally, Bacillus Calmette-Guerin (BCG) vaccines that use LAVs are being investigated for the prophylaxis of COVID-19  or a placebo  found that BCG vaccination had no effect on the incidence of SARS-CoV-2 or other respiratory infections over the course of 12 months . The pu2 months . DespiteCOVID-19 . AdditioCOVID-19 . CurrentCOVID-19  and by TCOVID-19 .(v) Summary of LAV development. LAVs for COVID-19 have not advanced as far in development as vaccines developed using other technologies. As of December 2022, COVI-VAC was the only LAV candidate in phase III clinical trials  vaccines are another well-established vaccine platform. This platform uses full virus particles generally produced via cell culture that have been rendered noninfectious by chemical  or physIWV vaccines have been a valuable tool in efforts to control many viruses. Some targets of IWV vaccines have included influenza viruses, poliovirus, and hepatitis A virus. Inactivated vaccines can generally be generated relatively quickly once the pathogenic virus has been isolated and can be passaged in cell culture , 51. Durin vivo. These vaccines generated nAb titers at concentrations similar to those evoked by recombinant protein vaccines (Past applications to human coronaviruses (HCoV) have focused predominantly on SARS-CoV-1. Preclinical studies have demonstrated that IWV SARS-CoV-1 vaccine candidates elicited immune responses vaccines , 55. Stuvaccines . Howevervaccines . In one vaccines . Indepenvaccines , 60. Thevaccines .Several whole-virus vaccines have been developed against COVID-19 and are available in countries around the world . As of 1(i) Sinovac’s CoronaVac. One IWV vaccine, CoronaVac, was developed by Sinovac, a biopharmaceutical company based in Beijing, China. The developers inactivated a SARS-CoV-2 strain collected in China with β-propiolactone and propagated it using Vero cells (–ro cells . The vacro cells . Adminisro cells . In phasro cells –64. The o cells – in Chinao cells –.n = 7) of Turkish participants aged 18 to 59 reported severe AEs  Sinopharm’s Covilo. Two additional IWV vaccine candidates were developed following a similar approach by the state-owned China National Pharmaceutical Group Co., Ltd., more commonly known as Sinopharm CNBG. One, known as BBIBP-CorV or Covilo, was developed in Beijing using the HB02 variant of SARS-CoV-2. The other was developed at Sinopharm CNBG’s Wuhan Institute using the WIV04 variant of SARS-CoV-2  Bharat Biotech’s Covaxin. Another IWV vaccine candidate was developed by Bharat Biotech International Ltd., which is the biggest producer of vaccines globally, in collaboration with the Indian Council of Medical Research (ICMR) National Institute of Virology (NIV). This candidate is known as Covaxin or BBV152. Preclinical studies of Covaxin in hamsters  (n = 31) also neutralized the Omicron variant   and thos variant . TherefoThe authorization of Covaxin has also offered opportunities to monitor how well the clinical trial results translate into a real-world setting. Additionally, an effort to monitor AEs and COVID-19 cases following vaccine rollout reported that most side effects were mild and that cases were rare, even though these data would seem to have been collected during the severe wave of COVID-19 brought on by the Delta VOC in India in early 2021; at the same time, the sample sizes were extremely small . SimilarIt is not yet clear what level of protection Covaxin offers beyond 6 to 8 months after the second vaccine; consequently, the potential requirement of a booster immunization is being explored . FurtherHowever, the WHO approval of the Covaxin has been delayed , and in In the past, problems that arose during the manufacturing of IWV vaccines could present safety issues, but oversight of the manufacturing process has helped to improve IWV vaccine safety . NeverthMore concern has arisen around the issue of effectiveness due to the reduced neutralizing activity of IWV vaccines against VOC relative to the index strain. In several cases, estimates of VE have varied widely across different trials of a single vaccine. Such issues are likely to be exacerbated by spatiotemporal differences in viral evolution, though in the case of the very high estimate generated by the Turkish trial of CoronaVac , the des133–As new vaccines are approved by the WHO, more time elapses since many received the primary series, and new variants emerge, booster recommendations are likely to increase. Therefore, IWV vaccines have played an important role in vaccine access during the initial phase of vaccination against COVID-19, but many IWV vaccinees may receive booster doses developed with emergent vaccine technologies like DNA and mRNA. In head-to-head comparisons, these types of vaccines were typically found to outperform IWV vaccines , leading to IWV vaccines, and then to purify proteins from viruses cultured in eggs (circa 1920) 900, lead. The pur+ T cell responses  and 96.4% against viral specimens lacking the 69–70del polymorphism  was administered . This stAnother notable protein subunit vaccine development program came out of Cuba. Concerned about their ability to access vaccines, especially given the United States’ embargo , health Pichia pastoris as a low-cost alternative to mammalian cell expression systems  to cultivate the recombinant proteins that form the basis of this protein subunit vaccine  that then infects the plant cells  and P.1 (Gamma) variants were predominant . GenomicSubunit vaccine technology is one of the best-represented platforms among COVID-19 vaccine candidates. Development programs are under way in many countries around the world, including low- and middle-income countries . To dateSubunit platforms offer some unique advantages. Cuba’s successful vaccine development program highlights the fact that protein subunit vaccines can be developed using low-cost technologies. Additionally, they are more feasible to store and transport . Hoping The efficacy and effectiveness of these vaccines are also very high, especially for Nuvaxovid, Abdala, and SOBERANA 01/02/Plus, for which estimates exceeded 90%. Unfortunately, there seem to be limited studies directly comparing the immunogenicity of subunit vaccines to that of nucleic acid vaccines, and comparing efficacies across trials is subject to bias . All theThe unprecedented deployment of COVID-19 vaccines in under a year from the identification of SARS-CoV-2 led to a new challenge: the formation of rapid global vaccine production and distribution plans. The development of vaccines is costly and complicated, but vaccine distribution can be just as challenging. Logistical considerations such as transport, storage, equipment , the workforce to administer the vaccines, and a continual supply from the manufacturers to meet global demands all must be accounted for and vary globally due to economic, geographic, and sociopolitical reasons –248. As –However, the distribution of these doses is not uniform around the globe. Latin America leads world vaccination rates, with at least 82% of individuals in this region receiving one vaccine dose, followed by the United States and Canada (81%), Asia-Pacific (81%), Europe 70%), the Middle East (58%), and Africa, with only 33% as of November 2022 . It is e0%, the MOne effort to reduce these disparities is COVAX, a multilateral initiative as part of the Access to COVID-19 Tools (ACT) Accelerator coordinated by the WHO, Gavi, the Vaccine Alliance, and the Coalition for Epidemic Preparedness Innovations (CEPI), the last two of which are supported by the Bill and Melinda Gates Foundation. Their intention is to accelerate the development of COVID-19 vaccines, diagnostics, and therapeutics and to ensure the equitable distribution of vaccines to low- and middle-income countries , 253. COAdditionally, the vaccine technologies available differ widely around the globe. As we review elsewhere , wealthiWhen vaccines first became available, the wealthy nations of North America and Europe secured most of the limited COVID-19 vaccine stocks . ThroughStill, many nations, especially in Africa, are reliant on the COVAX Facility, which has promised 600 million doses to the continent . The COVIn any case, COVAX provides access to COVID-19 vaccines that may otherwise have been difficult for some countries to obtain. COVAX aimed to distribute 2 billion vaccine doses globally by the end of 2021 . AccordiIn general, deciding on the prioritization and allocation of the COVID-19 vaccines is also a challenging task due to ethical and operational considerations. Various frameworks, models, and methods have been proposed to tackle these issues with many countries, regions, or U.S. states devising their own distribution and administration plans –267. The–Logistical challenges and geographical barriers also dictate the availability of certain vaccines. Many countries have had poor availability of ultralow-temperature freezers, leading to challenges of distribution for vaccines, such as mRNA vaccines, that require storage at very low temperatures –272. Fur–274–Another major challenge to global vaccine distribution is vaccine hesitancy, which the WHO has designated a leading global health threat . Polling283–290–Overall, the vaccine landscape remains heterogeneous even as the pandemic nears its third year, with certain vaccines much more accessible in high-income countries than in low- and middle-income countries. The vaccines described in this review, which were developed using well-established technologies, have played a crucial role in improving the feasibility and accessibility of vaccination programs worldwide. While the novel technologies have received the bulk of public attention in countries like the United States, these more traditional vaccine platforms also provide safe and highly effective protection against SARS-CoV-2. Although companies developing cutting-edge technologies, namely, Moderna and Pfizer/BioNTech, reported very high efficacies (greater than 90%) in their clinical trials , the effMuch attention has been focused on the most novel vaccine technologies that have been deployed against SARS-CoV-2, but the established vaccine platforms discussed here have all made a significant impact on human health during the 20th century and in some cases even earlier. The COVID-19 pandemic has demonstrated new potential in these established technologies. In the early 2000s, these technologies were explored for managing SARS-CoV-1 , 303, buWhile these tried-and-true technologies do not always produce vaccines with the highly desirable VE reported in mRNA clinical trials (which exceeded 90%), the efficacies are still very high, and these vaccines are extremely effective at preventing severe illness and death. Furthermore, some vaccine development programs using established technologies, especially protein subunit vaccines, have seen remarkably high VE and vaccine effectiveness. Some protein subunit vaccine phase III trials generated VE estimates of over 90%, comparable to those in the mRNA vaccine trials. Additionally, in some cases, such as Cuba’s highly successful vaccine development program, these vaccines have been developed by and for low- and middle-income nations. As a result, the greater accessibility and stability of these vaccines make them extremely valuable for the global effort to mitigate the loss of life from SARS-CoV-2. The outcomes of the response to COVID-19 suggest that these established vaccine technologies may continue to play an important role in tackling future viral threats.


Epidemiological studies have shown that almost all physical illnesses coexist with psychiatric disorders or psychological problems, and the severity of mental illness is positively correlated with the duration and severity of physical illness. Liaison consultations are valuable in identifying and treating psychiatric disorders, but the rate of psychiatric follow-up after consultation is low in outpatients. This study aimed to investigate the factors influencing post-discharge psychosomatic follow-up visits in patients undergoing psychiatric liaison consultation in general hospitals and construct a Nomogram prediction model for patients’ post-discharge psychosomatic follow-up visits. Medical record data of inpatients who received psychiatric liaison consultations at Xi’an International Medical Center Hospital in China from September 2019 to September 2020 were analyzed. Lasso regression and multivariate logistic regression analyses were conducted to screen independent influences on the occurrence of post-discharge psychosomatic follow-ups in patients undergoing psychiatric liaison consultations. Risk prediction column line graphs were constructed using R software, and the models were evaluated. Of the 494 inpatients who received psychiatric liaison consultations, 115 patients (23.279%) (mean age = 54.8 years) went for post-discharge psychosomatic follow-up, while 379 patients (mean age = 59.3 years) had no record of psychosomatic follow-up. Furthermore, occupation, interval.time, diagnosis, out.antipsychotics, and recommendations.followup were independent factors influencing post-discharge psychosomatic follow-up. The model accurately predicted post-discharge psychosomatic follow-up behavior of inpatients who received psychiatric liaison consultations. Lastly, the clinical decision curve analysis showed that the model had good validity for clinical application. Patients who received a psychiatric liaison consultation with a ≤ 10-day interval between admission to the hospital and application for consultation, were discharged with prescribed medication, and had a clear written medical order for a follow-up consultation had an increased probability of psychosomatic follow-up after discharge. Consultation-liaison psychiatry (CLP) is an important development in the area of mental health. It is a well-established treatment model in several developed countries , whereasThis is a retrospective case study aimed at constructing a Nomogram prediction model for factors influencing patients’ post-discharge psychosomatic follow-up visits.Medical record data of inpatients who received psychiatric liaison consultations at Xi’an International Medical Center Hospital from September 2019 to September 2020 were collected.Inpatients at Xi’an International Medical Center Hospital who received psychiatric liaison consultations between 1 September 2019 and 1 September 2020, including inpatients in emergency holding rooms.Inpatients whose cases did not require follow-up consultations.Finally, a total of 494 medical records of patients who received psychiatric liaison consultations at Xi’an International Medical Center Hospital from September 2019 to September 2020 were retrospectively collected.(1) Basic patient information: age, interval.time , department , t.time , residence , occupation ; (2) consultation records: reason ; diagnosis ; treatment ; in.antipsychotics ; out.antipsychotics (whether medication was taken after discharge); recommendations.followup ; (3) follow-ups (whether patients made the follow-up visit).Obtained the patients’ visit records for 1 month after discharge from the hospital, as well as their medical history records and consultation records. The research process is shown in The Lasso (least absolute shrinkage and selection operator) regression and multivariate logistic regression analyses were conducted to screen for factors influencing patients’ post-discharge psychosomatic follow-up visits. Risk prediction column line graphs were constructed using R software, and the models were evaluated.p < 0.05 being considered statistically significant. SPSS 22.0 software was used to process the data.Measurement data were described as The Lasso regression was performed to screen the factors influencing patients’ post-discharge psychosomatic follow-up, and binary logistic regression was used to construct a predictive model for patients’ post-discharge psychosomatic follow-up. The model was validated internally and externally by plotting the receiver operating characteristic (ROC) curve and calculating the area under the curve. The prediction model was evaluated through calibration curve analysis and clinical decision curve analysis.p < 0.05), and recommendations.followup (p < 0.001).Of the 494 patients who received psychiatric liaison consultations at Xi’an International Medical Center Hospital from September 2019 to September 2020, 115 patients went for follow-ups in the psychosomatic department, and 239 patients did not go for a follow-up visit. As shown in Lasso regression controls the correlations between the screening variables by adjusting the lambda parameter, and the higher the value of lambda, the stronger the screening variables, and reducing the coefficients of non-characteristic variables to zero. The Lasso regression analysis showed that the optimal value of lambda was 0.008, which resulted in the best outcomes for the screened variables. The positive factors influencing patients’ post-discharge follow-up included occupation, interval.time, diagnosis, out.antipsychotics, and recommendations.followup, as illustrated in Lasso regression was applied to screen the variables for multi-factor logistic regression analysis, and the results showed that occupation, interval.time, diagnosis, out.antipsychotics, and recommendations.followup were independent positive factors influencing patients’ post-discharge follow-up, with no multicollinearity among the factors, as shown in The Nomogram prediction model had a consistency index (C-index) of 0.914, and after 1,000 Bootstrap self-samplings, the C-index was 0.896. The area under the ROC curve was 0.957 see . As showp < 0.05). Students had the highest percentage of follow-up visits. In a related study, the psychiatric follow-up rate in the adolescent inpatient group was 97.6%  (p < 0.05). Patients with longer hospitalization intervals were more depressed and anxious due to the increased treatment cost and the inability to return to everyday social life under economic and environmental pressure. A similar phenomenon was observed in patients hospitalized for prenatal pregnancy (p < 0.05) in the percentage of follow-up visits depending on the interval between the time of admission and application for consultation. Patients who developed significant psychiatric symptoms during a short hospital stay often had psychosomatic problems before admission which were identified after admission to the hospital.There was also a significant difference in the proportion of patients opting for follow-up visits based on the interval of hospital stay: patients who went for follow-ups had significantly shorter intervals of hospital stay than those who did not come back for repeat visits . In contrast, there was a significant difference in the follow-up rate of patients with different diagnoses (p < 0.05). Anxiety-depression disorders and schizophrenia/paranoid psychosis had the highest patient follow-up rate, suggesting that psychiatric liaison consultations in general hospitals are more oriented toward patients with non-organic psychiatric disorders.There was no significant difference in the overall patient follow-up rate regarding the reason for requesting a consultation (p > 0.05) in the follow-up rate of patients who took medication or a combination of medication and psychological/physical treatment modalities. No significant difference was found in follow-up visits between patients considering whether or not they took medication during hospitalization (p > 0.05). However, there was a significant difference in follow-up visits of patients who were discharged with or without prescribed psychiatric medications (p < 0.05). The study found that patients’ attitude toward medication was a key factor influencing their follow-up rate, while patient compliance with treatment was negatively correlated with cognitive-psychological responses and positively correlated with patients’ trust in their psychiatrist (There was no significant difference (hiatrist . Some pahiatrist . The morhiatrist .p < 0.001) in the follow-up of patients with and without a clear written medical order recommending a follow-up visit. Wang and Wang (There was also a significant difference (and Wang  suggest Often, a semi-open interview is needed during the relatively short time between consultations to gather information about the impact of physical illness on the patient, the patient’s feelings about hospitalization, if the patient is confident in the treatment, and if there is any conflict between the patient and the supervising physician or healthcare provider. Many patients go through a difficult situation during the consultations and may show signs of regression and want to be understood .Psychodynamic interpretation of observed patient cognitions and behaviors plays an important role in psychiatric liaison consultations. The psychiatric liaison consultant should observe patients’ attitudes and choose appropriate diagnostic language, paying attention to the cultural meanings of statements . CommuniIn this study, patients who received a psychiatric liaison consultation with a ≤ 10-day interval between admission to the hospital and application for consultation, were discharged with prescribed medication, and had a clear written medical order for a follow-up consultation had an increased probability of psychosomatic follow-up after discharge. Following working methods in CLP can effectively improve participants’ compliance with follow-up recommendations. First, in the consultation process, different methods of explaining and communicating psychosomatic diseases should be adopted according to the individual conditions of the participants. Second, prescribe a more concise drug use plan before the end of the consultation. Third, written down advice when the consulted participant is discharged includes detailed medication guidance and clear recommendations for follow-up visits, and a take certain amount of time explaining the content and establishing a trusting relationship between doctors and participants.There are some limitations of this study. First, the study data were collected from only one hospital with a small sample size. Second, there were disaggregated data on patient use of physical therapy versus psychotherapy. Finally, patients were prescribed medication for 1 month at the time of discharge, which limited the follow-up duration to 1 month, and the study had to set a short follow-up observation period. However, patients might not have been able to visit the hospital for the follow-up on time due to various reasons, and the follow-up rate might have increased over an extended period, which was not taken into consideration in the design of this study.The original contributions presented in this study are included in this article/supplementary material, further inquiries can be directed to the corresponding author.All authors contributed to the conceptualization of the study and approved the submitted version.


Lichen planus (LP) is a chronic inflammatory skin condition characterized by the six Ps  often causing physical, emotional, and psychological stress for the person affected. Drug-induced LP has been described after the administration of drugs like antihypertensives, non-steroidal anti-inflammatory drugs (NSAIDs), and biologics like adalimumab and etanercept. Currently, there is a dearth of studies discussing the association between LP and dupilumab. Here, we present the case of a young adult female who developed LP 24 months after treatment with dupilumab for severe atopic dermatitis. We also conducted a review of the literature discussing the association between LP and dupilumab. Lichen planus (LP) is an autoimmune-mediated inflammatory dermatosis characterized by purple, pruritic, polygonal papules, and plaques affecting the skin, mucous membranes, and nails ,2. StudiA 22-year-old female with a history of severe AD Figure , asthma,However, after 24 months of therapy, she presented with pruritic, purple flat-topped papules distributed throughout her body, predominantly on the legs, arms, abdomen, and gluteal area Figures -4. A skiHowever, after six months, a new onset of LP lesions occurred, which were self-limited within three months. Her dermatologist did not recommend discontinuing dupilumab due to her history of severe AD, current LP resolution, and risk-benefit analysis. At the 24-month follow-up visit with her primary physician, it was revealed the patient continued to use dupilumab for AD, had residual post-inflammatory scarring and hyperpigmentation Figure  in the aCutaneous LP usually presents on flexor surfaces like the wrists, antecubital region, and popliteal region and has white lacy lines overlying the lesions called "Wickham striae". LP’s association with the development of psychological problems also warrants thorough investigation about its potential causes and addressing them .Recent literature has identified a possible correlation between biologics  and the development of lichenified drug eruptions (LDE) ,13. In lWhile the previous reports discussed a potential correlation between the initiation of dupilumab and the development of LP, other studies described the treatment of LP with dupilumab -16. PousAlthough not the same as LP, LP pemphigoides (LPP) is a similar skin eruption characterized by a combination of LP and bullous pemphigoid. Li et al. reported the case of a 69-year-old man with a 20-year history of mucosal LP, who developed red papules and plaques over a one-year period and was diagnosed with LPP. He failed treatment with IV prednisolone 50 mg daily and halometasone triclosan ointment. After minimal improvement with the initial regimen, dupilumab was then added with clinical improvement on day three and significant improvement at the two-month visit . AdditioAlong with LP and LPP, the initiation of dupilumab has also been correlated with the development of psoriasiform dermatitis. For example, Fowler et al. reported a case of a 54-year-old male with a history of severe AD who was treated with dupilumab. He had marked improvement in his severe AD after one month; however, he developed biopsy-proven psoriasiform dermatitis eight months after treatment with dupilumab. Initial treatment involved discontinuation of dupilumab with marked improvement of psoriasiform dermatitis at his two-month follow-up appointment . Next, Fowler et al. presented a case of a 49-year-old female with a history of moderately severe AD treated with dupilumab after an initial course of topical corticosteroids and phototherapy failed. After 18 months of dupilumab treatment, she developed psoriasiform dermatitis treated with clobetasol ointment twice daily which resulted in significant improvement .These findings support the hypothesis that blocking IL-4 and IL-13 signaling pathways by dupilumab can modulate the immune response and may treat LP and LPP . The devThe discrepancies reported may be attributed to several factors, including patient heterogeneity, variations in disease characteristics, and differences in treatment regimens. LP itself encompasses various subtypes and individual responses to treatment can vary. The interplay between dupilumab, genetic predisposition, immune dysregulation, and co-existing conditions may influence the outcomes observed in LP patients. Table Although many studies show promising evidence that dupilumab may treat LP, other studies have shown that dupilumab may actually induce LP or other inflammatory dermatoses. It thus remains unclear whether dupilumab induces or cures LP. Due to the lack of studies and clear evidence guiding clinicians on dupilumab’s role in the treatment or induction of LP, future researchers should conduct studies with large sample sizes and a diverse population of patients. This will result in clear risk stratification about whether dupilumab can be safely prescribed for patients.


Cell population data (CPD) parameters related to neutrophils, such as fluorescent light intensity (NE-SFL) and fluorescent light distribution width index (NE-WY), have emerged as potential biomarkers for sepsis. However, the diagnostic implication in acute bacterial infection remains unclear. This study assessed the diagnostic value of NE-WY and NE-SFL for bacteremia in patients with acute bacterial infections, and those associations with other sepsis biomarkers.Patients with acute bacterial infections were enrolled in this prospective observational cohort study. For all patients, a blood sample, with at least two sets of blood cultures, were collected at the onset of infection. Microbiological evaluation included examination of the blood bacterial load using PCR. CPD was assessed using Automated Hematology analyzer Sysmex series XN-2000. Serum levels of procalcitonin (PCT), interleukin-6 (IL-6), presepsin, and CRP were also assessed.p < 0.005, respectively), and were significantly correlated with the bacterial load determined by PCR . To assess the diagnostic value for bacteremia, receiver operating characteristic curve analysis was used. NE-SFL and NE-WY showed an area under the curve of 0.685 and 0.708, respectively, while those of PCT, IL-6, presepsin, and CRP were 0.744, 0.778, 0.685, and 0.528, respectively. Correlation analysis showed that the levels of NE-WY and NE-SFL were strongly correlated with PCT and IL-6 levels.Of 93 patients with acute bacterial infection, 24 developed culture-proven bacteremia and 69 did not. NE-SFL and NE-WY were significantly higher in patients with bacteremia than in those without bacteremia (This study demonstrated that NE-WY and NE-SFL could predict bacteremia in a manner that may be different from that of other indicators. These findings suggest there are potential benefits of NE-WY/NE-SFL in predicting severe bacterial infections. Sepsis is a life-threatening organ dysfunction due to a dysregulated host response to infection. It is a major problem in hospitalized patients worldwide, with high mortality . To prevCell population data (CPD) obtained using hematology analyzers has recently attracted attention as a new method for early detection of sepsis, which has enabled the expansion of information available from the complete blood count . The SysAmong CPD generated by Sysmex XN analyzers, fluorescent light intensity of the neutrophil area (NE-SFL) and/or fluorescent light distribution width index of the neutrophil area (NE-WY) have been reported as potential biomarkers for sepsis or bacteremia. A few studies have investigated the diagnostic utility of NE-SFL and NE-WY for predicting bacteremia . Park etIn the present study, we evaluated the accuracy and usefulness of CPD, NE-SFL and NE-WY, as biomarkers for culture-proven bacteremia in hospitalized patients, in comparison with the other commercialized sepsis biomarkers in Japan, including CRP, PCT, presepsin, and IL-6. Furthermore, we measured the bacterial load in the blood using polymerase chain reaction (PCR) to determine whether NE-SFL/NE-WY is truly affected by the presence of bacteria in the blood.The primary objectives of this study were to assess the diagnostic value and clinical utility of NE-SFL/NE-WY for bacteremia in hospitalized patients who developed acute infection. The secondary objective was to assess the association between NE-SFL/NE-WY and commercialized sepsis biomarkers.This prospective observational study was primarily designed to investigate the clinical utility of CPD obtained using Automated Hematology analyzer Sysmex series XN-2000  and was approved by the Ethics Committee of Toyama University Hospital  in accordance with the tenets of the Helsinki Declaration. We recruited all consecutive patients who developed acute infections at the Toyama University Hospital between July 1, 2017, and January 31, 2018. Informed consent was obtained from all the patients.The inclusion criteria were as follows: (1) men or women aged ≥18 years (2) patients who developed acute infection, clinically diagnosed as bacterial in origin, and (3) culture examinations (at least two sets of blood cultures) submitted before antimicrobial therapy.Bacillus, Corynebacterium, or Propionibacterium, were identified after 48–72 h of incubation with only one bottle or one set of bottles, it was diagnosed as contamination, as described in the previous report (Isolation of bacteria from at least one set of blood culture was defined as confirmed bacteremia (culture-proven bacteremia). If less virulent bacterial species, such as coagulase-negative staphylococci, s report , 13.According to the Third International Consensus Definition for Sepsis and Septic Shock (Sepsis-3) , ‘definiThe exclusion criteria were as follows: (1) deniable acute infection, that is, acute exacerbation of collagen disease, tumor fever and (2) lack of sufficient clinical information, and (3) definite diagnosis of fungemia. The details of patient enrollment are shown in Blood samples were collected from each participant at the onset of infection. We obtained data on selected CPD of neutrophils from the blood sample database of our central medical laboratory.n = 37) at Toyama University Hospital. The volunteers were hospital staff with no known underlying disease. Blood sampling was conducted under afebrile conditions, and serum was stored and utilized for CPD. Written informed consent was obtained from all the volunteers prior to the blood sampling.Control blood samples were obtained from healthy immunocompetent volunteers , as previously described . Briefly® 8,000; Roche Diagnostics K.K., Japan).The serum levels of CRP, PCT, IL-6, and presepsin were measured as sepsis biomarkers, at the time of enrollment. Among the biomarkers, IL-6 and presepsin were measured by SRL, Inc. and LSI Medience Corporation, while the others were measured in the laboratory at our hospital, as routine examinations ) and GraphPad Prism 9 (GraphPad Software) were used for statistical analysis.Background factors are expressed as median (interquartile range) or number (percentage). To evaluate the differences between the two groups, the Mann–Whitney test and Pearson’s chi-squared test were used to compare continuous and nominal variables, respectively. Receiver operating characteristic (ROC) curves and the respective areas under the ROC curve (AUC) were generated using GraphPad Prism 9 software . In each ROC analysis, the cutoff value for the detection of bacteremia was determined using the nearest point relative to the left corner of each ROC curve. The association between each pair of sepsis biomarkers or bacterial load was determined using Spearman’s rho correlation coefficient. Statistical significance was set at Bacillus cereus was isolated from one of the sets of blood culture, after more than 48 h-incubation, was determined as contamination, and subsequently categorized as ‘infection without bacteremia’. Finally, 24 patients with culture-proven bacteremia and 69 patients without bacteremia were included for further analysis.Detailed information on patient enrollment is presented in The clinical characteristics and laboratory findings of the 93 patients included in this study are summarized in p = 0.011). The most frequent causative bacteria for bacteremia were Enterobacteriaceae , followed by Staphylococcus spp. .The results of bacterial load and causative bacteria identified from blood culture are summarized in Among the cell population data measured using Sysmex’s automated hematology analyzer, NE-SFL and NE-WY were significantly higher in patients with bacteremia than in those without bacteremia ,B. ThereFurthermore, ROC curves assessing these biomarkers for the diagnosis of bacteremia in acute infections were constructed and analyzed. The AUC of NE-SFL was 0.685 , and that of NE-WY was 0.708  ,D. Amongp = 0.190), while that of NE-WY increased to 0.744 (p = 0.005) , the AUC of NE-SFL decreased to 0.632 (= 0.005) .r = 0.384 and 0.374, p < 0.005, respectively).As shown in r = 0.57; p < 0.001) and NE-WY , followed by PCT (r = 0.56 and r = 0.59) and presepsin   . HoweverIn an additional analysis assessing the correlation between these biomarkers in definite sepsis patients, the correlation between NE-SFL/NE-WY and other parameters was similar to that in patients with acute infection .This study demonstrated the significant diagnostic value of NE-SFL and NE-WY for detection of bacteremia in patients with acute infection. The definite correlation between blood bacterial load and NE-SFL/NE-WY, determined by PCR, demonstrate that these parameters are affected by initial bacterial invasion into the blood. Among the sepsis biomarkers, NE-SFL/NE-WY were strongly associated with PCT and IL-6, but not with presepsin or CRP. To the best of our knowledge, this study is the first to document an association between CPD and sepsis biomarkers, including IL-6 and presepsin in acute bacterial infection.In this study, we assessed the diagnostic value of NE-SFL and NE-WY in patients who developed acute bacterial infections, with or without culture-proven bacteremia. The ROC curve for bacteremia in bacterial infection analyzed using NE-SFL and NE-WY revealed a relatively high AUC of 0.685 and 0.708, respectively. Together with the definite correlation between NE-SFL/NE-WY and bacterial load in the blood, we suggest that NE-SFL and NE-WY both have predictive value to detect bacteremia among patients with acute infection. Moreover, NE-WY showed a relatively strong correlation with PCT and IL-6 in patients with definite sepsis compared to NE-SFL, as shown in NE-SFL and NE-WY are postulated to reflect the immaturity or activation of neutrophils because high fluorescence intensity indicates a high RNA/DNA ratio in immature cells. NE-SFL reflects the increase in proportion of the amount of cellular DNA and RNA, while NE-WY reflects the degree of heterogeneity of the neutrophil population. In the early phase of bacteremia, the mobilization of juvenile leukocytes with high nucleic acid content increases in the peripheral blood, resulting in a high NE-SFL . SimultaIn this study, we determined the quantitative bacterial load of patients using the PCR method , which iAmong different biomarkers which have been proposed to predict sepsis or bacteremia, the main attributes of successful and effective biomarkers are high sensitivity, specificity, possibility of bed-side monitoring, and financial accessibility . To dateIn this study, IL-6 and PCT showed the highest predictive value for the presence of bacteria, whereas presepsin and CRP showed a relatively lower predictive value, than NE-WY/NE-SFL. Of note, the sepsis biomarkers IL-6, PCT, presepsin and CRP are released from various other non-neutrophil immune cells , 28. Thep = 0.002) for the prediction of 28-day mortality in 757 patients with bacterial infection, whereas the AUC of presepsin for detecting culture-proven bacteremia was lower than that of PCT . As NE-SFL/NE-WY showed a higher AUC than presepsin, we consider presepsin to predict mortality rather than the presence of bacteremia in sepsis patients. The lack of fatal sepsis cases in this study may have also affected the diagnostic value of presepsin.Presepsin, the soluble fraction of cluster of differentiation 14 (CD14), is a sepsis biomarker that is released into circulation when monocytes are activated after binding with lipopolysaccharides (LPS) and LPS-binding proteins , 30. RecBased on these findings, we suggest the potential synergistic benefit and interaction between NE-WY/NE-SFL and conventional sepsis biomarkers. As NE-WY/NE-SFL determination incurs no additional costs other than routine examination by the automated differential, these CPD parameters have strong potential to be routine sepsis biomarkers that predict bacteremia or severe infection in acute bacterial infections.This study had several limitations. First, the single-center observational study design may have resulted in selection bias. Second, the relatively small sample size, particularly regarding patients who developed culture-proven bacteremia, may limit the reproducibility of the results. However, because this study focused on the association between CPD, sepsis biomarkers, and bacterial load, we believe that these limitations did not have a major effect on our conclusions.In this study, we demonstrated that NE-SFL and NE-WY measured using the Sysmex XN-2000 have a high diagnostic efficacy for prediction of bacteremia in acute bacterial infections. We also found that NE-SFL and NE-WY are strongly associated with the blood bacterial load, determined by PCR. In addition to the diagnostic value and substantial financial accessibility, the significant association with conventional sepsis biomarkers suggest potential benefits of NE-WY/NE-SFL in routine use in predicting severe bacterial infections. To further advance the early detection and understanding of bacteremia in acute bacterial infections, more investigation into the diagnostic value of CPD, particularly with NE-WY and NE-SFL is warranted.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Toyama University Hospital Ethics Committee (29–152). The patients/participants provided their written informed consent to participate in this study.YM and HN designed and interpreted the clinical data and experimental findings. YM, KN, and HN prepared the manuscript. YM with the assistance of TU, AM, YH, NK, and MK collected the clinical data and blood. YM and HN contributed to the analysis of the experimental and microbiological findings. YM and KN confirmed the accuracy of the statistical analysis. YM, HN, TU, AM, YH, NK, MK, YI, KN, YY, and IK contributed to the discussions throughout the work. All authors contributed to the article and approved the submitted version.HN received research funding on a contract basis and joint research funding from Sysmex Corporation.NK and YI were employed by the company Sysmex Corporation. Author MK was employed by the company Subsidiary of Sysmex Corporation. The authors declare that this study received funding from Sysmex Corporation. The funder had the following involvement in the study: study design, analysis, interpretation of data.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.https://www.frontiersin.org/articles/10.3389/fmed.2023.1156889/full#supplementary-materialThe Supplementary material for this article can be found online at: Click here for additional data file.


Conventional glucocorticoids (C-GC) replacement regimens have a detrimental effect on skeletal health in patients with adrenal insufficiency (AI), ultimately leading to an increased fracture risk. The novel dual-release hydrocortisone (DR-HC) formulations are characterized by a more favourable safety profile on various clinical endpoints. Data comparing the impact of C-GC and DR-HC on bone, however, are scarce.Twenty-seven patients with autoimmune primary AI  were evaluated to compare bone-related parameters between the two treatment groups.2, p=0.025) and at femoral neck . Moreover, they were characterized by a lower trabecular bone score  and by a higher mean number of vertebral fractures per patient . TBS was the best predictor of fracture risk, with a pseudo-R2 of 0.593; moreover, at mediation analysis, it was able to fully explain the observed detrimental effect of C-GC, compared to DR-HC, on fracture risk.No significant differences between the two treatments groups were observed with respect to bone turnover markers. Patients treated with C-GC showed a lower bone mineral density (BMD) at lumbar spine (LS; 0.791 ± 0.195 vs. 0.942 ± 0.124 g/cmThese results suggest that DR-HC is associated with less bone-related complications compared to C-GC in patients with PAI. Moreover, TBS seems to play a pivotal role in the mediation of the relationship between glucocorticoid treatment regimens and fracture risk. Patients affected by adrenal insufficiency (AI) require the chronic administration of a glucocorticoid replacement therapy . AlthougThe exogenous administration of systemic glucocorticoids exerts a detrimental effect on bone metabolism, ultimately leading to an increased fracture risk, which is related both to the dose and to the duration of the ongoing glucocorticoid treatment –14. FromEven though the alteration of bone metabolism is mainly reported in case of glucocorticoid treatments for immunosuppressive and anti-inflammatory purposes, a long-term replacement therapy with C-GC regimens has been demonstrated to exert a negative impact on skeletal health as well, though to a lesser extent , 17. A d®) was developed to maintain cortisol levels in a more physiological range, better reproducing the endogenous cortisol rhythm both when evaluated by serum cortisol  preparation  type 2, one by APS type 4, and five by autoimmune isolated Addison’s disease.The following exclusion criteria were applied: (a) APS type 1; (b) hypo- or hyperparathyroidism; (c) hyperthyroidism; (d) end-stage chronic kidney disease; (e) current or previous treatment with anti-osteoporotic drugs .All pre-menopausal women were studied in the early follicular phase. Female patients with primary ovarian insufficiency were under appropriate replacement therapy at the time of the study, as well as male patients with primary hypogonadism. Patients with autoimmune hypothyroidism were under appropriate treatment with levothyroxine at the time of the study. Patients affected by vitamin D insufficiency received adequate supplementation.The following parameters were evaluated for each patient: age, sex, disease duration, current treatment duration (defined as the duration of therapy with the current formulation and dosage), hydrocortisone equivalent (HCeq) dose, smoking habit, weight, body mass index (BMI), creatinine, fasting glucose, HbA1c, serum and urinary calcium, serum and urinary phosphate, parathyroid hormone (PTH), 25-OH vitamin D (25(OH)D), bone alkaline phosphatase (BAP), osteocalcin, urinary crosslinks, bone mineral density (BMD) at lumbar spine (LS), femoral neck (FN) and total hip (TH), trabecular bone score (TBS) at LS, and number of vertebral fractures at vertebral morphometry.The study was approved by the local Ethics Committee and was in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all included patients.Blood samples were taken in the morning between 8 and 9 am, after an overnight fast. Serum PTH (ng/L), BAP (µg/L) and osteocalcin (μg/L) were tested by chemiluminescence immunoassay . Serum 25(OH)D (µg/L) was tested by chemiluminescence microparticle immunoassay . Urinary crosslinks (nmol/mmol of creatinine) were tested by crosslinks method  with fluorescent detection based on high performance liquid chromatography . All other biochemical variables were assayed in plasma, serum or urine using standard methods.® software . The coefficient of variation of TBS measurements was equal to 1.2%. Vertebral morphometry was performed on lateral spine images obtained by DXA scan; conventional spinal radiographs (T4-L4) in the lateral and the anteroposterior projections would have been performed in case on unclear or inconclusive findings at lateral spine DXA imaging  at L1-4 LS, FN and TH, using a Hologic QDR 4500 densitometer. Fractured vertebrae were excluded from the calculation of BMD and its derived parameters. The coefficient of variation of BMD measurements was equal to 1.0% at all examined sites. T-scores were calculated by comparing BMD results with those obtained in a sex-matched Caucasian population at peak of bone mass. Z-scores were calculated by comparing BMD results with those obtained in an age and sex-matched Caucasian population. TBS was evaluated from LS DXA scans using the TBS iNsight imaging , but thiContinuous data were summarised using mean and standard deviation (SD) for normally distributed variables, and median and interquartile range (IQR) for non-normally distributed variables. Count data were summarised using the mean number of observed events per patient. Categorical data were summarised using percent values. Normality of continuous variables was assessed through Kolmogorov-Smirnov test. Differences between treatment groups were evaluated by Student t-test or by Mann-Whitney U-test for continuous variables, by exact Poisson regression for count variables, and by Fisher’s exact test for categorical variables. The same tests have been applied to evaluate differences between patients with and without vertebral fractures.All the bone-related parameters that were significantly different between treatment groups at univariate analysis were further analysed by analysis of covariance (ANCOVA) if continuous-type, or by multivariable exact Poisson regression if count-type; adjustments for age, disease duration, current treatment duration, HCeq dose, 25(OH)D levels, and HbA1c levels were performed.Univariate and multivariable exact Poisson regressions were used to further define the most relevant factors associated with vertebral fractures, considering as potential predictors the glucocorticoid treatment regimen (C-GC vs. DR-HC), together with all the other parameters found to be significantly associated with fractures at univariate analyses. Finally, a mediation analysis was performed in order to assess whether the impact of glucocorticoid treatment regimen on fracture risk could be explained by one or more of the bone-related parameters that have been analyzed; a mediation model aims to uncover and elucidate the mechanism that lies beneath an observed relationship between an independent variable and a dependent variable via the inclusion of a third variable, known as a mediator variable , 32; thrA cut-off of 0.05 was adopted for the definition of statistical significance. Statistical analysis was performed using STATA 17 .Thirteen patients were treated with C-GC replacement therapy . Fourteen patients were treated with DR-HC (single dose in the morning). In addition, all patients were treated with fludrocortisone (0.025-0.1 mg/day in the morning). All patients reported adequate adherence to prescribed treatments. The main anthropometric, clinical and biochemical characteristics of the patients are reported in Comparing patients treated with C-GC and those treated with DR-HC, those belonging to the first group showed a tendency towards an older age , while no differences were found in terms of sex , disease etiology/subtype , disease duration , current treatment duration , and HCeq dose  D, and PTH  and at FN , while only a non-significant trend could be observed at TH  D level and HbA1c), using ANCOVA for continuous-type data and multivariable exact Poisson regression for count-type data , and lower TBS  compared to those without vertebral fractures , lower LS T-score , lower FN T-score , lower FN-BMD , while TBS always maintained a significant association with the outcome .Among the parameters that significantly differed between patients with and without vertebral fractures, TBS was the one that showed the best predictive performance at univariate Poisson regression, with a pseudo-RFinally, the hypothesis of a mediating effect of TBS in the relationship between glucocorticoid treatment regimen (C-GC vs. DR-HC) and fracture risk was tested in a mediation analysis model. The retrieved results showed that, in our cohort, the detrimental effect of C-GC on fracture risk was entirely explicable through the mediation of a reduced TBS; in fact, the direct path from the treatment regimen to fracture risk lost any statistical significance (p=0.875); on the other hand, the indirect path passing through TBS showed a significant mediating effect of this variable   on skeletal health in a group of patients with PAI. Both biochemical and imaging parameters were assessed, and possible mediators of the relationship between glucocorticoid treatment regimens and fracture risk were analysed. Overall, our data seemed to suggest a more favorable bone-safety profile in patients treated with DR-HC; in fact, these patients displayed higher BMD values, higher TBS values, and a lower fracture rate compared to those treated with C-GC. Given the observational nature of this study, a possible role of confounding variables cannot be excluded in this regard; although not significantly, patients treated with C-GC were older than those treated with DR-HC, and this may have contributed to the differences in bone health parameters between the two groups; overall, however, our findings were essentially confirmed also after adjusting for age, disease duration, current treatment duration, HCeq dose, 25(OH)D levels and HbA1c.To the best of our knowledge, only two studies provided, so far, a comparison between C-GC and DR-HC with respect to bone-related endpoints. The first one, published in 2018 by Frara et al. , was a rFrom a pathophysiological point of view, glucocorticoid-induced osteoporosis (GIO) is characterised by a preferential loss of trabecular bone, with a lesser impact on cortical bone; as a consequence, the spinal column is the skeletal site that is most affected, with a preferential loss of BMD at LS and a more prominent increase in vertebral fracture risk , 34. OveIn recent years, alternative parameters of skeletal fragility have been sought, in place of BMD, for a better fracture risk assessment in patients with primary and secondary osteoporosis –47, inclIn our study, in agreement with previous literature , 29, we 2 of 0.593. Notably, none of the other considered variables could improve this performance when added to the model, thus emphasizing the pivotal role of TBS for the assessment of fracture risk in this clinical setting.The key role of TBS in our study, however, became even more evident in the analysis of the predictors of vertebral fractures. Overall, our data showed a significant difference in terms of vertebral fracture risk between the two treatment groups, with a significantly higher number of fractures in patients treated with C-GC. This result is in line with the one reported by Guarnotta et al. , who repMoreover, a mediation analysis model was used to analyze the possible mediating role of TBS in the association between glucocorticoid treatment regimens (C-GC vs. DR-HC) and fracture risk. In this analysis, the total effect of the glucocorticoid treatment regimen on fracture risk was partitioned into direct and indirect effects, considering TBS as a possible mediator. Interestingly, the whole detrimental role of C-GC on fracture risk could be explained by the indirect path passing through TBS, while the direct path from the treatment regimen to fracture risk lost any statistical significance. In other words, TBS was able to capture the entire association between the glucocorticoid treatment regimen (C-GC vs. DR-HC) and fracture risk: the treatment regimen had a significant impact on TBS, and, in turn, TBS had a significant impact on fracture rate, but no significant direct  impact of the treatment regimen on fractures could be detected.With respect to biochemical parameters, in our study, bone turnover markers did not significantly differ between the two treatment groups. Nevertheless, a borderline-significant trend towards lower levels of osteocalcin in patients treated with C-GC could be seen. This difference is in line with the findings by previous authors , 29, andOur study had some limitations. First, it was a proof-of-concept study with a limited sample size; the obtained results should be considered as preliminary and need to be confirmed in larger cohorts. Second, it had a cross-sectional design, and did not evaluate the effect of treatments over time; this permits to infer associations, but it does not allow to establish a link of causality. Third, the assignment to treatment regimen was not randomized and, thus, even if we evaluated the influence of possible covariates by multivariable analyses, the presence of a residual confounding cannot be excluded.In conclusion, our study suggests a better safety profile of DR-HC, compared to C-GC, in terms of bone-related complications in patients with PAI. These results are in line with the more favorable pharmacological profile of DR-HC, which is able to better reproduce the endogenous cortisol rhythm, thus leading to less side effects related to glucocorticoid excess. Notably, TBS seems to play a pivotal role in the mediation of the relationship between glucocorticoid treatment regimens and fracture risk. This finding is coherent with the specific impairment of bone microarchitecture that is determined by glucocorticoid excess, which affects bone quality rather than bone density.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving humans were approved by “Comitato Etico Interaziendale - AOU Città della Salute e della Scienza di Torino”. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.FB contributed to data analysis and manuscript writing. MB and MP-C contributed to manuscript review and editing. JG, LC, and MCDC contributed to data collection. VC contributed to data collection and manuscript writing. EG and MP supervised the manuscript drafting. RG contributed to work conceptualization and final draft supervision. All authors approved the manuscript in its final form. All authors contributed to the article.