A retrospective analysis was performed with the aim of understanding whether the risk factors showed in the literature for medication-related osteonecrosis of the jaws (MRONJ) in cancer patients are also relevant in osteoporotic patients taking antiresorptive drugs (ARDs). Data were retrospectively pooled from health records of patients on ARDs who requested a dental visit between January 2006 and April 2020 in the Dental Unit at Fondazione Ca’ Granda IRCCS Ospedale Maggiore Policlinico, University of Milan. A total of 434 patients were included. The following variables were collected: sex, age, smoking habit, type of ARD, duration of treatment, route of administration, therapeutic indication, concurrent systemic therapies and pathologies. Statistical analysis confirmed the relevance of chemotherapy, smoking, and immunosuppressive drugs as risk factors. In addition, a higher frequency of MRONJ in osteoporotic patients was reported in our cohort in association with an immunodeficiency disorder of variable origin. In conclusion, the identification of individual risk-profile before dental treatments is crucial for prevention. Anamnesis should include main risk factors, such as immunosuppression, dental extractions, smoking, trauma, and poor dental health. Nevertheless, our suggestion for dental professionals is to conduct a complete medical history of patients who mention long-term per oral therapies with ARDs for osteoporosis. Osteoporotic, as well as cancer patients, may also benefit from periodic monitoring of the ARDs therapy in order to prevent MRONJ. Osteonecrosis of the jaws (ONJ) associated with the use of drugs was first reported in the literature by Marx in association with bisphosphonates (BF) . It has ARDs are currently among the most prescribed drugs in the world and represent the gold standard for treatment and/or prevention of multiple myeloma, bone metastases, malignant hypercalcemia (tumor-induced), some solid tumors , as well as osteoporosis and some bone disorders such as Paget’s disease and osteogenesis imperfecta. MRONJ rate greatly differs between cancer and osteoporotic patients. In the first case, ARDs are taken intravenously (i.v.) and incidence varies between 1.0 and 8.0%, while in the second case, the therapy is taken perorally (p.o.) and MRONJ occurrence varies between 0.2 and 0.4% ,8.Risk factors for MRONJ have been extensively investigated in patients with cancer, as necrosis often occurs after the use of ARDs for prevention of bone metastases ,10,11. TAt present, prevention is still the most significant approach for protecting the oral health of patients treated with ARDs since none of the available therapies proved to be effective in treating MRONJ, which remains a disabling complication with pejorative development . For thiIn this perspective, the “Progetto Bifosfonati—Project Bisphosphates” (PB) was set up at the Fondazione Ca’ Granda IRCCS Ospedale Maggiore Policlinico in Milan to assist patients who are about to start or are currently undergoing therapy with ARDs. The goal of PB is to deliver a specialized dental service to all patients, including those from various hospital wards and private clinics. The influx of such a variety of patients allowed us to evaluate each patient via standardized medical history and data collection. The aim of the study was to carry out a retrospective statistical analysis on data collected from the PB regarding the incidence of MRONJ, and to investigate if known systemic risk factors of MRONJ have the same relevance in cancer and osteoporotic patients taking ARDs. This study is a single center retrospective epidemiological research on medical records collected in the PB. Data was collected from the patients’ clinical records according to selection criteria exemplified in Since 2006, the PB has offered first visit service to anyone about to start taking ARDs or already undergoing therapy, whether or not osteonecrosis is present. The aim of PB is to create a personalized treatment path based on counselling, monitoring and prevention.Upon entering the Unit of Restorative Dentistry, every patient is asked to grant consent to the medical treatment and data processing. PB uses a customized medical record which includes an in-depth medical and dental history. Particular attention is paid to data regarding risk factors for MRONJ, therapy in progress and patient lifestyle.For each patient, the following parameters were collected: sex, age, smoking habits, clinical motivation for taking ARD, type of ARD taken, duration of ARDs therapy, other drugs taken , metformin, strontium ranelate, hormonal replacement therapy (HRT) and antiangiogenic therapy), concurrent pathologies and pre-existing medical conditions . Cases of MRONJ presenting clinical or radiographic evidence were identified following the criteria defined by AAOMS 2014 . The sample was divided into different subgroups with specific characteristics in order to compare the occurrences of MRONJ. Firstly, sex and age were considered: patients were divided into five age groups . Secondly, groups based on the therapy were selected; the type of drug, the number of ARDs, and the duration of the treatment were taken into consideration. As far as the duration of the therapy is concerned, patients were divided into nine classes . Then, the sample was divided into three sorted groups depending on indication to treatment with ARDs: Oncological group (G1), osteoporotic group (G2), and a mixed group composed of patients with indication of both cancer and osteoporosis (G3). Based on a combination of parameters, increasingly specific and less numerous subgroups were selected. The Cochran–Mantel–Haenszel Test was used as mass test, where applicable, otherwise the Fisher exact test was repeated on the different strata. Where mass test gave relevant results, the odds ratio (OR) was used to find conditions with significant differences between groups. The significance level was chosen to be 0.05 and, where necessary, post-hoc correction was applied using the Bonferroni method. While analyzing the correlation between age and prescribed drug, the Kruskal–Wallis test was used.Furthermore, an electronic search of Medline (PubMed), Cochrane, SSCI , and SCI (Science Citation Index) databases from 1990 to present was performed to collect data on the epidemiology of bisphosphonates. Results of this research were used to compare our findings. The following search words were used: antiresorptive-related osteonecrosis of the jaw (ARONJ), MRONJ, bisphosphonates, denosumab, ARDs, osteoporosis, bone metastasis, risk profile and preventive protocols.Below are the results of the analyses performed to describe the characteristics of our sample in relation to noteworthy conditions and presumed risk factors for MRONJ. Out of 434 patients included in this study, 34 patients developed MRONJ. Among all visited patients, only eight referred to us before starting ARDs treatment. Sample characteristics are showed in In order to analyze the incidence of MRONJ by age, the cohort was divided into five age groups . Even though the incidence of MRONJ is higher between 60–69 and 70–79, no correlation was statistically significant among age groups , not eveMRONJ occurred in 5 males and 29 females, for an OR (F:M) = 1.47; however, there was no statistically significant difference in the number of cases between the two groups.According to duration of treatment, the sample was divided into nine classes , and a Fisher test was performed. This subdivision is an arbitrary choice, made to populate the groups in a more homogeneous way.p-value = 0.42)  .The analysis showed that 79 patients took ARDs for cancer (G1), 298 for osteoporosis (G2), while 57 presented both diseases (G3). The most common oncological diseases are listed in order of frequency: breast cancer (68), multiple myeloma (22), prostate cancer (12), cutaneous melanoma (4) . p-value = 0.03).G1 had a higher incidence of osteonecrosis (15.8%). According to the z-test, this difference was statistically significant when compared to patients in G2 and G3 .The number of MRONJ cases did not seem to be affected by the type of cancer detected in each patient: breast cancer (14/68); myeloid cancer (6/22); prostate cancer (1/12); skin cancer (1/4). In fact, these differences are not statistically significant according to the two-tailed Fisher test , as shown in Many patients took a combination of more than one drug. The following results were therefore obtained considering the sample size equal to the total number of drugs taken. The incidence of necrosis is significantly associated with the type of ARD taken .As far as clodronate is concerned, fewer cases than expected were found. Results also showed that the probability of developing necrosis increased when two ARDs were taken together or subsequently. The number of cases of MRONJ was significantly higher in the group of patients who took two drugs (OR (1: 2) = 1.67, p-value = 0.01482)  compared to all other cases (0.01482) .In this analysis, the following diseases were considered: anemia, diabetes, hypo- and hyperthyroidism and autoimmune diseases. Many patients had a combination of multiple diseases; the sample size therefore corresponds to the total number of diseases present in the cohort. This sample was divided into specific groups based on pathology. The incidence of MRONJ in each class was compared to the incidence in patients without concurrent diseases. No statistically significant difference was reported.In this analysis, the following drugs were taken into consideration: antidepressants (D1), chemotherapy (D2), corticosteroids (D3), sodium levothyroxine (D4), immunosuppressants (D5), proton pump inhibitors (PPI) (D6), metformin (D7), strontium ranelate (D8), thalidomide (D9), HRT, methimazole (D10). Many patients took multiple drugs; the sample size therefore corresponds to the total number of medications taken plus the number of patients not taking any. The sample was stratified into classes based on the above-mentioned drugs, in addition to a group for patients not taking any other medications besides ARDs.The incidence of necrosis was compared between groups receiving the drug and the group without any intake. The comparison of the ORs is shown in p-value = 0.019), corticosteroids , thalidomide . The number of cases of necrosis for each type of ARD in relation to the intake of all other drugs was included in a further analysis, which highlighted evidence that certain drug combinations are related to an increased incidence of MRONJ.A statistically significant difference for OR appeared for the following classes of drugs after Bonferroni correction: chemotherapy . Furthermore, we reported eight patients taking alendronate with MRONJ, and four of them were on a long-term therapy with immunosuppressant drugs like corticosteroid or leflunomide. A second analysis was performed comparing groups of patients taking ARDs in combination with other drugs to the groups of patients who received the same ARD but were not taking any other drugs.These data, tested for significance in OR, are not confirmed after the post-hoc correction. Due to the considerable number of combinations, we have a small number of patients with which to verify these specific events.Considering only G2, there seems to be a higher incidence of MRONJ in the case of association between alendronate and immunosuppressants. The significance, however, is not confirmed after the post-hoc correction.A total of 43 patients were taking or had taken hormonal replacement therapy (HRT) and at least one ARD at the same time. Out of 34 patients reporting MRONJ, five patients were on HRT, resulting in OR = 1.64. According to the z-test, this difference was not statistically significant.p-value = 0.04636).MRONJ occurred in 29 smokers (S) and 5 non-smokers (N), for an OR (S: N) = 0.83. This difference in the number of cases between the two groups was marginally significant, according to the z-test  [In our cohort, the mean age of patients who did not develop MRONJ was 68.52, while for those who developed the complication it was 70.03. The latter is slightly higher in comparison to Vereb et al. (66.80), but overlapping with Rogers et al.  ,29. No s< 0.001) .Our study confirmed the prevalence of MRONJ in female subjects with a male/female ratio of 1: 7.2. Vereb et al. recently found a ratio of 1: 2.1, and Owosho et al. of 1: 1.3, while Pazianas et al. found a ratio that seems similar to ours, ranging from 1: 8 to 1: 5.8 ,31,32. TMenopause is one of the unchangeable risk factors for osteoporosis, which is why postmenopausal women are particularly at high risk of developing osteoporosis from the age of 50. It is not a coincidence that we find an incidence of 10.60% in males and 7.40% in females. In fact, the male sample is almost entirely constituted by oncological patients, while the female one more often comprehends an increased number of patients affected by metabolic pathologies. The diagnosis of osteoporosis, and therefore the administration of ARD drugs, is constantly increasing . This phThe duration of ARDs therapy as a risk factor for MRONJ is a controversial discussion in international literature. In a 2009 review, Palaska et al. found a time to onset (TTO) of 1.8 years for zoledronate and 4.6 years for alendronate . Other aA recent multicenter study, based on TTO, found an average TTO for the entire cohort of 3.2 years, but specifically 2.2 years for zoledronate and 6 years for alendronate . LazarovIn our study, the increase in osteonecrosis cases related to the duration of therapy with ARDS was not statistically significant.The incidence of MRONJ in patients with osteoporosis associated with intake of ARDs p.o. in our cohort was higher than expected 5.08%). In the literature, the incidence of MRONJ in osteoporotic patients has rarely been assessed and was found to be about 0.01–2.27% .08%. In ,39. In 2In our survey, we recorded a prevalence of 26.32% for zoledronate. In the literature, the incidence of MRONJ in patients with zoledronic acid therapy varies within a wide range: 2.90–38.00%, which overlaps with our data ,42,43,44Our survey also found a high incidence of MRONJ for pamidronate 35.29%), higher than the average in literature (4.00–18.00%) .29%, hig,42,44.Alendronate is the most frequently administered drug among ARDs ,45. Indep = 0.014) [p = 0.0224). However, it does not pass the post-hoc test on the critical value: the main problem is the relatively low incidence that would require a larger sample. According to our analysis, the administration of antiangiogenic drugs in combination with ARDs increases the risk of development of MRONJ too (p = 0.0002). However, little is known about the incidence and prevalence of MRONJ in patients with exclusive antiangiogenic therapy [Moreover, the role of corticosteroids and immunosuppressants taken for autoimmune diseases may require further investigation: in the research of Bendilayi et al., these therapies turned out to be associated to a greater inhibition of bone remodeling if associated with oral ARDs . Chiu et= 0.014) . Later w= 0.014) ,51. In a= 0.014) . In our  therapy , and futOur data confirm the chemotherapeutic drug association with MRONJ, which was first reported in literature by Marx , and hasp = 0.3442). Lastly, the habit of smoking appears to be an important risk factor for MRONJ in our analysis (ORs (S: N) = 0.83). As is known, smoking increases vasoconstriction, and this can lead to an ischemic situation, favoring ONJ according to a study by Izzotti conducted in 2013 [p = 0.04) and by Quispe et al. (p = 0.049) [p = 0.115) [As for the additional risk factors considered, a cohort study examined the presence of potential risk factors for MRONJ in a population of 60,000 individuals in need of surgical treatment and found that the risk was greater in patients with rheumatoid disease and use of PPI, independently associated with MRONJ . We anal= 0.049) ,61. Othe= 0.115) .We present a statistical analysis of data collected form a diverse sample including all clinical cases sensitive to the administration of ARDs. This sample represents the common clinical case studies for dentists. Our results strengthen the knowledge of risk factors of MRONJ and are of help in daily practice. We selected a set of risk factors verified by previous studies. We also considered some secondary factors which themselves can change bone metabolism, and whose association is documented by less solid evidence. The link between all these risk factors and necrosis events was reported in the results and discussion. There are some limits to this research: it was conducted at a single center and on a limited sample. The statistical methods used are appropriate for interpreting the characteristics of the phenomenon, but a larger sample could give us a more representative image of reality. For this reason, we cannot make further considerations about the relationship between medical history and MRONJ without decreasing the reliability of our conclusions. We have highlighted the possible link between MRONJ and conditioning aspects of the medical history (for example of autoimmune diseases). However, due to the small sample size, we were unable to carry out specific analyses on the synergies and interactions between drugs. A multi-center study will allow us to progress in the analysis of these aspects. Moreover, we cannot exclude that the incidence rates for MRONJ that we reported were influenced by an upstream selection made by doctors or dentists who send patients to the PB to prevent the risk of MRONJ induced by ARDs. Our findings lead us to the conclusion that there is an underestimation of the risk of MRONJ associated with ARDs therapy in patients with dental problems. Bibliographical research confirmed a lack of awareness among dentists regarding osteonecrosis. Dentists should be trained to identify the high-risk profile for MRONJ of these patients and possibly refer them to highly specialized centers for consultation. Since MRONJ has a multifactorial etiology, patient care must be managed with a multidisciplinary approach. We encourage communication and collaboration between the different professionals involved in managing this complication. As a first step toward prevention, oncologists should recommend their patients to undergo a dental examination before starting treatment. With regards to specific subgroups of osteoporotic patients undergoing long-term p.o. therapies with ARDs, they are particularly vulnerable to side effects of corticosteroids. Doctors prescribing ARDs for osteoporosis should advise patients to inform their dentist about the ongoing therapy and schedule periodic visits to re-evaluate the ARDs treatment.


P value < 0.001). In the subgroup analysis, according to ethnicity, East Asian patients with END had elevated levels of NLR compared to those without END . However, the difference in the Caucasian group was not significant . In the subgroup analysis according to the type of stroke, the NLR levels in patients with hemorrhagic stroke who developed END were similar to those without END . Vice versa, in the ischemic stroke group, patients with END had elevated levels of NLR compared to those without END . NLR is a unique inflammatory biomarker whose increase in END suggests an immune system dysfunction in the pathogenesis of the disease.In light of the growing emphasis on classifying stroke patients for different levels of monitoring intensity and emergency treatments, we conducted a systematic review of a wide range of clinical studies, according to the preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines, with no restrictions on the language or publication date, to analyze the potential of the neutrophil-to-lymphocyte ratio (NLR) as an early neurological deterioration (END) risk predictor. A comprehensive search was carried out in PubMed, Scopus, and Web of Science databases from the inception to March 13, 2022. Nine articles were included in our study. Stroke patients with END had significantly higher NLR levels than the those without END (SMD = 0.73; CI 95% = 0.42-1.05,  Early neurological deterioration (END) refers to the worsening of symptoms days and weeks after a stroke . DiffereThe NLR is a biomarker that represents the balance between these two elements of the inflammatory response: adaptive immunity (as indicated by the lymphocyte count) and innate immunity (as indicated by the neutrophil count) . It is dThese systematic review and meta-analysis were performed according to the preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines. A comprehensive search was carried out in PubMed, Scopus, and Web of Science databases from the inception to March 13, 2022. The following keywords were used:  AND (stroke) AND (neutrophil to lymphocyte ratio OR NLR). References listed in the original reports were searched manually to find any missing articles and further potentially relevant articles.The inclusion criteria were as follows: (1) case-control or cross-sectional studies, (2) a population including adult patients with stroke, including ischemic and hemorrhagic ones, (3) compared stroke patients with END with those without END, (4) reported the quantitative blood NLR level as mean ± standard deviation (SD) or median (range or interquartile range), and (5) full text being available. The exclusion criteria were as follows: (1) animal studies, review, case reports, comments, or letters; (2) studies that enrolled subjects with any concomitant disorders such as cancer; and (3) duplicate publication.The titles and abstracts of the identified studies were evaluated by two authors independently. Potentially, relevant articles identified in the initial assessment were further screened in full text. Data concerning the first author's name, country, year of publication, stroke type, sample size, and NLR levels were extracted independently by two authors. Any discrepancies were resolved by a third reviewer or by discussion.The Newcastle-Ottawa scale (NOS) method with scores ranging from 0 to 9 was adopted to evaluate the quality of the studies . The NOSI2) test and Q-statistic were used to assess the heterogeneity across studies. I2 values of 25%, 50%, and 75% represented small, moderate, and high levels of heterogeneity, respectively. A random effects model would be adopted if significant heterogeneity was found. The method introduced by Wan et al. was adopted to estimate the mean and SD values using the median, range, or IQR values [The statistical analysis was conducted using Stata 11.2 software . The standard mean difference (SMD) and corresponding 95% confidence interval (CI) were reported. The inconsistency index   (The nine studies –23 repor 0.0001) . The END< 0.001) .P value < 0.001). However, the difference in the Caucasian group was not significant   .P value = 0.07). Vice versa, in the ischemic stroke group, patients with END had elevated levels of NLR compared to those without END   .P value = 0.13) (The results of studies on the role of NLR in END showed no publication bias (Egger's test  = 0.13) .Inflammation is a hallmark of stroke progression and etiology . InflammThe findings of our study show that there was a significant difference in NLR values between stroke patients who developed END and those who did not. NLR values were found to be higher in those who had END. Our findings imply that NLR is a distinct inflammatory marker that may reveal crucial physiologic abnormalities in the development of END.Severe diseases such as stroke stimulate the generation of neutrophils in the bone marrow and can lead to lymphopenia in a variety of ways . So, relNeutrophils are essential components of innate immunity that help to increase proinflammatory responses . On the In the case of END, a neuroinflammatory pathogenesis hypothesis has gotten a lot of attention , 31. To CRP, TNF-alpha, IL-4, IL-6, IL-8, and IL-10 are among inflammatory mediators that have been linked to END , 34. IL-NLR is a simple biomarker that may be derived during admission from a white blood cell differential and requires no additional time and work. According to recent research, NLR has high sensitivity and specificity for predicting END –23. HoweThere are a few limitations in our research that must be addressed. To begin with, the study sample size for determining the NLR value in some subgroups, such as Caucasians and patients with hemorrhagic stroke, was limited, and hence, our findings may not be properly powered to draw conclusions about such values. It is also worth noting that NLR values differ by race, which could explain why geographic analysis for NLR had no significant results among Caucasians. It is probable that some populations do not undergo typical hematopoiesis changes after a stroke, and hence, NLR is not useful in those areas. A meta-analysis also carries the risk of study heterogeneity. More than one approach was used to diagnose END among included studies, and, among those used, there is a possibility of user variability due to their subjective nature. As a result, these studies may have varied rates of missed diagnoses, which could compromise their validity.The findings of our investigation support a link between NLR levels and the development of END in stroke patients. NLR is a unique inflammatory biomarker whose increase in END suggests an immune system dysfunction in the pathogenesis of the disease. Furthermore, our data suggest that NLR is a viable biomarker that may be easily introduced into clinical settings to help predict and prevent END. Finally, the development of new therapeutic modalities and biomarkers will help us better prevent and treat END, lowering long-term mortality and morbidity.


Central sleep apnea (CSA) is a common and serious comorbidity mainly occurring in patients with heart failure (HF), which tends to be underdiagnosed and has not been widely studied. Overnight polysomnography (PSG) is the gold standard for diagnosing CSA; however, the time and expense of the procedure limit its applicability. Portable monitoring (PM) devices are convenient and easy to use; however, they have not been widely studied as to their effectiveness in detecting CSA in patients with HF. In the current study, we examined the diagnostic value of PM as a screening tool to identify instances of CSA among patients with HF.A total of 22 patients under stable heart failure conditions with an ejection fraction of <50% were enrolled. All patients underwent PM and overnight PSG within a narrow time frame. The measurements of the apnea–hypopnea index (AHI), hypopnea index (HI), central apnea index (CAI), and obstructive apnea index (OAI) obtained from PSG, automatic scoring, and manual scoring of PM were recorded. The results obtained from PSG and those from PM  were compared to assess the accuracy of PM.P = 0.01). Nonetheless, mean AHI measurements showed statistically significant differences between PSG and automatic scoring of PM , as well as between automatic and manual scoring of PM . Central sleep apnea was detected by PM; however, the results were easily misread as obstructive apnea, particularly in automatic scoring.Among the patients, CSA in 11 patients was found by PSG. The AHI measurements performed using manual scoring of PM showed a significant correlation with those performed using PSG (r = 0.69; PM devices could be used to identify instances of central sleep apnea among patients with HF. The results from PM were well-correlated with standard PSG results, and manual scoring was preferable to automated scoring. Congestive heart failure (CHF) is a major disorder ubiquitous in the general population . CHF affPolysomnography (PSG) is considered the gold standard for diagnosing sleep apnea in both obstructive and central types , 5; howeIn this study, we assessed the efficacy of portable monitoring devices as a screening tool for central sleep apnea in patients with CHF. Also, we compared the results obtained using automated PM and manual PM scoring with those obtained using PSG.This study included patients who visited the cardiology clinic of the Chang Gung Memorial Hospital between June 2018 and June 2019. The inclusion criteria were adult patients (at least 20 years old), those with a left ventricular ejection fraction of <50%, and those with stable heart failure (a stable heart condition under medication control for at least 3 months prior to the study). A total of 41 patients who fit the criteria were included in the study. All patients underwent portable sleep monitoring, PSG, echocardiography, and blood tests following enrollment. PSG was performed within 1 month of testing using a portable monitoring device. A flowchart illustrating the study protocol is presented in The study analysis was performed using a type 3 portable monitoring (PM) device , which comprised two respiratory effort bands (the chest and the abdomen), a nasal cannula pressure transducer to detect airflow, and a finger pulse oximetry sensor (oxygen saturation and heart rate) . Both auThe criteria dictating the use of the PM to score apnea and hypopneas were based on guidelines published by the American Academy of Sleep Medicine (AASM), version 2.5 . It shouFull overnight PSG was performed by a technician attendant in a sleep laboratory, and the data were analyzed in accordance with recommendations outlined in the 2014 AASM Guidelines, version 2.5 . PSG senAn echocardiographic study was performed by a cardiologist using a GE Vivid Q machine  to confirm ejection fractions of <50%. M-mode echocardiography and two-dimensional echocardiography were performed in standard  views with the patient in the supine or the left lateral position. The parameters of left ventricle (LV) dimensions and functions were measured using standard procedures, and the ejection fraction (EF) was determined using Simpson's method. In total, two patients were excluded because the EF was higher than 50%.t-test for normal distributions, and unpaired Wilcoxon's test for non-normal distributions. A p < 0.05 was considered statistically significant. Bland–Altman analysis was used to study the absolute differences of AHI measurements using PM and PSG. The correlation analysis was performed using Spearman's correlation coefficients.Descriptive statistical analysis was performed. The data were presented as mean and standard deviation (SD), including all performance metrics. Statistical analysis was performed using Prism version 5  and SPSS Statistics version 20.0 . The two groups were compared using unpaired Student's A total of 41 patients underwent portable monitoring, PSG, and echocardiography. Of the 41 patients, 19 patients failed to complete the study due to an inability to enter overnight PSG within 1 month, a refusal to continue due to inconvenience, an ejection fraction (EF) of >50% in follow-up echocardiographic analysis, or mortality . Comparin = 11) experienced CSA during the overnight PSG session. The presence of CSA in patients with heart failure was associated with BNP levels exceeding those of patients without CSA  (P = 0.04). No significant between-group differences were observed in terms of age, EF, etiology of heart failure, severity of heart failure , or underlying comorbidities . No correlation was observed between the automatically scored PM and PSG   . The Bla = 0.05) , 4 illusP < 0.001), as well as between automatic and manual scoring of PM . In the mean scores of HI measurement, we also observed statistically significant differences between manual PSG and automated PM scores . The PM device reliably detected obstructive and central sleep apnea events; however, the incidence of central sleep apnea events detected by PM was lower than that detected by PSG. No statistically significant differences were observed between PSG and PM scores for the CAI or between PSG and automatic PM scores for the OAI , OAI, CAI, and mixed sleep apnea index (MAI) obtained by PSG with those obtained by PM scoring  is shown in  the OAI .In this study, manual scoring of PM is strongly correlated with PSG in terms of the AHI, CAI, and OAI; however, the severity of PM estimate tends to be underestimated compared with PSG. The PM device was found to be effective in detecting central apnea events, but CSA events are easily misread as OSA events when measured by automatic scoring compared with when measured by manual scoring. Overall, the PM device underestimated the AHI and hypopnea events, and manual scoring was shown to be more accurate in estimating the AHI and hypopnea events than automatic scoring.CSA is highly prevalent in patients with HF; however, most cases are undiagnosed due to a lack of typical symptoms and a lack of resources for PSG testing , 13. TheThe reliability of portable monitoring devices was uncertain, and researchers have yet to establish the reliability of PM devices in identifying CSA , 17. AurIn the current study, PM was performed in a sleep laboratory, and each PM reading was manually checked to ensure accuracy in the detection of CSA. Our study demonstrated that PM could be used to identify central sleep apnea events; however, PM often misread central apnea events as obstructive apnea due to poor airflow signals. Thus, it appears that automated PM results should be checked manually. We observed that the scoring of PM  underestimated sleep apnea events, and that standard PSG and manual scoring were superior to automatic scoring of PM. This study demonstrates the efficacy of PM in identifying central sleep apnea. Our findings challenge previous recommendations, discouraging the use of portable sleep monitors for patients with HF or for the detection of CSA .There are a few limitations to this study. First, the sample size was small due in part to a large percentage of the patients dropping out of the study. Second, PSG and PM readings could not be compared in our study since they were conducted at different time periods, unlike in previous studies in which both devices were measured at the same time. Third, we were well-aware of the fact that the Medibyte is a type 3 PM device and that there is a lack of detailed information on the efficiency of the device in detecting CSA in previous studies. Moreover, a limitation of PM is its inability to distinguish between sleep and wake periods. So, it is likely that PM underestimates the number of apnea and hypopnea incidences due to the use of total recording time, instead of total sleep time. Although PM devices are increasingly used, instead of PSG testing, in clinical practice for detecting OSA, prospective studies and large population samples are needed to verify the diagnostic accuracy of the PM device in identifying CSA.A portable monitoring device is a viable tool for the identification of central sleep apnea in patients with heart failure. The incidence of central sleep apnea in the current study was underestimated; however, PM devices provided valuable data, particularly in light of the enormous number of patients with heart failure and the difficulty in enrolling patients for PSG.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 Institutional Review Board of Chang Gung Memorial Hospital (IRB No. 201701305A3). Written informed consent to participate in this study was provided by the patients/participants.L-PC, S-WL, N-HC, and M-SW contributed to the study conception and design. Material preparation and data collection were performed by N-HC, K-CH, M-SW, and C-HL. Data analysis was performed by P-HT, H-CH, and L-PC. The first draft of the manuscript was written by P-HT, L-PC, and N-HC. M-JH, S-WL, K-CH, C-HL, W-CL, H-CH, and M-SW commented on the previous versions of the manuscript. All authors read and approved the final manuscript.


Sepsis is a life-threatening condition, and biomarkers are needed to diagnose sepsis fast and accurately. We aimed to perform this meta-analysis to investigate the diagnostic value of calprotectin on sepsis in critically ill patients.The investigators searched MEDLINE, Embase, Web of Science and Cochrane Library. Studies were included if they assessed the diagnostic accuracy of serum calprotectin for sepsis in intensive care unit (ICU). We estimated its diagnostic value and explored the source of heterogeneity. The bivariate model and the hierarchical summary receiver operating characteristic (HSROC) curve were used in the meta-analysis.Six records assessing 821 patients were included in this meta-analysis. The pooled sensitivity, specificity, positive likelihood ratio (PLR), and diagnostic odds ratio (DOR) were separately as 0.77, 0.85, 5.20, 0.27, respectively. The Fagan's nomogram showed post‐test probabilities of 91% and 35% for positive and negative outcomes, respectively. Subgroup analysis indicated that sepsis definition could be a possible source of heterogeneity, but there’s no sufficient data to investigate sepsis-3 definition. Sensitivity analysis suggested that two studies could affect the stability of pooled results.On the basis of our meta-analysis, calprotectin is a helpful marker for early diagnosis of sepsis on ICU admission. Sepsis is a leading cause of mortality and critical illness worldwide and is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection . The SeqTherefore, biomarkers may play a vital role in the timely diagnosis and management of sepsis. C-reactive protein (CRP) and procalcitonin (PCT) are widely used biomarkers, but their diagnostic accuracy has been challenged . It is rCalprotectin is a calcium-binding protein that was originally found in neutrophils and was named major leukocyte protein L1. It is a 24-kDa heterodimer composed of light [myeloid-related protein 8 (MRP8)] and heavy (MRP14) chains (8 and 14 kDa), also named S100A8 and S100A9, which belong to the S100 protein family . Recent In consequence, we aimed to perform this meta-analysis to synthesize the current evidence and investigate the diagnostic value of calprotectin on sepsis.We constructed a protocol of complete meta-analysis that adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards . The proThe investigators searched MEDLINE, Embase, Web of Science, and Cochrane Library using the search term “ AND .” Two investigators (R-YG and Y-ZH) independently searched the databases from the establishment of these databases until January 2022 and reran the search before the final analysis. The research was done without language or publication period restrictions, and unpublished studies were not searched.Studies that assessed the accuracy of serum calprotectin for differentiation between critically ill patients with sepsis and those without sepsis were included. Sepsis could be diagnosed using any recognized diagnostic criteria, and there are no restrictions on the types of study design eligible for inclusion. All retrieved articles were initially screened by title and abstract. Subsequently, the relevant ones were rescreened by full text. The selection was done independently by two investigators (R-YG and Y-ZH). If there were any discrepancies in the process of the study selection, they would turn to a third party. EndNote was used for recording decisions.Two investigators (R-YG and Y-ZH) independently extracted the data from individual reports, including first author, year of publication, study location, population setting, admission category , sepsis definition, and sample size. We also recorded true positive (TP), false positive (FP), false negative (FN), true negative (FN), sensitivity, specificity, area under the curve (AUC), and optimal cutoff value of calprotectin for the diagnosis of sepsis. If there was any disagreement between the two reviewers in the process of data extraction, it was resolved by a third party. We contacted the corresponding authors when further information was needed. If no response was received after sending a reminder, the study would be excluded. The data extracted were recorded in an Excel spreadsheet.The quality assessment was done by two independent investigators using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool . This evHierarchical models are increasingly being accepted as standard methods for the meta-analysis of diagnostic test accuracy studies . Therefop < 0.05 represented significant threshold effects. The I² statistics was used to evaluate heterogeneity induced by a non-threshold effect. Different I² values reflected low (<30%), moderate (30%–50%), and high (>50%) degrees of heterogeneity.Heterogeneity induced by threshold effect was calculated by testing Spearman correlation, and Subgroup analyses were performed according to varied factors to identify the causes of heterogeneity. To examine the stability of the results, sensitivity analysis was also performed. It was analyzed with a method of reducing one article at a time, and the effect of a single study on the meta-analysis was evaluated. Publication bias was examined by Deeks’ funnel plot asymmetry test. All statistical analyses were performed using MetaDiSc (version 1.4) and STATA (version 15.1) software.in vitro studies, duplicates, and irrelevant articles, a total of 22 full-text references were screened for eligibility. Among them, nine did not meet our selection criteria, and seven had insufficient data to construct a 2 × 2 contingency table. Finally, six records were included in our meta-analysis .The QUADAS-2 tool was applied to evaluate the quality of the six studies, and the detailed results were shown in The HSROC curve for all included studies is depicted in 2I was 71.4% for DOR, indicating that substantial heterogeneity exists among them, while the threshold analysis p value was 0.54, giving no evidence of a threshold effect.We performed a heterogeneity analysis of the six studies. The 2I = 68.5%) and 4.53 , respectively. According to the population setting, the six studies were divided into “adult” subgroup and “neonate” subgroup. Pooled DOR was 21.56  and 15.42 , respectively. Similarly, two studies used the ACCP/SCCM definition for sepsis and they made up the “ACCP/SCCM” subgroup, while the other four made up the “others” subgroup. Pooled DOR was 39.53  and 12.16 , respectively. The results of the subgroup analysis were shown in We then performed a subgroup analysis to explore the cause of heterogeneity. The subgroup analysis was based on admission category, population setting, and sepsis definition. There are five studies focused on patients treated by physicians and constituted the medical subgroup, while two studies focused on patients undergoing surgery and were termed the surgery subgroup. The pooled DOR was 12.23 (95% CI 3.82–39.15, In the sensitivity analysis, two studies  could afSepsis is a life-threatening condition caused by a dysregulated host response to infection. Sepsis alters innate and adaptive immune responses and thus hampers immune homeostasis . We now Many studies have suggested that PCT is a biomarker for the early diagnosis of sepsis. However, different pathogens are believed to induce varied levels of PCT, and viral infection or ssystemic inflammatory response syndrome caused by noninfectious diseases can elevate the PCT level in critically ill septic patients . SeveralCalprotectin is a protein secreted extracellularly from neutrophils and monocytes or is released into pus after cell disruption or death . The solOur results indicated that serum calprotectin on ICU admission could be a practical marker of sepsis. To the best of our knowledge, this is the first meta-analysis reporting the diagnostic value of calprotectin for sepsis on ICU admission, and the results are promising. Although heterogeneity existed, we performed a subgroup analysis and a sensitivity analysis to reduce it.In the subgroup analysis, calprotectin showed well diagnostic value in both “surgical” and “medical” subgroups, indicating that serum calprotectin could be a potential biomarker to identify sepsis from noninfectious inflammatory disease. Heterogeneity still existed, so admission category was not the main cause of heterogeneity. We then analyzed if the population setting could affect the results, since it was reported that serum calprotectin levels were massively elevated after birth then slowly decreased during the first month of life . HoweverSensitivity analysis showed that studies conducted by Our meta-analysis has several limitations. First, this meta-analysis included only six studies, and seven other studies associated with this topic were excluded because of insufficient data. Second, significant heterogeneity exists between these studies. As a result, we performed a subgroup analysis and a sensitivity analysis. In the subgroup analysis, sepsis definition turned out to be a source of heterogeneity, but there are no sufficient data to investigate the sepsis-3 definition. The broad and variable definition of sepsis is a common limitation in all sepsis biomarker studies, and the heterogeneities affected the results. Third, all of the studies included selected the test threshold to optimize sensitivity and specificity; it may lead to overestimation of test performance. However, there is no commonly accepted calprotectin threshold for sepsis. This limitation is still inevitable.In conclusion, serum calprotectin on ICU admission plays an important role in the timely diagnosis of sepsis. However, further studies are required to confirm this finding.The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.R-YG contributed to study design, search strategy, screening of studies, data extraction, and statistical analysis, as well as writing the manuscript. H-MJ contributed to screening of studies and data extraction, as well as assisted in editing the manuscript. Y-ZH contributed to search strategy, screening of studies, and data extraction. B-SQ performed the quality assessment and PY synthesized the data. XKZ and WXL contributed in revising the manuscript. L-FH conceived of the study, contributed to study design and provided general supervision. All authors contributed to the article and approved the submitted version.The 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.


Delayed diagnosis and inaccurate judgment of the severity of the disease may be the principal reasons for the poor prognosis associated with neonatal midgut volvulus. We aimed to develop a nomogram model that timely assesses the risks of intestinal ischemia and necrosis in the neonate with midgut volvulus.We retrospectively analyzed the clinical data from neonates with midgut volvulus who were admitted to Guangzhou Women and Children’s Medical Center from January 2009 to December 2019. Univariate and multivariate analyses were used to obtain independent factors to build a predictive model. The independent factors were used to develop the nomogram model.P < 0.001). The sensitivity was 90.48%, and the specificity was 93.10%. A nomogram model was established using the six independent predictors, with a C-index of 0.859 and a favorable consistency between the predicted and actual intestinal ischemia and necrosis rates according to the internal validation.Heart rate, mean arterial pressure, serum C-reactive protein, serum sodium, serum albumin, and pH levels were independent predictors for intestinal ischemia and necrosis in patients with midgut volvulus. The area under the receiver operating characteristic curve (AUC) of the predictive model was 0.985 (95% confidence interval, 0.966–0.999; The constructed nomogram model could be a superior tool for predicting intestinal ischemia and necrosis in neonates with midgut volvulus. Midgut volvulus (MGV) refers to a condition in which the midgut twists around the axis of the superior mesenteric artery and is often related to malrotation . The incIn this study, we aimed to develop a nomogram model based on objective clinical data available within 2 h of admission to predict whether neonates with MGV have intestinal ischemia and necrosis. This new model is expected to help clinicians accurately estimate the urgency of treating neonates with MGV and perform super emergency operations to improve the prognosis.Neonates with a preoperative suspected diagnosis of MGV admitted to Guangzhou Women and Children’s Medical Center from January 2009 to December 2019 were enrolled in the present study. The preoperative suspected diagnosis was based on medical history, physical examination, ultrasound, or upper gastrointestinal radiography. The final diagnosis of MGV and bowel ischemia and necrosis was determined based upon the operative and pathologic findings. Patients with a surgically confirmed absence of midgut volvulus were excluded. Cases with severe cardiac malformations, congenital diaphragmatic hernia, gastroschisis, omphalocele, and other digestive tract malformations were also excluded.n = 21) or a non-intestinal ischemia and necrosis group (n = 87), with the latter population randomly selected from among 210 cases without intestinal ischemia and necrosis.Patients were apportioned to an intestinal ischemia and necrosis group  was employed for the internal validation of the predictive model. The independent factors were used to develop the nomogram model. The predictive accuracy of the nomogram was determined by concordance index (C-index) calculation and calibration plots.The present study was approved by the ethics committee of Guangzhou Women and Children’s Medical Center (no. 192A01), and written informed patient consent was obtained from each patient’s family.t-test. Variables showing statistical significance (P < 0.05) in the univariate analysis were brought into the logistic regression and further screened by stepwise regression. Hosmer-lemeshow test and receiver operating characteristic (ROC) curve were used to evaluate the prediction model. An internal validation of the prediction model was carried out by leaving one cross-validation. The nomogram prediction model was established using the RMS package of R version 3.6.1 . The nomogram was internally validated using bootstraps with 2,000 resamples. We used the Harrell concordance index (C-index) in the nomogram to assess the model performance, and a two-sided P value < 0.05 was considered to be statistically significant. A flowchart displaying the process of building the nomogram is shown in We performed statistical analysis using SAS version 9.4 . Categorical variables were expressed as numbers and percentages and were compared using the chi-squared test and Fisher’s exact probability test. Measurement data that were not normally distributed are represented by median (interquartile range) values. Comparisons between two groups were performed by the Wilcoxon rank-sum test. Meanwhile, those data conforming to normal distribution were described by mean ± standard deviation values, and comparisons between the two groups were performed by P > 0.05; (1) Intestinal ischemia and necrosis during the operation were found in 21 of the final 231 cases (9.1%). There was no significant difference in sex, gestational age, delivery method, or birth weight between the two groups (P < 0.01); the incidences of abdominal distension, heart rate (HR), and mean arterial pressure measured within 2 h after admission in the former group were significantly higher than those in the latter group . In the intestinal ischemia and necrosis group, the levels of white leukocytes, C-reactive protein (CRP), glucose, and blood potassium detected within 2 h of admission were significantly higher than those in the non-intestinal ischemia and necrosis group, while the levels of hemoglobin, blood sodium, serum albumin, pH, and base excess (BE) were significantly lower than those in the non-intestinal ischemia and necrosis group (P < 0.05).(2) According to univariate analysis, the median age at admission and the incidence of biliary vomiting in the intestinal ischemia and necrosis group were significantly lower than in the non-intestinal ischemia and necrosis group  In the multivariate analysis, HR, mean arterial pressure (MAP), CRP, serum sodium, albumin (ALB), and pH value determined within 2 h after admission were the independent predictors of intestinal ischemia and necrosis in patients with MGV .The prediction model formula established was as follows:P = 0.998; max-rescaled R2 = 0.837). The area under the ROC curve was 0.985 . When P > 0.2 , it was judged as intestinal ischemia and necrosis. Leave-one-out cross-validation (LOO-CV) was employed for the internal validation of the predictive model. The accuracy was 92.59%, the sensitivity was 90.48%, the specificity was 93.10%, the positive predictive value was 76.00%, and the negative predictive value was 97.59% , it is considered indicative that the patient has intestinal ischemia and necrosis. After 2,000 bootstrap self-help sampling verifications, the nomogram model predicted intestinal ischemia and necrosis with a C-index of 0.859 and a corrected C-index of 0.855, with good discrimination. The correction curve is shown in The nomogram model is constructed according to the factors in the multivariate logistic regression model . The totA high index of suspicion for midgut volvulus is based on the history and physical examination findings. In neonates, MGV typically presents with the sudden onset of bilious vomiting, and soon after the onset of vomiting, the lower abdomen may appear scaphoid. With complete obstruction, the patient develops intestinal ischemia with abdominal distension, bloody stools, and lethargy. Doppler ultrasonography or upper GI contrast radiography can assist doctors in the diagnosis. If the diagnosis of midgut volvulus is highly suspected, the nomogram model can be used to identify whether intestinal ischemia or intestinal necrosis is present.For example, if a patient highly suspected of having midgut volvulus has an HR of 120 beats/min, a score of 21 points is assigned; for a MAP of 70 mmHg, a score of 16 points is assigned; for a CRP level of 75 mg/L, a score of 26 points is assigned; for an Na concentration of 135 mmol/L, a score of 24 points is assigned; for an ALB concentration of 40 g/L, a score of 20 points is assigned; for a pH value of 7.42, a score of 35 points is assigned. Then, the total score is 142 points, and the probability of intestinal ischemia and necrosis is 0.3; thus, it is judged that the patient has intestinal ischemia and necrosis, and we should immediately give the patient absolute priority for surgery.MGV is often caused by congenital intestinal malrotation, a variation in intestinal position, and incomplete mesenteric attachment. Approximately 75% of MGV cases occur in the first year of life, and most cases occur during the neonatal period , 13.The prognosis of patients with MGV displays a polarizing trend, with children exhibiting a good prognosis achieving a quality of life similar to that of the normal population, while children exhibiting a poor prognosis suffer serious complications, such as short bowel, total intestinal necrosis, and even death . The incIn our study, based on univariate and multivariate logistic regression analyses, it was concluded that HR; MAP; pH; and serum CRP, sodium, and albumin levels are independent predictors for intestinal ischemia and necrosis in patients with MGV. Using these predictors, we developed a nomogram to visualize the results of the regression analysis; when the total score exceeds 140 points (P = 0.20), it is considered indicative of the patient having intestinal ischemia and necrosis.P < 0.05).Intestinal necrosis often appears as dehydration and shock, and the early manifestations of shock are increased HR and increased blood pressure. Silvia et al. reported that the major risk factor for death among neonates with an intestinal volvulus is hemodynamic instability . A stranP < 0.05). We plan to further verify some of our novel findings in subsequent studies.In addition, we newly uncovered serum albumin – a negative acute-phase reactant synthesized by the liver – as an independent risk factor for intestinal necrosis caused by MGV. However, in the presence of systemic inflammation, the liver synthesizes acute-phase proteins other than serum albumin. Therefore, some people posit that low serum albumin levels reflect an inflammatory state . HoweverThere were several limitations of our current study. As this study was a preliminary and single-center retrospective study and the number of cases included was relatively limited, the findings need to be externally evaluated in a greater number of neonates with MGV. In the future, a larger prospective study involving multiple centers and a larger number of patients should be undertaken to validate and improve the nomogram.HR, MAP, serum CRP, albumin, serum sodium levels, and pH values were the factors closely related to intestinal ischemia and necrosis. The constructed nomogram model, which combines the HR, MAP, serum CRP, albumin, serum sodium levels, and pH values, can be a superior tool for predicting intestinal ischemia and necrosis in neonates with midgut volvulus.The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Guangzhou Women and Children’s Hostipal. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.XG, ZW, and WZ: study concept and design. XG: drafting of the manuscript, statistical analysis, and interpretation of data. WZ, ZW, and QH: critical revision of the manuscript for important intellectual content. JY and JL: administrative, technical, or material support. All authors contributed to the manuscript revision, read, and approved the submitted version.The 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.


Functioning and non-functioning adrenocortical adenoma are two subtypes of benign adrenal adenoma, and their differential diagnosis is crucial. Current diagnostic procedures use an invasive method, adrenal venous sampling, for endocrinologic assessment.This study proposes establishing an accurate differential model for subtyping adrenal adenoma using computed tomography (CT) radiomic features and machine learning (ML) methods. Dataset 1  was collected to develop the models, and Dataset 2 (54 patients) was utilized for external validation. Cuboids containing the lesion were cropped from the non-contrast, arterial, and venous phase CT images, and 1,967 features were extracted from each cuboid. Ten discriminative features were selected from each phase or the combined phases. Random forest, support vector machine, logistic regression (LR), Gradient Boosting Machine, and eXtreme Gradient Boosting were used to establish prediction models.The highest accuracies were 72.7%, 72.7%, and 76.1% in the arterial, venous, and non-contrast phases, respectively, when using radiomic features alone with the ML classifier of LR. When features from the three CT phases were combined, the accuracy of LR reached 83.0%. After adding clinical information, the area under the receiver operating characteristic curve increased for all the machine learning methods except for LR. In Dataset 2, the accuracy of LR was the highest, reaching 77.8%.The radiomic features of the lesion in three-phase CT images can potentially suggest the functioning or non-functioning nature of adrenal adenoma. The resulting radiomic models can be a non-invasive, low-cost, and rapid method of minimizing unnecessary testing in asymptomatic patients with incidentally discovered adrenal adenoma. Adrenal adenomas are common tumors, and their prevalence in the general population is about 6% , althougBoth FAA and NAA are benign adrenal adenomas. The clinical diagnosis of the two diseases is mainly through endocrine tests for hormone levels or medical imaging . EndocriIntervention methods are different for the two types of adrenal adenomas. FAA can cause hormone abnormalities, so further examination of hormone levels is required and treatment usually involves surgery . Most NANon-invasive computed tomography (CT) can generate high-resolution images and has become a routine examination method. In addition, many features can be extracted from CT images for quantitative analysis . In oncoRadiomic studies of adrenal adenomas have been carried out. Elmohr et al.  conducteThe purpose of this study is to establish an accurate model to distinguish FAA from NAA using CT radiomic features and machine learning methods. This model may provide a non-invasive, low-cost, and rapid method of adrenal adenoma stratification to help patients with NAA avoid unnecessary invasive hormone tests. Our study contributes to this goal in three ways. First, a CT radiomic model is developed for differentiating functioning from non-functioning subtypes of adrenal adenoma in a non-invasive, low-cost, and rapid way. Second, the tedious step of manual segmentation of adrenal adenoma from CT images is replaced by simple cropping of a cuboid containing the target adrenal adenoma region to extract three-dimensional features. Third, a combination of radiomic features obtained from multiple phases of CT images improves classification performance.Two datasets were collected in this study. Dataset 1 was from The First Affiliated Hospital of China Medical University and was used to develop the machine learning model. Dataset 2 was from Shengjing Hospital of China Medical University and was utilized for external validation. The Ethics Committee of The First Affiliated Hospital of China Medical University and Shengjing Hospital of China Medical University approved this retrospective study, and informed consent was waived.The experimental subjects were patients who had been diagnosed with adrenal adenomas. The data mainly included patient clinical records and contrast-enhanced CT images. Specifically, the clinical data were the patient’s age, gender, examination time, and pathological type. Each CT scan included images of arterial, venous, and non-contrast phases. The three-phase CT images were used in all cases.After screening, a total of 289 patients with lesions larger than 2 cm were included in Dataset 1. There were 191 patients with FAA  and 98 with NAA. In subsequent experiments, Dataset 1 was randomly divided into training  and test  sets. The training and test sets contained different patients to ensure that they were independent. In Dataset 2, there were 54 patients (30 FAA and 24 NAA). Table Figure In the process of cuboid cropping, the central point of the adrenal adenoma was determined first, and then a 64*64*32 cuboid was automatically cropped from the CT image to ensure that the cuboid completely contained the lesion area. In the experiment, the cuboid was cropped from the non-contrast, arterial, and venous phase CT images and used as the region of interest (ROI). One radiologist with 8 years of experience in abdominal imaging cropped the cuboids and another radiologist with 10 years of experience examined and confirmed the cropped results.Pyradiomics software  was usedFeature selection is performed to identify critical and discriminative features and reduce over-fitting risk in the final prediction model . First, Only the training set data is used in feature selection. By calculating the coefficients of each variable in the LASSO, the features of the model can be sorted in order of importance from high to low. For every phase of the CT images, the top 10 features were used to train the subsequent two-category classifiers.The radiomic features from the three phases of CT images were combined to improve the classification performance. First, a two-sample t-test was conducted for features from each phase. Second, the radiomic features that had significant differences were obtained from the three phases of CT images and concatenated into a vector. Third, LASSO regression was used to calculate the coefficients of each feature in the vector. Fourth, the features were sorted and the top 10 features were selected to build the models.Five machine learning algorithms, RF , 34, SVMThe models using single-phase CT features, multi-phase fusion CT features, and radiomic-clinical features were trained, tested, and compared. An independent test set in Dataset 1 was used to evaluate the performance of the model using measures of accuracy (ACC), specificity, sensitivity, and area under the curve (AUC). Receiver operating characteristic (ROC) curves were drawn. Moreover, models with and without the hyperparameter optimization were also compared. Dataset 2 with 54 patients served as the external validation to investigate the model’s generalization capability.The machine learning algorithms were completed using the open-source Python Scikit-Learn library  , Imc2_V, SZNN_N, and ClusterShade_N were greater in FAA than in NAA. By contrast, NAA had higher mean values for the other features.Figure Table (a) shows the ROC curves of the five models. The results show that LR yielded the best performance, with precision, recall, and accuracy of 76.5%, 74.0%, and 78.4%, respectively, and the AUC value was 0.78.The experiment used a grid-search algorithm to optimize the model’s hyperparameters. As a comparison, we first used the models without parameter optimization for prediction analysis. Table 5(b) shows the ROC curves of these models. Among them, LR performed best, with precision, recall, accuracy, and AUC values of 85.3%, 76.6%, 83.0%, and 0.86, respectively. Parameter optimization improved the accuracy and AUC of the models.Table 5(c) shows the ROC curve of the five models. The accuracy of the models did not increase significantly after adding the clinical information as a feature, but AUC did increase significantly. Among the models, LR still performed best, with precision, recall, and accuracy values of 85.3%, 76.6%, and 83.0%, respectively, and an AUC of 0.86.Meanwhile, the patients had statistically significant age differences, so this clinical information was added to the training feature set to train the models and evaluate the effect of age. Table 5The p-value of the Delong test from the ROC curve for the LR models among the four CT image sets (three single phases and a combination of the three phases) is shown in Fig. In the external validation dataset, the performance of the five machine learning models using radiomic-clinical features is presented in Table In this study, CT radiomic features extracted from CT images have been utilized to differentiate between functioning and non-functioning adrenal adenomas using machine learning models. Differences in demographic and clinical characteristics were observed between the two groups. Ten discriminative features from three-phase CT images were identified and analyzed while differentiating between the two subtypes. The accuracy of the final prediction using LR can reach as high as 83.0%.Adrenal adenomas are common urinary tract tumors. For tumor-based diseases, patients and their families are concerned about effective treatment, and early diagnosis of the disease is of great importance for determining the proper method and timing of subsequent treatments .FAA and NAA require different follow-up treatments, including the type of medication and the need for surgery with its attendant risks. There are several difficulties with the current methods of clinical diagnosis. Radiologists cannot always make an accurate diagnosis directly from CT images, which can lead to unnecessary treatment . CurrentUsing our models described here, the accuracy of differentiating FAA from NAA was more than 80%. This method can help doctors quickly estimate the type of adrenal adenoma, rapidly determine the corresponding effective treatment plan, and minimize unnecessary lab testing of patients who do not present with hormonal imbalance. In addition, this method is completely non-invasive, simple, and fast. The only material required is the patient’s CT images, which are routinely collected in the clinic.Most of our patients with FAA and NAA were female, which is consistent with the results of previous studies showing that the incidence of adrenal adenomas is higher in women , 42. In Cluster Shade is a quantity that describes the skewness and uniformity of the GLCM, with higher values indicating greater asymmetry about the mean. The value of Cluster Shade in assessing FAA is higher than that for NAA, which indicates NAA has a more uniform gray level distribution in CT images. Because of the differences in tumor cells that make up FAA, tumor cell morphology may be heterogeneous, thus increasing the heterogeneity of FAA in histopathology , 46.SZNN is a measure of the variability of size zone volumes throughout the image, with a lower value indicating more homogeneity among zone size volumes in the image. The SZNN feature value for FAA was greater than for NAA, and therefore NAA was more homogeneous. The etiology of FAA includes extensive adrenal hyperplasia, which may show clinical, morphological, and molecular heterogeneity . Long RuFrom the experimental results, we have found that among the classification models trained after the fusion of equivalent features from the three phases, LR had the best performance, with an accuracy of 83.0%. Compared with the LR models that only used a single-phase feature, performance improved significantly . The Delong test  confirmeTable Second, more information about the tumor was obtained in our study by fusing features from non-contrast-, arterial- and venous-phase CT images. Koo et al.  analyzedThird, the model we developed can diagnose both FAA and NAA. At the same time, we collected patients’ CT data from two hospitals for validation. Previous studies have primarily focused on the distinction between benign and malignant adrenal adenomas , 51, whiThis study has a few limitations. First, although the number of cases of each subtype was larger than in previous studies, the sample size was relatively small, with about 100 NAA patients. Second, all patients were retrospectively registered from hospitals in the same region, and therefore the generalizability of the model is unclear. In the future, more data from multiple hospitals in multiple regions needs to be collected for testing and verification. Third, the final LR accuracy of the three-phase classification is 83.0%. Although it is a satisfactory result, the prediction would have been in error for nearly one-fifth of the patients with adrenal adenoma. We expect more high-quality CT images from different hospitals to be collected shortly, and advanced deep-learning methods may further improve the model’s predictive power. Additionally, more clinical non-image information can be used to optimize the model.The radiomic features from the lesion region in three-phase CT images can potentially suggest the functioning or non-functioning nature of adrenal adenoma. The discriminative features identified here may help in understanding the heterogeneity of adrenal adenoma. The resulting radiomic models can be a non-invasive, low-cost, and rapid method to reduce unnecessary testing in asymptomatic patients with incidentally discovered adrenal adenoma.


BackgroundThe aim of this study was to investigate the relationship between the triglyceride-glucose (TyG) index and peripheral artery disease.MethodologyThis was a single-center, observational, retrospective study that included patients evaluated with color Doppler ultrasonography. A total of 440 individuals, 211 peripheral artery patients and 229 healthy controls, were included in the study.ResultsThe TyG index levels were significantly higher in the peripheral artery disease group than in the control group . The multivariate regression analysis conducted to determine the independent predictors of peripheral artery disease revealed that age (odds ratio (OR) = 1.111, 95% confidence interval (CI) = 1.083-1.139; p < 0.001), male gender , diabetes mellitus , hypertension , coronary artery disease , white blood cell count , creatinine , and TyG index  were independent predictors of peripheral artery disease. The cut-off value of the TyG index in predicting peripheral artery disease was determined to be 9.06 with a sensitivity of 57.8% and a specificity of 70% .ConclusionsHigh TyG index values can be used as an independent predictor of peripheral artery disease. Peripheral artery disease is a commonly encountered disease in the population, usually with atherosclerosis as its etiology, with high morbidity and mortality . AccordiThe risk factors of atherosclerosis such as advanced age, hypertension, hyperlipidemia, diabetes, smoking, and chronic kidney failure are important in the development and course of peripheral artery disease . ParticuMany methods are used to measure insulin resistance. Although the gold standard method for the detection of insulin resistance is the hyperinsulinemic-euglycemic clamp technique, it is utilized in clinical studies rather than being used routinely because it is time-consuming and costly to be performed in clinical practice . Due to Doppler ultrasonography is a rapid, non-invasive test that can be applied bedside in the anatomical evaluation of peripheral arteries and in the determination of the morphology of artery stenosis. It provides anatomical and functional information in peripheral artery disease and has a sensitivity of 92% and a specificity of 97% in the prediction of artery stenosis .The most common symptom seen in peripheral artery disease is intermittent claudication . HoweverStudy design and participantsThis was a single-center, observational, retrospective study of patients with peripheral artery disease. We included 211 consecutive patients with a diagnosis of peripheral artery disease. A total of 229 subjects without peripheral artery disease served as the control group. All included patients visited either the Cardiology or Cardiovascular Surgery department at Bahçelievler State Hospital, Istanbul between October 01, 2017, and October 01, 2022.At the time of diagnosis, patients under the age of 18, those with malignancy, those with chronic kidney failure and chronic liver disease, pregnant women, those receiving antidiabetic and antihyperlipidemic therapy, and those with active infection or chronic inflammatory disease were not included in the study.The study conformed to the principles outlined in the Declaration of Helsinki and was approved by the local ethics committee of Istanbul Bakirkoy Dr. Sadi Konuk Training and Research Hospital .Data collectionHypertension was defined as systolic blood pressure  ≥140 mmHg or diastolic blood pressure  ≥90 mmHg in clinical measurements or the use of antihypertensive drugs . DiabeteA Toshiba Applio500 (TUS A500) ultrasonography device and an 11 MHz linear probe were used in the arterial Doppler assessment of the lower extremity of the patients. The patients were evaluated from the aorta distal to the ankle after resting for 15 minutes. The proximal assessment of the popliteal artery and trifurcation arteries was performed in the prone position, while other arteries were evaluated in the supine position. Maximum velocities, flow form, and spectral changes were analyzed in the Doppler ultrasonography assessment. The peak systolic velocity ratio was calculated by dividing the maximum velocity at the narrowest part of any stenotic segment by the maximal velocity at 1.5-2 cm proximal to the stenosis. A ratio of 2 or greater was regarded as severe stenosis (over 50%). The diagnosis of occlusion was made in the case of no flow in the artery .2.Blood samples were taken from the antecubital vein after 12 hours of fasting. The hematological parameters were determined using an XT-4000i Hematology Analyzer . The biochemical analyses to detect alanine aminotransferase, aspartate aminotransferase, creatinine, and lipid profile  were performed with the AU5800 Clinical Chemistry System . The following formula was used to calculate the TyG index: TyG index ln[TG (mg/dL) fasting blood glucose (mg/dL)/2] . Body maStatistical analysisAll statistical analyses were conducted using IBM SPSS Statistics version 22.0  and MedCalc version 12.3.0.0 software packages. Normally distributed numerical variables are presented as mean ± standard deviation, whereas those that were not normally distributed are presented as median (minimum-maximum). To compare two independent samples, the independent-sample t-test was used when the normality assumption was met, whereas the Mann-Whitney U test was performed when not. The categorical variables are presented as number and percentage values, and the Pearson chi-square test was employed to compare the groups in terms of categorical variables. Correlations between parameters were determined by the Pearson correlation test for the normally distributed variables and by the Spearman correlation test for the non-normally distributed variables. Univariate and multivariate regression analyses were performed to identify risk factors for peripheral artery disease. Receiver operating characteristic (ROC) analysis was conducted to determine the cut-off positivity value of the TyG index. A p-value of less than 0.05 was considered statistically significant.Demographic characteristics and laboratory results of the patients included in our study are presented in Table The presence of coronary artery disease p < 0.001), cerebrovascular disease (p = 0.019), diabetes mellitus (p < 0.001), hypertension (p < 0.001), and hyperlipidemia (p = 0.01) was higher in the peripheral artery disease group than in the control group , and TyG index  levels were significantly higher in the peripheral artery disease group than in the control group. There were no significant differences between the groups regarding other parameters , creatinine , triglyceride , C-reactive protein (CRP) , white blood cell (WBC) count  = 1.111, 95% confidence interval (CI) = 1.083-1.139; p < 0.001), male gender , diabetes mellitus , hypertension , coronary artery disease , WBC , creatinine , and TyG index  were the independent predictors of peripheral artery disease  = 0.689; 95% CI = 0.640-0.738; p < 0.001) , total cholesterol , low-density lipoprotein-cholesterol , WBC , CRP , and age , and negatively with high-density lipoprotein  (Table The main finding of our study is that the TyG index was higher in patients with peripheral artery disease than in patients in the control group. The relationship between the TyG index and cardiovascular diseases has been previously reported in various studies. In this study, with the use of multivariate analysis, we noted that a high TyG index value was an effective parameter in predicting peripheral artery disease.Atherosclerosis and the cardiovascular diseases it leads to are the most common causes of death worldwide . ChronicHyperinsulinemia and increased insulin resistance are known to play a role in the pathophysiology of atherosclerosis through more than one mechanism. These can be listed as the disruption of the balance between nitric oxide and endothelin-1, which are vasodilator and vasoconstrictor substances that play a role in the maintenance of vascular tone in endothelial cells, against nitric oxide; increased chronic inflammation; vascular smooth muscle cell proliferation; and increased connective tissue in the vessel wall ,26. PlasThe TyG index, which can be easily calculated from fasting glucose and triglyceride levels, is an effective parameter demonstrating insulin resistance. After being associated with insulin resistance, it has been shown that the TyG index also positively correlates with the development of type 2 diabetes . It is mThe relationship of the TyG index with atherosclerotic cardiovascular diseases has been demonstrated in many studies. In a study investigating the SYNTAX score and major adverse cardiovascular events of 438 patients with non-ST-segment elevation acute coronary syndrome, the TyG index was found to be an independent predictor of cardiovascular outcomes . In anotIn a meta-analysis of eight cohort studies that included 5,731,234 participants with no known prior atherosclerotic cardiovascular disease, high TyG index values were associated with increased stroke, atherosclerotic cardiovascular disease, and coronary artery disease, independent of age, gender, and diabetes status [Smoking is one of the most important preventable risk factors that play a role in the development of atherosclerosis. Endothelial damage and inflammation increase as a result of elevated oxidative stress due to smoking . With enDyslipidemia and hypertension are two important risk factors in the development of atherosclerosis and play an important role in cardiovascular diseases. Clinical studies have revealed that high serum cholesterol levels and hypertension are among the leading risk factors for peripheral artery disease, as in coronary artery disease . Every 4CRP is an acute-phase protein synthesized in the liver during infection and inflammation, and its role in the course of atherosclerosis, which is an inflammatory process, has been shown in numerous studies . In a stLimitationsThe biggest limitation of our study is that it was a single-center and retrospective study. Because insulin level was not routinely studied in patients, HOMA-IR values were not calculated, and their comparison with the TyG index results was not performed. Furthermore, grading peripheral artery disease in a larger sample group and revealing its variation with the TyG index could have strengthened our study.It is important to screen and detect at-risk individuals before atherosclerosis-related diseases and related complications occur for preventive cardiology. In our study, the TyG index, which is a predictor of atherosclerosis, was found to be significantly higher in patients with peripheral artery disease than those in the control group. These results suggest that patients with a high TyG index value may be at risk for peripheral artery disease. Using the TyG index, patients at risk of peripheral artery disease can be early detected, and a decrease in mortality and morbidity can be achieved by preventing related complications.