LMNA-related and unrelated Familial Partial Lipodystrophy.Lipodystrophies are a heterogeneous group of diseases characterized by the selective loss of subcutaneous adipose tissue and ectopic fat deposition in different organs, including the liver. This study aimed to determine the frequencies of liver steatosis (LS) and liver fibrosis (LF) in a sample of individuals with LMNA-related FPLD and 15 women with unrelated FPLD. LS and LF were assessed using transient elastography (TE) with FibroScan®. Anthropometric and biochemical variables were included in a multiple linear regression analysis to identify the variables that were independently related to liver disease.This cross-sectional study included 17 women with Regarding the presence of LF, 22 (68.2%) women were classified as having non-significant fibrosis, and 10 (31.8%) were classified as having significant or severe fibrosis. Regarding LS, only six women (20.7%) were classified as having an absence of steatosis, and 23 (79.3%) had mild to severe steatosis. After multiple linear regression, waist circumference  was found to be independently related to LS and LF. Among the biochemical variables, only triglyceride levels were independently related to LS but not LF.In women with FPLD, visceral fat accumulation appears to be the most important determinant of liver disease, including LF, rather than fat scarcity in the lower limbs. Familial Partial Lipodystrophy (FPLD) is a group of heterogeneous diseases characterized by selective loss of subcutaneous adipose tissue.Non-alcoholic fatty liver disease (NAFLD) is an important complication of FPLD that can develop early in the course of disease and may progress to end stage liver disease.Transient Elastography (TE) with FibroScan is a noninvasive method that can provide useful information on both the degree of liver steatosis (LS) and fibrosis (LF).Our study uses TE to determine the frequency of LS and LF in individuals with FPLD, and to determine which anthropometric/biochemical variables would correlate with LS and LF.Our findings suggest that waist circumference was a significant parameter that independently correlates with both LF and LS. These findings reinforce the role of excess visceral fat in addition to fat loss in the lower limbs in the severity of NAFLD in patients with FPLD. LMNA gene [Familial Partial Lipodystrophy (FPLD) is a group of heterogeneous diseases characterized by selective loss of subcutaneous adipose tissue and ectopic fat deposition in the liver, muscle, pancreas, and other organs, and are associated with metabolic repercussions of insulin resistance (IR), such as diabetes mellitus (DM), hypertriglyceridemia, and non-alcoholic fatty liver disease (NAFLD). Traditionally, they are classified according to the extent of body fat loss  and etiology (genetic or acquired) –3. AmongMNA gene , 2. In cMNA gene .Partial lipodystrophies usually present with the absence of fat in the limbs, hips, and buttocks, along with deposition of excess fat in the cervical, facial, and intra-abdominal regions. The lack of fat develops during childhood and/or puberty –5, and tAs expected, a background of IR and reduced ability to store triglycerides may predispose patients with lipodystrophy to a high prevalence of NAFLD . Indeed,Thirty-two women with FPLD were sequentially selected from the outpatient clinics of the Metabolism Unit of the State Institute of Diabetes and Endocrinology  from January 2020 to June 2021. Clinical diagnosis of FPLD phenotype was determined using criteria from previous reports [Deficiency of subcutaneous body fat  was considered after physical examination by two experienced physicians and confirmed with low skinfold thickness in the anterior thigh according to caliper measurements in men (≤ 10 mm) and women (≤ 22 mm). PCOS was defined according to the Rotterdam criteria with no other known causes. DM was identified as two fasting glucose measurements ≥ 126 mg/dl or use of antidiabetic agents, and glucose intolerance was characterized as fasting glucose ≥ 100 mg/dl (IGF) or glucose ≥ 140 mg/dl after the oral glucose tolerance test. Hypertriglyceridemia was diagnosed with triglycerides ≥ 150 mg/dl, and low HDL-cholesterol level was defined as < 50 mg/dl.2). The patients in this study had no evidence of other forms of liver disease and had alcohol consumption of < 40 g/week.Exclusion criteria were age under 18 years, pregnancy or breastfeeding, presence of acquired forms of lipodystrophy , and severe renal disease  sequencing of the entire coding region of the genes and the flanking intronic regions ABCA1 AGPAT2 AKT2 APOA5 APOC2 BSCL2 CAV1 CAVIN1 CFTR CIDEC CTRC CYP27A1 GPIHBP1 LIPA LIPE LMF1 LMNA LMNB2 LPL MFN2 PLIN1 POLD1 PPARG PRSS1 PSMB8 SMPD1 SPINK1 ZMPST). LMNA-related FPLD diagnosis was confirmed by molecular analysis of the LMNA gene – Sanger sequencing .FPLD-negative patients showed no mutations in the The study protocol was approved by the local ethics committee, and all of the subjects gave their written informed consent. Each patient underwent a physical examination was, and previous medical records were analysed to verify the historical details.2). Waist circumference was determined at the midpoint between the lowest rib and iliac crest. WHR was defined as the ratio of the waist girth to the largest circumference of the hip, measured at the greater trochanter. Skin thickness was assessed using standardized techniques with a Lange caliper  on the triceps and the anterior thigh on the right side of the body. The mean of three repeated measurements was calculated for each site [The following anthropometric data were recorded from all participants: body weight (kg), height (m), waist circumference, waist-to-hip ratio (WHR), and blood pressure. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters (kg/mach site .Blood samples were collected between 6:30 am and 8:00 am after overnight fasting (12 h). Plasma glucose levels were determined using the glucose-oxidase method. The cholesterol content of the lipoprotein fractions and triglycerides were measured enzymatically. Plasma leptin levels were determined by enzyme-linked immunosorbent assay (ELISA).Transient elastography was performed using FibroScan®. Participants were examined at the University Hospital of the Federal University of Rio de Janeiro, Brazil. The examinations were performed by a single experienced physician after four hours of fasting. At least ten measurements were obtained with the patient in the supine position.≥ 280 dB/m: S3—advanced steatosis. Fibrosis was classified as follows: LSM ≤ 6.9 kPa: F0/F1—absent or minimal fibrosis; 6.9 < LSM < 8.4: F2—moderate fibrosis; LSM ≥ 8.4: F3/F4—advanced fibrosis.Steatosis was quantified using the controlled attenuation parameter (CAP), and the following cut-offs were applied: CAP ≤ 248 dB/m: S0—steatosis absent; 248 < CAP ≤ 268 dB/m: S1—mild steatosis; 268 < CAP ≤ 280 dB/m: S2—moderate steatosis; CAP t-tests were used to compare parametric variables, and the Mann–Whitney test was used for nonparametric variables. The strength of the linear relationship between the two continuous variables was evaluated using Pearson’s correlation coefficient or Spearman’s correlation coefficient. Multiple linear regression was used to identify the variables independently related to liver steatosis (CAP) and liver stiffness (LS). The level of statistical significance was 5%.Statistical analysis was performed using GraphPad InStat 3.00 for Windows 95 . Parametric data are presented as mean ± standard deviation (SD), and nonparametric data are presented as median . Unpaired LMNA-related and 15 with unrelated FPLD). The mean age of the sample was 49.1 ± 11.7 years old; the median BMI was 25.5 kg/m2 ; mean WC and hip circumference were 95.2 ± 14.6 cm and 96.0 ± 14.5 cm, respectively; and median WHR was 0.96 . The individuals with LMNA-related FPLD belonged to eight families. Twelve women were heterozygous for c.1444 C > T variant p.R482W, three individuals harbored c.1445G > A p.R482Q, and one harbored the heterozygous variant c.1396AOG p.N466D, all in exon 8. One woman had a heterozygous variation c.1744 C > T p.R582C in exon 11. Some of these variants have been previously reported [A total of 32 women were included  and non-affected areas, and metabolic complications related to severe IR. Most patients presented with DM (n = 12), hypertriglyceridemia, and acanthosis. None of them showed mutations in LMNA gene.Fifteen women were included in the Quantification of steatosis revealed that six individuals (20.7%) had no steatosis (S0), two individuals (6.9%) had mild steatosis (S1), one individual (3.4%) had moderate steatosis (S2), and 20 individuals (68.9%) had severe steatosis (S3). Data from 3 patients were missing. Fibrosis evaluations showed 22 (68.2%) individuals with nonsignificant fibrosis (F0/F1), three individuals (9.4%) with moderate fibrosis (F2), and seven individuals (21.8%) with advanced fibrosis (F3/F4).r = .46; P = .015; Fig. r = .52; P = .0056). In contrast, no correlation was found between CAP and age , BMI , or hip circumference . After multiple linear regression analysis, only WC remained independently related to CAP (P = .023).Correlation analysis was used to determine the anthropometric parameters associated with liver steatosis. Data were not available for five individuals. A positive correlation was found between CAP and both WC , WC , and WHR . A borderline significant relationship was found between LSM and age . After multiple linear regression, only WC remained independently related to LSM (P = .006).The same analysis was conducted for patients with liver fibrosis. Data were not available for two individuals. A positive correlation was found between LSM and BMI  or HDL cholesterol . However, a positive correlation was found between CAP and triglycerides . In multiple linear regressions, both WC and triglycerides, as independent variables, were independently associated with liver steatosis . Regarding fibrosis, a significant correlation was found between liver stiffness and both leptin  and HDL cholesterol  but not with triglycerides . In a multiple linear regression analysis using WC, leptin, and triglycerides as independent variables, only WC remained independently related to liver stiffness (P = .006).Biochemical variables were also analyzed to determine whether laboratory parameters were associated with liver steatosis and fibrosis. Regarding steatosis, no correlation was found between CAP and leptin  has already been partially described in lipodystrophy patients . Interes(P = .006). Notably, our patients were leaner (median BMI 25.5 versus 27.3 kg/m2) and presented a lower WHR (0.96 versus 0.99), with less metabolic derangements, as compared to this trial cohort.Some case series have described the frequency and severity of NAFLD in patients with FPLD. In a descriptive analysis of a trial cohort of 23 individuals with partial lipodystrophy (seven with FPLD type 2), Ajluni et al.  found a 2 but with excess visceral fat, noting that this appears to be a distinct group of patients with a particular pathophysiology, including genetics [Although the current data cannot prove causality, our study reinforces the importance of central fat distribution in NAFLD pathogenesis in a FPLD population. A recent meta-analysis by Pang et al. investigated the association between central and general obesity and NAFLD in a non-lipodystrophy population. They found that WC was a better predictor for NAFLD than BMI, although both were associated with an increased risk of NAFLD . In anotgenetics . Finallygenetics . AltogetLMNA-linked group. In contrast, Malandrino et al. [Conflicting evidence exists regarding how visceral fat affects metabolic disruption in patients with lipodystrophy. Guillín-Amarelle et al.  comparedo et al.  did not Additionally, Lotta et al.  found thOur study has several limitations. First, a liver biopsy was not performed to confirm liver steatosis or fibrosis. However, the use of TE with a controlled attenuation parameter has demonstrated good accuracy in quantifying the degrees of liver steatosis and fibrosis . Second,Our data suggests that NAFLD is highly prevalent in the FPLD population. This reinforces the importance of early screening of affected patients. The strength of this study was the use of a non-invasive method to screen for both LS and LF. However, further studies evaluating patients with FPLD should be conducted to validate this tool.In conclusion, it seems plausible to consider that among the predominant mechanisms described in the development of NAFLD in FPLD patients, visceral fat accumulation might be an important driver of disease progression.


Timely and successful extubation is an essential step forward in clinical practice to minimize complications of mechanical ventilation and unsuccessful weaning processes. Thus, research into predictive factors of weaning outcome to optimize spontaneous breathing trial (SBT) precision before extubation is critical in intensive care practices. In this study, we aimed to investigate the predictive factors of the weaning outcome before and during SBT in mechanically ventilated patients.2 and PaO2 levels, respiratory rate (RR), SpO2, mean arterial pressure (MAP), heart rate (HR), and central venous pressure (CVP) values at the start of SBT, 3 min later, and at the end of SBT were measured. These values, along with the patients' clinical characteristics, were then investigated to determine if there was any correlation between these variables and the weaning outcome.In this cross‐sectional study, 159 mechanically ventilated patients who were eligible for SBT were enrolled. Of these patients, 140 had successful extubation, whereas the remainder failed. Each patient's PaCO2, SpO2, duration of mechanical ventilation (MV), length of intensive care unit (ICU) stay, and SBT process, as well as underlying disease, was positively correlated with extubation/weaning failure. While age, gender, vital signs , sequential organ failure assessment (SOFA), and acute physiology and chronic health evaluation (APACHE) scores had no significant correlation with patients' extubation outcomes.Our analysis revealed that increase in CVP, independent of hemoglobin (Hb) concentration, PaOAccording to our findings, integrating CVP assessment into SBT besides routine indices measurement and monitoring can be considered for the prediction of weaning outcome in critically ill mechanically ventilated patients. SBT estimates the risk of unsuccessful weaning by analyzing the physiological responses to the respiratory effort induced by the cessation of positive pressure breathing during a 30–120‐min period.Cardiovascular dysfunction is being recognized as a frequent cause of weaning failure that can be successfully treated. Clinically, it may be challenging to diagnose and distinguish cardiovascular pathophysiology as a primary risk factor or contributor to weaning failure from noncardiac causes, demanding high suspicion for its early diagnosis and intervention.Given the above reflection, we aimed to investigate the predictive factors of the weaning outcome before and during SBT in mechanically ventilated patients, with the hypothesis that an early rise in CVP during SBT might be a signal of heart failure and unsuccessful extubation/weaning.22.1This cross‐sectional study was carried out on critically ill patients undergoing mechanical ventilation who had been hospitalized for more than 48 h in the ICUs of Shohada and Imam Reza hospitals . The protocol of this study was reviewed and approved by the Ethics Committee of Tabriz University of Medical Sciences (IR.TBZMED.REC.1399.364), and all participants or their next of kins were fully informed of the information and provided written consent.2.22 ≤ 50%, PaO2/FiO2 > 200, positive end‐expiratory pressure (PEEP) <6 cmH2O during 4–6 h before SBT), and an adequate cough reflex, arterial pH ≥ 7.35, the presence of a CVP catheter, and hemoglobin (Hb) above 10 g/dL. Conversely, age less than 18 years, persistent neurological impairment with a low level of consciousness, uncontrolled infection/sepsis, unstable hemodynamics, medium to high‐dose vasopressor‐dependence, need for norepinephrine more than 0.3 μg/kg, presence of tracheostomy tube, and a do‐not‐resuscitate (DNR) order were all exclusion criteria.We recruited 159 patients based on the following inclusion and exclusion criteria. The main criterion for inclusion in this study was that the patient met the clinical criteria for weaning or SBT. Additional inclusion criteria were stable hemodynamics, assisted mechanical ventilation (FiO2.32O and PEEP: 5–6 cmH2O). SBT was performed with a T tube connected to oxygen while the patient was supine and at 30°, with no change in the patient's position during SBT. The co‐executor of the protocol determined the duration of the T tube at 120 min, and if tolerated, the patient was prepared for extubation. If the patient exhibited signs of intolerance during this period, SBT was discontinued and the patient was returned to PSV. Clinical criteria used to determine whether SBT was successful were a respiratory rate (RR) <35, less than a 20% rise over baseline heart rate (HR), oxygen saturation (SpO2) >90%, any change less than 25% in blood pressure, and the absence of signs of increased respiratory work or respiratory distress . The decision to extubate a patient after successful SBT and optimal consciousness was made based on the patient's clinical status. If the patient's condition remained stable after extubation for 48 h, the extubation was considered successful, and clinical follow‐up was discontinued after 48 h. Conversely, if extubation/weaning failed within 48 h, patients were re‐intubated, and the reasons for the need for re‐intubation, the duration between the patient's spontaneous breathing and the need for mechanical ventilation, PaCO2 and PaO2, RR, SpO2, mean arterial pressure (MAP), HR, and CVP variables were evaluated and recorded during re‐intubation and after intubation. Also, oxygen therapy was performed with conventional O2 therapy. After extubation, all patients received O2 via face mask . If the condition worsened, they would receive noninvasive ventilation or would get intubated and undergo mechanical ventilation, depending on their condition.Patients who were eligible for SBT were ventilated with pressure support ventilation (PSV) and PEEP before the procedure, as per the department's protocol , length of intensive care unit (ICU) stay, duration of mechanical ventilation, Hb concentration, acute physiology and chronic health evaluation (APACHE) score, sequential organ failure assessment (SOFA) score, HR, RR, MAP, SpO2, and CVP. Statistical analyses were performed using the statistical software package SPSS version 23.0 . The p < 0.05 was considered statistically significant.The normal distribution of the data was evaluated using the Kolmogorov–Smirnov test. Parametric variables were expressed as mean ± SD (standard deviation) and nonparametric variables were expressed as a median. As well, nominal variables were expressed as percentages. To compare parametric and nonparametric variables, the Mann–Whitney 3A total of 159 patients were recruited, comprising 110 (69.2%) men and 49 (30.8%) women. Patients ranged in age from 28 to 78, with a mean age of 62. The baseline characteristics of patients are presented in Table p = 0.256), age (p = 0.69), and BMI (p = 0.81) had no significant impact on extubation outcome. However, in contrast to diagnosed disease (p = 0.734), patients' underlying comorbidities (p = 0.02) had a significant impact on the extubation outcome. Also, compared to patients with successful extubation, ICU length of stay (p = 0.007), duration of mechanical ventilation (p = 0.001), and SBT duration (p = 0.01) were significantly greater in patients with extubation failure. On the other hand, the Hb concentration (p = 0.02) was significantly higher in successful extubation patients compared to extubation failure patients. While, there was no significant difference found in APACHE score (p = 0.59), SOFA score at baseline (p = 0.64) and extubation (p = 0.13), and CVP during mechanical ventilation (p = 0.56) among patients with successful and failed extubation.According to our analysis, patients' gender  and PaO2 (p = 0.002) were substantially higher in patients who were successfully extubated compared to their unsuccessful counterparts, but there was no significant difference in their values at baseline and 3 min after SBT initiation. Likewise, in extubation failure patients, the CVP was significantly higher 3 min after SBT started (p < 0.0001) and at the end of SBT (p < 0.0001) compared to patients with successful extubation , so our results may not be applicable to that particular subset of patients.52, SpO2, duration of MV, length of ICU stays, and SBT process, as well as an underlying disease were associated with extubation/weaning failure. It was shown that age, gender, vital signs , SOFA, and APACHE scores had no significant correlation with patients' extubation outcome. The success or failure of SBT is based on a combination of objectively measured and clinically assessed parameters. The integration of routine CVP measurement in this algorithm should be investigated further in future studies to establish its potential to predict the chance of an earlier diagnosis of patients who would have a failed weaning after SBT. Furthermore, despite limitations, these findings may enable clinicians to execute more timely and effective interventions to maximize the chance of weaning success.In summary, in this cross‐sectional study of mechanically ventilated patients who were eligible for SBT, rises in CVP independently of Hb concentration, PaOAli Akbar Ghamari: Conceptualization; data curation; investigation; methodology. Keivan Amini: Conceptualization; data curation; investigation; methodology. Amin Daei Sorkhabi: Conceptualization; data curation; investigation; methodology; writing—original draft; writing—review & editing. Aila Sarkesh: Investigation; writing—original draft; writing—review & editing. Seyed Hadi Saghaleini: Investigation; writing—review & editing. Roghayeh Asghari: Investigation. Mansour Rezayi: Conceptualization; writing—review & editing. Ata Mahmoodpoor: Supervision; writing—review & editing.The authors declare no conflict of interest.All procedures were carried out with the approval of the Ethics Committee of Tabriz University of Medical Sciences (IR.TBZMED.REC.1399.364).The lead author Ata Mahmoodpoor affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned  have been explained.


The current study aimed to examine the relationship between early adaptive schemas and eating disorder symptomatology in adults.M = 25.70, SD = 7.04). Participants completed an online questionnaire, which included The Young Positive Schema Questionnaire (YPSQ), Eating Disorder Examination‐Questionnaire (EDE‐Q) and demographic measures.A cross‐sectional, correlational design was used to collect data from 352 females and 36 males aged between 18 and 49 years (Four separate hierarchical multiple regression analyses showed that high levels of Healthy Boundaries and low levels of Optimism significantly predicted lower Restraint, Eating Concern, Shape Concern and Weight Concern scores. Additionally, higher scores in Emotional Openness and Social Belonging significantly predicted lower Eating Concern, while higher scores in Self‐Care significantly predicted lower levels of Shape Concern.The findings highlight the protective function that certain early adaptive schemas may play in mitigating eating disorder symptomatology. Moreover, the findings allude to potential modifiable therapy targets in the treatment of eating disorders. Further research is needed to investigate any differences in early adaptive schemas between eating disorder diagnoses. Higher Optimism scores predicted worse Restraint, Shape Concern, Weight Concern and Eating Concern scoresHigher scores in Healthy Boundaries, Emotional Openness, Social Belonging and Self‐Care predicted lower scores in a variety of EDE‐Q outcome measures, including Restraint, Shape Concern, Weight Concern and Eating ConcernA unique set of early adaptive schemas may mitigate the development of pathological eating cognitions and behaviours1Eating disorders are accompanied by some of the highest fatality rates across mental disorders . Early models of CBT emphasized the roles in which disordered eating and maladaptive attitudes towards weight and shape contributed to the maintenance of eating disorder pathology  for some eating disorder presentations such as bulimia nervosa and binge eating disorder, long‐term treatment outcomes have remained inconsistent  and body mass index (BMI) ranged from underweight (11.94 kg/m2) to obese . More than two‐thirds of participants had completed vocational education or training such as a diploma (14.7%), bachelor degree (40.2%), master's degree (14.2%) or PhD (2.3%), while a quarter of participants had completed secondary school (25.8%) and 2.8% had completed Year 10 as their highest level of education. Most participants identified as North American (47.7%), while other participants identified as Australian (14.4%), British (11.2%), European (7.4%) or other nationality (6.3%). Just over half of participants (50.8%) reported having a current eating disorder diagnosis from a registered health professional, although only 14.4% were receiving treatment for their diagnosis, while nearly a quarter (24.2%) had previously received treatment and more than half (57.7%) had never received treatment.Participants were 36 males (9.3%) and 352 females (90.7%) recruited from social media. Age ranged from 18 to 49 years  to a score of 6 (Describes me perfectly). Sample items include the following: “I like to do well but don't have to be the best”  and “I trust that people won't leave me, do I don't act needy and drive them away” (Stable Attachment). Scores are averaged for the total scale and each subscale, with higher scores reflecting greater endorsement of positive schemas. The YPSQ has demonstrated moderate internal consistency in nonclinical samples, with Cronbach's alpha ranging from .62 to .93  to 6 (Every day). Sample items include the following: “Have you been deliberately trying to limit the amount of food you eat to influence your shape or weight (whether or not you have succeeded)?” (Restraint) and “Have you had a definite fear of losing control over eating?” (Eating Concern). Scores are averaged to obtain four subscale scores and a global score, with higher scores indicating more severe eating disorder pathology. The measure also addresses key behavioural aspects of eating disorders, including reported frequency of objective bingeing and purging episodes over a 28‐day period, although these items were not reported in the present study. The EDE‐Q has shown moderate internal consistency in women with various eating disorder diagnoses; Cronbach's alpha ranged from .58 to .78 for the Restraint subscale, .44 to .78 for the Eating Concern subscale, .68 to .85 for the Shape Concern subscale and .51 to .76 for the Weight Concern subscale . To maintain confidentiality, prize draw was via an external survey link, and the winner was chosen randomly by an individual who was independent from the current study.3.5p < .05. Statistical Package for the Social Sciences  program was used for all statistical analyses. To assess whether early adaptive schemas negatively predicted eating disorder symptomatology, four separate hierarchical multiple regression analyses were conducted. To control for their possible influence on the outcome variable, age and BMI were entered in the first block, following previous eating disorder research  was considered adequate given the analysis indicated that 143 would be the required sample to detect a medium effect size (ƒ2 = 0.15) using standard alpha (α = .05), power of .80 and 16 predictor variables. Prior to conducting the primary analyses, data were screened for univariate and multivariate outliers and violations of normality. The assumptions of linearity, homoscedasticity, collinearity, independence of errors and multivariate normality were met.An a priori power analysis was calculated using G*Power , while the EDE‐Q subscales exhibited intercorrelations ranging from .69 to .80 (p < .01).Descriptive statistics and correlations between study variables are presented in Table 4.2Four separate hierarchical multiple regression analyses were conducted to assess which, if any, early adaptive schemas predicted eating disorder symptomatology, as measured by the four EDE‐Q subscales.4.2.1R2 = .04, F = 15.61, p < .001. The addition of the 14 early adaptive schema subscales in the second block significantly accounted for an additional 16% of variance in Restraint scores, ∆R2 = .16, ∆F = 5.25, p < .001. The overall model significantly predicted Restraint, R2 = .20, F = 6.10, p < .001. By Cohen's . Of the 14 subscales, Optimism was the strongest predictor, accounting for 1.3% of significant unique variance in Restraint scores. That is, increased Optimism was associated with more Restraint. All other subscales did not contribute significantly to the variance in Restraint scores.In predicting Restraint, as shown in Table s Cohen,  conventi4.2.2R2 = .10, F = 41.95, p < .001. The addition of the 14 early adaptive schema subscales significantly accounted for an additional 27% of variance in Eating Concern, ∆R2 = .27, ∆F = 11.04, p < .001. The overall model significantly predicted Eating Concern, R2 = .37, F = 14.12, p < .001, Cohen's f2 = .57. Of the 14 subscales, Optimism, Emotional Openness and Spontaneity, Social Belonging and Healthy Boundaries were the strongest predictors, accounting for 1.2%, 1%, 1% and 2.3% of significant unique variance in Eating Concern scores, respectively. That is, increased Emotional Openness and Spontaneity and Healthy Boundaries were associated with less Eating Concern, while higher Optimism was associated with greater Eating Concern. All other subscales did not contribute significantly to the variance in Eating Concern scores.In predicting Eating Concern, as shown in Table 4.2.3R2 = .03, F = 12.89, p < .001. The addition of the 14 early adaptive schema subscales significantly accounted for an additional 31% of variance in Shape Concern, ∆R2 = .31, ∆F = 12.36, p < .001. The overall model significantly predicted Shape Concern, R2 = .34, F = 12.75, p < .001, Cohen's ƒ2 = .52. Of the 14 subscales, Optimism, Healthy Boundaries and Self‐Care were the strongest predictors, significantly accounting for 1.2%, 1.4% and 1% of unique variance in Shape Concern scores, respectively. That is, greater Healthy Boundaries and Self‐Care scores were associated with less Shape Concern, while higher Optimism was associated with greater Shape Concern. All other subscales did not contribute significantly to the variance in Shape Concern scores.In predicting Shape Concern, as shown in Table 4.2.4R2 = .03, F = 12.24, p = .001. The addition of the 14 early adaptive schema subscales significantly accounted for an additional 28% of variance in Weight Concern, ∆R2 = .28, ∆F = 10.68, p < .001. The overall model significantly predicted Weight Concern, R2 = .31, F = 11.07, p < .001, Cohen's ƒ2 = .45. Of the 14 subscales, Optimism and Healthy Boundaries were the strongest predictors, significantly accounting for 1.1% and 1.5% of unique variance in Weight Concern scores, respectively. That is, increased Healthy Boundaries was associated with less Weight Concern, while higher Optimism was associated with greater Weight Concern. All other subscales did not contribute significantly to the variance in Weight Concern scores.In predicting Weight Concern, as shown in Table 5To our knowledge, this is the first study to investigate the relationship between early adaptive schemas and eating disorder symptomatology in adults and provides a preliminary contribution to the understanding of how positive beliefs may be protective against eating disorder cognitions and behaviours. The findings indicated that five of the 14 early adaptive schemas predicted eating disorder outcome measures. In support of the exploratory hypothesis, higher levels of Healthy Boundaries, Emotional Openness and Spontaneity, Social Belonging and Self‐Care predicted lower levels of eating disorder symptoms across various EDE‐Q subscales. Unexpectedly, higher levels of Optimism were associated with worse eating disorder pathology across all subscales. Overall, the findings provide evidence for certain early adaptive schemas as novel concepts that may mitigate the development of cognitions and behaviours associated with eating disorder symptomatology.Given the paucity of research examining early adaptive schemas and markers of eating disorder pathology, the findings may be viewed through the lens of positive clinical psychology and schema theory. In general, the findings partially align with the body of schema literature in the eating disorder research field. While the present study identified five of the 14 early adaptive schemas as significant predictors of various eating disorder outcomes, previous research has consistently reported strong positive associations between the majority of early maladaptive schemas, except Entitlement and various eating disorder measures  were associated with worse eating disorder psychopathology, which is not supported by previous research. For example, a recent study found that optimistic individuals reported lower levels of cognitive restraint and emotional eating and had a lower risk of developing an eating disorder (Robert et al., 5.1Several limitations need to be considered in the present study. First, the correlational study design indicates that causation and direction of relationships cannot be inferred. Although schema theory proposes that schemas are formed in early childhood and adolescence, it may be the case that the development of weight and shape‐related beliefs occurred prior to the development of early adaptive schemas. This is especially relevant, given that children are being exposed to body‐related attitudes via parents and media at younger ages (Daragnova, Due to the exploratory nature of the present study, differences in early adaptive schemas between eating disorders diagnostic groups were not examined. Given the differences in schema processes between diagnostic groups (e.g., Waller et al., Finally, it should be highlighted that although a combined predictive variance of between 16% and 31% was observed for all subscales, each early adaptive schemas accounted for less than 2% of the variance in eating disorder symptomatology scores. Little is known about the nature of the relationship between positive psychological constructs and eating disorder outcomes. Despite a large body of schema therapy research validating the presence of early maladaptive schemas in individuals with eating disorders, the present findings concerning the predictive nature of specific early adaptive schemas on eating disorder outcomes remain putative due to the complexity of factors that contribute to eating disorder aetiology and maintenance. For example, while disrupted attachment relationships and unmet emotional needs have been consistently implicated in eating disorder pathology, research has identified factors such as genetics and trait perfectionism as potential covariates. Moreover, the present findings should not be exclusively interpreted in the context of schema therapy, especially given Louis et al.  suggesti5.2Within the burgeoning field of positive psychology, the concept of early adaptive schemas offers a complementary conceptualization to the existing knowledge of eating disorder aetiology and treatment. Early maladaptive schemas provide insight into unmet core emotional needs in early life that may contribute to the development of unhealthy shape and weight‐related beliefs. In contrast, early adaptive schemas shed light on significant positive childhood and adolescent experiences that may contribute to the mitigation of eating disorder symptomatology and possibly development of positive beliefs about one's body and shape. This study provides preliminary evidence of specific early adaptive schemas associated with lower levels of eating disorder symptomatology. Within the context of the treatment setting, early adaptive schema measures may function as a complementary therapeutic target, alongside early maladaptive schemas. Moreover, focussing on early positive experiences that have contributed to adaptive unconditional core beliefs may improve weight‐ and shape‐related beliefs about oneself in the treatment of eating disorders.6The present study found that greater Healthy Boundaries were associated with lower levels of eating disorder psychopathology. In contrast, greater Optimism was associated with worse eating disorder psychopathology. Moreover, Emotional Openness and Social Belonging and Self‐Care were important in predicting lower levels Eating Concern and Shape Concern, respectively. Given that this is the first study to demonstrate the relationship between early adaptive schemas and eating disorder cognitions and behaviours, this evidence, although putative, sets the stage for future research to identify causal effects of early adaptive schemas on eating disorder symptomatology.The authors wish to declare that no conflict of interest exists.


Few studies have investigated the efficacy of comprehensive therapies, including immunotherapy, for gastric cancer with synchronous liver metastases (GCLM). We retrospectively compared the effect of immunochemotherapy and chemotherapy alone as conversion therapies on the oncological outcomes of patients with GCLM.n = 33) and chemotherapy‐alone (n = 67) groups.The clinicopathological data of 100 patients with GCLM from February 2017 to October 2021 at our institution were retrospectively analyzed. Patients were divided into immunochemotherapy (p = 0.029) and disease control rate  than the chemotherapy group. The immunochemotherapy group showed better tumor regression in the gastric mass, metastatic lymph nodes, and liver lesions than the chemotherapy group. Ten (30.3%) patients in the immunochemotherapy group and 13 (19.4%) patients in the chemotherapy group underwent surgery after conversion therapy. However, the difference was not statistically significant. The overall survival (OS) and progression‐free survival (PFS) rates were better in the immunochemotherapy group than in the chemotherapy group. Treatment‐related adverse events occurred in 24 (72.7%) and 47 (70.1%) patients in the immunochemotherapy and chemotherapy groups, respectively.Baseline clinicopathological data did not differ significantly between the two groups. The immunochemotherapy group had a higher overall response rate (59.4% vs. 44.0%, As a conversion therapy for GCLM, immunotherapy yielded better primary and metastatic tumor regression and survival benefits, with no increase in adverse events compared to chemotherapy. As a conversion therapy for GCLM, immunotherapy yielded better primary and metastatic tumor regression and survival benefit, with no increase in adverse events than did chemotherapy. Consequently, based on the MDT concept, this study aimed to explore the efficacy, safety, and extent of tumor response to immunotherapy combined with chemotherapy in patients with GCLM and the value of surgical intervention after conversion therapy to provide a high‐level scientific reference for comprehensive treatment of such patients.22.1This retrospective study included 166 patients diagnosed with GCLM between February 2017 and October 2021 at the Department of Gastric Surgery of Fujian Medical University Union Hospital. The inclusion criteria were as follows: pathological diagnosis of GC via surgery/endoscopic biopsy; liver metastasis confirmed on abdominal contrast‐enhanced computed tomography (CT), hepatic magnetic resonance imaging (MRI), positron emission tomography (PET)‐CT, or liver biopsy; and the presence of complete clinical and follow‐up data. The exclusion criteria were as follows: palliative resection after admission, incomplete pathological data, metachronous liver metastasis, missing survival data, and refusal to undergo treatment. Finally, 100 patients with GCLM were included, of whom 33 and 67 were classified into immunochemotherapy and chemotherapy groups, respectively .2.3The immunochemotherapy group included patients who received immune checkpoint inhibitors consisting of PD‐1 inhibitors  at least once as conversion therapy. The chemotherapy group included patients who received chemotherapy alone, mainly based on 5‐FU, as a conversion therapy. Patients with HER2 positive receive additional treatment with trastuzumab therapy. Before deciding on the chemotherapy regimen, all patients should be informed of the relevant treatment benefits, risks, and costs, and each patient has the right to choose whether to use PD‐1 inhibitors: immunochemotherapy or chemotherapy alone. Informed consent was obtained from all patients at our center before receiving treatment.Tumor response was assessed using CT, MRI, or PET‐CT every two to three treatment cycles. The ongoing chemotherapy regimen was continued in patients with stable disease (SD) but was switched to second‐line chemotherapy in patients with progressive disease (PD). Resectability of the gastric primary tumor, tumor activity of the metastatic lymph nodes, and liver metastatic lesions were continuously assessed during conversion therapy. Second‐line chemotherapy regimens were administered to patients with progressive tumors unsuitable for surgical resection.2.4Tumor response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1The MDT team assessed the tumor resectability based on patient information, including imaging data and individual patient characteristics. The team consisted of two experienced gastrointestinal surgeons: a hepatic surgeon, a gastroenterologist, an interventional physician, an oncologist, a radiotherapy physician, a pathologist, and a radiologist.2.5Currently, there are no guideline recommendations and no multicenter prospective clinical trial data to support the indication of radical surgery for GCLM. According to references and the experiences of our center,2.6According to previous studies, the cutoff values for the maximum diameter of liver metastases and the number of liver metastases were 4 cm and three lesions, respectively.t‐test or the Mann–Whitney U‐test. We used the chi‐squared test or Fisher's exact test to compare the categorical variables of clinical characteristics. Statistical analyses were performed using SPSS 22.0 (SPSS Inc.) and R software (version 3.5.1). The association between relevant clinicopathological variables and OS was assessed using the Cox proportional hazards model. Stepwise backward variable removal was applied in the multivariate model to identify the most accurate and parsimonious set of predictors. Statistical significance was set at p < 0.05.Continuous variables were analyzed using Student's 33.1p > 0.05). The median follow‐up time was 18 months (range: 1–58).Table 3.2n = 2), 38.0% (n = 38), 12.0% (n = 12), and 39.0% (n = 39), respectively. Nine (9%) patients were not evaluated. The overall response rate (ORR) was 40% (n = 40), and the disease control rate (DCR) was 52% (n = 52). In the immunochemotherapy group, the CR, PR, SD, and PD incidence rates were 3.0% (n = 1), 54.5% (n = 18), 12.1% (n = 4), and 27.3% (n = 9), respectively. One (3%) patient could not be evaluated. In the chemotherapy group, the CR, PR, SD, and PD incidence rates were 1.5% (n = 1), 29.9% (n = 20), 11.9% (n = 8), and 44.8% (n = 30), respectively. Moreover, eight (11.9%) patients could not be evaluated. There were significant differences in the ORR  and DCR  between the immunochemotherapy and chemotherapy‐alone groups. The immunochemotherapy group showed better overall remission of primary GC, metastatic lymph nodes, and liver metastatic lesions than the chemotherapy‐alone group . There was no significant difference in the surgical rates between patients with a maximum liver metastasis size of ≤4 and >4 cm , between patients with less than three metastatic lesions and equal to or more than three liver metastatic lesions , and between patients with less than two metastatic organs and equal to or more than two metastatic organs    in the immunochemotherapy group and 13 (19.4%) in the chemotherapy group, with no significant difference  Figure . All 23 5) Table .3.4p < 0.05)  . For multiple‐site metastases, the OS and PFS of the immunochemotherapy group were similar to those of the chemotherapy group . Survival curves (OS and PFS) of patients who receiving ≥3 cycles of conversion therapy were significantly better than those of <3 cycles whether either all patients or subgroups (p < 0.05)  Figure . The OS ) Figure . Figure ) Figure .Table 3.5p < 0.05). Further multivariate analysis suggested that immunochemotherapy, CRP ≤ 0.5, differentiated histological type, surgical resection, and at least three cycles of conversion therapy were independent protective factors for OS . Univariate analysis revealed that immunochemotherapy, ASA score, tumor location, surgical resection, and number of conversion therapies were significant factors for PFS (p < 0.05). Further multivariate analysis showed that immunochemotherapy and surgical resection were independent protective factors for PFS   level, histological type, surgical resection, maximum size of liver metastatic lesions, and number of conversion therapies were significant factors for OS  Table .3.6Treatment‐related adverse events are shown in Table 4The liver is the main target organ for the hematogenous metastasis of GC. Shitara et al. summarized 67 randomized clinical trials, including 12,656 patients with AGC, and found that the incidence rate of liver metastasis was 44%.In this study, we compared the oncological efficacy of immunochemotherapy and chemotherapy in patients with synchronous GCLM. The results confirmed that the overall efficacy against GCLM, ORR, and DCR in patients who received immunotherapy was significantly better than that in patients who received chemotherapy alone. In 2018, Bando et al. conducted a Phase II study on paclitaxel combined with ramucirumab and found that the ORR of patients with advanced unresectable GC who received immunotherapy combined with chemotherapy reached 54.8%.In this study, patients who received immunochemotherapy had significantly better OS and PFS rates than those who received chemotherapy alone. Further analysis showed that among patients with liver metastases only, those receiving immunochemotherapy had better OS and PFS than those receiving chemotherapy alone. Simultaneously, immunochemotherapy and surgical treatment were independent protective factors for prognosis, indicating that surgical resection after immunochemotherapy could improve the survival of such patients. The wider the spread, the poorer the prognosis. An appropriate systemic treatment regimen can achieve tumor downstaging and micrometastasis killing, thereby increasing the likelihood of radical resection of the primary tumor. As a novel method, immunotherapy can rapidly attack and effectively shrink target lesions so that additional or better therapeutic options can be explored or implemented. Gastric tumor resection can greatly reduce the macroscopic and potentially immunosuppressive tumor burden, eliminate the source of new metastases, and improve the symptoms caused by gastric injury, thereby further promoting the efficacy of immunotherapy and chemotherapy.This study has several limitations. First, this was a single‐center retrospective study, which may have inherent selection bias, including some patients with distant metastasis other than liver metastasis, response to chemotherapy, and performance status. Such bias might have affected the results. Second, many studies have confirmed that perioperative chemotherapy can improve the surgical resection and survival rates. However, there is no standard chemotherapy strategy for patients with GCLM, which leads to inconsistent chemotherapy regimens. Patients in the immunochemotherapy group did not receive PD‐1 inhibitors in any cycle. Finally, in this study, HER2 data for some patients could not be obtained, and combined positive score measurements were not conducted. However, the ATTRACTION‐2 study showed that the PD‐1 inhibitor group had excellent OS regardless of PD‐L1 expression.5Immunochemotherapy showed acceptable safety and good oncological efficacy in patients with synchronous GCLM and could significantly improve the long‐term prognosis of such patients. Moreover, immunotherapy combined with chemotherapy can be used to provide an opportunity for surgical resection. In clinical practice, individualized treatment should be administered to patients with synchronous GCLM.Guang‐Tan Lin: Writing – review and editing (lead). Zhi‐Yu Liu: Writing – original draft (lead). Zhi‐Xin Shang‐Guan: Software . Gui‐Rong Zeng: Visualization (lead). Jianxian Lin: Resources (lead). Ju Wu: Formal analysis (lead). Qi‐yue Chen: Methodology (lead). Jian‐Wei Xie: Writing – review and editing (lead). Ping Li: Supervision (lead). Chang‐Ming Huang: Conceptualization (lead). Chao‐Hui Zheng: Project administration (lead).This work was supported by the Joint Funds for the Innovation of Science and Technology, Fujian Province (2021Y9042). The support funds for Fujian Province Medical “Creating high‐level hospitals, high‐level medical centers, and key specialty projects (MWYZ [2021] No. 76).There are no conflicts of interest or financial ties to disclose from any of the authors.The study was approved by the Institutional Review Board at the Fujian Medical University Union Hospital. The data obtained after obtaining consent were approved by the scientific research project .Informed consent was obtained from all the participants included in the study.Supplementary material S1:Table S1 Time point response: patients with target and non‐target diseases .Table S2 Best overall response when confirmation of CR and PR is required .Table S3 Demographic and baseline characteristics of the two groups.Table S4 Surgical and postoperative outcomes.Table S5 Comparison among different studies of tumor response and prognosis.Figure S1. Surgical conversion rate for the different groups.Figure S2. Prognosis of different conversion therapies and surgery. (A) Overall survival; (B) progression‐free survival.Figure S3. Survival analysis. Relationship between the number of (A) conversion therapies and OS and (B) conversion therapies and PFS. OS and number of conversion therapies in the (C) immunochemotherapy group and (D) chemotherapy‐alone group. OS, overall survival; PFS, progression‐free survival.Click here for additional data file.


Long coronavirus disease (COVID), characterized by persistent and sometimes debilitating symptoms following a severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, has garnered increasing attention as a potential public health crisis. Emerging evidence indicates a higher incidence of hearing loss in individuals who have had COVID 2019 (COVID‐19) compared to the general population. However, the conclusions were inconsistent, and the causal relationship between COVID‐19 and sensorineural hearing loss remains unknown.Q test, Mendelian randomization (MR)‐Egger intercept test, MR‐pleiotropy residual sum and outlier, and leave‐one‐out analysis, to validate the robustness of our results.To addresses this outstanding issue, we performed Mendelian randomization analysis to detect the causal association between COVID‐19 and hearing loss using the largest genome‐wide association study data to date in the European population and confirmed the results in the East Asian population. Comprehensively sensitive analyses were followed, including Cochran's p = .537; OR = 0.995, 95% CI = 0.956–1.036, p = .823; OR = 0.995, 95% CI = 0.967–1.025, p = .76). Replicated analyses in the East Asian population yielded consistent results. No pleiotropy and heterogeneity were found in our results.Our results suggested that there is no causal association between COVID‐19 and the risk of hearing loss in the European population. Neither the susceptibility, hospitalization, and severity of COVID‐19 on hearing loss (inverse variance weighted method: odds ratio (OR) = 1.046, 95% confidence interval (CI) = 0.907–1.205, In conclusion, our MR results do not support a genetically predicted causal relationship between COVID‐19 and sensorineural hearing loss. Thus, the associations observed in prior observational studies may have been influenced by confounding factors rather than a direct cause‐and‐effect relationship. More clinical and mechanism research are needed to further understand this association in the future. This viral outbreak has spread across the world, leading to significant mortality and morbidity on a global scale.Hearing loss seriously interferes with the quality of life, however hearing loss following COVID‐19 infection has been controversial for years. Previous studies about the incidence of sensorineural hearing loss during the COVID‐19 pandemic had conflicting results.Mendelian randomization (MR) is a research approach that uses genetic variants as natural experiments to assess potential causal relationships between an exposure  and an outcome .22.1We gathered our summary‐level genome‐wide association studies (GWAS) data from published research, all of whose data had been authorized by institutional review boards. A two‐sample MR method was conducted to detect the causal association between hearing loss and three types of COVID‐19 infection.2.2We performed MR studies based on summary statistics of GWAS in the European population and validated the results in the East Asian population. Summary statistics for COVID‐19‐related traits in both European and East Asian populations were sourced from the latest release of the COVID‐19 Host Genetics Initiative GWAS meta‐analyses. These summary statistics encompass three distinct sets of genetic instruments, specifically focused on SARS‐CoV‐2 infection, hospitalized COVID‐19 cases, and severe COVID‐19 cases. GWAS summary statistics for sensorineural hearing loss in European population were obtained from the FinnGen consortium R9 release data .2.3p < 5 × 10−8 was employed to screen single nucleotide polymorphisms (SNPs) in European population. Because of a limited number of SNPs meeting genome‐wide significance in East Asian population, we used SNPs with a more relaxed threshold (p < 5 × 10−6) as potential IVs of COVID‐19 in East Asian population. To ensure the independence of IVs in our analysis, we implemented a linkage disequilibrium (LD) clumping procedure. Specifically, we utilized a clumping window of 10 MB and set a stringent LD threshold of R2 < 0.001 based on European ancestry reference data from the 1000 Genomes Project. Meanwhile, to avoid bias owing to the employment of weak instruments, F statistics were calculated for each SNP to measure the statistical strength, and only strong IVs (F‐statistics >10) for each of our exposure of interest remained. Ambiguous and palindromic SNPs of which the effect cannot be correct in the harmonizing process were excluded. To mitigate the risk of false positives in MR analysis, we excluded SNPs that are directly associated with the outcome.Similar to most MR studies, a genome‐wide significance threshold of www.phenoscanner.medschl.cam.ac.uk), a database of human genotype‐phenotype associations, to detect whether these IVs were associated with the potential risk factors of outcome, including hypertension, smoking, diabetes, and viral infection,We also scanned with the PhenoScanner V2 , resulting in a significance threshold of p < .017.Random‐effect inverse‐variance weighted (IVW) method was used as the main analysis, which combined the Wald ratio of each SNP on the outcome and obtained a pooled causal estimate, to verify the causal relationship between COVID‐19 and hearing loss. If horizontal pleiotropy was not existed, the IVW method would be impartial.33.1http://www. phenoscanner. medschl. cam. ac. uk/),F‐statistic of each SNP was calculated and removed the SNP with F‐statistic <10. After removing potential confounders associated with outcome and weak genetic instruments, ultimately we got 10 IVs for SARS‐CoV‐2 infection, 28 IVs for hospitalized COVID‐19, and 22 IVs for severe COVID‐19, were included in the MR analysis of European population. The used genetic instruments of exposures in European population were shown in Table We performed MR studies based on summary statistics of GWAS in the European population and validated the results in the East Asian population. Detailed information for the data sources was presented in Table 3.2p = .537; OR = 0.986, 95% CI = 0.941–1.032, p = .54; OR = 0.998, 95% CI = 0.961–1.037, p = .923). The results from MR‐Egger and weighted median were consistent with IVW results . Leave‐one‐out sensitivity analysis showed that no SNPs independently drove the results, indicating the reliability of our results  = 1.046, 95% confidence interval (CI) = 0.907–1.205, re Table . Then were Table . The MR ts Table .3.3To make our results more robust, we also detect the causal relationship between COVID‐19 and hearing loss in East Asian population. The IVs of COVID‐19 in East Asian population were selected by the same criteria of European population. The used IVs of exposures in East Asian population were shown in Table 4In our study, we investigated the potential causal relationship between COVID‐19 and hearing loss using three complementary MR methods. Our MR analysis did not provide strong evidence to support a causal association between COVID‐19 and the risk of hearing loss in both European and East Asian populations. These findings suggest that other factors or mechanisms may contribute to hearing loss in individuals affected by COVID‐19, and further research is needed to fully understand this relationship.Viral infections are known to cause hearing loss, ranging from mild to profound, and can affect one or both ears. This hearing loss can be conductive or sensorineural in nature.The inconsistent findings in previous observational studies examining the association between COVID‐19 and hearing loss could be attributed to several factors: First, the sample size is too small, which affect the accuracy of the results.This study had several advantages. First, MR analysis was considered as natural randomized controlled trials which are widely accepted in causal research. Compared to the observational study, using MR design, our study is largely free from reverse causation and residual confounding. Besides, GWAS summary data used in this study were obtained from the largest scale of meta‐studies to date, ensuring the strength of instruments in the MR analysis. Third, we verified the causal association between COVID‐19 and hearing loss in two population, which make results more robust.p < 5 × 10−8), we thus relaxed the P threshold in East Asian population. Second, there may be participants who are included in both the exposure (COVID‐19) and outcome (hearing loss) groups, but it was difficult to accurately quantify the proportions of these participants. Third, there are different subtypes of sensorineural hearing loss, such as presbycusis, noise‐induced hearing loss, sudden sensorineural hearing loss and others. Detailed subgroup analyses were unable to be performed since summary statistics rather than raw data were used in the analysis.However, this study also had some limitations and should be noted while interpreting the results. First, since the limited number of SNPs reached genome‐wide significance (Long COVID posts a global health challenge for the society. To deal with long COVID, it is important to understand the relationship between COVID‐19 and its symptoms. Previous conflicting evidence on the relationship between COVID‐19 and hearing loss may mislead the treatment strategies for long COVID‐19. Our findings help to understand COVID‐19 on hearing loss and provide valuable suggestions for the diagnosis and treatment of long COVID‐19.5In conclusion, our MR results do not support the causal association between COVID‐19 and sensorineural hearing loss. Our findings help to understand COVID‐19 on sensorineural hearing loss and provide valuable suggestions for the diagnosis and treatment of long COVID‐19. More clinical and mechanism research are needed to further understand this association in the future.Fengyang Wang: Investigation; methodology. Qiuyuan Yin: Data curation; funding acquisition; investigation; methodology.The authors declare no conflict of interest.This research has been conducted using published studies and consortia providing publicly available summary statistics. All original studies have been approved by the corresponding ethical review board, and the participants have provided informed consent. In addition, no individual‐level data were used in this study. Therefore, no new ethical review board approval was required.Supporting information.Click here for additional data file.


To evaluate the polyphenol content and antioxidant activity of the sumac samples, a Folin–Ciocalteu assay (FCR) and ferric ion reducing antioxidant power (FRAP) assay were used, respectively. L‐glutamic acid was assessed using a Megazyme L‐glutamic acid assay. Compusense software was used to assess the sensory evaluation attributes of free‐living older adults and younger adults receiving different doses of sumac in butternut squash soup. Nutritics software was used to assess food intake following the addition of 0.37 g of sumac to soup. CIBS was selected based on a preliminary assessment in vitro for L‐glutamic acid, antioxidant, and polyphenol content of six varieties of sumac. Sensory evaluation results revealed that the difference in perceived intensity of brown color between the soup samples with different doses of CIBS was greater in the younger adults' group (p = .001) than in older adults (p = .037). In addition, the food intake study found that during the ad libitum lunch, older adults consumed more energy , protein , carbohydrate , and fat  after soup with sumac compared to control soup. The overall findings of this study suggest that the addition of sumac to food may have a potential benefit in enhancing ad libitum lunch intake in older adults leading to effective management of malnutrition. This may promote healthy aging and minimize the burden and the consequences of anorexia of aging as main public health concerns.Aging is accompanied by a decline in appetite and food intake with associated deficiencies in both macronutrients and micronutrients. The aim of this study was to investigate the impact of adding Iranian brown sumac  This article investigated the impact of adding polyphenol and glutamic acid‐rich Iranian brown sumac into butternut squash soup on sensory attributes and food intake among older and younger adults. The results showed that soup with sumac improved energy and macronutrient intake in older adults at an ad libitum lunch compared to a control soup. The overall findings of this study suggest that the addition of sumac to food may have a potential benefit in enhancing ad libitum lunch intake in older adults leading to effective management of malnutrition. All sumac samples belonged to the 2.1.2The test food used was butternut squash soup prepared using 25% reduced salt vegetable stock cubes. Pasta, vegetable oil, and tomato sauce were used for the ad libitum lunch. All these ingredients were purchased from local supermarkets.2.2The FRS and FBS were first air‐dried for 4 weeks, away from direct light and then ground into powder using mortar and pestle. The extraction for polyphenols was completed by adding 0.2 g of sumac sample into 4 mL of the solvents–distilled water, 80% acetone, and 80% ethanol. The samples were transferred to a shaking water bath and then incubated for 2 h at room temperature away from light. The samples were then centrifuged at 3000 rpm for 10 min  to separate the supernatant used as sumac extract. The total antioxidant capacity (TAC) of each sumac extract was assessed using a Ferric ion reducing antioxidant power (FRAP) assay  without sumac and test soups with four different doses of CIBS sumac: 0.25% , 0.50% , 0.75% , and 1% . The soup was prepared with butternut squash (500 ± 10 g), low‐salt vegetable stock (4.5 ± 0.2 g), and water (1 L). Each participant received 100 mL of soup in a 4 oz polystyrene pot container. The doses of CIBS sumac were added to the containers before the warm soups were poured into containers and mixed well with the soup by stirring, ahead of serving. Participants were blinded to the samples that were served in both sessions with at least a 2‐day wash‐out in between; three samples in the first and two in the second. The samples were coded using the Compusense software (Compusense Inc), and served at room temperature along with water and three crackers for cleansing participants' palates between the soup samples. All sessions were carried out at room temperature (21°C) in individual sensory booths lit by artificial light at Oxford Brookes Centre for Nutrition and Health (OxBCNH).2.3.2Participants were given 150 g of butternut squash soup in each session: with no added sumac (SC), 1% CIBS added at the end of cooking (SSE), or 1% CIBS added during cooking (SSC). The soup was heated for 30 min before serving. The participants were provided with an ad libitum lunch (pasta with tomato sauce), 10 min after the soup was served. The participants were blinded to the soup sample they received. The pasta was weighed (180 ± 1 g) and served along with a glass of water (340 mL) at room temperature  via email, mail, or in person. A signed consent form was returned prior to the first test session. All participants completed a health questionnaire; older adult participants were also asked to complete a Functional Ability Health Questionnaire  of Oxford Brookes University (Registration No: 161059). A total of 40 participants were recruited, between July 2017 and December 2017, based on the following inclusion criteria  and separated into two groups. The older adults group had 20 free‐living participants  aged over 65 years and the younger adult group comprised 20 participants  aged 18–35 years old. The study was a randomized, crossover repeated measures design using a 9‐point hedonic scale method for measuring degrees of liking, whereby numerical values were assigned for verbal classification  of Oxford Brookes University on 13 March 2018 (Registration No: 181174). The study was retrospectively registered with Clinical Trials.Gov (NCT05534152). A total of 40 healthy male and female participants were recruited, between July 2018 and March 2020, based on the following inclusion criteria  through several avenues and divided into two groups. Each group had 20 participants. In the older adults group, who were free living, 11 healthy females and nine healthy males took part in the study; in the younger adults group, 15 females and five males participated. The energy and macronutrient intake at the baseline were calculated based on 24‐h dietary recall by the participants. In this randomized, crossover repeated measures design study, the participants were randomly allocated to different sessions using Research Randomizer . Data were analyzed for normality using Shapiro–Wilk's tests. The results are presented as mean ± standard deviation (SD). The significance level was set to 2.6.1p < .05. For data not normally distributed, the results were analyzed using a nonparametric Kruskal–Wallis test between sumac samples' types, and the significance level was set to p < .05. In order to assess the relationship between the antioxidant activity and polyphenol content of all the sumac samples, a Pearson correlation test was run.Based on the results for normally distributed data, a parametric one‐way analysis of variance (ANOVA) with a post hoc test (using Tukey adjustment) was applied to determine significant differences within sumac samples and between solvents. The significance level was set to 2.6.2d = 0.5, α of 0.05 and power of (1‐ß) 0.80, a total of 35 participants was required.A nonparametric Friedman test was used to evaluate the differences in sensory attributes between soup samples in older and younger adult groups, while a Wilcoxon test was run to determine differences in pairwise comparisons. Comparisons between the average intake of energy and macronutrients for older and younger adults were done using a Mann–Whitney test. The sample size determination was conducted using G*power (Version 3.1.9.7) which indicated that for a medium effect size of 2.6.3d = 0.5, α of 0.05 and a power of (1–ß) 0.95, a sample size of 16 was required in each group to detect a difference in energy intake of 45 kcal  to energy and nutrient intakes within older and younger adult groups, repeated measures ANOVA was applied for normally distributed data. Furthermore, comparisons of food intake between the two groups of adults were done using a Mann–Whitney test, or an independent t‐test depending on the normality of the data. In this study, G*power (v. 3.1.9.7) indicated that for a two‐tailed test with a medium effect size of 33.1p < .05) with the highest antioxidant activity for 80% ethanol. Moreover, compared with other commercial sumac samples, CIBS followed by FBS showed higher activities (p < .05) in all three assays. There was a significant (p < .01), strong positive correlation between the polyphenol content and antioxidant activity of the sumac samples in all solvents: water, r = 0.813; 80% acetone, r = 0.887; and 80% ethanol, r = 0.623.Table 3.2t (38) = −32.6, p = .001, d = 10.4). On average, the age of older adults, in the food intake study, was higher than that of younger adults, with a large effect size of d = 8.9 (t (38) = −26.8, p = .001). However, no difference was observed in the comparison between the weight and height of older and younger adults in both sensory evaluation and food intake studies (p > .05).Forty participants (20 older adults and 20 younger adults) volunteered to take part in the sensory evaluation study Table . The res3.33.3.1p > .05) between the soup samples for any of the liking attributes or the intensity of lemony flavor, salty flavor, or red color. However, the addition of sumac to soup samples resulted in an increased intensity of perceived brown color compared with the SC sample (p < .037); (χ2 (4) =10.2) among older adults. Despite an overall positive difference, a pairwise comparison showed no statistical differences between the soup samples (p > .05).The mean scores for the liking and intensity attributes of all the soup samples rated by older adults are presented in Figure 3.3.2The mean scores for the liking attributes'  and intensity attributes'  for different soup samples in the younger adults group are presented in Figure x2(4) = 23.5; p = .001; 2‐tailed). Pairwise comparisons revealed a large effect between the SC samples with LS and HS , SC with TS , and SC with MS .A Friedman test identified a statistical difference in the intensity of the brown color of CIBS soup samples compared to SC soup among younger adults  = 2.3, and d = 1.3.Overall, analysis of the effect of different doses of sumac in soup samples compared with an SC sample showed no differences in liking and intensity of any attributes between older and younger adults, except for the brown color of soup TS, at 3.4p = .907) between the test sessions among older adults. The consumption of ad libitum pasta showed no statistical differences between the test sessions among older or younger adults, p = .075 and p = .49, respectively.Unlike the younger adults, the older adults did not consume their soup fully in all sessions. Yet, there were no statistical differences observed in soup intake (3.4.12(20) = 8.6; p = .014), protein  = 7.4; p = .025), carbohydrates  = 8.7; p = .013), and fat  = 12.6; p = .002) with higher intakes in the SSC session compared with SSE (Table p > .05). There was no impact on evening meal intake following the addition of CIBS sumac to soup samples between both groups of adults (p > .05). No statistical differences were observed in energy and macronutrient profiles of the all‐day food intake between the test sessions in either older adults or younger adults.Results of ad libitum lunch among older adults showed a significant difference between the test sessions for energy  following ad libitum lunch. However, protein intake was higher during the evening meal following the SSC soup test (p = .003) with higher intake by younger adults than older adults. Furthermore, more intake of protein was observed after SSE (p = .006) and SSC (p = .004) sessions on all‐day food intake between the groups with greater consumption in younger adults.The macronutrient intake of ad libitum lunches, evening meals, and all‐day after the test sessions  between older adults and younger adults was analyzed Table . Added C4The current study compared the food intake within and between older adults and younger adults and confirmed a reduction in food intake with aging, which has been reported previously  of sumac, so it was difficult to differentiate the brown color and flavor of the samples  was the sample most preferred by both groups of adults. Additionally, the increase in doses of sumac had no adverse effects on the acceptability and liking attributes of soup samples. It can be suggested that sumac, which contains L‐glutamic acid, is a promising natural additive, to replace salt, with the aim of increasing food intake in older adults and improving the taste and flavor of food. Hence, the outcome of this study is a promising approach in response to global health concerns over malnutrition in older adults, potentially contributing to reductions in healthcare costs.Nasim Soleymani Majd: Conceptualization ; data curation (lead); formal analysis (lead); funding acquisition (lead); investigation ; methodology ; project administration (lead); resources ; software ; validation ; visualization ; writing – original draft (lead); writing – review and editing (supporting). Shelly Coe: Conceptualization ; data curation ; methodology ; project administration ; supervision ; writing – review and editing . Helen Lightowler: Conceptualization (lead); data curation (supporting); formal analysis (supporting); funding acquisition (lead); investigation ; methodology ; project administration (supporting); resources (lead); software ; supervision ; validation ; visualization ; writing – original draft (supporting); writing – review and editing (supporting). Pariyarath Thondre: Conceptualization ; data curation ; formal analysis ; funding acquisition ; investigation ; methodology ; project administration ; resources ; software ; supervision (lead); validation ; visualization ; writing – review and editing (lead).The authors declare that they do not have any conflict of interest.This study was approved by the Institutional Review Board of Oxford Brookes University.Written informed consent was obtained from all study participants.


The cardiodynamicsgram (CDG), a novel noninvasive method, extracts dynamic ST‐T segment information from an electrocardiogram (ECG) through deterministic learning.The CDG can reflect anomalous functional information in coronary artery disease (CAD).We retrospectively enrolled 456 patients with suspected CAD who underwent coronary computed tomography angiography (CCTA) from January 2020 to 2022, followed immediately by standard 12‐lead ECG acquisition. Positivity for CAD were defined as CCTA ≥ 50% or CT‐derived fractional flow reserve (CT‐FFR) ≤ 0.8. A CDG value <0 was considered negative; otherwise, it was considered positive. We also evaluated the diagnostic performance of the CDG in the ECG‐diagnosis‐negative subgroup and in patients who had undergone invasive coronary angiography (ICA) after CCTA.n = 223), the accuracy of the CDG was 80.27%, with an AUC of 0.842 (95% CI: 0.790−0.895). Among the 11 patients with CAD confirmed by ICA, 10 were diagnosed positive by the CDG. Furthermore, the CDG values and CT‐FFR were correlated .Of 362 patients, 168 (46.41%) were positive for CAD, and 178 (49.17%) were men. The median age was 59 (52−66) years. The accuracy of the CDG in the diagnosis of CAD was 79.56%, with a sensitivity, specificity, and the area under the receiver operating characteristic curve (AUC) of 75.60%, 82.99%, and 0.836 (95% CI: 0.794−0.878), respectively. Similarly, in the ECG‐diagnosis–negative subgroup (The ECG‐based CDG has relatively high specificity and accuracy for the diagnosis of CAD and reflects functional cardiac information to some extent. It has the potential to be used as a screening tool for suspected CAD patients before CCTA. In this study, using coronary computed tomography angiography and CT‐fractional flow reserve as reference standards, the electrocardiogram‐based cardiodynamicsgram was found to have relatively high specificity and accuracy for the diagnosis of coronary artery disease. CADcoronary artery diseaseCCTAcoronary computed tomography angiographyCDGcardiodynamicsgramCT‐FFRcomputed tomography‐derived fractional flow reserveECGelectrocardiogramICAinvasive coronary angiography1Coronary artery disease (CAD) is one of the most common cardiovascular diseases leading to death in the global population.Coronary computed tomography angiography (CCTA) is the preferred diagnostic test for CAD,Clinically, the electrocardiogram (ECG) is the most common test for patients with suspected CAD.Precise, easy, rapid, and noninvasive tools for screening CAD in the clinic are urgently needed. Hence, this study attempted to evaluate the diagnostic performance of the CDG in detecting CAD using CCTA and CT‐FFR as reference standards. We also analyzed the correlation between CDG values and CT‐FFR.22.1This retrospective study included 456 patients with suspected CAD who underwent CCTA at Shandong Provincial Hospital from January 2020 to 2022. All patients underwent standard 12‐lead ECG examination immediately after a CCTA scan. Patients were excluded if they had known CAD , structural heart disease , atrial fibrillation, heart failure, infective endocarditis, pacemaker implantation, radiofrequency ablation, or poor image quality  was used for image acquisition. Before scanning, patients (except for patients with hypotension) were treated with a sublingually applied nitroglycerine pump spray to dilate the coronary arteries and received breath‐hold training to reduce respiratory motion artifacts.The nonionic contrast agents iohexol 30.0−55.0 mL and 0.9% sodium chloride injection 30.0−55.0 mL were injected into the peripheral vein on the back of the hand at a flow rate of 4.0 mL/s using a double‐barrel autoinjector. The aortic root was selected as the region of interest (ROI), and the CT attenuation value was monitored in the ROI. The CCTA scan was automatically triggered with a 5 s delay when the CT attenuation value reached 100 HU. The scanning area was from the aortic arch 1−1 cm below the diaphragmatic surface of the heart.The scan parameters were as follows: collimator 192 × 0.6 mm, layer thickness 0.75 mm, rotation time 0.25 s/turn, and tube voltage 70−120 kV. A prospective or retrospective ECG gated spiral scan mode was selected depending on the patient's heart rate and respiratory control.2.3For analysis, all images were transferred to a Siemens workstation with semiautomatic image segmentation software . The axial image reconstruction section thickness was 0.75 mm, the reconstruction increment was 0.5 mm, and the smoothed convolution kernel was Bv40. Image postprocessing techniques include maximum intensity projection, multiplane reconstruction, curved plannar reconstruction, and volume rendering. The results of CCTA are diagnosed by two specialists with 10 years of experience in diagnostic cardiovascular imaging, respectively. When there is a disagreement, the two specialists discuss the decision. Stenosis severity was classified into the following groups: 0%, 1%−24%, 25%−49%, 50%−69%, 70%−99%, and 100%. CCTA results were defined as positive if at least one epicardial coronary artery with a stenotic degree ≥50% and diameter ≥2.0 mm.2.4CT‐FFR analysis was performed using cFFR software . This software is based on a deep learning model and predicts the FFR values of coronary arteries. After importing the CCTA images into the software, the coronary centerline and lumen were automatically identified and later manually corrected if necessary. Then, a coronary tree was generated with different colors representing different CT‐FFR values. The CT‐FFR was measured for all vessels of diameter ≥1.8 mm in the coronary tree, the lesion‐specific CT‐FFR  was recorded in patients with vascular stenosis, and the vessel‐specific CT‐FFR  was recorded in patients without plaques.2.5Transracial artery puncture was chosen for the ICA procedure. Iodixano was used as a contrast agent. Stenosis severity was classified as follows: 0%, 1%−24%, 25%−49%, 50%−69%, 70%−99%, and 100%. ICA results were defined as positive if at least one epicardial coronary artery had stenosis ≥50% and diameter ≥2.0 mm.2.6The digital 12‐lead ECG information of the patients was recorded using an electrocardiograph (Mindray Bene‐Heart R12) with a 1000 Hz sampling rate and 0.1 µV resolution. Participants were in the resting state and supine position. The ECG data were recorded for at least 20 s for further analysis. The 12‐lead ECG was diagnosed with ischemic changes if any of the following conditions were present, and the patient was considered positive: (1) New ST‐elevation: ≥0.2 mV (men) or ≥0.15 (women) in chest leads V2−V3, and/or ≥0.1 mV in all leads other than V2−V3; (2) New horizontal or down‐sloping ST‐depression ≥0.05 mV in two adjacent leads; (3) T‐wave inversion ≥0.1 mV in two adjacent leads with obvious R‐wave or R/S > 1. The ECG results are diagnosed by two specialists with 10 years of experience in ECG diagnosis, respectively. When there is a disagreement, the two specialists discuss the decision.2.7The CDG was generated as follows. First, the digital 12‐lead ECG were filtered to eliminate interference such as power frequency(50 Hz), baseline drift, motion artifact, EMG, and so on. Then, we transformed the 12‐lead ECG signals into the 3‐lead ECG vector signals by linear transformation matrix of Kors.N represents the number of data points in the CDG, dn1 represents the distance between the nth data point and its nearest data point, dn2 represents the distance between the nth data point and its nearest data point after 10 steps, and F represents the Fourier transform of the CDG. Finally, a linear support vector machine was used as a classifier to train the screening model for CAD. The CDG value is defined as the distance between the SHI and THI and the classification boundaryThen, the shapes of the CDG were interpreted by evaluating the spatial characteristics based on the Lyapunov index and the temporal characteristics based on the Fourier transform of the CDG.CDG value is calculated automatically using the computer program by data analyst who is blind to clinical information.According to the data of patients with normal or roughly normal chest pain from previous studies, a linear classification boundary was obtained from a CAD detection model established by using machine learning algorithm of linear kernel SVM as follows:The distance of the case samples to the linear classification boundary was a CDG value, the judgment standards were a CDG value ≥0 for positive and <0 for negative.2.8t‐test was used for normally distributed data, and the Mann−Whitney U test was used for nonnormally distributed data. Categorical variables are presented as counts (percentages) and were compared using the χ2 test or Fisher's exact test. The performance of the CDG and standard 12‐lead ECG in diagnosing CAD were assessed using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity. The relationship between CDG values and CT‐FFR was assessed by using Spearman's correlation analysis. The reproducibility of CT‐FFR values was tested using interclass correlation coefficient. A two‐tailed p value <.05 was considered statistically significant. All statistical analyses were conducted using statistical software .The Kolmogorov−Smirnov test was used to check the assumption of a normal distribution. Normally distributed variables are expressed as the means ± standard deviations. Nonnormally distributed variables are expressed as the median (IQR). Student's 33.1p < .001) and more likely to have hypertension (p = .002) than negative patients  years, and 178 (49.17%) were male. A total of 94 (20.61% [94/456]) patients were excluded. A baseline comparison showed no significant differences in sex, body mass index, hypertension, diabetes, hyperlipidemia, or smoking history between positive and negative CDG patients. However, positive patients were older (3.2There were 168 (46.41%) positive and 194 53.59%) negative CAD patients. Using CCTA and CT‐FFR as a reference standard, the CDG achieved an accuracy of 79.56%, sensitivity of 75.60%, and specificity of 82.99% in diagnosing CAD, and the corresponding AUC was 0.836  had a negative ECG presentation. In these patients, the accuracy of the CDG in diagnosing CAD was 80.27%, with a sensitivity and specificity of 74.04% and 85.71%, respectively, and an AUC of 0.842  patients underwent ICA, and the interval between ICA and CCTA ranged from 3 to 59 days. Among them, 2 patients had a degree of stenosis on ICA < 50% , and 11 patients had ICA ≥ 50% .3.3p < .001. When stenosis on CCTA ≥ 50% was used as a reference, the CDG value of 0.84 (−0.46 to 2.13) in the positive CAD group was significantly higher than the −1.60 (−3.28 to 0.24) in the negative CAD group (p < .001). When CT‐FFR ≤ 0.8 was used as a reference, the CDG value of 0.84 (0.14−2.20) in the positive CAD group was still higher than the −1.97 (−3.70 to −0.46) in the negative CAD group  versus −2.24 (−3.84 to −0.59), 4According to the 2016 update of the stable chest pain guideline, the National Institute for Health and Care Excellence recommends that CCTA be the first‐line test for stable chest pain patients or for nonanginal chest pain patients with ECG changes suggesting underlying CAD.Diagnosing with the standard 12‐lead ECG mainly depends on the physician's visual assessments, resulting in a certain degree of subjectivity, and tiny changes are frequently missed.In this study, the SHI representing the spatial dispersion and the THI representing the temporal dispersion were calculated separately, and CDG value was generated using machine learning algorithm of linear kernel SVM. Each cardiac beat in the CDG graph represented the change rule of each ST‐T segment signal in the ECG vector diagram, thus the dispersion of the CDG represented the consistency of the changes in each ST‐T segment signal of the ECG vector diagram. CDG value was correlated with the degree of temporal dispersion, the larger the CDG value, the more scattered the CDG graph and the less consistent changes in the ST‐T segment of each cardiac cycle. Conversely, the smaller the CDG value value, the more regular the CDG graph and the stronger the consistency of the ST‐T segment of each cardiac cycle.n = 223) with negative diagnoses by 12‐lead ECG. The results similarly showed that the CDG had a high accuracy (80.27%) in diagnosing CAD. In addition, we are the first group to evaluate the CDG using hemodynamic parameters as a reference standard with impressive diagnostic performance , which is higher than that when CCTA alone is used as a reference standard . This outcome can be explained by the fact that functional abnormalities do not necessarily occur when there is an obstructive lesion in the coronary arteries.CAD has a high prevalence worldwide, and to date, CCTA has been considered a preferable, reliable noninvasive examination method for diagnosing this disease.r = −.395, p < .001). In patients with suspected CAD, especially those with a negative ECG diagnosis, higher CDG values indicate a greater likelihood of obstructive stenosis or hemodynamic abnormalities in the coronary arteries, thus suggesting that these patients should be further examined as early as possible.Because the ICA examination is the gold standard for diagnosing CAD,Several limitations of this study should be noted. First, this is a single‐center retrospective study, and the diagnostic performance of the CDG needs to be confirmed further in a multicenter study with a larger sample size. Second, most of the included population did not meet the criteria for ICA testing, and so ICA or invasive FFR were lacking as a gold standard for validating the diagnostic performance of the CDG, even though many studies have shown that the CT‐FFR has equal diagnostic performance to the invasive FFR.5The ECG‐based CDG generated by deterministic learning can efficiently distinguish CAD and non‐CAD. Additionally, this performance was verified with different reference standards and subgroup analyses. This method can be used as a rapid and reliable noninvasive screening tool for suspected CAD patients before the CCTA examination, prompting potential positive patients to undergo further testing early or to reduce unnecessary CCTA testing.Ying Wang carried out the study, participated in the study design, and wrote the final manuscript. Jiaxin Sun carried out the study and participated in its design and in drafting of the manuscript. Weihua Zhao contributed to the managed the literature search. Lin Li participated in the interpretation of data. Cong Wang, Xinxin Yu, Kui Sun, and Hui Gu participated in the study, and interpretation of data. Qinghua Sun and Ximing Wang conceived the study. All authors read and approved the manuscript.The authors declare no conflict of interest.Supporting information.Click here for additional data file.


Dorea, Erysipelotrichaceae, Stercoris, etc. in the intestinal tracts of rats fed a high‐fat diet. Therefore, MOC can be included in lipid healthy dietary patterns to lower lipid characteristics and restructure the intestinal microbiota. Future clinical trials are required to determine the therapeutic effects and mechanisms of hypolipidemia.Macadamia oil cake (MOC) is a type of macadamia nut by‐product, that is extremely rich in amino acids and has beneficial health effects. It lowers blood lipid levels and regulates the intestinal microbiota. MOC effectively attenuated total cholesterol (TC), triglyceride (TG), low‐density lipoprotein cholesterol (LDL‐C), and high‐density lipoprotein cholesterol (HDL‐C) levels in model rats. Depending on the morphology of the colon, MOC can effectively attenuate damage to the tissue structure. The 16S rDNA gene of the rat intestinal microbiota was sequenced using Illumina PE250 high‐throughput sequencing technology, and the changes in the intestinal microbiota in each group are discussed. Supplementing MOC at different doses significantly increased the microbiota of  Macadamia oil cake (MOC) can effectively attenuate the total cholesterol (TC), triglyceride (TG), low‐density lipoprotein cholesterol (LDL‐C), and high‐density lipoprotein cholesterol (HDL‐C) of the model rats and show that MOC can be included in a lipid‐healthy dietary pattern to lower lipid characteristics and restructure intestinal flora. We have found that the percentage of palmitoleic acid in macadamia nuts from different regions of Guangdong is between 9.9% and 14.2% (unpublished data). Studies have shown that a macadamia nut‐rich diet can decrease total cholesterol and LDL cholesterol and modulate the risk factors for coronary artery disease . After oil extraction using supercritical carbon dioxide, the MOC was used in the experimental procedures.2.2SPF‐grade SD rats  were purchased from Southern Medical University (SCXK (Yue) 2016–0041, Guangzhou, China). The rats were maintained in a special feeding box containing sufficient fodder and potable water. The feeding environmental conditions were as follows: temperature 18–24°C, humidity 40%–70%, air change ≥8 times/hour, dark/light cycle (12 h each). After 1 week of acclimation, 10 rats were housed in two cages supplied with normal fodder as the normal control group. Forty rats were housed in eight cages (five rats per cage) and fed a high‐fat diet (model group). Normal fodder and high‐fat diet were obtained from Jiangsu Synergetic Pharmaceutical Biological Engineering Co., Ltd. After 4 weeks, the rats on the high‐fat diet were randomly assigned to four groups: (1) the model group was orally administered distilled water once daily, (2) the model group+ MOC low‐dosage group was orally treated with 1 g/kg/BW once daily, (3) the model group+ MOC medium‐dosage group was orally treated with 2 g/kg/BW once daily, and (4) the model group+ MOC high‐dosage group was orally treated with 4 g/kg/BW once daily. All animal care procedures were approved by and performed in accordance with the guidelines of the Institutional Animal Care and Use Committee of Hainan University, China.2.32 asphyxiation. Blood samples were collected in sterilized tubes and centrifuged at 3500 × g for 15 min. Separated serum samples were collected. The colons from each rat were dissected and collected. Fecal samples were collected from the colon and immediately snap‐frozen. All of the samples were stored at −80°C for subsequent analyses.After treatment with MOC for 4 weeks, all rats were fasted overnight and anesthetized. All the rats were sacrificed by CO2.4The contents of TC, TG, LDL‐C, and HDL‐C in serum were determined using kits purchased from the Nanjing Jiancheng Bioengineering Institute according to the manufacturer's instructions.2.5The colon samples were dehydrated for 12 h, embedded in a YD‐6D biological tissue embedding machine for 1.5 h, sectioned, spread, and baked. The sections were placed in xylene for 10 min for dewaxing followed by 100% ethanol, 95% ethanol, 80% ethanol, and purified water for 3 min each for hydration and then stained with hematoxylin dye for 30 s, differentiated with 1% hydrochloric acid alcohol for a few seconds, washed with running water for 3 min, returned blue by bluish liquid for a few seconds, washed with running water, dyed with eosin for 1 min, washed with running water, and dehydrated . Using ultra‐clean adhesive film, the samples were observed using a white‐light microscope.2.6DNA was extracted from fecal samples, and the conserved region of rDNA was amplified using specific primers with barcodes. The PCR amplification was carried out according to the designated sequencing area, and the PCR products were quantified with a QuantiFluor™ fluorometer. The purified amplification products were mixed in equal amounts, the sequencing connector was connected, the sequencing library was constructed, and an Illumina PE250 device was used for sequencing. After filtering the low‐quality reads, the reads were assembled, the dual‐end reads spliced into tags, and the tags filtered to obtain clean tags. They were then clustered, the chimeric tags detected in the process of cluster comparison were removed, and the effective tags of the data were obtained. After obtaining the OTU, OTU abundance statistics based on the effective tags were calculated, and principal component analysis was conducted on the relative abundance of various groups.2.7p < .01 was considered extremely significant.The data were analyzed by analysis of variance (ANOVA) and the least significant difference using SPSS 20.0 software. For all analyses, p‐values <.05 were considered statistically significant, and 33.1p < .01), indicating that the hyperlipidemia model was successful. Compared to the model group, except for TC and HDL‐C in the high‐dose MOC group and HDL‐C in the model group (p < .05), there were significant differences between the other experimental groups and the model group (p < .01)  Figure .3.21) group, the intestinal tissue structure was normal, the mucosal layer structure was complete and arranged in an orderly manner, and no necrosis or shedding of epithelial cells was observed. Inflammatory cell infiltration was not observed in the tissues, and edema was not evident in the submucosa. In the hyperlipidemia model group (G2) group, the intestinal tissue structure was highly abnormal, part of the crypt structure of the mucosal layer has been lost, and focal infiltration of inflammatory cells and swelling of lymph nodes were observed. In the low‐dose MOC (G3) group, the intestinal tissue structure was slightly abnormal, minor edema was observed in the submucosa, the tissue gap was slightly enlarged, and connective tissue hyperplasia was observed. Inflammatory cell infiltration was not observed in these tissues. In the medium‐dose MOC (G4) group, the intestinal tissue structure was slightly abnormal. In the visual field, the submucosa exhibited slight edema, the tissue gap was slightly enlarged, the connective tissue was proliferative, and there was no obvious inflammatory cell infiltration in the tissue. In the high‐dose MOC (G5) group, the intestinal tissue structure was moderately abnormal, edema was observed in the submucosa, the tissue gap was slightly enlarged, connective tissue hyperplasia and focal infiltration of inflammatory cells were observed, and the inflammatory cells were mainly lymphocytes  and the hyperlipidemia model group (G2), the addition of protein seeds  to the diet increased the diversity level of intestinal microbiota in hyperlipidemia mice to a certain extent, but the effect was not significant  per sample. The α‐diversity analysis showed that compared with the healthy control group , Pullicaecorum and Butyricicoccus in the model group (G2) were significantly increased, whereas celatum, F16, TM7, and CW040 were significantly reduced ; writing – original draft . Tengfei Xie: Methodology ; writing – review and editing . Shijun Wu: Methodology ; writing – review and editing . Guang Yang: Writing – original draft . Jinyun Zhang: Writing – original draft . Jie Song: Writing – original draft . Guifang Yang: Writing – original draft .There is no conflict of interest.