Data about reperfusion injury (RI) following acute arterial mesenteric ischemia (AAMI) in humans are scarce. We aimed to assess the prevalence and risk factors of RI following endovascular revascularization of AMI and evaluate its impact on patient outcomes.Patients with AAMI who underwent endovascular revascularization (2016–2021) were included in this retrospective cohort. CT performed < 7 days after treatment was reviewed to identify features of RI . Clinical, laboratory, imaging, and treatments were compared between RI and non-RI patients to identify factors associated with RI. Resection rate and survival were also compared.p = 0.01). On multivariate analysis, a decreased bowel wall enhancement on baseline CT (HR = 8.2), an embolic cause (HR = 7.4), complete SMA occlusion (HR = 7.0), and higher serum lactate levels (HR = 1.4) were associated with RI. The three-month survival rate was 78%, with no difference between subgroups (p = 0.99). However, the resection rate was higher in patients with RI .Fifty patients  were included, and 22 were diagnosed with RI (44%) after a median 28 h (22–48). Bowel wall hypoattenuation and mucosal hyperenhancement were found in 95% and 91% of patients with post-interventional RI, respectively. Patients with RI had a greater increase of CRP levels after endovascular treatment , an occlusion of the superior mesenteric artery (HR = 7.0), an embolic cause (HR = 7.4), and higher initial serum lactate level (HR = 1.4) were identified as predictors of reperfusion injury.Bowel wall hypoattenuation, hyperenhancement of the mucosa, and increase in CRP levels after revascularization were key diagnostic features of reperfusion injury.The online version contains supplementary material available at 10.1186/s13244-022-01339-9. Acute mesenteric ischemia is defined by the association of mesenteric vascular insufficiency (that can be occlusive or non-occlusive) with ischemic gut injury . Arterial acute mesenteric ischemia (AAMI) is a life-threatening condition, associated with a dismal prognosis: nearly 100% mortality rate without appropriated bowel resection or revascularization . EndovasIschemia–reperfusion injury (RI) following mesenteric ischemia is caused by restoring blood flow in a damaged bowel leading to additional cell injury . The undAbundant research in animal models has focused on histological , 20 and Preclinical imaging studies using computed tomography (CT) or magnetic resonance imaging (MRI) to assess RI are scarce –28. In cThus, the purpose of this study was to assess the prevalence and risk factors of RI in a cohort of AAMI patients treated by endovascular revascularization and evaluate its impact on patient outcomes.The Institutional Review Board approved this single-center retrospective observational study (CRM-2205-266), performed according to the ethical standards of the Committee on Human Experimentation of our institution and reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.All patients with AAMI that were prospectively admitted to the intestinal stroke center unit of Beaujon Hospital  were considered. Inclusion criteria were: (i) patients diagnosed with arterial occlusive mesenteric ischemia on contrast-enhanced CT and (ii) who were treated by endovascular revascularization. Exclusion criteria were as follows: (i) patients who underwent surgery (any laparotomy or laparoscopy) before undergoing follow-up CT after endovascular revascularization, (ii) patients without CT within seven days from the endovascular revascularization, and (iii) presenting with bowel thickening on CT before revascularization. We chose to exclude patients who underwent laparotomy for open revascularization or bowel resection because surgery could influence the appearance of the bowel. We hypothesized that RI could resolve in patients evaluated by CT more than 7 days after revascularization and therefore those patients were excluded. Patients with bowel thickening before revascularization could have RI caused by spontaneous clot dissolution and were also excluded. Patient history, clinical, laboratory , creatinine, C-reactive protein (CRP)), and pathological data were prospectively obtained, as well as additional treatments and patient outcomes. CTs were retrospectively reviewed by two abdominal radiologists in consensus (M.R. and L.G. with 12 and 3 years of experience) who were unaware of the final diagnosis of RI or not.In our cohort, the diagnosis of AAMI was based on an association of (a) acute intestinal symptoms , (b) arterial involvement on CT (severe stenosis or occlusion of the superior mesenteric artery), (c) related bowel abnormalities consistent with ischemic injury on CT , and d) the absence of alternative cause. It should be noted that bowel abnormalities could be missing in very early forms of this disease. In these cases, a diagnosis of AAMI was considered if the three other criteria were all met. The final diagnosis was determined by an on-call group of AAMI experts, including gastroenterologists, surgeons, and radiologists. SMA lesions were retrospectively graded according to Society of Cardiovascular Computed Tomography guidelines for the interpretation and reporting of CT coronary angiography  as minimAll admitted patients were treated according to the institutional treatment protocol established by Corcos et al. . After aWhen considered to be technically possible , endovascular revascularization was systematically proposed as an upfront treatment except in patients with an initial high probability of extensive intestinal necrosis assessed by the Clichy score  .Endovascular revascularization was either performed by an interventional radiologist or a vascular surgeon depending on the availability of each team at the time of the diagnosis. Endovascular revascularization methods included stenting, thrombus-aspiration and/or in situ thrombolysis. The choice of method was decided considering the first SMA angiogram and the pre-treatment CT. Either manual (with a 50-mL syringe) or mechanical  thrombus-aspiration was typically performed for clots in the medial part of the SMA. When complete recanalization of all branches was not obtained, transluminal angioplasty with stenting  or intra-arterial thrombolysis  could be used in adjunction to the thrombus-aspiration, depending on the localization of the residual occlusion/stenosis. Stenting was preferred for proximal lesions (embolic or atherothrombotic), and thrombolysis was attempted in case of distal clots . Technical success was defined as successful arterial recanalization during completion angiogram with no residual significant stenosis . This definition is arbitrary as there is no consensus or recommendation on technical success of endovascular revascularization in AAMI as opposed to cerebral  or myocardial (blush grade) revascularization. Technical failure was defined as no improvement after the recanalization attempt. In patients who underwent thrombolysis, the completion angiogram was the one obtained at the end of treatment, i.e., when the intra-arterial thrombolysis catheter was removed.If the endovascular treatment failed technically or did not improve the clinical status, laboratory tests , or follow-up imaging, patients were referred for open revascularization and surgical bowel resection, when needed. Perioperative complications of endovascular revascularization were recorded according to the Society of Interventional Radiology guidelines  but not A follow-up CT was performed in our institution within 7 days after revascularization even in the absence of clinical symptoms or biological abnormalities to assess the result of the treatment on the bowel and the splanchnic vasculature. A CT was also performed in patients with clinical symptoms or biological abnormalities to search for possible AAMI recurrence or complication.  persistence and survival.p < 0.05 was considered to be significant. Variables associated with the occurrence of reperfusion injury in univariate analysis (p < 0.05) were entered in a Cox proportional hazards regression model. Two models were computed: a classic “all-in-one” model including all significant variables on univariate analysis, and a two-step chronological model considering pre-revascularization characteristics, first, then treatment-related variables. Independent variables were used to compute a predictive score for the occurrence of RI, and confidence intervals for the receiver operating characteristics curve were calculated. All analyses were performed using Prism version 9.0.0  and the Statistical Package for the Social Sciences (SPSS) .Results are presented as medians (interquartile range), means ± standard deviations (SD), or the number of cases (percentage of cases). Patients with and without reperfusion injury were compared with the Student’s t test or the Mann–Whitney test for continuous variables and the Fisher exact test for categorical variables. Survival was calculated as the delay between the date of revascularization and death by any cause. The survival curves were presented using the Kaplan–Meier method and compared using the log rank. Tests were two-sided, and From January 2016 to October 2021, 316 patients who were admitted for AAMI were screened. Two hundred and twenty-six (71%) had an AAMI. After applying the exclusion criteria, 50 patients  were included. , a > 70% stenosis in four patients (8%), a 50 to 70% stenosis in 11 patients (22%), a 25% to 50% of stenosis in three patients (6%), and a < 25% stenosis in two patients (4%).The technical success rate was 92% (46/50 patients). Stenting was used in 21/50 patients (42%), intra-arterial thrombolysis in 24/50 patients (48%), and thrombus-aspiration in 20/50 patients (40%). Fifteen patients (30%) were treated with a combination of techniques (Table n = 2), false aneurysms (n = 3), or hemorrhagic shock . Two patients had mild complications: One procedure was complicated with the appearance of a small distal clot at the end of the intervention without clinical consequences, and in another one, a small SMA ileal branch was perforated during catheterization with contrast extravasation but was spontaneously resolutive.Severe complications occurred in 6/50 patients (12%), all related to the femoral access (hematoma (p < 0.01) and intra-arterial thrombolysis (p = 0.02) , abdominal pain , elevated serum lactate levels , hemoglobin drop , inflammatory syndrome , and clinical aggravation . On follow-up CT, complete and partial recanalization of the SMA was obtained in 23/50 (46%) and 19/50 (38%) patients, respectively (Table Follow-up CT was performed a median of 39 h (18–65) after revascularization. The reasons for performing follow-up CT were: systematic follow-up n = 4; 48%, aReperfusion injury was identified in 22 of the 50 patients (44%) on the CTs performed a median of 28 h (22–48) after revascularization. Mean bowel wall thickening in the bowel segment with RI was 8.5 mm (7–9). Bowel wall edema was the most frequent co-finding . Hyperenhancement of the mucosa, fat stranding, and fluid adjacent to the involved bowel loop was found in (20/22 patients (91%), 20/22 patients (91%), and 18/22 patients (82%)), respectively. Draining veins were dilated in 20/22 patients (91%) confirming venous turgescence. Intra-luminal hemorrhage was found in 4/22 patients (18%). The jejunum was involved in 11/22 (50%) patients, the ileum in 16/22 73%), the right colon in 3/22 (14%), and the left colon in 4/22 patients (18%). Nine patients (41%) had more than one bowel segment involved , with higher initial serum lactate levels (p = 0.02) and WBC (p = 0.02). There was a statistical trend associating a higher Clichy score (2 or 3/3) with RI (p = 0.05). No significant difference was found in terms of age at revascularization (p = 0.93), or initial CRP level . The median delay between the initial CT and revascularization was longer in patients without a RI (p < 0.01).Patients who developed RI were more frequently women (p < 0.01), and they had a higher rate of complete SMA occlusion (p < 0.01) with lesions located in the middle or distal part of the SMA (p < 0.01). Seventeen patients with RI initially had a decreased bowel wall enhancement (77%) of the bowel segment displaying RI, compared to three patients (11%) without RI (p < 0.01). No significant difference was found in terms of celiac trunk stenosis (p = 0.68) or bowel dilatation (p = 0.77).On CT, the cause of AAMI was more frequently arterial emboli in RI patients (p = 0.07) or bloody diarrhea  after revascularization was not significantly different between patients with and without RI (Table p = 0.02). The median CRP was 146 mg/L (110–204) after revascularization in RI patients vs. 62 mg/L (21–129) in patients without (p < 0.01). The median CRP increased by 371% (100%–495%) after revascularization in patients with RI versus 5%  in patients without RI (p < 0.01). There was no difference in median lactate change after revascularization: − 6%  in RI patients versus 0%  in non-RI patients (p = 0.42).The occurrence of abdominal pain , an embolic cause , complete occlusion of the SMA , and higher initial lactate levels  were independent predictors of the occurrence of RI  in the first step and procedure-related variables  in the second step. The same variables were independently associated with the occurrence of RI: decreased bowel wall enhancement , an emboli cause , complete occlusion of the SMA , and higher initial lactate levels .Based on these findings and after removal of the variable of lactate because of its lower weight, the rate of RI in the study population increased from 7% in patients with no predictive factors to 36%, 50%, and 81% in patients with 1, 2, and 3 factors, respectively Fig. . This CTp = 0.03). Transmural necrosis on pathology was found in 2/7 resected patients with RI and 1/2 patients without RI and resected. The remaining 6/9 patients had limited mucosal or submucosal necrosis. Mean resected bowel length was 80.0 cm (46–115) in patients with RI and 48 cm (16–80) in patients without RI (p = 0.33).Secondary bowel resection was required in 9/50 patients (18%), with a greater proportion in patients with RI  than in those without , with no difference according to the occurrence of RI ; Fig. In the 22 patients with RI, the median follow-up was 354 days (66–989). After one-year follow-up, 11/22 patients were alive (61%) and 4/22 were lost to follow-up. In the 11/22 alive patients, five patients had a normal bowel on CT, one patient had a persistent and isolated jejunal thickening on CT and five did not undergo a follow-up CT.This is the first study to evaluate RI in occlusive AAMI in humans. In this selected patient cohort, around 45% of the patients experienced RI, especially those who displayed a decreased bowel enhancement, a complete occlusion of the SMA on pre-treatment CT, in whom the cause was embolic and who presented with higher initial lactate serum levels. RI was also favored by an embolic cause, complete occlusion of the SMA, and higher initial lactate serum levels.Despite a substantial amount of preclinical data assessing the biological or pathological process of bowel RI , 20, no Symptoms  after revascularization may be considered signs of persistent ischemia (incomplete treatment). However, they may also be due to reperfusion injury. Interestingly, the lactate and WBC were not discriminant, but the CRP level significantly increased after treatment in patients with RI, possibly due to bacterial translocation, as described in preclinical ischemia–reperfusion models . These dReliable prediction of RI in cases of AAMI potentially will potentially improves patient management. We identified several factors that could be helpful in clinical practice. Decreased bowel wall enhancement on pre-treatment CT was the strongest predictive factor (hazard radio > 8.0). The diagnostic value of this finding has been well described in occlusive AAMI –51, althRI did not negatively influence patients’ short-term survival. However, the rate of secondary bowel resection was higher in patients with RI. This could be for two reasons. First, as discussed above, ischemia was more severe in patients with initial RI. Second, the clinical presentation  may lead to more frequent surgical exploration and thus bowel resection. This shows the difficulty of managing RI, and the need to raise awareness about this event, which is underestimated and still poorly understood in clinical practice . Thus, wOur study has certain limitations. First, the study design was retrospective, although it was based on a prospective institutional database. Moreover, the study cohort was relatively small due to the stringent inclusion and exclusion criteria  to exclude any possible confounders.n = 12). Thus, the risk of underestimating RI remains low.The absence of systematic follow-up CT can represent a bias. However, nearly half of the follow-up CT (24/50) were performed with the objective to evaluate the quality of the revascularization even in patients with normal clinical and biological parameters. We can hypothesize that these patients had a low probability of necrosis and consequently a low probability of RI (because RI patients had a higher Clichy score). Furthermore, the number of patients excluded from the analysis because of no follow-up CT is relatively low  may be discussed. It was defined as a complete or partial revascularization on the final angiogram which was purely arbitrary. Partial revascularizations may present as a large spectrum, from residual significant stenosis of the distal SMA to an occlusion of the third jejunal artery. However, technical success was not significantly associated with the occurrence of a reperfusion injury. Technical failure accounted in four patients and absent revascularization at control CT in eight patients. Therefore, four patients with technical success had a rethrombosis between the final angiogram and the control CT. This unfavorable evolution can occur and can be explained by multiple causes such as prothrombotic states (caused by systemic inflammation from AAMI), SMA intimal lesions , or insufficient anticoagulation/anti-platelet therapy.Finally, the study did not include a validation cohort; thus, the present results require further validation.In conclusion, RI is frequent following endovascular revascularization of occlusive AAMI. It is more frequent in patients with decreased bowel wall enhancement on pre-treatment CT, an embolic cause, and complete occlusion of the SMA, all features suggesting more severe ischemia. The rate of RI increases with the number of predictive factors. Nevertheless, the occurrence of RI does not impair short-term survival. Therefore, physicians and radiologists should be more aware of this entity to avoid unnecessary laparotomy and bowel resection.Additional file 1: Table. CT protocol for the assessment of mesenteric ischemia.


P = 0.736), but the procedure and ablation time were significantly longer . There was no significant difference in the change in TTE parameters and the number of rehospitalizations. For patients with PeAF and HF, CA appears to improve left ventricular function. Additional ablation does not improve outcomes and has a significantly longer procedure time. Trial registration number is as follows: ChiCTR2100053745 .The optimal catheter ablation (CA) strategy for patients with persistent atrial fibrillation (PeAF) and heart failure (HF) remains uncertain. Between 2016 and 2020, 118 consecutive patients with PeAF and HF who underwent the CA procedure in two centers were retrospectively evaluated and divided into the pulmonary vein isolation (PVI)-only and PVI + additional ablation groups. Transthoracic echocardiography (TTE) was performed at baseline, one month, and 12 months after the CA procedure. The HF symptoms and left ventricular ejection fraction (LVEF) improvements were analyzed. Fifty-six patients underwent PVI only, and 62 patients received PVI with additional ablation. Compared with the baseline, a significant improvement in the LVEF and left atrial diameter postablation was observed in all patients. No significant HF improvement was detected in the PVI + additional ablation group than in the PVI-only group (74.2% vs. 71.4%,  Heart failure (HF) remains a significant cause of mortality worldwide. Atrial fibrillation (AF) is a common type of arrhythmia in patients with HF . AF and For paroxysmal AF (PaAF), pulmonary vein isolation (PVI) has always been the cornerstone of CA, with a satisfactory success rate and reliable safety, since recognising the crucial triggering role of the pulmonary veins . HoweverThis was a multicenter, retrospective study of 118 consecutive patients with PeAF and HF who underwent their first CA procedure in the First Affiliated Hospital of Dalian Medical University and the Central Hospital of Zhuanghe City between January 2016 and December 2020. Patients with previous ablation procedures for AF, congenital heart diseases, or cardiac surgical atriotomy were excluded. Written informed consent was obtained from all enrolled patients. The local ethics committees approved this study.n = 56) and a PVI plus additional ablation group (Group B: n = 62)  .All patients received optimal HF management and at least three weeks of anticoagulation prior to the CA procedure. Antiarrhythmic drugs were discontinued for at least five half-lives. The presence of an atrial thrombus was excluded by transesophageal echocardiography (TEE) one day before or on the day of the procedure. During the CA procedure, a decapolar catheter was positioned in the coronary sinus for atrial pacing via the right femoral vein. Transseptal puncture guided by a modified Brockenbrough technique was carried out using 8 F long sheaths . An initial heparin bolus was given immediately following the transeptal puncture, and the target ACT was maintained at 300–350 seconds by continuous heparin infusion. A PV mapping catheter  was used for mapping PV potential. A saline-irrigated ablation catheter  was applied for mapping and ablation using electroanatomic mapping systems .The endpoint of CA for the PVI-only group was complete electrical PVI, as demonstrated by the absence of PV potentials or PV-left atrium conduction. A direct current electric conversion was performed, and then PVI was verified. In the PVI plus additional ablation group, additional ablation ) was performed to achieve a bidirectional block or to restore sinus rhythm. If the sinus rhythm was not restored, direct current electric conversion was carried out. If typical atrial flutter was documented before the procedure or induced during the procedure, cavotricuspid isthmus (CTI) ablation was performed.All patients were followed up monthly in the clinic for at least 1-year postablation. Anticoagulation therapy was prescribed for at least two months. All patients underwent standardized 2-dimensional transthoracic echocardiography (TTE) imaging at baseline, one month, and 12 months. The LVEF was determined according to Simpson's rule from left ventricular end-diastolic and end-systolic volumes in apical 5- and 2-chamber views. The parameters on TTE at postablation were calculated as the average of parameters at one month and 12 months. Successful CA was defined as no atrial tachycardia more than 30 s after the blanking period (3 months after the CA procedure) without antiarrhythmic drugs. The number of all-cause deaths and hospitalizations was obtained at 12 months. Thromboembolic and bleeding complications were also recorded.The definition of HF with recovered LVEF (HFrecEF) was consistent with the majority of studies in the literature, including the following: (1) the documentation of a decreased LVEF <40% at baseline, (2) >10% absolute improvement in the LVEF, and (3) a second measurement of the LVEF >40% .t-test or nonparametric Mann–Whitney U test was performed for comparisons between groups for quantitative data. For categorical variables, chi-squared tests or Fisher's exact tests were used. A 2-tailed P value <0.05 was considered statistically significant.Data analysis was performed with SPSS 22.0 . Quantitative data are expressed as the mean ± standard deviation (SD) if normally distributed and as the median  if nonnormally distributed. The homogeneity of variance was tested by the Kolmogorov–Smirnov Goodness-of-Fit test. Categorical data are expressed as frequencies and percentages. An unpaired A total of 118 patients  were included in this study. Among them, 56 (47.5%) patients underwent PVI-only ablation (Group A), and 62 (52.5%) patients received additional ablation (Group B). The baseline characteristics of these patients are shown in P=0.001; ablation time: 104.5 ± 7.8 min vs. 84.2 ± 7.9 min, P=0.001, For all patients, the procedure time was 130.6 ± 12.0 min, and the ablation time was 94.9 ± 12.8 min. The procedure and ablation time in the PVI + additional ablation group were significantly longer than those in the PVI-only group  patients received additional linear ablation , 23 (37.1%) patients received CTI, and 3 (4.84%) patients received linear ablation + CFAE ablation   to a postablation mean of 49.2% (49.2 ± 9.8%)  .P=0.27).Compared with the baseline, a significant improvement in the LVEF and left atrial diameter postablation was observed in all patients . HoweverIn the present study, we found that CA of AF for patients with HF and PeAF can significantly improve the LVEF and decrease the LA diameter. Compared with PVI only, additional ablation beyond PVI did not significantly improve the outcome of patients with HF and had a longer procedure time. Thus, PVI alone may be more appropriate for patients with HF and PeAF.Several RCTs have shown that rhythm control, especially CA, is superior to rate control for patients with HF and AF , 13. TheThe effect of CA on AF in patients with HF with preserved EF (HFpEF) is unclear. The restoration of sinus rhythm is critical for improving outcomes in patients with HFpEF . A subgrThe results and outcome of CA in patients with PeAF are currently unsatisfactory. It is well known that arrhythmogenic mechanisms beyond the pulmonary veins are often involved in patients with PeAF. The prevailing CA strategies beyond PVI for PeAF include targeting mechanisms and anatomical ablation, and recently, Zefferino Palam et al. have well summarized the current CA strategies in this article . CFAEs aIt seems that PVI alone is not sufficient for PeAF, but relevant clinical trials have demonstrated that PVI alone can serve as a sole strategy for PeAF. In the PRECEPT  trial, including patients with PeAF <1 year, the primary ablation procedure was PVI-targeted with an overall clinical success rate of 80%, although 45% of patients received additional ablation . These rThis study has some limitations. First, this is a retrospective study. However, most patients underwent the CA procedure within the last three years, and the procedures were performed by four experienced operators, and only 7.1% of patients were lost to follow-up, helping to minimize bias. Second, the sample size was limited, but there were relatively few patients with HF and PeAF who were willing to undergo CA. Third, ECG and 24-h Holter monitoring in the clinic, rather than an insertable cardiac monitor, have the potential to underestimate AF recurrence. Not all patients underwent 24 h Holter monitoring; thus, we cannot accurately measure AF recurrence. Fourth, this study did not mention some CA strategies, such as ablation of intramural ganglionated plexuses, Marshall ligament, and rotors, as they were not carried out in our center. Finally, a multipolar catheter that allows a better characterization of the atrial substrate, such as PentaRay, was not used in all patients in our study.For patients with PeAF and HF, CA appears to improve the left ventricular function. Additional ablation beyond PVI is common in CA of PeAF; however, it does not improve outcomes and had a significantly longer procedure time. Therefore, PVI alone may be more appropriate for patients with HF and PeAF.


Staphylococcus aureus, is associated with significant morbidity and mortality. Blood purification using haemoadsorption (HA) may attenuate the inflammatory response. We investigated the effect of intraoperative HA on postoperative outcomes in S. aureus IE.Sepsis caused by infective endocarditis (IE), due to S. aureus IE undergoing cardiac surgery were included in a dual-centre study between January 2015 and March 2022. Patients treated with intraoperative HA (HA group) were compared to patients not treated with HA (control group). The primary outcome was vasoactive-inotropic score within the first 72 h postoperatively and secondary outcomes were sepsis-related mortality (SEPSIS-3 definition) and overall mortality at 30 and 90 days.Patients with confirmed n = 75, control group, n = 55). Significantly decreased vasoactive-inotropic score was observed in the haemoadsorption group at all time points . Importantly, sepsis-related mortality  and 30-day  and 90-day overall mortality  were also significantly lower with haemoadsorption.No differences in baseline characteristics were observed between groups  is the leading cause of IE, and the significantly increased mortality rate has remained high despite increasingly effective diagnostic and therapeutic procedures .Postoperative sepsis followed by organ failure is an important cause of morbidity and mortality in patients undergoing cardiac surgery for infective endocarditis (IE) [1].  Staphylococcus aureus (S. aureus) is the leading cause of IE, and the significantly increased mortality rate has remained high despite increasingly effective diagnostic and therapeutic procedures . Finally, cardiac device-related IE requiring simple retraction without cardiopulmonary bypass (CPB) or isolated tricuspid IE was excluded. EuroSCORE II was calculated using the online calculator . The study was performed in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines and was reviewed and approved by the institutional ethics committee and Institutional Review Board (19-8743-BO) in Essen and by the Institutional Study Centre (SZ_W_134.21-I-6) and Institutional Review Board (IRB-2021-031) in Nuremberg. An informed consent was waived due to anonymity.Eligible participants for the study included consecutive patients operated on for definite IE according to the modified Duke criteria (2 major or 5 minor or 1 major + 3 minor criteria) at the 2 participating centres  between January 2015 and March 2022. The present analysis was a retrospective evaluation of prospectively collected data. Only patients with HA being intraoperatively applied were included in the present analysis. The final study population was then limited to patients with blood culture-confirmed systemic The primary outcome was haemodynamic stability during the postoperative course over the first 72 h, defined by the vasoactive-inotropic score (VIS). Secondary outcomes included the incidence of sepsis-related mortality (according to SEPSIS-3 guidelines) , 30- andThe VIS was calculated using the following formula: VIS = dopamine dose (μg/kgBW/min) + dobutamine dose (μg/kgBW/min) + 100 × epinephrine dose (μg/kgBW/min) + 100 × norepinephrine dose (μg/kgBW/min) + 10 × milrinone dose (μg/kgBW/min) + 10 000 × vasopressin dose (IU/kgBW/min) as a dimensionless unit.® , was installed in a parallel circuit of the CPB machine during the surgical procedure at a flow ranging between 100 and 700 ml. Concomitant pathologies, although not related to IE, were treated simultaneously .Cardiac surgery was performed under general anaesthesia and endotracheal intubation. Preoperative transoesophageal echocardiography was performed to evaluate cardiac and valvular function. Standard aortic and caval cannulation techniques were applied. Intraoperative HA was routinely used in all consecutive patients since 2018. In the cases selected for intraoperative HA, a HA device, Cytosorb® is based on the extracorporeal blood purification that reduces excessive levels of inflammatory mediators with the aim of modulating the exaggerated immune response by reducing elevated levels of circulating cytokines and mitigating their detrimental downstream effects. In addition to removing cytokines, HA is able to remove S. aureus toxin and haemolysin from blood [® can be easily integrated into various extracorporeal circuits, such as continuous renal replacement therapy, CPB and extracorporeal membrane oxygenation. The device is filled with highly biocompatible, porous polymer beads covered with a divinylbenzen coating. Each polymer bead is between 300 and 800 μm in size and has pores and channels, giving it a large (40 000 m2) effective surface area for binding hydrophobic small- and middle-size molecules. Figure HA therapy with CytoSorbom blood . CytoSort-test or the Wilcoxon rank-sum test. Categorical data were expressed as number of patients and frequencies and compared using the chi-squared test. A P-value of <0.05 was considered statistically significant.Data were analysed using SPSS software version 25 . Continuous variables were expressed as mean standard deviation (SD) and the SOFA and VIS were presented as median and interquartile range, respectively, and compared using Student’s S. aureus infection. Seventy-five patients received intraoperative HA , while 55 patients operated on without HA served as controls . Preoperative baseline characteristics of the patients and types of valves affected are displayed in Table P = 0.27). The mean duration of preoperative antibiotic treatment was 11.5 (SD: 10.2) days versus 9.7 (SD: 8.3) days (P = 0.47) in the HA and control groups, respectively. Before induction of anaesthesia, 9 patients in the HA group and 8 in the control group were intubated and about 12% of the patients in both groups needed vasopressor or inotropic therapy. There were no statistical differences in terms of baseline demographics, comorbidities or preoperative haemodynamic and pulmonary status. Overall, 82 valves in the HA group and 68 valves in the control group were affected. Combined procedures were equally represented in both groups. In all patients, MSSA or MRSA was confirmed.From January 2015 to March 2022, a total of 130 patients underwent cardiac surgery with CPB for IE with confirmed Table P < 0.05 for all timepoints). The relative reductions in VIS also remained consistent over 72 h ranging between 59% and 82%. Sepsis-related death occurred in 6 patients in the HA group and in 12 patients in the control group (P = 0.02). Overall mortality was 17.3% in the HA group and 32.7% in the control group at 30 days (P = 0.03) and 21.3% vs 40.0% at 90 days (P = 0.03). This corresponds to a number needed to treat of 5 patients to save 1 life (at 90 days) and a relative mortality risk reduction of 46.8% compared to standard therapy. All secondary outcomes are summarized in Table The primary outcome was the vasopressor requirement for postoperative haemodynamic stabilization within the first 72 h after surgery. Cumulative vasopressor requirements were assessed using the standardized VIS and are summarized in Fig. P = ns). New, postoperative renal failure requiring haemodialysis developed in 38 patients, 16 in the HA group and 22 in the control group (P = 0.03). Re-operation for bleeding was required in 7 patients in the HA group and 12 patients in the control group (P = 0.07). Respiratory failure requiring reintubation occurred in 16 patients, 10 in the HA group and 6 in the control group, P = 0.79. There were no clinically relevant differences in the intensive care unit and hospital lengths of stay between the groups. All postoperative outcome parameters are shown in Table Postoperative parameters showed that mechanical circulatory support with extracorporeal membrane oxygenation was necessary in 4 patients, 2 in each respective group. Intra-aortic balloon pump support was applied in 4 patients, again 2 from each group. A new stroke occurred in 3 patients from the controls and 5 patients from the HA group . Second, intraoperative HA was easy to use, safe and significantly reduced postoperative vasopressor and inotropic requirements. Third, the use of intraoperative HA was associated with significantly fewer sepsis-associated deaths and resulted in significantly lower overall mortality.There were 3 main observations in the current study. First, patients undergoing cardiac surgery for acute S. aureus. Especially in patients suffering from endocarditis caused by Staphylococcus species, results are devasting compared to other bacteria [S. aureus is mainly defined by a huge repertoire of virulence factors, among which secreted toxins play a preeminent role [® is known to remove hydrophobic substances up to 60 kD, which also applies to the toxin of S. aureus as the potential underlying mechanism for postoperative sepsis and complications. Therefore, we hypothesized that removal of the S. aureus toxin could potentially result in improved haemodynamics in IE patients suffering from S. aureus endocarditis.To the best of our knowledge, this study is the first to evaluate the effect of intraoperative HA exclusively in patients with IE based on bacteria . In patibacteria , 15. Theent role . HA therS. aureus is associated with high rates of postoperative sepsis and increased mortality [Staphylococcus caused IE patients [S. aureus IE patients. Furthermore, this difference in mortality was reinforced by the favourable haemodynamic parameters in patients receiving intraoperative HA. As shown in Fig. et al. [et al. [IE caused by ortality , 17. A rpatients . Within . et al.  and Robe [et al. , demonst [et al. . In line [et al. .S. aureus, might help to select the most responsive patients for adjunctive HA.Meanwhile, the results of the multicentre randomized-controlled REMOVE study  have been published . The priP = 0.03). Furthermore, although failing to reach a statistically significant difference, patients from the HA group experienced less re-thoracotomies for bleeding (P = 0.07). Especially in patients presenting with IE the coagulation system is heavily affected and sometimes impaired leading to various types of coagulopathies [It is well accepted that patients with IE have an increased risk of postoperative renal failure , 25. In opathies .Staphylococcus per se is known as a destructive, dangerous, and versatile pathogen. In our cohort, we observed no differences in the preoperative risk profile of the patients, although they were not randomized, and all patients had definitive MRSA/MSSA infection. Recently, the current recommendations for surgical treatment of IE were reviewed by Wang and Fosbol [S. aureus, Wang and Fosbol concluded that in the prospective, multinational International Collaboration on Endocarditis registry of IE, S. aureus IE complicated by sepsis was not generally treated with surgery as S. aureus IE is associated with more frequent and severe complications. On the contrary, the majority of patients in the present study had an uncontrolled infection, severe regurgitation or fever on preoperative examination despite antibiotic pretreatment, implying liberal surgical indication as well as advanced complexity of the operated cohort.d Fosbol . RegardiS. aureus IE. Although this study was not a randomized controlled trial, both groups were comparable, but a selection bias cannot be completely excluded. In addition, groups were not adjusted by any possible confounder, which might also influence the results. In fact, also the time between diagnosis and treatment as well as the preoperative antibiotic treatment interval might influence the results. Beside this, it should be acknowledged that within the present work, by nature, only the SOFA scores of the survivors could be used for final evaluation. In the present analysis, we calculated the SOFA score for each postoperative day individually and it was not used as the primary outcome. Moreover, in the present analysis, we failed to present a detailed panel of postoperative cytokines. Nevertheless, to our knowledge, this is the first study to date investigating intraoperative HA in a subset of S. aureus IE patients. Finally, non-contemporary time bias throughout the time period of the present analysis cannot be completely ruled out and future larger trials might include post hoc matching tests.Our retrospective study focused on the effects of intraoperative HA on haemodynamics and postoperative outcomes in patients undergoing cardiac surgery with S. aureus, focusing on the postoperative need for vasopressor and inotropic support. This was based on our hypothesis that the removal of S. aureus endotoxin could be achieved by HA, which could be the cause for postoperative vasoplegia and poor outcomes. We could show that intraoperative HA appears to attenuate the severity of postoperative sepsis, reducing not only the need for vasopressors but also 30- and 90-day mortality in patients undergoing cardiac surgery for IE caused by S. aureus. Future studies are essential to confirm the current results in a larger population and to investigate the mechanisms underlying these effects.In conclusion, this study aimed to evaluate the outcome of patients with IE caused by Conflict of interest: Prof. M. Thielmann received speake’s fee for participation at Cytosorbents Symposium during 36th EACTS annual meeting, Prof. D. Wendt has been employed by Cytosorbents Inc. since January 2022.


Intensive care unit (ICU) nurses are at high risk of burnout and warranting attention. Existing literature found that work frustration was related to burnout, whilst perceived organization support influenced the association of work frustration with burnout. The purpose of this study was to investigate the relationship of work frustration and burnout among ICU nurses, and to examine the moderating effect of perceived organization support in their relationship.The cross-sectional study was conducted with a convenience sample of 479 ICU nurses from several 3 tertiary hospitals during December 2021 to May 2022. The Maslach Burnout Inventory-Human services survey (MBI-HSS), National Aeronautics and Space Administration Task Load Index (NASA-TLX) and perceived organization support Scale (POSS) were used to collect data. The PROCESS macro was performed to test the moderation effect of perceived organization support.r = 0.301, P < 0.001) and negatively correlated with perceived organizational support . The moderation model analysis showed that perceived organizational support could moderate the relationship between work frustration and burnout .The total score of burnouts was (55.79 ± 17.20), the total score of work frustration was (7.44 ± 1.86). Burnout was positively correlated with work frustration (The findings highlight the moderating role of perceived organizational support in the relationship between work frustration and burnout. Hence, interventions to reduce burnout among ICU nurses should consider targeting organizational support and work frustration.The online version contains supplementary material available at 10.1186/s12912-023-01180-5. Burnout is generally described as a long-term response to unmanageable work stress and a syndrome of cynicism and professional ineffectiveness, characterized by high sense of emotional exhaustion and depersonalization and low sense of personal accomplishment . AlthougPrevious studies have revealed several demographic and work-related variables linked to burnout among ICU nurses, such as age, gender, marital status, income satisfaction, work experience, professional title, and night shift –5. For iThe job demands–resources (JD-R) model proposes two relatively independent processes that job demands and resources may evoke health impairment and employee motivation, respectively . This moPerceived organizational support, as a valued job resource, refers to employees’ evaluation of the extent to which the organization help, affirmation and concern about their presence in the organization. According to theoretical and empirical evidence, perceived organizational support can produce a sense of responsibility and obligation to help the organization achieve goals, foster employee’s enthusiastic and positive work attitude , 24. MorIn light of the conceptual frameworks and practical concerns, the present study aimed to examine two hypotheses in Chinese nurses: (1) work frustration could be positively associated with burnout, and (2) perceived organization support could moderate the direct association between work frustration and burnout.α/2)2P(1-P)/δ2 and a twenty percent attrition rate [α/2 = 1.96, and δ = 0.05, whereas P was set as 0.5 due to large differences in the prevalence of burnout in nurses reported in previous studies and availability of maximum sample size. All ICU nurses who had obtained professional certificates and were independently responsible for clinical work. The exclusion criteria were as follows: (1) ICU nurses in departments with fewer than eight beds, (2) nurses who had worked less than one year, (3) nurses who were on vacation or going on leave to study, and (4) nurses who worked in both the ICU and the wards at the same time. ICU that had less than eight critical care beds typically do not care for ventilated patients for more than 24 h. Besides, according to guidelines for intensive care unit (ICU) construction and management in China 2006 edition [This study was a cross-sectional design and adhered to the STROBE statement. A convenience sample of ICU nurses was recruited from several tertiary hospitals in urban areas of Jinan, China between December 2021 and May 2022. The sample size was calculated as 462 based on the formula: N =  was used to assess nurses’ perception of work frustration. The NASA-TLX is primarily a measure of how an individual experiences the situational demands of work , 34. It The 8-item Chinese vision of the Survey of perceived organization support , 38 was The Chinese version of Maslach Burnout Inventory-Human services survey (MBI-HSS) was used to measure nurse’s burnout , 42. TheData analysis was conducted by SPSS version 26.0 . Mean, standard deviations or frequency, percentages were used to describe the characteristics of participants. Independent t test and analysis of variance analysis (ANOVA) were used to examine the differences in burnout and work frustration between sample characteristics. Pearson’s correlations were used to examine the associations among burnout, work frustration and perceived organizational support.P values reported were two tailed, and P value less than 0.05 was considered significant.The moderation model was conducted using the SPSS PROCESS V3.5 macro developed by Hayes. Model 1 was used to examine the moderation role of organizational support on the effect of frustration on burnout . The simThe demographic characteristics of ICU nurses were presented in Table Further analysis of differences in three subscales of burnout between sociodemographic characteristics showed in Supplementary Table Sr = 0.301, P < 0.001) and negatively associated with perceived organizational support . Besides, work frustration was negatively associated with perceived organizational support .Mean and standard deviations for the variables and correlations between the variables were shown in Table β = -0.152, P = 0.007) significantly accounted for 1.1% variance of burnout with a small effect size (f2 = 0.015). The pick-a-point method  significantly accounted for 1.8% variance of emotional exhaustion with a small effect size (f2 = 0.03). The pick-a-point method  to improve the conditions of their working environments and decrease their work frustration among ICU nurses. Perceived organization support was not only related to low level of burnout, but could also buffer the negative effect of work frustration on burnout. Thus, it could reduce ICU nurses’ burnout by providing nurses with organizational supports through demonstrating publicly to ICU nurse that the organization cares about their welfare, values their opinions, and is proud of their achievements .f2 = 0.015) in this study. Further validation by large sample size is warranted. In addition, self-reported results might be subject to information bias.Despite these Strengths, several limitations should be mentioned. First, due to the cross-sectional study design and small sample size, the causal inference among study variables and the generalizability of the results are limited. Hence, future research can be improved by longitudinal studies with larger multicenter sample size. Second, a single-item measurement was adopted to capture work frustration, which may limit the validity of the study findings. Future studies that employ a more comprehensive measurement of work frustration would further facilitate the understanding of the relationships addressed in this study. Third, the size of interaction effect detected is small . Table S2. Moderation model (n=479). Table S3. Conditional effects of work frustration on emotional exhaustionat different levels of organizational support (n=479). Fig.S1. The conditional effect of work frustration on emotional exhaustion at thevalues of perceived organizational support.


Adrenal mixed corticomedullary tumors (MCMTs) are single tumor masses composed of an intimately admixed population of both adrenal cortical cells and medullary components. Most medullary tumor components are pheochromocytomas; however, MCMTs composed of ganglioneuroma and adrenal cortical adenoma are extremely rare. The current case is a rare case of adrenal MCMT composed of ganglioneuroma and adrenal cortical adenoma with primary aldosteronism.A 49-year-old male was admitted because of hypokalemia and an adrenal mass. He was diagnosed with hypertension in his 20s and was taking blood pressure medications.Plasma aldosterone concentration 376.5 pg/dL  and potassium 2.8 mmol/L  were detected. The aldosterone-to-renin ratio [the ratio of plasma aldosterone concentration (ng/dL) to PRA (ng/mL/hour)] was 38. The saline loading test showed that serum aldosterone (49.4 ng/dL) was not suppressed, compared with the basal level (28.4 ng/dL). The adrenal venous sampling test showed that the aldosterone level markedly increased to 1521.2 pg/mL. Abdominal computed tomography revealed an enlarged relatively well-circumscribed multinodular mass (35 × 13 × 30 mm) in the right adrenal gland.Laparoscopic right adrenalectomy was performed under the clinical diagnosis of a functioning adrenal cortical adenoma.After laparoscopic right adrenalectomy, the serum aldosterone and renin levels returned to normal. The patient maintained a normal aldosterone level without recurrence for 16 months.Adrenal MCMTs of the ganglioneuroma and cortical adenomas in the ipsilateral adrenal gland are extremely rare. Adrenal MCMTs exhibit benign clinical behavior, with no metastasis or death due to the tumor. With the development of diagnostic imaging technology, it is possible to identify mixed tumors. However, surgical resection of adrenal gland is a common treatment and a final diagnosis should be made based on the pathological results after surgery. Because this is to rule out the occurrence of rare malignant tumors and confirm the pattern of mixed tumors. Ganglioneuroma (GN) is an asymptomatic benign tumor that occurs along the paravertebral sympathetic ganglia and rarely occurs in the adrenal medulla. Owing to its asymptomatic and hormonally silent nature, most cases are incidentally detected during imaging for unrelated reasons. Adrenal cortical adenoma, which is considered to be the most common component, is usually nonfunctional. However, when the tumor is functional, increases in testosterone, cortisol, and aldosterone may be induced.Adrenal mixed tumors comprise 2 histologically distinct adrenal tumors with a low incidence rate. Depending on whether it is an adrenal cortical or medullary component, adrenal mixed tumors are divided into composite tumors and mixed corticomedullary tumors (MCMTs).MCMT is an even rarer form and is composed of both adrenal cortical cells and medullary tumors. Here we report a rare case of a mixed adrenal tumor composed of functioning adrenal cortical adenoma and GN.A 49-year-old male presented to the hospital with gastrointestinal symptoms. On physical examination, the patient’s condition was normal. During the hospital examination, hypokalemia and adrenal mass were incidentally discovered. In his 20s, he was diagnosed with hypertension and taking blood pressure medication. An aldosterone test was performed to determine the cause of hypokalemia. Plasma aldosterone concentration 376.5 pg/dL , plasma renin activity (PRA) 0.9 ng/mL/hour , sodium 142 mmol/L , potassium 2.8 mmol/L  were detected. The aldosterone-to-renin ratio, the ratio of plasma aldosterone concentration (ng/dL) to PRA (ng/mL/hour), was 38. The saline loading test showed that serum aldosterone (49.4 ng/dL) was not suppressed, compared with the basal level (28.4 ng/dL). The adrenal venous sampling test showed that the aldosterone level markedly increased to 1521.2 pg/mL. Abdominal computed tomography (CT) reveals a 3.5 cm-sized, well-circumscribed, lobulated mass with heterogeneous enhancement and punctate calcification in the right adrenal gland  and cortical adenoma in the ipsilateral adrenal gland, suggesting that the adenoma was cortisol-producing. Simultaneous occurrence of adrenal cortical adenoma and GN with normal levels of aldosterone and renin, was reported by Rodriguez-Justo et al Lau presented with an unusual MCMT of the adrenal gland  with a history of hypertension for 15 years, controlled with medication.Takahashi et al presented a gonadotrophin-responsive virilizing adrenal tumor identified as a mixed GN and adrenal cortical adenoma in 1978. The adrenal mass was a circumscribed irregularly lobulated mass that was histologically GN containing numerous scattered groups of large polyhedral cells. After removal of the right adrenal tumor, the high serum testosterone level decreased to normal within 24 hours.,9 Three MCMT cases had composite pheochromocytoma-GN as medullary tumor with cortical adenoma.–11 These included 3 males and 3 females. Age ranged from 38 to 69 years old (mean 52.8 years old). The tumor diameter was 2.5 to 16.0 cm (mean 5.9 cm). There was 1 case each with increased testosterone, cortisol and aldosterone levels, and 2 patients had a history of hypertension  to characterize and treat MCMT.Writing – original draft: Yoo Na Kang.


This study aims to examine the effect of undernutrition on loss to follow-up (LTFU) in adults living with human immunodeficiency virus (HIV) receiving antiretroviral therapy (ART) in Ethiopia. We conducted an institution-based retrospective cohort study using medical records of 844 adults living with HIV receiving ART between June 2014 and June 2020 at Debre Markos Comprehensive Specialized Hospital (Northwest Ethiopia). The effect of undernutrition on LTFU was examined using a proportional hazards regression model after adjusting potential confounders. The significance level was set at p < 0.05. At the end of the study period, 109 (12.9%) participants were considered LTFU, with an overall LTFU incidence of 5.3 per 100 person-years . The incidence of LTFU was higher in undernourished participants (8.2 per 100 person-years) compared to well-nourished participants (4.3 per 100 person-years). After adjusting for potential confounders, the adjusted risk of LTFU among undernourished participants was two times higher than in their well-nourished counterparts . This study found that undernutrition significantly increased the risk of LTFU among adults living with HIV on ART. Ethiopia is one of the SSA countries with a high prevalence of HIV2. Although there is no cure for HIV infection, antiretroviral therapy (ART), a combination of three or more antiretroviral drugs, enables PLHIV to live longer, healthier lives3. Since 2016, all PLHIV have been eligible to start ART as soon as possible, regardless of their clinical status3. As of December 2020, 25.7 million (73%) PLHIV were on ART worldwide1.Although the human immunodeficiency virus (HIV) is a global public health concern, sub-Saharan Africa (SSA) is the most affected region. Of the 37.7 million people living with HIV (PLHIV) worldwide in 2020, more than two-thirds (67%) were from SSA5, including SSA6. A collaborative analysis has shown that 18.8% of adults living with HIV in SSA were lost to ART follow-up7. A systematic review and meta-analysis from Ethiopia found that LTFU among adults living with HIV was 15.2% throughout follow-up8. LTFU has been associated with various unfavourable treatment outcomes, such as frequent hospitalizations, high risk of treatment failure, high rate of mortality, and high risk of opportunistic infections (OIs)9. SSA based studies have shown that the most common risk factors of LTFU in adults living with HIV are poor ART adherence, being younger, being male, not disclosing HIV-status, advanced World Health Organization (WHO) clinical disease stage (III and IV), low CD4 cell count, not taking co-trimoxazole preventive therapy (CPT), not taking isoniazid preventive therapy (IPT), and being undernourished14.Despite the dramatic increase in access to ART, high rates of loss to follow-up (LTFU) remain a significant challenge, especially in resource-limited settings, with HIV-care related LTFU emerging as a public health issue in low- and middle-income countries (LMICs)18. Undernutrition may indirectly increase the risk of LTFU as it accelerates disease progression from HIV to acquired immunodeficiency syndrome (AIDS) and increases the occurrence and recurrence of OIs20. Undernourished patients may not return to the health facility for ART refill and miss their appointments due to frequently being sick or feeling generally unwell21. However, a Ugandan study showed that overweight (BMI > 30 kg/m2) participants are at lower risk of LTFU22. This could be explained as being overweight is the leading risk factor of non-communicable diseases (NCDs), especially hypertension and diabetes23. Overweight HIV-infected patients may benefit from the program, as regular health education on medication adherence is a component of care for patients with NCDs24.Various studies conducted in Africa have shown that undernutrition is significantly associated with a higher risk of LTFU in adults living with HIV receiving ART25. To meet this ambitious target, optimizing retention in ART care is an effective strategy. In line with this agenda, the Ethiopian government has adapted various strategies to reduce LTFU in PLHIV, such as adherence support through phone calls and tracing patients who have missed their appointments. Despite these interventions, LTFU from ART is still a significant challenge for health care professionals. As mentioned above, undernutrition is one of the main factors significantly associated with LTFU among PLHIV. Understanding the impact of undernutrition on LTFU is essential for designing and implementing evidence-based interventions. However, studies examining the impact of undernutrition on LTFU in this population are scarce in SSA, and none has been conducted in Ethiopia. Thus, this study aimed to examine the impact of undernutrition on LTFU in adults living with HIV receiving ART by considering undernutrition as an exposure variable. The findings of this study will help clinicians to develop targeted interventions to reduce undernutrition related LTFU. It will also inform further interventional studies.The United Nations Sustainable Development Goal (SDG #3) aimed to end the epidemic of HIV/AIDS by 203027. DMCSH is the only referral hospital in the East Gojjam Zone in the Amhara Region, located 300 km from Addis Ababa, the capital of Ethiopia, and 255 km from Bahir Dar, the capital of the Amhara region. It serves over 3.5 million people in East Gojjam Zone and neighbouring zones. The hospital commenced offering chronic HIV care and ART services in 2005. Out of the total 1209 PLHIV who started ART at DMCSH between June 2014 and June 2020, 1177 (97.4%) were adults. Adulthood was defined as patients’ ≥ 15 years of age since this population is considered and treated as adults in Ethiopia for treatment purposes.This study used a part of data came from a large retrospective cohort study conducted to examine the effects of undernutrition on treatment outcomes among adults living with HIV on ART between June 2014 and June 2020 at Debre Markos Comprehensive Specialized Hospital (DMCSH), Northwest Ethiopia. Therefore, the detailed methodology was described in our previously published two papers28. Patients were excluded from the study if they were transferred to DMCSH without baseline information and without a recorded date for the outcome of interest (LTFU). Furthermore, pregnant women were excluded as the nutritional assessment is different from other HIV-positive adults29.The study population was all adults living with HIV who started ART at DMCSH between June 2014 and June 2020 and received ART for at least one month. All patients aged 15 years or older were defined as adults, consistent with the Ethiopian ART treatment guidelines30. Undernourished participants were considered as the exposed group, and their well-nourished counterparts were considered as the unexposed group. The following parameters were taken into consideration: proportion of unexposed (well-nourished) group with lost to follow-up (P0 = 19%); proportion of exposed (undernourished) group with lost to follow-up (P1 = 27%); r of 1:1; α of 5%; power of 80%; and Zα/2 of 1.96. The P0 and P1 values were taken from a previous Ethiopian study10. The sample size calculated based on the above parameters was 802. Allowing for 10% contingency, the records of 892 study participants were selected from the total records of HIV-positive adults who started ART at DMCSH between June 2014 and June 2020 (n = 1177) using a computer-generated simple random sampling technique. Initially, a list containing the medical registration number (MRN) of all adults living with HIV initiated ART between June 2014 and June 2020 was obtained from the health management information system unit of the DMCSH. Then, a random number was generated for each patient using Microsoft™ Excel. Lastly, randomly generated numbers were used to select a sample of 892 participants from all adults living with HIV who started ART at DMCSH between June 2014 and June 2020. The final sample included 844 records after 48 records were excluded  level. Variables extracted from the follow-up data included ART eligibility criteria, ART regimen, OIs during follow-up, ART adherence, regimen change, CPT, IPT, treatment failure, and patient outcomes. Sociodemographic measurements recorded at ART initiation were considered as baseline data. However, for other variables, such as laboratory tests, the most recent values were used as predictors. Two epidemiologists specialized in HIV currently working at DMCSH were recruited as data collectors.28. At the end of follow-up, participants were classified as event (lost) or censored (not lost). Censored was considered when participants died or were still alive under ART at the end of follow-up (30th of June 2020) or formally transferred to other health facilities. The follow-up time was calculated in months from the date of ART initiation until the date of event (LTFU) or censoring (other than lost).The outcome of this study was the occurrence of loss to follow-up (LTFU) after ART initiation. LTFU was defined as patients missing an ART appointment for at least one month231. All participants (n = 227) with a BMI of below 18.5 kg/m2 were the exposure group of this cohort.Undernutrition was diagnosed when participants had a body mass index (BMI) below 18.5 kg/mCovariates (confounders) included sociodemographic variables, clinical and immunological variables, and follow-up variables, as mentioned in the data collection section.32. Family size refers to the number of individuals in the family. Family size was classified as < three or ≥ three standards established by previous research33.Residency was classified as urban and rural. Under the Ethiopian Central Statistical Agency (CSA), urban is considered if the local area contains 2000 or more inhabitants. In addition, urban areas include all administrative capitals of regions, zones, and woredas (districts), with at least 1000 people primarily engaged in non-agricultural activities or areas that the administrative official declares to be urban28. ART adherence was classified as good, fair, or poor, calculated from the total monthly dose of ART drugs (n = 60). Good is compliance equal to or greater than 95% or ≤ 3 missed doses per month; fair is defined as 85–94% compliance or between 4 and 8 missing doses per month; and poor as compliance of less than 85% or ≥ 9 missed doses per month28.Disclosureof HIV status was recorded as disclosed and not disclosed. According to current Ethiopian ART guidelines, patients are considered as disclosed their HIV status if they have disclosed their HIV status to at least one person 28.Functional status was classified as working, ambulatory, and bedridden. Working was defined as being capable of going out of home and do routine activities, including daily work. Ambulatory was defined as capable of self-care and being able to use the toilet unsupported. Bedridden was defined as incapable of basic self-care 3), mild immunosuppression (CD4: 350–499 cells/mm3), advanced immunosuppression (CD4: 200–349 cells/mm3), and severe immunosuppression (CD4 < 200 cells/mm3)34. In addition, the WHO has implemented a clinical staging system based on clinical symptoms beyond CD4 cell count listed herein28:Clinical stage I Usually asymptomatic, except persistent generalized lymphadenopathy.Clinical stage II One of the following clinical presentations is present: moderate unexplained weight loss (5–10% of presumed or measured body weight), recurrent upper respiratory tract infections , herpes zoster, angular cheilitis, recurrent oral ulceration, papular pruritic eruption, fungal nail infections, and seborrheic dermatitis.Clinical stage III At least one of the following conditions is present: unexplained severe weight loss (> 10% of presumed or measured body weight), unexplained chronic diarrhoea > one month, unexplained persistent fever (intermittent or constant > one month), persistent oral candidiasis, oral hairy leucoplakia, pulmonary tuberculosis, severe bacterial infections , acute necrotizing ulcerative stomatitis, gingivitis or periodontitis, unexplained anaemia, neutropoenia, and/or chronic thrombocytopaenia.Clinical stage IV At least one of the following severe conditions is present: HIV wasting syndrome, pneumocystis jirovecii, recurrent severe bacterial pneumonia, chronic herpes simplex infection , oesophageal candidiasis , extra pulmonary tuberculosis, Kaposi sarcoma, cytomegalovirus infection (retinitis or infection of other organs), central nervous system toxoplasmosis, HIV encephalopathy, extra pulmonary cryptococcosis, disseminated non-tuberculous mycobacterial infection, progressive multifocal leukoencephalopathy, chronic cryptosporidiosis, chronic isosporiasis, disseminated mycosis , lymphoma , symptomatic HIV-associated nephropathy or cardiomyopathy, recurrent septicaemia , invasive cervical carcinoma, and atypical disseminated leishmaniasis.The WHO staging of HIV has four levels to determine the degree of immunodeficiency based on CD4 cell count: no significant immunosuppression . Moreover, we checked the patterns and mechanisms of missing values. Variables included in the imputation model were sex, residence, WHO clinical disease staging, ART adherence, nutritional status, baseline OIs, CPT, and IPT. Finally, diagnostic plots for multiple imputation were employed to assess the distributions of observed, imputed, and completed data (multiple imputation diagnostic test).Data for 208 (24.6%) CD4 cell counts and 50 (5.9%) haemoglobin (Hgb) levels were not available from patient records. Multiple imputation (MI) was undertaken using a multivariate normal imputation model. Before MI, Little’s MCAR test2) tests were used to compare the frequencies of sociodemographic, clinical, and follow-up characteristics between undernourished and well-nourished groups. The Kaplan–Meier survival curve was used to visualize the survival time of loss to follow-up. A generalized log-rank test was used to compare survival curves between undernourished (exposed) and well-nourished (non-exposed) groups. Bi-variable and multivariable proportional hazards regression models were fitted. The proportionality assumption of the proportional hazards regression model was assessed using the Schoenfeld residual test. In the bi-variable analysis, variables with p-values ≤ 0.25 were included in the multivariable analysis for adjusting confiders. Results from the final model were reported as adjusted hazard ratios (AHRs) with 95% confidence intervals (CIs). The significance level was set at p < 0.05. All statistical analyses were carried out using Stata™ Version 16.Chi-square , and the Amhara Regional Public Health Research Ethics Review Committee (Ref. no: 816). All methods were performed in accordance with the relevant guidelines and regulations. As the study was based on existing medical records of PLHIV, participants' verbal or written informed consent was not feasible, and a waiver of consent was granted. Data were entirely de-identifiable for the authors and data collectors, as the data abstraction tool did not include participants’ unique ART numbers and names.Of the 844 participants included in the final sample, more than three-quarters  were from urban areas. The cohort included 227 (26.9%) undernourished and 617 (73.1%) well-nourished participants. The median age of participants at ART initiation was 32 years (IQR: 26–40). More than half  were female, 18.3% (n = 154) had never married, and 25.8% (n = 218) had attended at least primary school. Homemakers accounted for 16.9% (n = 143) of the sample; 66.9% (n = 565) had disclosed their HIV-status, and 55.3% (n = 447) were from a family of less than three people (see Table Forty percent (n = 337) of patients had at least one opportunistic infection at ART initiation, and most  participants were classified as working functional status. Nearly a third  had severe immunodeficiency, and 43.7% (n = 369) were in WHO clinical stage I. The majority  of patients were not anaemic at ART initiation. More than half  started ART through a test and treat approach. Most participants  started an Efavirenz-based ART regimen, and 31.4% (n = 264) had a regimen change from baseline. CPT and IPT was not received by 26.9% (n = 227) and 37.6% (n = 317) of participants, respectively. During the study period, 23 (2.7%) patients experienced ART treatment failure, and 267 (31.6%) patients developed new OIs  of participants had died, 12.9% (n = 109) were lost to follow-up, 18.6% (n = 157) were transferred out to other health facilities, and 61.0% (n = 515) were alive and on ART   in undernourished participants was higher compared to well-nourished participants (4.3 per 100 person-years); with the risk of LTFU in undernourished patients, being double that of well-nourished patients.36. However, our finding is lower than studies conducted in Uganda (7.5 per 100 person-years)22 and Ethiopia (10.9 per 100 person-years)10. The above variations might be due to differences in sample sizes, follow-up periods, study settings, and population characteristics. In this regard, the follow-up periods of Ugandan22 and previous Ethiopian studies10 were three and four years, respectively. The follow-up period of our study was six years. In addition, our study included a referral hospital, whereas the Ugandan study included both hospital and health centres. Therefore, the lower LTFU rate in this study might be due to the differences in the quality of care provided at hospitals and health centres, as hospitals provide advanced care and commonly have more specialised staff.The overall incidence of LTFU in our study (5.3 per 100 person-years) is consistent with a study conducted in Zimbabwe (5.75 per 100 person-years)17. A study from South Africa also revealed that half of the lost cases were observed in the first six months of ART follow-up37. A Nigerian study also found that half (51%) of the LTFU cases occurred within the first 30 days following ART initiation. The high rate of LTFU in the early stage of ART follow-up might be because newly diagnosed individuals visiting ART clinics may not be fully prepared to engage in HIV care, as ART is a lifelong medicine, requiring repeated counselling, and psychological preparation28. Although rapid ART initiation has improved the clinical outcomes of patients, particularly for those with very low CD4 cell counts, observational studies have shown that starting ART on the same day as HIV diagnosis may increase the risk of LTFU because patients need frequent counselling and psychological preparation before starting ART38. The WHO guidelines also mentioned the limitation of the test and treat approach, such as it increases the risk of LTFU39. Another possible explanation of high LTFU in the first year of follow-up could be due to ART-associated adverse drug reactions that are very common during the first year of ART. Studies suggested that ART-related adverse reactions negatively affect adherence, indirectly affecting LTFU42.The study found that of the total lost cases, more than three-fourths  were seen in the first year of follow-up. This finding is supported by a study conducted in Guinea, which reported LTFU at one year was 42%14, Uganda22, South Africa43, and Malawi16. This may be the results of undernourished patients being more likely to have underlying health conditions and eat less nutritious foods, which may directly impair clinic attendance21. In addition, food insecurity and undernutrition are significant predictors of poor ART adherence45. A qualitative study from Ugandan identified different mechanisms that explain how food insecurity leads to poor ART adherence46. Accordingly, patients believe that in the absence of food, ART increases appetite and causes hunger. Patients also believe that the side effects of ART can be aggravated without access to adequate food. Another reason is that they experienced competing demands of paying for food costs, transportation costs, and medical expenses. Lastly, they forget or are unable to take ART while working or searching for food46.Our study found that the risk of LTFU in undernourished patients was two times higher as compared to their well-nourished counterparts. This finding is in line with studies conducted in Tanzania47. Our study also showed that out of all the registered deaths (n = 63), 26 cases (42.3%) were from undernourished individuals. A systematic review and meta-analysis from LMICs found that advanced WHO clinical disease staging was significantly associated with higher risk of LTFU48. Advanced WHO clinical disease stage increases the risk of LTFU in various ways. Patients with WHO stage III or IV are more likely to have OIs and are bedridden most of the time, which can make it difficult for them to stay engaged in HIV care. In addition, HIV patients with advanced disease stage are at higher risk of premature death from severe OIs, especially during the first year. Therefore, these patients may have died at home but were not reported due to a passive surveillance system.Undernutrition could also indirectly contribute to a higher risk of LTFU by increasing disease progression from HIV to AIDS stage in PLHIVOne strength of our study is that it included relatively large sample size (n = 844). As we used a cohort study design, we were able to calculate the incidence rate of LTFU. However, this study has some limitations. Some important confounding factors, such as distance from the healthcare facilities and viral load, were unavailable due to data incompleteness. Moreover, the actual incidence of LTFU might be underestimated due to incomplete recording. Conversely, the actual incidence of LTFU may be overestimated because some patients classified as LTFU may have died or have started ART in other health care facilities without sufficient recording.Although Ethiopia has achieved remarkable success in increasing access to ART, LTFU is still a significant concern. The study found that undernutrition significantly increased the risk of LTFU among adults living with HIV on ART. This finding implies that different stakeholders should undertake various nutritional interventions and practical approaches to reduce LTFU and improve treatment outcomes in adults living with HIV. In addition, efforts must be made to improve the food security of people living with HIV across the country. Finally, further prospective studies by incorporating some confounders such as viral load and distance from health facilities are needed to examine the effects of undernutrition on LTFU.


Design A retrospective cohort study. Setting Hospital-based. Patient Population In total, 152 patients (288 eyes) diagnosed with KC at Chang Gung Memorial Hospital, Taiwan, were included. Previously managed patients and those with missing optical data were excluded. Observation Procedures Patients were divided into pediatric (≤ 18 years) and adult (> 18 years) groups. Demographics, clinical data, and optical variables were collected, including corrected distance visual acuity (CDVA), refractive error, and keratometric readings (K). Main Outcome Measure Optical variables at the final follow-up before aggressive treatment. Results In total, 20 pediatric (37 eyes) and 132 adults (251 eyes) patients were eligible for this study. The mean follow-up time was 2.98 years. Male predominance was observed in both groups. Both groups had similar clinical characteristics and optical variables at the initial diagnosis. Pediatric patients progressed significantly more rapidly in refractive errors, including spheres and cylinders, spherical equivalence, steep K, and flat K during the follow-up. However, significant change between the two study groups was only seen in sphere refractive error spherical equivalence. Conclusion Pediatric patients had more rapidly progressive KC than adult patients, so early detection and frequent follow-up for prompt interventions are necessary for these patients.To present the natural course of keratoconus (KC) and compare pediatric and adult patients.  It has been reported that the prevalence of KC was higher in Asian countries6. More importantly, progressive ectasia and bilateral and asymmetrical corneal distortion ultimately affect these patients’ vision-related quality of life if the patients do not receive appropriate management8.Keratoconus (KC), although traditionally classified as a rare disease, has an estimated prevalence of 1 in 37511. Optical correction with spectacles or rigid contact lenses could effectively enhance the quality of vision in patients with slow disease progression. In comparison, corneal cross-linking (CXL) has shown promising results in halting rapid disease progression.With the advancement of corneal imaging technology, early detection and interventions are becoming feasible. However, the treatment method is mainly determined by the pattern of disease progression and the severity of corneal ectasia12. The natural course refers to the progression of a disease process in an individual over time without aggressive treatment. Any treatment modalities that contact the cornea, including contact lenses or surgery, are considered an aggressive treatment for KC. In other words, correcting the visual acuity with spectacles is not an aggressive treatment for KC. Hence, the disease process from the initial diagnosis of KC up to treating with contact lenses or surgery is the natural course of KC.A detailed understanding of the natural history of KC is fundamental in making informed decisions on when their benefits outweigh the risks14. Ferdi et al. included 41 studies in their systematic review and 23 studies into their meta-analysis to describe the natural progression of KC based on 11,529 untreated eyes. They reported that younger patients (17 years old or less) and those with Kmax steeper than 55 D at presentation have a significantly greater risk of progression of the disease12. However, this systemic review and meta-analysis analyzed data at 12 months due to inconsistent follow-up duration across various studies, and most patients with KC were adults. Compared with adults, KC in children progresses more rapidly and is usually more severe at the time of diagnosis15. In addition, age may influence corneal cross-linking treatment in KC. A study of 119 KC eyes reported that pediatric cornea showed a more flattening effect after cross-linking than older patients and the better-corrected distance visual acuity after cross-linking16. Therefore, there is a need to identify the differences in disease progression between pediatric and adult patients with KC and explore the overall risk stratification of natural disease progression.Unfortunately, the natural history of KC is poorly understood17, maximum keratometry17, Scheimpflug from Pentacam19, or swept-source optical coherence tomography20. Amsler-Krumeich classification proposed in 1947 was used to grade KC based on keratometry and optical pachymetry22. The Belin ABCD classification introduced on the Pentacam has advantages in presenting anatomical changes seen in KC and other ectatic diseases22. In 2019, Robert et al. represented the Dutch Crosslinking for Keratoconus (DUCK) based on five domains: age, decrease in visual acuity, increase in refractive error, increase in keratometry readings, and perceived quality of vision for determining whether a cross-linking might be warranted23.There were multiple parameters for monitoring KC progressions, such as CDVAIn this study, we did a chart review of patients with KC in Chang Gung Medical Hospital (CGMH), Taiwan, and aimed to compare the KC’s clinical characteristics and natural progression among two age groups in Taiwan.n = 20) and > 18 years (n = 132). Male predominance was observed in both pediatric (65.0%) and adult (62.1%) groups. In the pediatric and adult groups, the mean age of KC diagnosis was 15.3 years and 27.4 years. The prevalence of atopic dermatitis was 5.0% and 6.1%, and the history of eye rubbing was 20.0% and 11.4%, respectively. Although the eye rubbing rate in the pediatric group was higher than the adult group, there was no significant difference between the two study groups (p = 0.2810). In 288 eyes, 32 (11.1%) presented with Vogt’s striae, and 25 eyes (8.7%) had Fleischer ring. The cones were recorded as nipple (11.5%), oval (55.9%), and globus (32.6%). There were similar results in Vogt’s striae or Fleischer ring, cone morphology, and location between the two study groups. In brief, there were no significant differences between pediatric and adult groups with clinical appearance, comorbidity, cone morphology, and location . There were no differences in cylinder refractive error, spherical equivalence, steep K, and flat K . For the entire group, the CDVA, sphere refractive error, cylinder refractive error, and spherical equivalence progressed significantly in the final visit compared with the initial presentation , while there was no significant progression in steep K and flat K. In the pediatric group, significant or borderline significant progression was seen in sphere refractive error (p = 0.0130), cylinder refractive error (p = 0.0238), spherical equivalence (p = 0.0052), steep K (p = 0.0339) and flat K (p = 0.0365). In the adult group, borderline significant progression was seen in CDVA (p = 0.0235), cylinder refractive error (p = 0.0407). The significance progression between the study groups was seen for sphere refractive error (p = 0.0071) and spherical equivalence (p = 0.0066), respectively  and sphere refractive error than adult ones , and a younger age at presentation (< 17 years) were significantly associated with increased progression (≥ 1.5 D) of Kmax at 12 months12. In our study, the pediatric patients had 49.64 D/44.71 D (steep K/flat K) at initial diagnosis, which progressed to 0.74 D/0.60 D at the end of an average follow-up of 3 years. Our pediatric patients seemed to have a relatively benign course compared to the meta-analysis results. This discrepancy may be due to different study designs and populations.Little is known about the natural course of KC, particularly in pediatric patients. L’eoni-Mespli’e et al. retrospectively reviewed 49 children with KC aged ≤ 15 years and 167 adults aged ≥ 27 years at diagnosis and found that it was often more advanced in terms of grading slit-lamp biomicroscopic findings and keratometry readings in children37. The Collaborative Longitudinal Evaluation of Keratoconus was a large prospective study of 2418 KC eyes with a mean age of 39.3 years. At the end of the follow-up, the patient’s BCVA lost 2 Snellen letters compared to the baseline, which was quite stable38. Wittig-Silva et al. conducted a clinical trial on progressive KC in patients 16 to 50 years of age and showed that at 24 months, the mean cylinder was stable (p = 0.15), but there was a significant progression of 1.2 D (p = 0.02) at 36 months39. Sahin et al. reported the cylinder change from − 4.4 D to − 5.3 D (p = 0.04) after a mean follow-up of 24 months using the Orbscan topography40. The mean patient age was 32.4 ± 15.2 years, so cylinder changes were presented in pediatric and adult patients. Our study shows no significant changes from the initial diagnosis to final steep K and flat K between pediatric and adult patients, but the progression was more rapid in the pediatric group.Or et al. compared pediatric KC patients with and without CXL and reported no change in the best-corrected visual acuity (BCVA in logMAR) from baseline to the 5-year follow-up (0.1–0.13)41. Several classifications for KC severity have been proposed. The oldest and most commonly used one is the Amsler-Krumeich classification, which includes simulated keratometry and total corneal refractive power42. The modified Krumeich classification divides the subjects into four stages depending on clinical characteristics, induced myopia or astigmatism, corneal radii, and thickness44. Belin and Duncan proposed a new staging system based on anterior and posterior average radii of curvature, thinnest pachymetry, and distance visual acuity45. Alio et al. reported a grading system based on the Red Tematica de Investigacion Coopertiva en Slaud classification, a functional scale of corrected VA46. Different methods integrating KC’s visual function or topographical characteristics will likely lead to better patient assessment and outcome. This study did not use any score to summarize the KC progressions. For instance, we could not compute the DUCK score because information about the perceived quality of vision was not available in our respective chart data. We could not use the modified Amsler-Krumeich classification either because it is poorly suited for assessing disease progression, and it has limited clinical usefulness for diagnosing earlier stage of KC24.Strictly speaking, there are no clear definitions for KC progression. Based on the Global Consensus on KC and Ectasia Diseases, progression is defined by a consistent change in at least two parameters, which are steepening of the anterior corneal surface, steepening of the posterior corneal surface, thinning, and/or an increase in the rate of corneal thickness change from the periphery to the thinnest point40. In our study, the pediatric group showed less affected CDVA by steep K than adult groups. One of the possible mechanisms is retinal photoreceptor density decreasing with age. Songhomitra reported 55 eyes from human donors aged 18 to 85 years and revealed that the annual photoreceptor cell loss was 0.2–0.4%47.In theory, KC is a progressive disease, and thus CDVA is not reversed with aging under natural conditions. In addition, patients with KC have a cylinder refractive error increase, which may lead to vision deterioration48. So, the adult KC group may present with worse CDVA than the pediatric KC group under the same steep K  due to the chart review's retrospective and low harm nature.First, we searched the electronic medical records of patients diagnosed with KC (ICD-9-CM: 371.6) during 2000–2017 at the Linkou and Taipei Chang Gung Memorial Hospitals, tertiary care centers in Taiwan. Next, we reviewed the charts to confirm the KC diagnosis by the presence of at least one characteristic slit-lamp biomicroscopic finding, including conical protrusion, Vogt’s striae, Fleischer ring, or any tomographic patterns of KC. The tomographic patterns of KC could be high central corneal power, thin central thickness, or a large difference between the power of the corneal apex and periphery. We excluded patients with a prior history of either diagnosis or treatments for KC at other institutions. Patients were followed from their first visit to our hospital until they were prescribed contact lenses or any surgical treatment. Among 392 patients diagnosed with bilateral KC, 162 were management-naïve patients, and 230 had a treated history from other clinics. After excluding 10 patients with missing optical data, 152 patients (288 eyes) were enrolled in this study. Noted that steep K and flat K information was unavailable in 16 eyes (= 5.3%) Fig. .Figure 451. The tomographic data were derived from three different devices, the combined Placido scanning-slit system (Orbscan II) , the integrated system of Placido disc topography, and dual Scheimpflug tomography (GALILEI G4) , and the rotating Scheimpflug camera (Pentacam) , in chronological order of device acquisition from 2000 to 2017.We classified the cone shapes as nipple , oval (large and 5 ~ 6 mm in diameter), and globus  according to the classical descriptions of topographic presentationsBecause all patients in our study received the same steep K and flat K measurement from the autorefractor at the initial and during follow-up visit, we used the steep K and flat K from autorefractor instead of tomography to analysis the corneal curvature in order to reduce inter-machine variation.Demographic and clinical characteristics, as well as optical variables, were reviewed and collected. This included eye rubbing behaviors, comorbidity of atopic dermatitis, date of KC diagnosis, slit-lamp biomicroscopic findings, uncorrected distance visual acuity (UDVA), corrected distance visual acuity with spectacles (CDVA), refraction, keratometry reading (K) including steep K and flat K, and tomographic measurements. The Snellen VA was converted to the minimum angle of resolution VA (Log MAR) logarithm for the statistical analysis.52. This significance level (or type I error) was set at 0.05. We used a sequential Bonferroni-type procedure for multiple testings to maintain the overall type I error of 0.05. The p values of multiple tests in Tables p values < i/46. All statistical analyses were performed using the SAS version 9.4 .Descriptive statistics were used, such as mean, standard deviation, and frequency. Scatter plots with correlation coefficient (r) were used to show the strength and direction of the linear relationship between two continuous variables. Wilcoxon rank-sum test or Fisher’s exact test was made to compare the data between the pediatric and adult group, where appropriate. Wilcoxon signed-rank test was made to compare the data within the group, where appropriate. Because of the non-independence of the corrected distance visual acuity (CDVA) of two eyes repeatedly measured over time, we utilized the generalized estimating equation (GEE) to examine the relationship between CDVA and steep K. The within-subject correlation matrices in GEE were exchangeable