Renal and respiratory failure were reduced in Group 2, but not significantly. Conclusions: The use of the adjuncts enabled the achievement of improvement in mortality and SCI prevention in TAAA OSR. Although a refined surgical technique, mortality and morbidity are still noteworthy in this complex aortic field.Background: In the last decade, advances in surgical techniques, and the introduction of adjuncts for organ protection, have modified the approach for thoracoabdominal aortic aneurysm (TAAA) surgical repair. The aim of this study is to determine whether the contemporary approach influenced the outcomes. Methods: From 1989 to 2022, patients who had received elective open surgical repair (OSR) for TAAA at our institution were retrospectively analyzed. This series has been divided in two groups: Group 1 (1989–2009), and Group 2 (2010–2022). Patients included in Group 1 were those treated with a selective use of adjuncts, and Group 2 included patients treated with the systematic use of adjuncts. Results: A total of 1107 patients were treated . The surgical management was significantly different between the two groups. The in-hospital mortality was significantly different between the two groups (Group 1: 13.4%, Group 2: 8.1%;  Thoracoabdominal aortic aneurysm (TAAA) open surgical repair (OSR) is one of the most extensive procedures performed in vascular surgery, and is a formidable challenge for surgeons, anesthesiologists and patients alike. This procedure, generally performed in elderly patients afflicted by multiple comorbidities, owing to both the technical difficulties of aortic reconstruction and the organ stress suffered. As a result, TAAA OSR is associated with not negligible mortality and morbidity rates ,2,3,4,5.In parallel with the advancements in the OSR technique, endovascular techniques have emerged as an appealing alternative for the treatment of the thoracoabdominal diseases, with encouraging results . In thisIn this study, we report an analysis of our experience in TAAA OSR, together with a description of the evolution of our therapeutic approach. This experience has influenced our treatment protocol and improved our results.Patients who had received OSR for TAAA at our institution between January 1989 and December 2022 were prospectively included in a database and retrospectively analyzed. Clinical data from patients with TAAA were analyzed for preoperative characteristics and comorbidities, intraoperative details, and outcomes. Patients with contained ruptured or clearly ruptured TAAA were excluded from the analysis.During this 33-year experience, the preoperative, intraoperative, and postoperative management of patients with TAAA, treated by means of OSR, has changed, with the introduction of several modifications. These adjunctive maneuvers and technologies, grouped under the name of “adjuncts”, have been progressively introduced into the clinical practice, initially in selected cases, and then routinely. In order to evaluate the role of these adjuncts, and their impact on the postoperative results, the overall experience has been divided in two consecutive groups: Group 1 (from January 1989 to December 2009), and Group 2 (from January 2010 to December 2022). Thus, in Group 1, patients from the early experience treated with a selective use of some adjuncts were included, while, in Group 2, patients from the more recent experience were included, treated with the systematic use of all the currently available adjuncts.Patients gave written informed consent for the anonymous collection of their data for the study in the consent form provided by our institution and approved by our Institutional Review Board, in accordance with Italian law.2. Our routine preoperative screening includes an evaluation of the carotid and peripheral artery axis by means of color-coded duplex Doppler. Lung function is tested by means of chest X-rays, blood gas analysis, and respiratory functionality tests. When severe chronic obstructive pulmonary disease (COPD) is present, and the patients’ general and anatomical conditions are adequate, home respiratory therapy, physiotherapy, and correction of risk factors (smoking cessation), are carried out by the patients, eventually also with the use of bronchodilator drugs and cortisone. Renal function is tested with blood tests and chronic renal failure is defined as an estimated glomerular filtration rate < 60 mL/minute/1.73 mProvided that there are no specific contra-indications, the preferred imaging modality used at our center is multidetector computed angiography tomography (CTA) scanning. New and updated postprocessing software have been introduced in order to allow a complete evaluation of the images, including useful measuring tools such as multiplanar reconstruction, surface and volume rendering. A preoperative, thorough evaluation of the CTA with the postprocessing software allows a complete analysis of the aorta, the collateral vessels, and also of the spinal cord (SC) vasculature . PatientSpinal cord ischemia (SCI) is one of the most dreadful complications in patients who undergo TAAA OSR, and it may affect both perioperative and long-term outcomes because of multiple and severe medical complications directly related to the neurologic damage ,11,12,13After the preoperative maneuvers, and the patient positioning, the surgical procedure is initiated. The surgical technique used for TAAA OSR at our institution has been previously described . BrieflyAfter the LHBP is started, the thoracic aorta is gently sequentially cross-clamped: the proximal clamp is placed at the most convenient site, usually after the left subclavian artery (LSA), or between the left common carotid artery (LCCA) and LSA; the distal clamp is placed few centimeters below the proximal one. The descending thoracic aorta is then transected and separated from the esophagus, and non-critical intercostal arteries are ligated. The proximal end of the graft is sutured to the descending thoracic aorta using a running suture reinforced with felt pledgets. The clamp is then removed and applied onto the distal thoracic aorta above the celiac axis; the aortotomy is then extended to the diaphragm and the intercostal arteries are identified and temporarily occluded. The reattachment of critical patent intercostal arteries (from T7 to L2) to the aortic graft may play a critical role in spinal cord protection . In thisFinally, an end-to-end anastomosis with the distal aorta is performed and the last clamp removed. A specific surgical approach, with avoidance of sequential aortic cross-clamping, was adopted in the case of extensive aortic wall thrombosis in order to reduce the risk of thrombus mobilization and embolization . To reduDespite the surgical experience, TAAA OSR may cause high rates of intra- and perioperative bleeding, and the need for blood product transfusions, also considering that the loss of large amounts of blood not promptly replaced is associated with hypotension and may be an adjunctive risk for SCI and organ hypoperfusion in general. On the other hand, blood transfusion may be associated with well-known complications and lung injury; thus, management of bleeding is considered of paramount importance in TAAA OSR . The rotAll the adjuncts used during TAAA OSR, and their times of introduction are summarized in As primary endpoints were considered the perioperative outcomes, defined as occurring within the first 30 days after surgery or during the hospital stay if >30 days, and included: 30-day mortality, respiratory failure , permanent SCI, renal failure  classification), myocardial ischemia, major stroke, mesenteric ischemia (with need of intervention), and need of re-intervention  . During t-test; categorical data were analyzed using the chi-square test. Statistical significance was defined as a p-value < 0.05. All analyses were performed with the Statistical Package for Social Sciences software , version 26.0 for MacOS. Descriptive statistical analysis was performed using numbers and percentages for discrete variables, mean ± standard deviation for continuous variables, and median and interquartile range for variables with a non-normal distribution. Continuous variables were compared by the Student’s p 0.021), but the two groups were similar for preoperative COPD. A significantly higher rate of TAAA OSR was performed in patients with previous aortic surgery (p 0.033) in Group 2. Demographics and baseline characteristics of both groups are summarized in From 1989 to 2022, a total of 1107 patients underwent elective TAAA OSR at our institution. The OSR was performed for TAAA I–III extensions in 80.8% of the cases, mainly for degenerative etiology. The entire cohort was divided in two groups; 455 patients were included in Group 1, while 652 patients were included in Group 2. The two groups were similar for the majority of the preoperative characteristics, except for smoking habits and history of aortic surgery; patients in Group 1 had a significantly higher rate of history of smoking (p = 0.044). Different techniques have been used for intercostal artery reattachment, such as aortic island, selective bypass, or loop bypass  with the inclusion of CT, SMA, and both the renal arteries was the preferred approach (57.4%), in Group 2 smaller patches associated with selective bypasses were preferred (59.7%) . Lastly,p bypass . Intraprp = 0.004). Likewise, the rate of permanent SCI was significantly lower in Group 2 if compared to Group 1 (p = 0.023), with an incidence of 7.8% and 11.9% respectively; the overall rate of permanent SCI was 9.5% (105/1107). Among the patients who experienced permanent SCI, 47 patients (44.8%) presented with an early SCI , and 58 patients (55.2%) presented with late SCI symptoms. The overall 30-day mortality was 10.3% (114/1107); the causes of death were multiple organ failure (MOF) in 44 cases, cardiac complications  in 36 cases, bleeding in 12 cases, systemic embolization in 14 cases, and stroke in 8 cases. If compared to Group 1, the mortality rate in Group 2 was significantly reduced . A slightly positive trend was also noted concerning the incidence of postoperative myocardial ischemia, stroke, mesenteric ischemia, and need for re-intervention, but was not statistically significant. The overall postoperative outcomes, and the specific results of the two Groups are summarized in The overall incidence of respiratory failure was 29.1% (322/1107), with 31.9% in Group 1, and 27.1% in Group 2; renal failure occurred in 5.8% of the cases, 7.2% in Group 1, and 4.7% in Group 2. Both respiratory failure and renal failure were reduced in the second period (Group 2), but the difference was not statistically significant , and Group 2 (January 2010–December 2022: 652 pts) were created in order to include in the second period the routine use of most of the adjuncts. The two groups were similar for the majority of preoperative characteristics, except for history of smoking and previous aortic surgery . In Group < 0.001). With the development of surgical experience, the aortic neck between the LCCA and the LSA was considered a “safer zone” for proximal cross-clamping, if compared to the aortic portion distal to LSA, and was frequently preferred during extent I–II TAAA OSR. A better aortic quality with a lower risk of wall lesions was observed at this level, and this aortic region was considered the preferred zone for a safer proximal clamping in 16.7% of the cases in Group 2. A trend toward smaller aortic patches was also observed in Group 2, with a significant reduction in the number of Carrel patches with the inclusion of four vessels and an increase in three-vessel Carrel patches associated with selective bypass (p < 0.001). This change in the surgical approach was performed after the observation of visceral aortic patch aneurysms during the follow-up, in order to reduce the risk of subsequent dilatation [p = 0.044); many reasons may help to explain this significant variation between the two groups, among them, the increase in surgical experience, the updated evidence regarding the protective role of this procedure, and the intraoperative use of MEP&SSEP, have played a role and may explain this significant difference between the two groups [Since 1989, when the first TAAA OSR was performed at our institution, with the “clamp and go” technique, many things have changed from the surgical point of view, but the majority of the modifications have been introduced during the last decade. The surgical strategy was significantly different between Group 1 and Group 2 concerning the site of aortic clamping, the technique used for visceral vessel reconstruction, and the frequency of intercostal artery reattachment . Althouglatation ,32. A moo groups ,20,33,34p < 0.001); it has been preoperatively placed in all the patients with extent I–III TAAA treated by means of OSR, without specific contraindications, and only selectively in patients with extent IV, considered at high risk for spinal cord ischemia. However, in accordance with recent evidence, a word of caution needs to be given about CSFD; in fact, it comes with possible complications that should be taken into account [Concerning the different organ protection strategies, in 2010, we introduced the CoroCTA as a routine part of the preoperative workup. Significantly flow-limiting coronary artery stenosis was addressed before TAAA OSR with percutaneous interventions, using bare-metal stents when possible, or bypass . Since 2 account . LHBP is another essential tool during this surgery, and its protective role in TAAA OSR has been well known since the early 1990s, when we also started to employ this adjunct . This paIntraoperative neuro-monitoring with MEP&SSEP offers another advantage in the complex field of SC protection. It allows continuous intraoperative control of the SC function with the possibility of immediately detecting impairments in SC blood supply and applying adjunctive maneuvers to restore an adequate inflow to the SC, such as: increasing arterial pressure proximally and distally to the clamp with LHBP, early reattachment of hypogastric arteries, and the selective reattachment of critical intercostal arteries . Jacobs’p = 0.026) and a lower volume of fresh frozen plasma . In addition, patients in the ROTEM group showed a significant decrease in the occurrence of pulmonary complications  [Renal failure is one of the most feared complications during and after TAAA OSR, and it is known to be associated with perioperative mortality. For this reason, renal protection strategies have a key role during TAAA OSR, and above all, include perfusion of the kidneys using cold crystalloid solutions . Cold La⁄4 0.01) . Lastly,⁄4 0.01) . p 0.004), and SCI prevention (p = 0.023) in our recent experience. The use of this multimodal approach has also led to a reduction in respiratory failure, renal failure and many other postoperative complications, but the impact was not statistically significant. As reported in In addition, the approach actually used at our center may be considered not only multimodal, but also multisystem; in fact, a single adjunct may play different protective roles; for example, LHBP has a protective SC effect, but also avoids visceral ischemia and cardiac afterload. In the same way, preoperative CoroCTA has a role in preventing cardiac complications, but cardiac problems could led to hemodynamic instability, with possible low perfusion for SC and visceral vessels; these considerations are applicable for the majority of the adjuncts using during TAAA OSR. Although the dawn of TAAA endovascular repair is clearly upon us, it is not yet clear whether this approach will benefit all patients or only select groups of them. At this time, also in accordance with the currently available guidelines, TAAA OSR it is not an “old-fashioned” approach but it still needs to be considered a valid treatment option, or even the first treatment option, in patients with long life expectancy, and in patients with genetically triggered aortic disorders . TAAA OSStudy limitations include the retrospective design using data from a single center. The retrospective nature of this study also limits the possibility of evaluating other preoperative, intraoperative, and postoperative features that might have influenced the outcomes. In addition, it should be underlined that the time-point chosen to divide the entire cohort into two groups with respect to the adjuncts  was liberally decided by the authors of this paper. The time-point was decided in order to include in Group 2 the more recent experience, and the patients treated with the systematic use of all the currently available adjuncts, in respect of their time of introduction. We have presented our single-center experience with TAAA OSR, which spans approximately three decades. The use of the different adjuncts in a multimodal and multisystem approach enabled us to achieve a significant improvement in mortality and SCI prevention, and an improvement, although not significant, in the rate of other postoperative complications after 2010. Although we have refined our surgical technique and our multimodal approach over time, in an effort to prevent early death and life-altering complications, continued improvements are needed in this complex aortic field.


Thus, our findings show that the therapeutic use of vitamin D on fatigue in people with MS could be considered. Nevertheless, due to the lack of agreement on the dose to be applied, it is recommended to use it under medical prescription. Vitamin D supplementation has been considered a possible treatment to reduce the risk of disease activity and progression in people with multiple sclerosis (MS). However, its effect on disease symptoms remains unclear. The aim of this meta-analysis was to conduct a systematic review to assess the effect of vitamin D on fatigue in this population. The systematic review was conducted using the MEDLINE, Cochrane Library, Embase and Web of Science databases from inception to May 2023. Randomized controlled trials (RCTs) reporting pre–post changes in fatigue after vitamin D supplementation were included. Pooled effect sizes and 95% confidence intervals (95% CIs) were calculated by applying a random effects model with Stata/SE . The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. A total of five studies with 345 individuals  were included. A significant reduction in fatigue was perceived when vitamin D supplementation was compared with a control group: −0.18 (95% CI: −0.36 to −0.01; I Multiple sclerosis (MS) is an autoimmune and inflammatory chronic disease of the central nervous system that constitutes one of the leading causes of disability among young adults . MultiplAlthough the etiology of MS is still uncertain, it is likely that the interaction between genetic and environmental factors, along with others, contributes to its appearance ,11. SomeVitamin D is a fat-soluble steroid hormone produced predominantly in response to ultraviolet B (UV-B) irradiation of the skin . The maiThus, the aim of this systematic review and meta-analysis was to synthesize the evidence from clinical trials and to estimate the effect of VD administration on fatigue in people with MS.The Cochrane Collaboration Handbook  and the Two reviewers (R.F.-R. and SR-G) independently searched the MEDLINE (via PubMed), Cochrane Library, Embase (via Scopus), and Web of Science (WoS) databases from inception to May 2023. The databases were reviewed to identify randomized controlled trials (RCTs) aimed at determining the effectiveness of VD supplementation on fatigue in people with MS. No language restrictions were applied. Moreover, the reference list of the selected studies and the list of references of other systematic reviews and meta-analyses were reviewed for additional relevant studies. The Mendeley desktop find and merge duplicates tool was employed to search for duplicates, and a third reviewer peer-reviewed the search process (M.J.G.-P.). Further details of the search strategy used for each database are available in The search criteria according to the PICOS strategy were as follows: (i) Participants: people with MS; (ii) Intervention: VD supplementation; (iii) Comparison: no intervention, participants treated with a placebo, or with another intervention that also received an intervention group; (iv) Outcome: fatigue; and (v) Study design: RCTs. The exclusion criteria were as follows: (1) studies where VD intervention could not be isolated, and (2) studies not reporting enough data to calculate effect size.Two authors (P.L.-M. and A.T.-C.) independently extracted the following information from each included study: (1) first author name and publication year; (2) country; (3) sample characteristics: sample size , mean for age, body mass index (BMI), disease severity, type of MS and disease duration, and baseline level of VD; (4) intervention characteristics: duration, frequency and dose of the intervention, adherence, and side effects; and (5) outcomes: fatigue scale. The authors attempted to contact corresponding authors to request information on missing data from the studies and, when this was not possible, the study was excluded. Disagreements in data extraction were resolved by consensus.For the characteristics of the disease, we extracted the severity and duration of MS. The disease severity was reported through the Expanded Disability Status Scale (EDSS), considering score between 0 and 5 as mild EDSS and a score ≥ 5 as severe EDSS ,31, and Studies reported the 25(OH)D baseline level in ng/mL or nmol/L, and for analyses, the nmol/L unit was converted to ng/mL. Fatigue was measured through one or more self-report questionnaires. When the fatigue scale was subdivided by domains, we used the total score for the analyses. When studies applied more than one test for reporting an outcome, a combined estimate was calculated. Moreover, when studies were inversely scaled , the mean in each group was multiplied by −1.Two researchers (S.R.-G. and M.J.G.-P.) independently assessed the risk of bias of the included studies using the Cochrane Collaboration’s tool for assessing risk of bias (RoB2) of RCTs . Any disRandom effect models were used to estimate the pooled standardized mean differences (SMDs) and their 95% confidence intervals (95% CIs) of the effectiveness of VD supplementation on fatigue in people with MS. According to the Cochrane Handbook recommendations, we extracted the pre–post mean, standard deviation (SD), and sample size of each arm of the trials. For those studies that did not report these data, we collected the mean difference and standard error (SE) or SD of the change. In addition, when data were given as % relative change, this was applied to baseline measurements, and the effect size was calculated considering similar SD.2 statistic. I2 values of 0–40% were assumed to indicate “not important” heterogeneity, 30% to 60% represented “moderate” heterogeneity, 50% to 90% represented “substantial” heterogeneity, and 75% to 100% represented “considerable” heterogeneity. We accordingly considered their corresponding p-values and 95% CIs [Statistical heterogeneity between studies was examined using the I 95% CIs . To asse 95% CIs . All staA total of 1256 studies were identified through the systematic searches, of which 481 duplicated records were removed . Finally2) [The main characteristics of the included studies are available in 2)  accordinVitamin D supplementation varied across the included studies from 1 mcg to 50.000 IU. Additionally, the frequency (times per week) ranged from 1 to 7 in half of the studies ,37, and Of the included studies, one  had fourThe studies assessed the effect of VD supplementation through different fatigue scales. The most common fatigue scale used was the Fatigue Severity Scale (FSS) ,38,39. 2 = 0%) (When exploring the effect of VD supplementation on fatigue in people with MS (RCTs), there was a significant reduction in fatigue −0.18  .p = 0.551)  .The overall risk of bias assessment for RCTs showed that two studies (40%) presented high risk ,39, and Vitamin D has been administered as a supplement for decades in people with MS since its deficiency can be a pathogenic risk factor and influence the activity of the disease ,41. HoweIn recent years, growing interest has emerged in the potential beneficial effect of VD supplementation on fatigue in people with MS, but the results are controversial. A wide 2018 Cochrane review  that evaThe study of Achiron et al.  showed tCurrently, there is no consensus on the optimal dosing of VD intake as adjuvant therapy in MS . People It is necessary to emphasize that the baseline level of 25(OH)D is a very important parameter to consider since VD supplementation is more effective when applied to subjects with low basal levels ,52. AlthFurthermore, there is currently interest in disorders of sphingolipid (SL) metabolism in MS, as they play an important role in the regulation of the immune response and inflammation ,55. ReceSome limitations that might limit the robustness of our estimates should be acknowledged, such as the small sample size of the included studies. Nonetheless, in this systematic review and meta-analysis, a significant effect of VD on fatigue was detected, although RCTs with larger samples would be necessary to confirm these findings. Furthermore, there was wide variability in the duration of the treatment and the dose of VD used among studies, so further research is necessary to determine the optimal dose to improve fatigue in people with MS and understand the possible benefits and risks associated with these variables. On the other hand, due to the limited data about the type of VD administered, a complementary analysis could not be made to determine its influence on the results. In this regard, most of the studies that provided data used vitamin D3 ,38,39, wIn conclusion, this systematic review and meta-analysis suggests that supplementation with VD might have a significant effect on reducing fatigue in people with MS. Nevertheless, due to the lack of agreement on the dose to be applied, it is recommended to use VD under medical prescription. Future research to understand the optimal dose and duration of the treatment and studies in samples with lower baseline levels of 25(OH)D are needed to optimize clinical outcomes.


Background and Objectives: We aimed to analyse data on retinal artery occlusion (RAO) patients to explore correlations with acute ischaemic stroke (AIS), ST-elevation myocardial infarction (STEMI), and cardio/cerebrovascular comorbidities. Patients and Methods: Our retrospective cohort study included 169 RAO and 169 age- and gender-matched control patients. We examined the association of AIS, STEMI, and related comorbidities such as hypertension (HT), type 1 and type 2 diabetes , hyperlipidaemia, and ischaemic heart disease (IHD) with RAO. We also recorded atrial fibrillation in our RAO patients. Results: Our results demonstrated that RAO patients developed both AIS and STEMI at a significantly higher rate compared to controls (p < 0.001 for both). We also found that RAO patients had a significantly higher prevalence of HT and hyperlipidaemia  compared to controls. Multiple risk factors together significantly increased the odds of developing AIS and STEMI. Conclusions: Our results suggest that through identifying and treating the risk factors for RAO patients, we can reduce the risk of AIS, STEMI, and RAO of the fellow eye. Considering that ophthalmologists are often the first detectors of these cardiovascularly burdened patients, collaboration with colleagues from internal medicine, cardiology, and neurology is essential to achieve secondary prevention. The global population and average life expectancy at birth continue to increase over time. In addition, acute cardio- and cerebrovascular mortality is decreasing as the quality of care for ST-elevation myocardial infarction (STEMI) and cerebrovascular accidents (stroke) improves. However, cardio- and cerebrovascular events remain the leading causes of death globally ,2,3,4.Retinal artery occlusion (RAO) is a vascular disorder that affects the arterial network that supplies the inner two-thirds of the neuroretina ,6. This Cilioretinal arteries are an anatomical variant that occurs in 10–15% of people. These branches originate either directly from the choroid or from one of the posterior ciliary arteries. In those with such an arterial branch, in cases of CRAO, it may provide the minimum blood supply required to the macula lutea, resulting in less marked visual impairment. Inversely, these patients may have a rare form of arterial branch occlusion, i.e., cilioretinal artery occlusion. These branches arise either directly from the choroid or from one of the posterior ciliary arteries . There aOur retrospective cohort study aimed to investigate the association between RAO and the development of AIS and STEMI. We investigated the role of age and gender in the development of RAO, AIS, and STEMI in Hungarian patients. We also investigated the role of cardio/cerebrovascular risk factors in the development of RAO, AIS, and STEMI in our study patients. We aimed to analyse the combined effect of several risk factors on RAO, AIS, and STEMI development in Hungarian patients. We sought to determine whether treatment or reduction of risk factors could reduce the incidence of RAO, AIS, and STEMI (secondary prevention).Data on 181 RAO patients (114 CRAO and 67 BRAO) were examined at our clinic in the Eastern European region between 2009 and 2019. Data were retrospectively collected from our electronic database and the Hungarian national electronic database.A total of 169 RAO patients (106 CRAO and 63 BRAO) were retained for analysis. Risk factors were considered if they were recorded in the documentation. Comorbidities were recorded based on clinical data and the regular medications provided.Our study included adult patients with visual loss due to RAO within 1 week. The inclusion criteria comprised an RAO diagnosis based on anamnestic data  and characteristic fundus findings of diagnostic value .Our exclusion criteria were the presence of other ocular disorders , RAO associated with other retinal vascular disorders , suspected iatrogenic RAO . RAO patients whose electronic documentation was not accessible due to digital self-determination or who did not have adequate documentation of concomitant illnesses or medications used were also excluded from the study. For these reasons, 12 patients had to be excluded from the study.The patients’ age, gender, and RAO onset and type (CRAO/BRAO) were documented. The causes of death were analysed with particular regard to cardio- and cerebrovascular diseases. We also recorded whether patients had AF. Additionally, the temporal relationship between cardio/cerebrovascular death and RAO development was investigated.A total of 169 age- and gender-matched controls were selected from among hospital patients. The patients who were about to undergo cataract surgery and who did not have any retinal vascular disease in the electronic database were selected as controls. All preoperative controls underwent a complete ophthalmic examination in our clinic before surgery . For both groups, the presence of AIS, STEMI, and concomitant diseases, such as HT, T1DM, T2DM, atrial fibrillation (AF), hyperlipidaemia and IHD, as well as the time of onset, were recorded.Descriptive statistical analysis was performed comparing patient numbers, age, gender, AIS, STEMI, and comorbidity distribution between the RAO and control groups. Normality was evaluated using the Shapiro–Wilk test. Controls matched for age and gender were used, and the homogeneity of age and gender was assessed using the Mann–Whitney U test.Pearson’s Chi-squared test was performed to determine the difference in the prevalence of AIS, STEMI, and other investigated cardiovascular diseases between the RAO group and the control group. The two-proportion Z-test was used to examine the role of age and gender in RAO patients who developed AIS/STEMI within 10 years. To examine differences in AIS and STEMI risk, univariate logistic regression was used; in all cases, we adjusted for age and gender. Similarly, the role of HT, T1DM, T2DM, AF, hyperlipidemia, and IHD in AIS and STEMI development was examined in comparison with the controls. Multiple logistic regression analysis was used to investigate how multiple risk factors influence the development of AIS and STEMI in RAO patients.p < 0.05 were considered statistically significant.Statistical analyses were performed using Intercooled Stata v17 . All results with The demographic data of the RAO and control groups are summarised in p < 0.05). There were significantly more men in the RAO group than women (p = 0.007). The age and gender of RAO and control patients were homogeneous as per the Mann–Whitney U test. The average age in the RAO group was 64.18 ± 10.00 years, compared to 63.88 ± 10.43 years in the control group.Data from 169 patients with RAO (106 with CRAO and 63 with BRAO) were compared with data from 169 controls without any retinal vascular disease. Our data showed a non-normal distribution with the Shapiro–Wilk test .During the study period, the retinal vascular disease became bilateral in two patients: one developed CRAO, and the other developed BRAO in both eyes. Of the 169 RAO patients, 40 developed AIS and 32 had STEMI, representing a significant increase compared to the control group according to Pearson’s Chi-squared test . No significant difference was found between the two groups for T1DM, T2DM, AF, and IHD . Among 169 RAO patients, 32 cases of AF were found.Regarding comorbidities, which are also cardio/cerebrovascular risk factors, HT and hyperlipidaemia was found to be significantly more frequent in the RAO group than in the control group according to Pearson’s Chi-squared test  but not significant in proportion between the RAO group and the control group.We used the two-proportion Z-test to examine how the number of AIS and STEMI cases increases with age in 10-year intervals. We also analysed the role of advancing age as a risk factor and its pathogenetic role. We concluded that there is a large increase in the prevalence of both AIS and STEMI over the age of 50. In those aged between 60 and 70 years, the incidence of AIS and STEMI remains high, without major further changes. The difference in AIS and STEMI was significant between the two age groups . In addition, T1DM represents a 3.51-fold increase in risk ; AF, a 2.35-fold increase in risk ; hyperlipidaemia, a 2.30-fold increase in risk ; and IHD represents a 2.13-fold increase . The differences between RAO patients and controls were also significant for these risk factors . When combined with RAO, the presence of HT elevates the odds ratio to 11.65 . AF contributes to a 4.36-fold increased risk , while hyperlipidaemia shows a 2.66-fold increased risk . Additionally, if T1DM , T2DM , or hyperlipidaemia  is present as a third factor, the risk of AIS remains significantly elevated. The presence of IHD alongside RAO and HT does not increase the risk further . If HT is present along with RAO, the odds ratio increases to 4.93 . The presence of AF alongside RAO results in a 4.92-fold higher risk . Hyperlipidaemia combined with RAO is associated with a 3.34-fold increased risk . Furthermore, if T1DM , T2DM , or hyperlipidaemia  is present as a third factor, there is no additional increase in the risk. The co-existence of IHD with RAO and HT increases the odds ratio of developing STEMI even more than the preceding factors  can occur due to the occlusion of the central retinal artery caused by circulatory disturbance or embolus. Emboli most commonly originate from calcified plaques of the atherosclerotic carotid artery, but cholesterol embolism and thromboembolism are also common. The development of arterial plaques is influenced by factors such as hypertension, smoking, elevated cholesterol levels, and potential inflammatory processes within the inner layer of the arteries, leading to endothelial damage. This results in increased vascular permeability, initiating the accumulation of lipid and inflammatory components within the arterial wall through activated immune cascade mechanisms. Macrophages also participate in this process, leading to the formation of lipid-filled foam cells. In advanced stages, arterial plaques develop within the vessel walls, from which tiny emboli can obstruct the ophthalmic artery. Oxidative stress leads to an imbalance between antioxidants and free radicals, which damage normal cells and can also affect the vascular walls. Damage to the vessel wall can lead to atherosclerosis. As a result of vasoconstriction, the process worsens and the blood supply to the eye is disrupted .Arteriosclerosis plays a fundamental role in the development of RAO, AIS, and STEMI. With progressive age, multiple cardiovascular risk factors can lead to plaque formation in the aorta and the internal carotid artery or its branches, parts of which can break off, leading to the development of acute RAO, AIS, or STEMI through embolisation ,22,23,24In our retrospective cohort study , we investigated the role of age, gender, HT, T1DM/T2DM, AF, hyperlipidaemia, and IHD in RAO development. When analysing the role of age, we found that RAO, AIS, and STEMI rarely developed in people under 40 years of age. However, over 50 years of age, the incidence of AIS and STEMI increased in the RAO group. Further statistical analysis comparing RAO and non-RAO cases in terms of age revealed a strongly significant difference in those under and over 50 years of age . The patIn contrast to our results, a Korean study group only found a significant increase in stroke in RAO patients over 65 years of age . The difIn our study, men developed RAO at a significantly higher rate than women. However, Jeong et al. found no significant difference between genders . AccordiThe incidence of AF in patients with RAO is high. RAO patients with AF are significantly more likely to develop STEMI, although no significant increase in risk was found for AIS. AF most commonly develops as a result of the dilatation of the right atrium. A thrombus may develop in the right atrial auricle, which in the case of an open foramen ovale may even lead to embolisation, often resulting in ischaemic stroke or arterial occlusion . ArrhythHyperlipidaemia can play a role in the development of progressive atherosclerosis. In untreated hyperlipidaemia, plaques can form in the walls of blood vessels, affecting large vessels such as the intracranial vessels, the coronary artery, and also smaller vessels such as the central retinal artery. Excess circulating low-density lipoprotein cholesterol promotes the accumulation of cholesterol within arterial walls, triggering an inflammatory response and the formation of atherosclerotic plaques. These plaques can eventually lead to arterial stenosis and contribute to the development of cardiovascular diseases, such as coronary artery disease and stroke. In our patients with hyperlipidaemia associated with HT, the odds ratio for the development of AIS and STEMI was significantly increased .In agreement with other authors, we found that RAO patients developed AIS/STEMI significantly more frequently within 10 years of follow-up. Park et al. found a higher rate of ischaemic stroke within 1 week after RAO . Chang eThe main benefit of our work is the analysis of the co-occurrence of multiple risk factors within the RAO group. We demonstrated that the accumulation of one, two, or possibly three risk factors/cardiovascular diseases together increased the odds of developing AIS by a factor of up to 25 and those of developing STEMI by a factor of up to 5. Based on our results and given that the first examiner of RAO patients is often the ophthalmologist, some RAO, AIS, and STEMI cases can be prevented among these cardiovascularly burdened patients with a proper general medical examination and the treatment of accompanying diseases. Cooperation between ophthalmologists, neurologists, and cardiologists can prevent RAO and possibly also AIS/STEMI.As the first point of care for RAO patients, we should consider the increased risk of AIS/STEMI development. The patient should be referred to neurology/emergency care as soon as possible, where appropriate investigation  and secondary prevention  can prevent the development of severe pathologies in some cases ,42,43,44The main limitation of our study is that although we analysed patients’ medical records using a national electronic database in addition to using our clinic’s examination data, we were unable to access all patients’ records due to patient digital self-determination. A further difficulty was that the documentation was sometimes incomplete and did not always cover the risk factors under investigation. In the future, we plan to conduct more extensive and prolonged studies with a larger patient cohort that could provide a more comprehensive understanding of the interplay between RAO, AF, and the risk of AIS and STEMI. We also plan to collaborate with neurologist colleagues to analyse carotid Doppler scans and investigate the role of ACI stenosis in RAO patients.Considering the large number of patients and the long follow-up time, it is hoped that the abovementioned difficulties will not significantly affect the results. Furthermore, drawing the control group from the same institutional environment serves to control for certain confounding variables that might arise from differing institutional practices, patient demographics, or geographic factors.RAO is associated with an increased risk of AIS and STEMI, especially in patients with multiple cardiovascular risk factors. The early detection, proper medical examination, and treatment of accompanying diseases, through collaboration between ophthalmologists, neurologists, and cardiologists, can potentially prevent RAO, AIS, and STEMI in cardiovascularly burdened patients. It is crucial to recognise increased risk and promptly refer patients for appropriate investigations and secondary prevention measures. The use of clopidogrel or aspirin treatment can be beneficial for the secondary prevention of the development of RAO in the fellow eye, AIS/STEMI, provided that no contraindication arises.


Generalized pustular psoriasis (GPP) is a rare subtype of psoriasis that manifests as a generalized pustular eruption.A 31-year-old female was admitted to the hospital in June 2021 with a widespread erythematous, itchy, and scaly rash for a week. The patient has a 10-year history of psoriasis vulgaris.GPP complicated by a late-stage viral infection and early-stage renal damage.Weekly subcutaneous injections of 300 mg of secukinumab for a month, followed by monthly (every 4 weeks) injections of 300 mg of secukinumab for 20 weeks.The symptoms of pustules and erythema were reduced, and the patient reported pain relief soon after the first injection. The patient had no serious adverse reactions during treatment and follow-up.Secukinumab might be an optional treatment strategy for GPP. The clinical course of GPP is not predictable, and patients can go through periods of disease exacerbation and dormancy. GPP can lead to fatal complications, including sepsis, neutrophilic pneumonitis, neutrophilic cholangitis, and acute respiratory distress syndrome.Generalized pustular psoriasis (GPP) manifests as widespread inflamed, erythematous skin with an acute or subacute eruption of pustules. However, these drugs are limited by their slow onset and severe side effects. Secukinumab is a recently developed anti-IL-17 biologic which has shown good efficacy in the treatment of many patients with pustular psoriasis. This case report describes a GPP patient treated with secukinumab.Continued therapy is usually necessary to avoid the reoccurrence of flares in GPP. However, it can be difficult to determine the best treatment strategy due to a lack of high-quality data on the management of GPP. Traditional therapies for GPP include systemic acitretin, methotrexate, and cyclosporine.A 31-year-old female patient came to our hospital in June 2021 with a widespread erythematous, itchy, and scaly rash for a week. Her symptoms were aggravated after the use of ointment of unknown origin and black soybean tar by herself. The patient had a 10-year history of psoriasis, which was not adequately addressed and treated. The patients once received hormones to control the rash and compound glycyrrhizin tablets to control inflammation, dehydration, and other symptoms 2 years ago. After the symptoms improved, the patient took traditional Chinese medicine orally for a long time, and her condition was stable before this disease attack. The patient has no family history of psoriasis.On admission, the patient had diffuse erythema all over the body, and the feet, hands, and face were heavier. In addition, white scales were covered, and a thin film phenomenon was observed after the scales were scraped off, and needle-like pus was covered and partially fused into sheets Fig. A. The skhttp://links.lww.com/MD/I916). Skin wound ulcer and drug susceptibility testing showed a Staphylococcus aureus infection, which was treated with levofloxacin injection.The patient’s laboratory results led to a diagnosis of viral infection and early renal damage, which was treated by the nephropathy department  in weeks 0 to 4, followed by injections of 300 mg of secukinumab every 4 weeks for 20 weeks.Three days after the first injection of secukinumab, the pustules and erythema were significantly reduced, and the patient reported pain relief Fig. B. One weThis study reported a 31-year-old female patient with a 10-year history of psoriasis vulgaris who never underwent systemic treatment and later developed GPP. Combined with the descriptions made by the patient, the physicians hypothesized that the patient’s irregular history of hormonal medication could be the trigger. At admission, there was a late-stage viral infection and early renal damage combined with the patient’s medical history and treatment history. Given the patient’s condition, the physician’s experience, and available guidelines, secukinumab was selected for treatment, despite the fact that infection is an adverse reaction of secukinumab. The patient was treated with secukinumab for 20 weeks and followed up for 6 months without recurrence or serious adverse reactions. In another case series of 4 children, off-label treatment with secukinumab almost completely resolved the GPP lesions in all 4 patients after 1 month of treatment. In Japan, the latter evidence has led to the inclusion of secukinumab in the treatment guidelines for pustular psoriasis.The findings, in this case, corroborate those of a phase III study in Japan, in which 12 patients with GPP were treated with secukinumab alone or in combination for 12 weeks; most of the patient’s symptoms were improved and maintained until 52 weeks. the earliest assessment after starting secukinumab was 7 days, and 4 (36.4%) patients were very much improved, and 5 (45.5%) patients were much improved, supporting the early onset observed in the present study. A response in the psoriasis area-and-severity index score was also observed as early as 1 week in a pooled analysis of 2 phase III trials.In the case reported here, the pustules, erythema, and pain were significantly reduced as early as 3 days after the first injection of secukinumab. In the phase III trial by Imafuku et al,In conclusion, secukinumab might be an optional treatment for GPP. The symptoms of the reported patient with viral infections and early renal damage were improved after being treated with secukinumab without any serious adverse events.Thank the patient for the informed consent to this study.Conceptualization: Jiayan Li, Xue Gao, Yimiao Fang.Formal analysis: Jiayan Li, Xue Gao, Yimiao Fang.Writing – original draft: Jiayan Li, Lili Ma.Writing – review & editing: Lili Ma.


Hypovitaminosis D is a public health problem associated with several chronic inflammatory and immunological diseases, including psoriasis.This study aimed to determine the prevalence of hypovitaminosis D in patients with plaque psoriasis. A comparison was made between vitamin D levels in patients with psoriasis and those with other non-inflammatory dermatoses without photosensitivity. In addition, it evaluated the effects of the patients’ Fitzpatrick skin phototype and the season of the year on the serum levels of vitamin D.A retrospective cross-sectional study was conducted at an outpatient clinic in a university center in Juiz de Fora (MG), Brazil.A review of dermatology patients’ demographic data, including skin phototype and serum levels of 25-hydroxyvitamin D [25(OH)D], over 12 months in 2016.This study included 554 patients: 300 patients allocated to the plaque psoriasis group and 254 control patients with other dermatological diseases. Regarding the season of the year, 229, 132, 62, and 131 participants were evaluated in summer, autumn, winter, and spring, respectively. As for the skin phototype, 397, 139, and 18 patients had phototypes III, IV, and V, respectively. The serum levels of 25(OH)D were significantly lower in the psoriasis group (24.91 ± 7.16 ng/mL) than in the control group (30.37 ± 8.14 ng/mL).Hypovitaminosis D (< 30 ng/mL) was present in 76.66% of patients with psoriasis versus 53.94% of control patients. Vitamin D deficiency (< 20 ng/mL) was observed in 25% of the patients with psoriasis versus 8.66% in the control group (P < 0.001). The season and patient’s skin phototype were independent predictors of serum vitamin D levels. Psoriasis is a chronic inflammatory disease with a genetic predisposition involving the skin, joints, and immunological effector mechanisms, affecting approximately 2–5% of the world population. The pathogenesis is multifactorial, involving innate and adaptive immunity, and potentially associated with several comorbidities. Scientific literature suggests an association between psoriasis and inadequate levels of vitamin D. Therefore, it is believed that the prevalence of hypovitaminosis D is higher in patients with psoriasis. Although vitamin D analogs treat psoriasis, its exact mechanism of action and relationship with the disease is unclear.Vitamin D is a steroid hormone that acts genomically and non-genomically in different metabolic processes in most tissues. In the skin it plays several important biological functions in the physiology of keratinocytes and cells of innate and adaptive immunity. Several studies have demonstrated a high prevalence of vitamin D deficiency in the general population and its various associations with bone, autoimmune, inflammatory, hormonal, cardiac, and neoplastic diseases. and season of the year on the serum levels of 25(OH)D.The present study aimed to evaluate the serum levels of 25-hydroxyvitamin D [25(OH)D] in patients with plaque psoriasis. In addition, a comparison was made with levels in dermatology patients with other non-inflammatory dermatoses without photosensitivity. This study also aimed to explore the factors associated with vitamin D synthesis. It evaluated the effect of the patient’s Fitzpatrick skin phototypeA cross-sectional, retrospective, and comparative study was conducted from January to December 2016 at the Dermatology Service of the University Hospital of the Faculty of Medicine of Universidade Federal de Juiz de Fora (UFJF). The study included 554 patients: 300 patients with plaque psoriasis and 254 control patients with other dermatological diseases. The study reviewed 650 medical records: 350 patients treated at the psoriasis outpatient clinic with a standardized medical record, including serum levels of 25(OH)D, and 300 patients treated at the general dermatology outpatient clinic. Exclusion of patients in both groups was based on the lack of accordance with the inclusion and exclusion criteria, missing data in the medical records, and the patient belonging to a different geographic region. Fifty patients were excluded from the psoriasis group and 46 from the general dermatology group. As the medical records for this study were obtained from the Dermatology Service of a university hospital, the data were collected by postgraduate doctors and supervised by doctors, and standardized medical records were used. To minimize geographic effects on vitamin D levels, all included patients were from Minas Gerais State, Zona da Mata region, southeastern Brazil. The inclusion criteria were patients of both sexes, aged between 18 and 60 years, with a clinical or histopathological diagnosis of plaque psoriasis. The exclusion criteria were patients with other clinical forms of psoriasis; severe and decompensated systemic diseases ; thyroid and parathyroid diseases; malignant neoplasms, AIDS, and pregnancy; oral supplementation of vitamin D, bisphosphonates, systemic corticosteroids, and calcium; treatment with phototherapy or use of sunscreens; use of topical vitamin D analogs such as calcipotriol; and diseases with altered intestinal absorption or other autoimmune and photosensitivity diseases.This retrospective study was performed after the research was approved by our institution’s ethics committee . All the procedures involved in this study were in accordance with the Declaration of Helsinki of 1975, updated in 2013. the following parameters were adopted: values lower than 20 ng/mL were considered deficient, values from 20 ng/mL to lower than 30 ng/mL were considered insufficient, and values equal to or above 30 ng/mL were considered sufficient.The standardized medical records of each patient were reviewed, and the following variables were evaluated: sex, age, Fitzpatrick skin phototype, and season of the year in which serum levels of 25(OH) vitamin D were measured. All serum sample vitamin D levels were analyzed at the Biochemistry Laboratory of the University Hospital using the chemiluminescence technique . According to the American Association of Endocrinology,HTTPS://WWW.R-PROJECT.ORG/].A descriptive data analysis was performed, and the normality of distribution was assessed using the Shapiro–Wilk test. Levene’s test was used to test for homogeneity of variance. When the distribution and homogeneity of variance were met, Student’s t-test was used to test the differences in quantitative variables between the two groups. The Chi-square test (χ2) or Fisher’s exact test for less than five data points was used to test possible differences in the proportions of qualitative variables. Multivariate linear regression analysis was used to determine independent predictors of serum vitamin D. vitamin D was used continuously in multivariate regression. Season, skin phototype, sex, and age were used as determining variables. The significance level was set for all statistical analyses at 5% (P < 0.05). Analyses were performed using the R software package for Windows , and vitamin D receptor has been shown on keratinocytes.The exacerbation of psoriasis in winter may be partly due to low sun exposure and the subsequent low vitamin D production in the skin. Therefore, the therapeutic effect of UVB therapy in treating psoriasis may be, at least in part, mediated by UVB causing the synthesis of vitamin D in the skin. In addition, UVB therapy increased serum 25(OH)D levels in patients with psoriasis in parallel with disease improvement.Vitamin D appears to influence the innate and acquired immune systems with complex effects, which are still not completely elucidated. It has been shown that 1 α-hydroxylation produces active hormones within different immune system cells, where it exerts autocrine and paracrine effects. In contrast, vitamin D mainly inhibits the acquired immune system by reducing the expression of MHC class II and co-signaling molecules on antigen-presenting cells, decreasing the activity of TH1 and TH17 cells, and upregulating regulatory T cells. The final result is the promotion of regulatory and protective phenotypes of T-cells.The benefits of vitamin D analogs for psoriasis treatment are well established. A topical vitamin D analog is the first-line choice for managing psoriasis, either alone or in combination with topical corticosteroids. Unlike corticosteroids, which can be associated with tachyphylaxis, topically administered vitamin D analog treatment is long-term and effective without side effects in patients of all ages. in their review of the systemic use of vitamin D in psoriasis, examined the pros and cons of this treatment to determine whether systemic vitamin D would be a feasible therapeutic option for these patients and whether more large-scale studies are needed to determine the efficacy, optimal dosing, and adverse effects of vitamin D administration in patients with psoriasis. Genetic variation in vitamin D metabolism can lead to a personalized vitamin D response. Moreover, biomarkers of vitamin D status different from 25(OH)D status have been identified in new metabolic pathways of vitamin D.Stanescu et al.,Although sunlight was the primary source of vitamin D during more than 99% of human evolution, it is clear that mainly owing to increased longevity, people need to try to accomplish a delicate balance between limiting sunlight exposure, avoiding skin damage, and optimizing vitamin D status. In many cases, this balance implies that vitamin D supplementation is necessary. in 174 fishermen analyzed the relationship between sun exposure index, vitamin D levels, and clinical changes in the skin caused by the sun. Vitamin D deficiency was verified in only 11.46% of the patients due to chronic sun exposure in Brazil’s northeast region, with high levels of UVI throughout the year. The lack of association between our study and that conducted by Coutinho et al. can be explained by the fact that our study showed a higher prevalence of vitamin D deficiency, as it was performed in a geographic region with a variation in sun exposure according to the season of the year, as well as the presence of atmospheric pollution in the Southeast region. On the other hand, our findings are similar to those of Cabral et al., found in another Brazilian study in the Northeast region.A Brazilian study conducted by Coutinho et al.To the best of our knowledge, this is the first Brazilian study to assess the prevalence of hypovitaminosis D in dermatological patients for 12 months in an expressive cohort. Therefore, the data from this study can be considered representative of a considerable proportion of dermatological patients, including patients with psoriasis in Brazil.The limitations of our study include the absence of a dietary and sun-exposure survey (with time and duration of exposure). In addition, 25(OH)D production and degradation is a continuous process. Therefore, establishing an ideal period to study the effects of UV radiation on vitamin D production and its action on immunosuppression is a challenge in clinical research. Consequently, it needs to be better evaluated in prospective studies. In addition, as this study was cross-sectional, the patients were not followed up over a long period of restrictive selection criteria.Considering the geographic location in which the study was carried out, with moderate to high levels of ultraviolet radiation throughout the year and the predominance of skin phototype III, it can be concluded that daily solar radiation was insufficient to promote the adequate synthesis of 25(OH)D. Furthermore, vitamin D deficiency was greater in the psoriasis group. A negative association was found among 25(OH)D, psoriasis, and phototypes IV and V, and a positive association between 25(OH)D and summer. Future randomized, blinded, long-term studies investigating the role of vitamin D supplementation in psoriasis are necessary.


The neutrophil-to-lymphocyte ratio (NLR) is a marker of inflammation that can be obtained quickly, conveniently, and cheaply from blood samples. However, there is no research to explore the effects of sex and age on the relationship between the NLR and mild cognitive impairment (MCI) in community-dwelling older adults.A total of 3,169 individuals aged over 60 years in Shanghai were recruited for face-to-face interviews, and blood samples were collected. MCI was assessed by the Mini-Mental State Examination (MMSE) and the Instrumental Activities of Daily Living (IADL) scale, and neutrophil count and lymphocyte counts were measured in fasting blood samples. The NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count.p < 0.001) but not in men. Logistic regression showed that a higher NLR was an independent risk factor for MCI in women . In addition, the elevated NLR quartile was associated with an increased risk of MCI, especially in women older than 70 years .In females, the NLR in the MCI group was significantly higher than that in the cognitively normal group (2.13 ± 0.94 vs. 1.85 ± 0.83, Compared with males, female MCI patients had a significantly higher NLR than cognitively normal controls. In addition, elevated NLR was found to be significantly associated with MCI risk in women older than 70 years. Therefore, elderly Chinese women with a higher NLR value may be the target population for effective prevention of MCI. With the rise in the aging of the population, age-related cognitive decline has become a major global public health concern and caused a huge economic and social burden, particularly in developing countries . Mild coThe immune system is irreversibly impaired by aging, and that impairment is considered to be the most important risk factor for MCI. Inflammatory processes play a complex role in the progression of cognitive impairment . DisordeIn fact, age and sex may affect the relationship between MCI and NLR. A study from South America showed that the NLR had different age distribution characteristics between sexes. Many studies have demonstrated that sex hormones are closely linked to inflammation and cognitive impairment . CompareTherefore, the aim of this study was to explore the relationship between MCI and peripheral inflammatory markers in different sex and age groups and provide a theoretical basis for the prevention and identification of MCI through an increased understanding of MCI.All participants, who were residents from six communities in Shanghai, were invited to engage in a comprehensive geriatric assessment in Shanghai from 2019 to 2023, during which they completed a face-to-face interview questionnaire as well as a physical examination. The study was approved by the Ethics Committee of Shanghai University of Medicine and Health Sciences, and the methods were carried out in accordance with the principles of the Declaration of Helsinki.The inclusion criteria for this study were age 60 years or older and completion of relevant tests. The exclusion criteria were as follows: (1) persons with severe mental disorders, dementia, or other neurodegenerative diseases; (2) persons who did not provide informed consent or were unable to communicate with investigators; (3) persons with severe sensory impairments and unable to complete the assessment; and (4) persons for whom blood samples were not collected. A total of 4,046 participants were enrolled in the study. Of these, 310 individuals had an incomplete assessment of cognition and were excluded from the analysis. Additionally, 544 participants lacked blood samples, and 23 lacked other covariates and were also excluded from the analysis. The final analysis of the study included 3,169 participants .MCI was defined as patients with low cognitive ability [Mini-Mental State Examination (MMSE) score below the educational level cut point] and normal activities of daily living [Instrumental Activities of Daily Living (IADL) score ≥ 6] . The ChiPeripheral inflammatory cells, including white blood cell (WBC), neutrophil, lymphocyte, and monocyte counts, were assessed by a hematology analyzer XE-2100 (Sysmex). NLR values were calculated by dividing the absolute neutrophil count by the absolute lymphocyte count: neutrophil count/lymphocyte count.All participants were invited to participate in a face-to-face interview to answer a standardized questionnaire to obtain baseline data. Baseline data on sociodemographic characteristics, chronic disease status, and health behaviors were treated as covariates. Demographic characteristics included age, sex, height, weight, and education level. Health behaviors included smoking and alcohol consumption habits. Depressive symptoms were assessed using the Chinese version of the Geriatric Depression Scale (GDS), which was standardized in 1996 after its reliability and validity were tested . Nutritip values. p value for trend was calculated from a one degree-of-freedom trend test. A p value of less than 0.05 was considered to indicate statistical significance. Statistical analysis was performed using SPSS v26.0.The following data analysis was conducted to investigate the correlation between MCI and inflammation among different sexes. Sociodemographic and health-related characteristics were collected at baseline. Normally distributed data are expressed as the mean and standard deviation, while nonnormally distributed data are expressed as the median and quartile. The t test or Mann–Whitney U test was used to analyze differences in baseline characteristics. Categorical variables were expressed as percentages (%) and analyzed using the χ2 test. Logistic regression models were used to examine the relationship between MCI and peripheral inflammatory cells by sex. Adjusted model included age, BMI, education, depression, widow, hypertension, coronary heart disease, smoking, and drinking. Further, we explored the relationship between MCI and age and sex using logistic regression. Adjusted model included BMI, education, depression, widow, hypertension, coronary heart disease, smoking, and drinking. The results are expressed as odds ratios, 95% confidence intervals, and corresponding n = 3,169) stratified by sex. In men, participants with MCI tended to have a lower level of nutritional status and education but had high levels of depression and hypertension (p < 0.05). In women, participants with MCI tended to have a lower level of education, lymphocytes% and lymphocytes but had a higher level of age, neutrophils%, NLR, hyperlipidemia and platelets; in addition, they were more likely to be widows (p < 0.05) . The prevalence of MCI was 8.4% and 11.5% among men and women, respectively.  < 0.05) .p value for trend = 0.011) but not in younger women and men  declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the funding of Shanghai Municipal Health Commission (202240367), Capacity Building project of Local Colleges of Shanghai Science and Technology Commission (23010502800), and Shanghai Sailing Program (22YF1417900).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The result of this meta-analysis shows that the less expensive diagnostic technique is also the most sensitive for the diagnosis of ATFL tears. Ultrasound articles resulted to have non-heterogeneity . Conclusion: This meta-analysis demonstrates that US appears to be a highly sensitive diagnostic technique for diagnosing tears of the ATFL. Compared to MRI, the sensitivity of US result was higher.Objectives: Ankle sprains represent the second most common cause of emergency department access for musculoskeletal injury and lateral ankle ligament complex tears account for 850,000 cases annually in the United States with a relapse rate of 70%. Clinical examination is limited due to its subjectivity and the difficulty of identifying a specific involvement of the ligament; therefore, US and MRI are frequently requested. Therefore, the goal of this study is to analyze the available literature on the use of ultrasound (US) and magnetic resonance imaging (MRI) to diagnose injuries to the anterior talofibular ligament (ATFL) with a meta-analytic approach. Methods: According to PRISMA  guidelines, all studies regarding the diagnostic accuracy of ultrasound and magnetic resonance imaging ATFL injuries were searched and assessed. The data were obtained from two independent reviewers with 12 and 3 years of experience in meta-analysis. A QUADAS-2  checklist was carried out to assess the risk of biases. From the selected studies, the sensitivity, specificity, and accuracy data were extracted. Results: Nine studies were included. The results of the meta-analysis demonstrate a greater sensitivity for ultrasound  compared to MRI ,  Ankle sprains affect 1 in 10,000 people every day. They represent the second most common cause of emergency department access after acute low back pain . The mosBoth US and MRI have reported more than 90% accuracy in diagnosing ankle injuries, including tears to the ATFL . MRI is The PRISMA  guidelines were followed . Accordihttp://www.pubmed.org (accessed on December 2021)), Embase (http: //www.embase.com.proxy.medlib.iupui.edu/search (accessed on December 2021), ISI Web of Science (http://apps.webofknowledge.com (accessed on December 2021)), SpringerLink, ScienceDirect and Cochrane library (http://www.thecochranelibrary.com (accessed on December 2021)), until 1 January 2022. A manual review of the reference sources to integrate the initial research with other studies was done. All citations of the selected articles were checked to find additional relevant elements. It was not considered necessary to contact the authors to ask for additional data. The keywords used in the research by the authors were: ultrasonography, magnetic resonance imaging, anterior talofibular ligament and ankle.All the most relevant studies were identified regarding the diagnostic accuracy of ultrasound and magnetic resonance imaging ATFL tears. The data were obtained from two independent reviewers with 12 and 3 years of experience in meta-analysis (A.T. and G.C.) using major medical databases: PUBMED .No limitations regarding the year of publication of the article.Availability or ability to adequately extract at least a couple of the absolute numbers of true-negative and false-positive or true-positive and false-negative results. To include true-negative, false-negative, true-positive, and false-positive results in a meta-analysis, all four data must be available.We included studies published in English only.We excluded articles that did not provide data on the diagnosis of anterior talar ligament injury using US or MRI; ex vivo studies or biomechanical experiments; meta-analysis or review; and case reports.We also excluded studies that provided data on tears of the lateral ligament complex of the ankle using US and MRI but not specifically in relation to the ATFL.The two authors (A.T. and G.C.) independently examined the titles and abstracts of the identified articles to evaluate their content and their relevance to the research objective; then, the complete text was evaluated. Disagreements that arose during any stage of the selection process were resolved by consensus. If no agreement was found, an expert clinician (B.B.) was asked to resolve the disagreements. If the selection of an author is uncertain about any issue, this is resolved by discussing it or rereading the text. The authors A.T. and B.B. have more than 12 and 7 years of experience in musculoskeletal imaging and evidence-based medicine, both are active members of international scientific societies dealing with musculoskeletal disorders and one (A.T.) has been appointed with ESSR  Diploma. Another author (G.C.) has more than 10 years of experience in surgery and clinical practice in the ankle and foot. The three authors have extensive experience in meta-analysis.http://www.cebm.net/index.aspx?o=5653 (accessed on 5 March 2022)). Studies that did not report specific variables were excluded.The two authors (A.T. and G.C.) and a graduate student (G.C.) independently extracted data from suitable studies. Discrepancies were resolved by consensus. When available, the following data were extracted from the selected studies: first author, year of publication, type of imaging technique, number of patients (divided into groups in the case of controlled studies), mean age of patients (years), design of the study (prospective or retro-prospective), reference standard, classification and type of lesion, mean study duration (years), number of true-positive (TP), false-positive (FP), false-negative (FN) and true negative (TN). Categorical data are expressed in the number of cases or percentages. Continuous variables were reported as mean and standard deviation (SD) or mean and range. The level of evidence (LOE) of the studies was assigned based on OCEBM (Oxford Centre Evidence-based Medicine) .The quality assessment of the selected studies was independently assessed by the two authors (A.T. and G.C.) and the graduate student (G.C.) using the QUADAS-2  checklist, which evaluates four fields: patient selection, test evaluated in the study, reference standards, and diagnostic times. Each domain is rated as the risk of bias and the first three as applicability. The three authors then discussed the result of their quality assessments. Disagreements were resolved with consensus. The results of the quality assessment were recorded in a QUADS-2 form, downloadable from the web page: p values of 0.05 were considered statistically significant. The Galbraith plot was used to assess heterogeneity and detect potential outliers, and the forest plot was used to report a series of central values and their confidence intervals in a graphic manner so that they can easily be compared. In the forest plot, the central values are represented by markers and the confidence intervals by horizontal lines. The I2 statistic was used to describe the percentage of variation across studies that is due to heterogeneity rather than chance. I2 = 100% × (Q − df)/Q. I2 is an intuitive and simple expression of the inconsistency of studies’ results which does not inherently depend upon the number of studies considered. Statistical analysis was carried out under the supervision of a professional statistician (A.S.). We used statistical software .From the selected studies, the sensitivity, specificity, and accuracy data were extracted. A funnel plot for each diagnostic technique (US or MRI) was done to assess publication biases. For smaller studies with fewer patients, a Galbraith plot was made. The analysis was carried out separately in two subgroups, depending on the diagnostic technique (US or MRI). A forest plot was produced showing the sensitivity and specificity values with the corresponding confidence intervals (CIs). n = 568 articles, n = 527 after excluding duplicates. n = 449 were excluded after reading the title and n = 29 after reading the abstract. Of these, n = 49 and n = 40, we excluded after a careful reading of the complete text: n = 12 not in the English language; n = 3 performed in non-human; n = 3 case reports; n = 2 in vitro studies; n = 5 reviews; n = 1 done pediatric patients; and n = 13 without data necessary to extract the sensibility.The search process identified n = 4 studies regarding US and n = 5 dealing with MRI, for a total of n = 9 articles suitable for the meta-analysis. The detailed flowchart is reported according to PRISMA in n = 6 retrospective and only n = 3 prospective studies: n = 2 for US , whereas a weakness of US studies is the increased risk of bias compared to studies without an arthroscopic reference standard. Finally, studies in US had fewer patients and patients were older than those included in MRI studies. In addition, there is a lack of studies with direct comparison between US and MRI and in several studies, the reference standard is not always the same introducing potential biases.To diagnose an ATFL injury or tear, in addition to the clinical examination, an imaging exam is required. Indeed, the clinical examination is often unable to accurately diagnose ATFL tears. Stress radiography correlates little with real ligament damage; arthroscopy, a diagnostic and therapeutic standard, is invasive and, therefore, not of first choice. For this reason, the most appropriate and used methods are US and MRI. Among these, there is an important difference in availability, time of examination and costs, which weigh on patient and healthcare management costs ,20,21,23In our long-lasting experience in musculoskeletal imaging and clinical practice, almost every patient with a possible ATFL tear will undergo imaging with US or MRI. In our clinical practice, we follow an evidence-based approach as suggested by ESSR guidelines that we contributed to develop ,22. Indep < 0.0001; I° = 85.72%) dealing with MRI.The strengths of the articles on MRI are the presence of studies with minimal risk of bias, the largest number of patients and recent articles with the use of modern machinery such as 3 Tesla MRI and 3D fast spin echo sequences. Even with these notes in favor, the results showed heterogeneity between studies  . An artin = 7 out of n = 9 studies, whereas for Gun et al. [This study has several limitations. At first, the reference standard was not always arthroscopy; indeed, arthroscopy was the reference standard for n et al.  it was Mn et al.  it was Un et al. .This meta-analysis demonstrates that US appears to be a highly sensitive diagnostic technique for diagnosing tears of the ATFL. Compared to MRI, the sensitivity of the US result was higher.


The relationship between ankylosing spondylitis (AS) and glaucoma in the European population remains unclear. In the present study, we applied a two-sample Mendelian randomization (MR) method to investigate their causal relationship.MR analysis was conducted to validate the causal associations between AS with glaucoma using summary statistics from the genome-wide association studies of AS  and glaucoma . The inverse variance weighting method was performed to evaluate the causal relationship. The MR–Egger regression approach was applied to assess pleiotropy, while Cochran’s Q test was used to analyze heterogeneity. Subgroup analysis was performed according to primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG).P = 8.81 × 10-5). Pleiotropy and heterogeneity were not found in our study. In the subgroup analysis, AS was also causal with POAG  and PACG .The results of the MR study reveal a risk-increasing causal relationship between AS and glaucoma among European populations (OR = 1.35, 95%CI = 1.16–1.57, The results of the MR analysis suggested a causal relationship between AS and glaucoma in the European population. Further studies are needed to identify the specific mechanism between these two diseases. Glaucoma is a neurodegenerative disease characterized by the atrophy and depression of the optic disc and the defects of visual field and vision . Tham et+ T cells and the pathogenesis of glaucoma  is a chronic arthritis characterized by the inflammation of the spine and sacroiliac joints , 14. AS Mendelian randomization (MR) analysis, which incorporates genetic variation as an instrumental variable (IV), has been frequently used to evaluate the potential causal association between risk factors and disease results , 22. AccThe primary research of the genome-wide association studies (GWASs) from each nation had previously gained ethical consent, and the present analysis was based on publicly available summary-level data, which did not need additional approval. The publicly available summary data from the MR-Base platform were used in this study to assess the relationship between AS and glaucoma . To reduCortes et al.’s GWASs  r2< 0.001] was evaluated, and no LD was found. If a requested SNP was absent, the proxy SNP (LD at r2>0.8) from the 1000 Genomes Project was employed as the surrogate effect allele. In this case, LD proxy lookups are automatically provided by MR-Base  . FurtherAssessment of the Mendelian randomization assumptions−8; (II) the IVs do not influence glaucoma through other pathways than the AS; and (III) the instrument variables do not associate with confounders. In addition, there is some potential pleiotropy in instrumental effects, which may indicate potential violations of the assumptions underlying two-sample MR. Therefore, other sensitivity analyses were carried out using multiple imputation methods to test the robustness of MR results. Accordingly, the first assumption can be quantified by the strength of an association between a genetic variant and the risk factor. On top of that, we calculated the F-statistic to measure the strength of IVs (2). The phenotype variance explained (R2) was obtained from GWAS databases or original literature. If the R2 were not provided in the GWAS databases or literature, we would assess the strength of instruments based on 2 were associated with confounding factors for AS and glaucoma, our MR analysis would prove unable to estimate the causal effect of AS on glaucoma accurately. Consequently, we manually searched in all the published GWASs whether AS-related SNPs have secondary phenotypes other than AS. The cut-off date was on 30th August 2022. In addition, smoking represents a known risk factor for greater disease activity and worse functioning in AS patients  SNPs are strongly associated with AS, usually, to satisfy this condition, with a p-value less than 5 × 10h of IVs . This isanalysis , 32. Conpatients . Simultapatients . In conspatients . In addipatients –38. It cInverse variance weighting (IVW) is generally regarded as the main method in MR analysis to test the causality between exposure and the outcome: in the absence of pleiotropy , IVW returns the unbiased estimates of a causal effect so long as horizontal pleiotropy is balanced , 31. AccFinally, we performed Cochran’s Q test for the assessment of heterogeneity in order to assess whether the estimate of the causal effect of AS on glaucoma was consistent across each SNP . On top MR analysis was performed in R (version 3.6.3) with the package “TwoSampleMR” (version 0.5.6).-5) was associated with the risk of glaucoma. We further validated the results of IVW by WM  and MR–Egger , and the results are similar. In addition, in the subgroup analysis, AS was found to be causally associated to POAG  and PACG , respectively, and these associations were consistent in the methods of WM and MR–Egger, with similar causal estimates in direction and amplitude  Table 2.For the third hypothesis, we found no evidence that the included AS-associated SNPs have secondary phenotypes other than AS during our manual search. Moreover, the overall correlations between AS and confounders  were not statistically significant Table 3.Under the supposition of the 24 selected SNPs explaining a total of 24.4% variance of AS, the MR analysis had 100% power at a significance level of 0.05 to detect the previously estimated causal effect size of AS (OR = 1.35), suggesting a more reliable estimation of the causal effect.According to the results of Cochran’s Q test, there was no heterogeneity among these SNPs S6, S9In our study, MR analysis revealed a significant causal relationship between AS and glaucoma, which was the first large-scale MR study to investigate the correlation between AS and glaucoma. This study provided a better understanding of potential risk factors for glaucoma in AS patients.Ocular involvement is one of the most common extra-articular manifestations in AS patients. The pathogenesis of ocular disease in AS patients has yet to be elucidated. The fact that 15.8% of AS patients will develop anterior uveitis makes ophthalmologists pay more attention to AS in clinical practice, which is related to human leukocyte antigen (HLA)-B27 and the disease duration of AS . AS has It is worth noting that the MR analysis conducted in our study basically satisfied three key assumptions , which can remove the influence of most confounding factors and avoid reverse causality. MR analysis has given us a better understanding of potential risk factors for glaucoma.In the current clinical work, the conventional treatment of glaucoma has been directed toward controlling IOP, primarily because that is the proven modifiable risk factor for glaucoma. Topical drug therapy, which has been commonly used in the past, is being challenged by selective laser trabeculectomy, microinvasive glaucoma surgery, and sustained delivery methods. Surgery and drugs to reduce intraocular pressure and protect optic ganglion cells are effective ways to save the vision of glaucoma patients . HoweverThe association between AS and glaucoma is influenced by a number of intermediary phenotypes, which must be taken into account. It is widely known that anterior uveitis is an important clinical feature of AS, and its complications may lead to secondary glaucoma. The MR analysis revealed a clear causal association between AS and uveitis, as well as an inseparable correlation between uveitis and secondary glaucoma, which is an important intermediary factor when analyzing the relationship between uveitis and secondary glaucoma. However, the AS–uveitis–secondary glaucoma axis may be a significant confounding effect in MR analysis on the relationship between AS and primary glaucoma. Based on the nature of the data we used, AS could not be stratified by uveitis. In this study, we were also unable to separate AS from confounding factors. Therefore, we performed an MR analysis between AS and primary glaucoma to strengthen the validation of the causal relationship between AS and glaucoma. The results suggested that uveitis could not fully explain the relationships between AS and glaucoma, while internal mechanisms have not been clearly unmasked. In the analysis of the relationship between AS and glaucoma, uveitis complicated by AS has provided a mechanistic explanation that does impact the numerical results, even though this is within the expected range.Furthermore, we should keep in mind that there are still potential confounding factors in the study of AS and glaucoma, such as age, gender, medication use, and the duration of the type of glaucoma exposure. However, further analysis was difficult to conduct as the corresponding GWAS data were not available. In theory, we cannot rule out all possible confounds that may occur in MR analysis. The MR analysis (closest to a randomized controlled experiment) remains the most effective method for determining causality in the presence of confounders in the face of fewer research data and a lower likelihood of conducting a randomized controlled trial as it can minimize the effects of confounders and provides sufficient statistical power for causal estimation.There are also limitations to MR analysis. Firstly, our MR analysis included only 24 SNPs in published GWAS. Secondly, the samples involved in our study were limited to European populations, which may not apply to Asian or African populations who have a higher incidence of glaucoma. Therefore, larger sample studies with more AS-related SNPs and more ethnic groups may help provide more valid conclusions about the causal relationship between AS and glaucoma. Furthermore, genetic variation in the analysis can explain only a small amount of individual diversity. In other words, in social epidemiological investigations, the mean of the relevant group must be evaluated rather than the mean of the individual. Finally, we were unable to stratify the population according to medication usage, disease duration, the history of uveitis, and other factors to avoid potential biases caused by the aforementioned confounding factors, and we cannot completely rule out the possible influence of pleiotropic effects on the results.In conclusion, we conducted the first MR study and subgroup analysis to investigate the causal relationship between AS and glaucoma in the European population. Our study revealed a significant causal relationship between AS and glaucoma, especially POAG or PACG. We used MR analysis to mimic randomized controlled trials, which can avoid reversing causality and potential confounders common in conventional observational studies. However, the specific mechanism by which AS causes primary glaucoma requires further investigation.The original contributions presented in the study are included in the article/SL: Conceptualization, Data Curation, Methodology, Formal analysis, Writing- Original draft, Writing-Reviewing and Editing. MC: Data Curation, Methodology, Formal analysis, Writing- Original draft. QZ: Formal analysis, Writing-Reviewing and Editing. MF: Methodology, Formal analysis. WX: Methodology, Formal analysis. LB: Conceptualization, Supervision, Validation, Writing-Reviewing and Editing. All authors contributed to the article and approved the submitted version.